94 results on '"Richard D. Kim"'
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2. A phase II study of atezolizumab (ATEZO) and bevacizumab (BEV) in combination with Y90 TARE in patients (pts) with hepatocellular carcinoma (HCC): Y90+/- BEAT
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Renuka V. Iyer, Michael Petroziello, Nainesh Parikh, Richard D. Kim, Thatcher Ross Heumann, Daniel Brown, Kevin Kim, Yixing Jiang, Suvranu Ganguli, Eric Marks, Beau Toskich, Umair Majeed, Shamar Young, Rachna T. Shroff, Moh'd M. Khushman, Andrew Gunn, Filip Banovac, and Aiwu Ruth He
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Cancer Research ,Oncology - Abstract
TPS629 Background: The anti–PD-L1 antibody ATEZO prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF BEV can increase dendritic cell maturation, enhance T cell infiltration, and reduce myeloid-derived suppressor cells and regulatory T-cells in tumors. This combination has been FDA approved for first-line treatment of advanced HCC based on the IMbrave150 study. On the other hand, locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire. It is the standard of care for pts with intermediate-stage HCC (iHCC). Based on preclinical and clinical data, we hypothesize that the combination of Y90 TARE, BEV, and ATEZO induces synergistic tumor-killing. Methods: This is an open-label, multicenter, randomized phase II study of Y90 TARE and BEV plus ATEZO compared with Y90 TARE alone in pts with unresectable IHCC (NCT04541173). The primary study objective is to assess and compare the progression-free survival (PFS) (per mRECIST 1.1) of pts in each arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of TARE combined with ATEZO and BEV in pts with HCC. Exploratory objectives are to assess the role of the immunoscore and PD-L1 expression levels in the prediction of improved clinical outcome in pts receiving Y-90 TARE and BEV plus ATEZO; the composition of tumor-infiltrating immune cell subtypes in predicting response to a chosen therapy; how Y90 therapy affects the proportion of antigen-presenting cells in the tumor; and symptoms experienced by pts receiving TARE and BEV plus ATEZO treatment, using patient-reported outcomes. Eligible pts have either HCC that is not amenable to surgical resection, confirmed by pathology review, or at least BCLC stage B HCC outside of downstaging criteria. Other standard eligibility criteria apply. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE followed by ATEZO and BEV (Arm B). Pts will have TARE mapping during week (wk) 1 and TARE treatment during wk 2. In Arm B, pts will start BEV plus ATEZO 4 wks (±1 wk) after TARE treatment. Pts will have abdominal MRI or CT scans every 12 weeks, CT scans of the chest every 24 wks. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of TARE with BEV and ATEZO in the first 10 pts randomized to Arm B for two cycles. If there are no Grade ≥ 3 unexpected toxicities possibly, probably or definitely related to combined TARE plus BEV plus ATEZO, the study will continue to accrue 128 pts in total. Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Clinical trial information: NCT04541173 .
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- 2023
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3. Biomarker analysis to predict response in patients with metastatic mismatch repair proficient colorectal cancer treated with regorafenib and nivolumab
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Ruoyu Miao, Dae Won Kim, James Yu, Bence Kovari, Rutika Mehta, Jonathan R. Strosberg, Iman Imanirad, Seema Iyer, Mark Uhlik, Laura E. Benjamin, and Richard D. Kim
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Cancer Research ,Oncology - Abstract
228 Background: We previously conducted a phase I/Ib study with regorafenib and nivolumab in patients with refractory metastatic mismatch repair proficient (pMMR) colorectal cancer (CRC). This study aimed to investigate the biomarkers that predict the treatment response. Methods: Out of the 51 patients who received regorafenib and nivolumab, 22 archival pretreatment tumor samples were subjected to the Xerna TME Panel, a machine learning-based RNA-sequencing biomarker assay and were classified into one of four TME biomarker subtypes: Angiogenesis (A), Immune Active (IA), Immune Desert (ID), or Immune Suppressed (IS). Potential predictive biomarkers including the TME subtypes, KRAS (wild type vs mutant), PD-L1 (negative vs. positive, samples with > 1% tumor cells for PD-L1 were considered positive), CD8 expression (low vs. high), and Treg cells (low vs. high) in tumor microenvironment were evaluated for correlation with overall survival (OS), progression free survival (PFS) and disease control rate (DCR, defined as complete response + partial response + stable disease). Results: Among the 22 patients, 16 (72.7%) had liver metastasis and 15 (68.2%) had lung metastasis. KRAS mutation was found in 16 (68.2%) patients. 11/21 (52.4%) were positive for PD-L1. 12 (54.5%) had high CD8 expression, whereas 9/21 (42.9%) had high Treg cells in tumor microenvironment. Ten (45.5%) patients were classified as biomarker-positive (IA + IS subtypes) and 12 (54.5%) were biomarker-negative (A + ID) based on Xerna TME panel. Two (9.1%) patients achieved partial response, 12 (54.5%) had stable disease, and five (22.7%) developed progressive disease. The median PFS was 5.6 months and median OS was 13.1 months. No significant correlation was observed between RAS mutation (p = 0.664, p = 0.609), PD-L1 expression (p = 0.287, p = 0.173), CD8 (p = 0.152, p = 0.456) and PFS or OS. Low Treg was found to be associated with prolonged PFS (median: 9.8 vs. 1.9 months, p = 0.011) but not OS (p = 0.280). Similarly, only low Treg level was related with DCR (83.3% vs. 33.3%, p = 0.032). While not reaching statistical significance, Xerna TME biomarker-positive patients showed trends for higher median PFS (7.9 months vs. 4.1 months, p = 0.254), median OS (15.75 months vs. 11.9 months, p = 0.378), and higher DCR (70% vs. 58%, p = 0.675) compared to biomarker-negative patients. Additionally, the two patients with partial responses were Xerna TME biomarker-positive. Conclusions: Our study demonstrated that low Treg in tumor microenvironment is correlated with better prognosis in patients with refractory metastatic pMMR CRC who were treated with regorafenib plus nivolumab. Xerna TME panel analysis of these patients also showed trends for predictive clinical benefit. Prospective and larger cohort studies are needed to better define predictive biomarkers for this combination in the future.
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- 2023
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4. The role of socioeconomic deprivation in gastrointestinal cancer clinical trial enrollment at an NCI-designated comprehensive cancer center
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Daniel Strebig, Taymeyah E. Al-Toubah, Emily Coughlin, Rahul Mhaskar, Sylea Lowery, Ebin Mathew, Mitchell Capelli, Aishwarya Pattnaik, Kea Turner, Kedar Kirtane, Amina Dhahri, Richard D. Kim, Jennifer B. Permuth, Susan Thomas Vadaparampil, Jason B. Fleming, Jonathan R. Strosberg, and Benjamin Daniel Powers
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Cancer Research ,Oncology - Abstract
785 Background: Socioeconomic deprivation has been described as a barrier to cancer clinical trial participation. However, few studies have examined socioeconomic deprivation using patient-level or granular geocoded designations. To overcome this challenge, the Area Deprivation Index (ADI) was used to assess neighborhood socioeconomic deprivation in a cohort of gastrointestinal cancer clinical trial patients at an NCI-Designated Comprehensive Cancer Center. Methods: Patients enrolled in a gastrointestinal cancer clinical trial from 2008 to 2019 with an identifiable ADI national rank were identified. Socioeconomic deprivation was assessed using the ADI, a publicly available, validated dataset that ranks census block groups into percentiles using variables such as income, education, employment, and housing characteristics. For this study, ADI was categorized as quintiles listed in the table. Statistical analyses included Chi-square and Kruskal-Wallis tests. Results: The median age of the cohort (N=1,334) was 62.0 years. Most patients were male (54.3%). Race included White (88.2%), African American (6.8%), and Asian (1.5%) patients. Hispanic/Latinx patients made up 6.7% of the cohort. The median ADI was 46. The proportion of enrollees from lowest to highest ADI quintile was 11.2%, 29.3%, 27.3%, 19.1%, and 13.1%. Trial enrollment differed by ADI and age (p=0.019), gender (p=0.042), race (p
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- 2023
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5. Effect of immunotherapy on the survival outcomes in tumor mutational burden-high (TMB-H) microsatellite stable (MSS) metastatic colorectal cancer (mCRC): A single-institution experience
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Ola Gaber, Canan Karan, Christine Marie Walko, Todd C Knepper, Richard D. Kim, and Ibrahim Halil Sahin
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Cancer Research ,Oncology - Abstract
239 Background: The benefit of immunotherapy for patients with mCRC with high tumor mutational burden (TMB-H) has been widely debated. In 2020, the FDA approved the use of pembrolizumab for the treatment of patients with TMB-H unresectable or metastatic solid tumors, with TMB-H defined as ≥10 mutations/Mb on a commercial tissue-based assay, based on KEYNOTE 158 results. However, the clinical value of applying this universal cut off to mCRC needs further investigation. Methods: We queried Moffitt Cancer Center (MCC) databases for patients with MSS mCRC, harboring TMB-H (tested with tissue and/or liquid biopsies) who received immunotherapy between January 2018 and December 2021. Patients with incomplete records were excluded. Clinical data were extracted by trained staff from electronic medical records. Objective response rate was measured by using clinical assessment from chart review. Results: We identified 40 patients with TMB-H MSS mCRC 13 of whom received immune checkpoint inhibitor therapy. Female patients represented 31% (n=4) of the 13 treated patients. Median age for the patients was 60 years (range 34-71. Thirty-eight percent (n=5) of the primary tumors originated in the right side. Thirty-one percent (n=4) presented with stage 4 CRC at diagnosis. Histopathology was adenocarcinoma in 92% (n=12) and one had neuroendocrine differentiation. Tumors were well-differentiated 8% (n=1), moderately differentiated 46% (n=6), or poorly differentiated 23% (n=3). Four patients (31%) had POLE/ POLD-1 mutations. The objective response rate (ORR) was 31% (4/13) with responses limited to tumors only with POLE/ POLD-1 mutations (100%, 4/4). The median progression free survival (mPFS) was 3.8 months for the overall cohort and 28.5 months for patients with POLE/POLD-1 mutated tumors. Agent specific analysis showed mPFS for patients treated with pembrolizumab was 3.5 months (mean 5.2; range 0.6-15.7), and 3.4 months (mean 12.1; range 0.5-12.1) for patients treated with nivolumab. Five patients received immunotherapy in combination with regorafenib. The mPFS for these patients was 3.4 months (mean 3.8; range 0.5-8.0). Of five patients with TMB>30 (38%), 4 (80%) had POLE/POLD-1 mutated tumors. One case without POLE/POLD-1 mutations, but with a TMB>30 did not experience any response. Conclusions: Although TMB-H demonstrated therapeutic significance in the KEYNOTE 158 study, the utility of 10 mutations/MB as a universal cutoff warrants additional evaluation. Here we report that a TMB-H cutoff value of ≥ 10 for patients with MSS CRC was not associated with clinically meaningful response to immunotherapy, but patients with MSS CRC with POLE/ POLD-1 mutations may be more likely to benefit from immunotherapy.
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- 2023
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6. An open-label, multicenter, randomized phase II study of atezolizumab and bevacizumab with Y90 TARE in patients with unresectable hepatocellular carcinoma (HCC)
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Aiwu Ruth He, Filip Banovac, Renuka V. Iyer, Michael Petroziello, Daniel Brown, Laura Williams Goff, Richard D. Kim, Nainesh Parikh, Beau Toskich, Kevin Kim, Yixing Jiang, Suvranu Ganguli, Matthew H. Kulke, Samantha Ann Armstrong, Matthew Johnson, Rachna T. Shroff, and Gregory Woodhead
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Cancer Research ,Oncology - Abstract
TPS4177 Background: The anti–PD-L1 antibody atezolizumab (ATEZO) prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF bevacizumab (BEV) increases dendritic cell maturation, enhances T cell infiltration, and reduces myeloid-derived suppressor cells and regulatory T cells in tumors. ATEZO + BEV is FDA approved for first-line treatment of advanced HCC based on the IMbrave 150 study. Locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire and increases tumor antigen release. We hypothesize that the Y90 TARE + BEV + ATEZO combination induces synergistic tumor killing and prolongs progression-free survival in patients (pts) receiving Y90 TARE (HR = 0.6 when compared to Y-90 TARE alone). Methods: Eligible pts have HCC that cannot be surgically resected (confirmed by pathology review), is at least BCLC stage B, and is outside Milan criteria. Other requirements include ECOG PS of 0-1 at screening, measurable disease by RECIST 1.1, no prior systemic therapy, and FLR estimated at ≥ 40% post local therapy. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE + ATEZO + BEV (Arm B). Pts will have TARE mapping followed by TARE treatment. In Arm B, pts will begin TARE treatment followed by BEV + ATEZO (4 wks [± 1 wk] later). Pts will have abdominal MRI or CT scans every 12 weeks and CT scans of the chest every 24 wks. The primary study objective is to assess and compare pts' progression-free survival (per mRECIST 1.1) in each study arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of pts in Arm B. Exploratory objectives are to define the use of cellular and circulating biomarkers in the prediction of improved clinical outcomes of pts in Arm B. Symptoms experienced by pts in both arms using patient-reported outcomes will be assessed. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of Y90 TARE + BEV + ATEZO in the first 10 pts randomized to Arm B for two cycles, and if there are no grade ≥ 3 unexpected toxicities possibly, probably, or definitely related to combined TARE + BEV + ATEZO, continue to accrue 128 pts in total (current enrollment n- = 5). Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Enrollment began in September 2020. Clinical trial information: NCT04541173.
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- 2022
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7. Pembrolizumab (pembro) plus mFOLFOX7 or FOLFIRI for metastatic colorectal cancer (CRC) in KEYNOTE-651: Long-term follow-up of cohorts B and D
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Richard D. Kim, Mustapha Tehfe, Petr Kavan, Jorge Chaves, Jeremy S. Kortmansky, Eric Xueyu Chen, Christopher Hanyoung Lieu, Lucas Wong, Marwan Fakih, Kristen Renee Spencer, Qing Zhao, Raluca Predoiu, Chenxiang Li, David Carpenter, Pierre Leconte, and E. Gabriela Chiorean
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Cancer Research ,Oncology - Abstract
3521 Background: Response to antiPD-1 monotherapy is poor in patients (pts) with advanced microsatellite stable (MSS)/mismatch-repair proficient (pMMR) CRC. Combination of chemotherapy with antiPD-1 pembro may potentiate the antitumor immune response and provide greater antitumor activity than either agent alone. Combination of pembro and mFOLFOX7 or FOLFIRI in the ongoing phase 1b multicohort KEYNOTE-651 (NCT03374254) study in metastatic MSS/pMMR CRC showed antitumor activity. We present results with approximately 20 mo of additional follow-up. Methods: Pts had metastatic MSS/pMMR CRC and were previously untreated (cohort B) or received 1 prior line including a fluoropyrimidine + oxaliplatin (cohort D). Pts received pembro 200 mg Q3W + mFOLFOX7 Q2W (cohort B) or pembro 200 mg Q3W + FOLFIRI Q2W (cohort D). Primary end points were safety (DLT) and RP2D. Secondary end point was ORR per RECIST v1.1 by investigator review. DOR, DCR, and PFS per RECIST v1.1, and OS were exploratory end points. Results: Median study follow-up (range) at data cutoff (Oct 15, 2021) was 30.2 mo (25.0-43.6) for cohort B (n = 31) and 33.5 mo (25.2-43.2) for cohort D (n = 32). Treatment was discontinued in 29 pts (94%) in cohort B and 28 pts (88%) in cohort D, mostly because of PD (61% and 66%, respectively). At prior analysis (Feb 10, 2020), RP2D was confirmed as the starting dose in both cohorts; no new DLT had occurred. In cohort B, gr 3/4 TRAEs occurred in 18 pts (58%), most commonly neutropenia and decreased neutrophil count (both n = 5; 16%); 19 pts (61%) discontinued drug because of a TRAE. In cohort D, gr 3/4 TRAEs occurred in 17 pts (53%), most commonly, neutropenia (n = 7; 22%), diarrhea and fatigue (both n = 4; 13%); 3 pts (9%) discontinued drug because of a TRAE. There were no gr 5 TRAEs in either cohort. Efficacy by cohort and KRAS mutation status are below (Table). PD-L1 data and DNA/RNA-based biomarker data including GEP, consensus signatures, TMB, and LoF mutations will be included in the presentation. Conclusions: After 2.5 y of follow-up, the combination of pembro with either mFOLFOX7 or FOLFIRI continued to demonstrate a manageable safety profile with no new safety signals. Efficacy data from these single-arm cohorts appear comparable to historical data for current SOC. Clinical trial information: NCT03374254. [Table: see text]
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- 2022
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8. Pembrolizumab (pembro) plus binimetinib (bini) with or without chemotherapy (chemo) for metastatic colorectal cancer (mCRC): Results from KEYNOTE-651 cohorts A, C, and E
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Eric Xueyu Chen, Petr Kavan, Mustapha Tehfe, Jeremy S. Kortmansky, Michael B. Sawyer, E. Gabriela Chiorean, Christopher Hanyoung Lieu, Blase N. Polite, Lucas Wong, Marwan Fakih, Kristen Renee Spencer, Jorge Chaves, Chenxiang Li, David Carpenter, Pierre Leconte, and Richard D. Kim
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Cancer Research ,Oncology - Abstract
3573 Background: Response to antiPD-1 monotherapy is poor in microsatellite stable (MSS)/mismatch-repair proficient (pMMR) mCRC; the combination of antiPD-1 pembro + anti-MEK bini, with or without chemo, may improve upon this limited response. KEYNOTE-651 (NCT03374254) is an open-label phase 1b multicenter trial of pembro + bini (cohort A) or pembro + bini + chemo (mFOLFOX7 in cohort C, FOLFIRI in cohort E) in MSS/pMMR mCRC. Preliminary results from the dose-finding phase at 2 dose levels (DL) of bini are presented. Methods: Patients (pts) had MSS/pMMR mCRC and must have been previously treated with fluoropyrimidine, irinotecan, and oxaliplatin in cohort A, or with fluoropyrimidine + oxaliplatin-based regimen in cohort E; pts were previously untreated in cohort C. Pts received pembro 200 mg Q3W + bini 30 mg BID (cohort A, DL1), pembro 200 mg Q3W+ bini 30 mg BID + mFOLFOX7 Q2W (cohort C, DL1) or pembro 200 mg Q3W + bini 30 mg BID + FOLFIRI Q2W (cohort E, DL1). Bini dose escalation to 45 mg BID (DL2) was planned in cohorts A, C, and E, with a target dose-limiting toxicity (DLT) of 30%. Primary end point was safety (DLT). Secondary end point was ORR. DCR, PFS, and OS were exploratory. ORR, DCR, and PFS were assessed by investigator per RECIST v1.1. Results: Median study follow-up at data cutoff (Oct 15, 2021) was 36 mo (range, 32-43) for cohort A, 17 mo (2-24) for cohort C, and 11 mo (2-25) for cohort E. In cohort A, 1/6 pts (17%) had DLT at DL1; no DLT occurred in 14 pts (0%) at DL2. In cohort A, gr 3/4 TRAEs occurred in 3/6 pts (50%) at DL1 and 8/14 pts (57%) at DL2. In cohort C, 3/9 evaluable pts (33%) had DLT at DL1; thus, bini dose was not escalated to DL2. In cohort C, gr 3/4 TRAEs occurred in 9/11 total pts (82%). In cohort E, 1/5 evaluable pts (20%) had DLT at DL1 and 5/10 evaluable pts (50%) had DLT at DL2. Enrollment was stopped in cohort E, DL2 and bini dose was de-escalated to DL1; 2/4 additional pts (50%) had DLT at DL1 (total 3/9 pts [33%] had DLT in cohort E, DL1). In cohort E, gr 3/4 TRAEs occurred in 5/9 pts (56%) at DL1 and 10/11 total pts (91%) at DL2. No gr 5 TRAEs occurred in any cohort. ORR was 0% in cohort A; limited efficacy was seen in cohorts C and E (Table). Conclusions: Bini could be safely combined with pembro in cohort A. However, with bini + pembro + chemo, the 45-mg dose of bini was not well tolerated and required dose reduction to 30 mg. Addition of bini to pembro + chemo did not improve efficacy; therefore, enrollment was prematurely closed in cohorts C and E. Efficacy by KRAS mutation status will be shown. Clinical trial information: NCT03374254. [Table: see text]
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- 2022
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9. Efficacy and safety of NT-I7, long-acting interleukin-7, plus pembrolizumab in patients with advanced solid tumors: Results from the phase 2a study
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Aung Naing, Hirva Mamdani, Minal A. Barve, Melissa Lynne Johnson, Daniel Morgensztern, Anthony J. Olszanski, Robert A. Wolff, Shubham Pant, Marya F. Chaney, Tolani Adebanjo, Jean Fan, Richard D. Kim, and Scott Kopetz
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Cancer Research ,Oncology - Abstract
2514 Background: Checkpoint inhibitors (CPIs) are usually ineffective in patients (pts) with immune-cold microsatellite stable colorectal cancer (MSS-CRC) or pancreatic cancer (PDAC) and in those who progressed on previously treated with antibodies against PD1 or PD-L1. Here, we report the combination of NT-I7 plus pembrolizumab (pembro) on CPI-naïve MSS-CRC and PDAC cohorts, and patients (pts) with CPI-treated triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) cohorts of this ongoing phase 2a trial. Methods: Pts with CPI-naïve relapsed/refractory (R/R) MSS-CRC and PDAC, and CPI-treated R/R TNBC, NSCLC, and SCLC, were enrolled. NT-I7 (efineptakin alfa) 1200 µg/kg intramuscularly every 6 weeks and 200 mg pembro intravenously every 3 weeks were administered until disease progression/unacceptable toxicity. The primary endpoint of the Phase 2a is the objective response rate (ORR), assessed by RECIST v1.1 and iRECIST. The secondary endpoints are duration of response (DoR), disease control rate, progression-free survival, and overall survival. Results: As of 14 Jan 2022, 92 pts with metastatic or locally advanced cancer who had received a median of 3 prior treatments were enrolled in the study; 32 in PDAC, 28 in MSS-CRC, 22 in NSCLC, 6 in TNBC, and 4 in SCLC. The median age was 62 years [29-81], ECOG PS 0 in 23 (25%), 1 in 68 (74%) and 2 in 1 (1%). Among 71 evaluable pts, the median follow up (months) was 7.7, 5.3, 5.0, 3.7, and 2.4 in TNBC, MSS-CRC, NSCLC, PDAC and SCLC, respectively. The ORR was 50% (1/2) in SCLC, 12% (3/25) in MSS CRC, 8% (2/26) in PDAC 6% (1/16) in NSCLC and 0% (0/2) in TNBC per iRECIST; and 50% (1/2) in SCLC, 4% (1/25) in MSS CRC, and 4% (1/26) in PDAC per RECIST 1.1. All 7 responders are ongoing. The two PDAC pts had DoR over 1.35 months (mos) and 6.64 mos with the best tumor reduction 100% and 72% respectively. The one SCLC pt had DoR over 1.5 mos with the tumor reduction 67%. The one NSCLC pt had DoR over 2.73 mos with the tumor reduction 60%, and the three MSS-CRC pts had DoR 6.34, 2.96, and 0.03 mos with the tumor reduction 60%, 56%, and 43% respectively. A sustained and significant (approximate 3X from baseline) increase of peripheral lymphocytes in all arms was observed as shown in our previous report. Among 92 treated pts, NT-I7-related adverse events (AEs) occurred in 67 (72.8%) pts, including 52 (56.5%) Grade (G)1-2, 13 (14.1%) G3, and 2 (2.2%) G4. There were no NT-I7 related G5 AEs. Additional updated efficacy, safety and biomarker data will be presented. Conclusions: The combination of NT-I7 and pembro demonstrated antitumor activity and manageable toxicity profile in heavily pretreated pts with CPI-naïve MSS-CRC and PDAC and CPI-treated TNBC, NSCLC, and SCLC, suggesting that the addition of NT-I7 to CPI can overcome the primary resistance to CPI in the former group and acquired resistance in the latter. Clinical trial information: NCT04332653.
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- 2022
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10. Characterization of NTRK alterations in metastatic colorectal cancer
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Canan Karan, Elaine Tan, Humaira Sarfraz, Christine Marie Walko, Richard D. Kim, Todd C Knepper, and Ibrahim Halil Sahin
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Cancer Research ,Oncology - Abstract
e15569 Background: Increased molecular profiling ability has resulted in the recognition of important actionable genes that can be used to direct targeted therapies in colorectal cancers (CRC). Neurotrophin receptor tyrosine kinase (NTRK) gene fusions are one of these molecular alterations that are potentially actionable with novel targeted therapeutics. However, other biologically pathogenic NTRK alterations, including point mutations, are not yet actionable in CRC. This study aimed to characterize NTRK alterations, including fusions in metastatic CRC patients. Methods: Molecular characteristics of 917 patients with CRC were collected from the Moffitt Cancer Center Clinical Genomics Action Committee database. Demographic, clinicopathological, and molecular data and treatment history were abstracted from electronic medical records. Mutations with potential oncogenic activity are considered “potentially pathogenic”, while alterations with proven oncogenic activity such as fusions are considered “pathogenic”. Results: There were 917 patients with CRC from November 2013 to December 2021, and 77 of them had NTRK alterations excluding synonymous mutations (8.3%, 77/917). Six patients had potentially pathogenic NTRK alterations, including one NTRK rearrangement (0.6%, 7/917); however, only 1 patient had an actionable pathogenic NTRK1 fusion (0.1%, 1/917), while the others (70) were a variant of unknown significance (VUS). The majority of NTRK alterations were missense mutations (92%; 71/77). The NTRK1 fusion partner was LMNA and occurred in the setting of an MSI-H tumor (3.7%; 1/27). Among patients with pathogenic and potentially pathogenic alterations (N = 7), there was only 1(14%) patient who had low tumor mutation burden (TMB) (< 10 mut/MB). Most patients were older than 50 years (70.1%, 54/77) and male (58.4%, 45/77). Thirty-six patients (46..7%) had right-sided tumor, while 41 patients (53.2%) left-sided. Across all NTRK alterations cohort, MSI-H was found in 10.3% (7/77), and POLE/POLD1 pathogenic mutations were seen in 6.4% (5/77) patients. Conclusions: NTRK gene fusion is a relatively rare event (< 1%) in CRC, including the MSI-H subtype. The majority of NTRK alterations in CRC are VUS, and they are not actionable, and they tend to be seen in the tumors with high TMB (TMB > 10). Hypermutator tumors cause frequent VUS alterations in the NTRK gene with unknown clinical relevance.
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- 2022
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11. Clinical and molecular characterization of fusion genes in colorectal cancer
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Canan Karan, Elaine Tan, Humaira Sarfraz, Christine Marie Walko, Richard D. Kim, Todd C Knepper, and Ibrahim Halil Sahin
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Cancer Research ,Oncology - Abstract
e15568 Background: Next-generation sequencing (NGS) based molecular profiling technologies have revealed several oncogenic fusion genes that are actionable with small molecule inhibitors leading to practice change, particularly in lung cancer. The molecular and clinical characteristics of these gene fusions are not well defined in colorectal cancer patients (CRC). In this study, we aimed to define clinical and molecular characteristics of fusion genes in patients with CRC who underwent molecular profiling. Methods: Molecular characteristics of tissue confirmed 917 CRC patients were retrieved from the Moffit Cancer Center Clinical Genomics Action Committee database. Patients’ demographic and clinicopathological features and treatment history were collected from the database. All fusion genes were shown by hybridization-based NGS computational algorithms that determined cancer‐related genes, including single‐nucleotide variations, indels, microsatellite instability (MSI) status. Results: Among a total of 917 patients, 24 patients with CRC (2.6%) were found to have at least one fusion gene with a total number of 26 pathogenic fusions. The gene fusions are shown in Table. The most common, potentially targetable, fusion genes in our cohort were (1) RET fusions 0.5% (5/917), (2) ALK fusions 0.4% (4/917), (3) ROS1 fusions 0.2% (2/917), (4) NTRK1 fusion 0.1% (1/917), (5) NRG1 fusion 0.1% (1/917). Fusion genes were more common in MSI-H CRC (N = 27), and 3 (11.1%) patients with MSI-H CRC were found to have fusion genes [(RET (2) and NTRK(1)]. Fusion genes were present in both RAS wild-type (54%; 13/24) and RAS mutant (46%; 11/24) tumors. Most patients were older than 50 years (75%, 18/24) and had left-sided tumor (61.1%) tumor. Conclusions: Fusion genes are rare events in CRC. While fusion genes seem to be more prevalent in MSI-H CRC, RAS status does not correlate with the frequency of fusion genes. Actionable RET and ALK/ROS gene fusion are more common than NTRK fusion genes in this cohort of CRC patients.[Table: see text]
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- 2022
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12. Disparity of treatment-related adverse events and outcome in patients with early-onset metastatic colorectal cancer (mCRC)
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Lingbin Meng, Ram Thapa, Richard D. Kim, Damian A. Laber, and Hao Xie
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Cancer Research ,Oncology - Abstract
6560 Background: While the incidence of newly diagnosed early-onset mCRC has been increasing, disparity of treatment-related adverse events (AE) and outcomes of this patient population has been inadequately studied with inconclusive findings. We aimed to evaluate such age-related disparity and explore potential underlying causes. Methods: We used individual patient data from 3 clinical trials in Project Data Sphere where 756 and 467 patients with mCRC received first-line FOLFOX in study 1 (NCT 00305188, NCT00272051) and study 2 (NCT00364013), respectively. Clinical NGS data of 763 patients with mCRC from prospectively maintained Moffitt Clinical Genomics Database were used to assess genomic alterations. Patients were categorized into 3 age groups: 65 years. Continuous and categorical variables were compared with t test and χ2 test, respectively. Kaplan-Meier method and log-rank test were used for survival analysis. Benjamini-Hochberg procedure was used to adjust for multiple comparisons. Results: Among 1986 patients included, 341 (17.2%) in the 65 group had similar baseline characteristics. Outcomes: Patients in the 65 groups (15.5 vs 20.8 months, p=0.004) and shorter median PFS compared to the 50-65 (8.1 vs 9.4 month, p=0.039) and >65 groups (8.1 vs 8.6 months, p=0.07) in study 1. Findings were confirmed in study 2. Toxicity: Compared to other age groups, the
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- 2022
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13. Core homologous recombination mutations and improved survival in nonpancreatic GI cancers
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Elaine Tan, Junmin Whiting, Christine Marie Walko, Todd C Knepper, Hao Xie, Iman Imanirad, Estrella M. Carballido, Seth Felder, Jessica M. Frakes, Qianxing Mo, Jennifer Permuth, Richard D. Kim, Daniel A. Anaya, Jason B. Fleming, and Ibrahim Halil Halil Sahin
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Cancer Research ,Oncology - Abstract
663 Background: GI malignancies continue to be a major cause of cancer related deaths, despite advances in therapy options. In pancreatic cancer, the presence of homologous recombination mutations (HRM) has been shown to confer increased sensitivity to platinum chemotherapy. However, the role of HRM mutations in other GI cancers remains to be determined. The focus of this study is to evaluate the prognostic nature of core and noncore HRM in nonpancreatic GI cancers. Additionally, we aim to understand the predictive nature of these mutations related to platinum exposure. Methods: This was a retrospective review of patients at Moffitt Cancer Center with a primary stage IV nonpancreatic GI cancer treated with platinum therapy. All patients had next generation sequencing and were in the Clinical Genomics Action Committee database between 1/1/2013 and 11/1/2020. All patients had either a core HRM (BRCA1, BRCA2, PALB2) or noncore HRM (such as ATM, ATR, BARD1, BRIP1, FANCA, NBN, and RAD51). Patients were grouped into core HRM vs. noncore HRM. Response was stratified between responders (complete response and partial response) vs. non responders (stable disease and progressive disease), based on RECIST criteria. Progression free survival and overall survival were estimated using Kaplan-Meier method, and the log-rank test was used to assess the difference in progression free survival (PFS) and overall survival (OS) by HRM status and type of platinum therapy used. Results: There were 72 patients included in the study: the majority of patients were male (65.3%) and Caucasian (87.5%). Twenty-one (29.2%) patients had a core HRM and 51 (70.8%) had a noncore HRM. There was no significant difference in response rate between patients with core HRM and patients with noncore HRM for evaluable patients (n = 66): 20.0% of patients with core HRM vs. 21.7% of patients with noncore HRM demonstrated a response to platinum therapy (p = 0.41). An improved OS was noted for patients with core HRM vs. those with noncore HRM at 68.9 vs. 24.3 months (p = 0.019). An improved PFS was also seen in patients with core HRM at 10.4 months vs. 6.3 months with noncore HRM (p = 0.027). There was no difference in PFS based on type of platinum therapy used (oxaliplatin vs. carboplatin vs. cisplatin), while an improved OS was noted for patients treated with oxaliplatin vs. carboplatin vs. cisplatin at 43.1 vs. 28.2 vs. 16.0 months (p = 0.011). Conclusions: Our study demonstrated that in stage IV nonpancreatic GI malignancies treated with platinum therapy, patients with core HRM had a greater OS and PFS compared to those with noncore HRM, suggesting a potential prognostic and predictive role of these mutations. Further studies are needed to confirm our findings.
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- 2022
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14. A phase II study of TAS-102 (FTD/TPI) in combination with ramucirumab (RAM) in advanced, refractory gastric (GC) or gastroesophageal junction (GEJ) adenocarcinomas (GEAs)
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Rutika Mehta, Richard D. Kim, Maria E Martinez Jimenez, Kirsten Blue, Trenton Avriett, Emily Kelbert, Kara Miller, Christopher Ray, Tiffany Valone, Woojoo Lee, Youngchul Kim, and Dae Won Kim
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Cancer Research ,Oncology - Abstract
302 Background: The RAINBOW trial established the standard of care for treatment of metastatic GEAs with ramucirumab and paclitaxel after failure of fluoropyrimidine and platinum-based chemotherapy. While the combination achieved an objective response rate (ORR) of 28%, the incidence of any grade neuropathy was 46%. Therefore, there is an unmet need for novel treatment combinations that minimize the long-term toxicity of neuropathy. In a recently published Asian study, the combination of RAM+TAS-102 showed good disease control and acceptable toxicity profile. Methods: This was a single arm, single institution phase II trial using the combination of TAS-102 plus RAM in refractory GEAs. Patients (pts) received RAM 8mg/kg intravenously on day 1 and 15, and TAS-102 35mg/m2 orally twice daily on days 1-5 and days 8-12 every 28-day cycle. The primary endpoint was 6-months overall survival (OS) rate and secondary endpoints were progression free survival (PFS), ORR and safety profile. The trial was registered at www.clinicaltrials.gov (NCT03686488). Results: At data cut-off of August 15, 2021, 23 pts were enrolled. Baseline demographics are as follows: median age of 62 years (range: 23-74), median lines of prior therapy of 1 (1: 14 pts vs ≥2: 9 pts) and location of primary tumor (GEJ:19 vs GC: 4). 6-month OS rate was 56.2%. Median OS was 6.2 month (95% CI: 5.4-7.0) and median PFS was 4.9 months with median observation of 2.3 months. Of 17 evaluable pts defined as more than one baseline imaging, 1 (6%) had partial response (PR) and 15 (88%) had stable disease (RECIST v1.1). Eleven pts came off the study due to progression of disease, 8 for toxicities and 4 for consent withdrawal. Most common treatment-emergent adverse events (TEAEs) were diarrhea (39%), fatigue (39%) and hypertension (39%). Total 11 pts (48%) experienced grade 3 and 4 TEAEs, and most common Gr3 and 4 TEAEs were neutropenia (17%) and anemia (13%). Conclusions: The combination of RAM and TAS-102 showed very similar disease control rate as the study in Asia. The combination has now shown modest activity in advanced GEAs and should be investigated further now in the context of patients receiving immunotherapy-based treatment as first-line treatment. A randomized phase II study is currently enrolling patients with ramucirumab and TAS-102 or paclitaxel. Clinical trial information: NCT03686488.
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- 2022
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15. Association of BRAF V600E mutation with survival in patients with metastatic mismatch repair-deficient colorectal cancer
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Elaine Tan, Junmin Whiting, Hao Xie, Iman Imanirad, Estrella M. Carballido, Seth Felder, Jessica M. Frakes, Qianxing Mo, Christine Marie Walko, Jennifer Permuth, Richard D. Kim, Daniel A. Anaya, Jason B. Fleming, and Ibrahim Halil Halil Sahin
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Cancer Research ,Oncology ,neoplasms ,digestive system diseases - Abstract
174 Background: Colorectal cancer (CRC), while one of the most common cancer diagnoses, can behave heterogeneously based on molecular characteristics. A subset of patients (pts) with CRC are characterized with mismatch repair deficiency (MMR-d), these pts exhibit encouraging responses to immunotherapy. The predictive nature of various factors, such as BRAF status, age, and MMR-D protein loss type, have been investigated in pts with MMR-d CRC. However, the prognostic role of these factors has not been well established. The purpose of this study was to identify characteristics that influence survival in MMR-d mCRC. Methods: This study evaluated pts with MMR-d mCRC in the Flatiron database. Overall survival (OS) was determined from date of diagnosis of stage IV disease to date of death and stratified based on age greater than or less than 50 years, BRAF mutation status, RAS mutation status, and type of MMR gene loss. For statistical analysis, the Chi-Square test was implemented to determine the prognostic significance of clinical and molecular features. Univariate and multivariate analyses were determined through the Cox regression model. Results: There were 1,101 pts in the study. The majority of pts were older than 50 (79.7%), Caucasian (75%), and had ECOG 0-1 (83.4%). Among the 803 pts with known BRAF status, 44.3% (n=356) had BRAF V600E mutation and 55.7% (n=447) were BRAF wildtype. Pts with BRAF V600E mutation had OS of 18.9 months vs. 33.2 months for pts with wild type BRAF (HR 1.52, 95% CI: 1.25-1.86, p
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- 2022
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16. Updated results of a phase 1b study of regorafenib (REG) 80 mg/day or 120 mg/day plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC)
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William P. Harris, Max W. Sung, Dirk Waldschmidt, Ying A. Wang, Tatiane Cristine Ishida, Richard D. Kim, Udo Mueller, Barbara J. Brennan, Vittorio Luigi Garosi, Hong Zebger-Gong, Peter R. Galle, Anthony B. El-Khoueiry, and Roniel Cabrera
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Oncology ,Sorafenib ,Cancer Research ,medicine.medical_specialty ,business.industry ,hemic and immune systems ,chemical and pharmacologic phenomena ,Pembrolizumab ,medicine.disease ,First line treatment ,Multikinase inhibitor ,chemistry.chemical_compound ,chemistry ,Hepatocellular carcinoma ,Internal medicine ,Regorafenib ,medicine ,business ,medicine.drug - Abstract
4078 Background: REG, a multikinase inhibitor, and PEMBRO, an anti-PD-1 mAb, are approved as monotherapies in advanced HCC after progression on sorafenib. This phase 1b dose-finding study investigated first-line REG plus PEMBRO in advanced HCC. Methods: Patients (pts) in the first cohort received a starting REG dose of 120 mg/day orally for 3 weeks (wks) on/1 wk off, which could be escalated (160 mg) or reduced (80 mg) in later cohorts, plus a fixed dose of PEMBRO 200 mg IV every 3 wks. Due to a high dose modification rate in the REG 120 mg cohort, an exploratory REG 80 mg cohort was introduced. Primary objective was safety and tolerability; secondary aims were to assess the maximum tolerated dose (MTD), recommended phase 2 dose, and anti-tumor activity. Results: 35 pts started on REG 120 mg/day and 22 on REG 80 mg/day. Median age was 66 yrs (range 29–81), 84% of pts were male, 70%/30% had ECOG PS 0/1, 26%/74% were BCLC stage B/C, 100% were C–P A, 46% had extrahepatic spread, and 32% had macrovascular invasion. MTD of REG was 120 mg/day. Grade (Gr) 3/4 treatment-emergent adverse events (TEAE) occurred in 86% of pts on REG 120 mg and 50% on REG 80 mg (Table). Most common Gr 3/4 TEAE for REG 120 mg/80 mg were AST increased (23%/9%), lipase increased (20%/5%), ALT increased (17%/9%), and hypertension (17%/9%). TEAE led to REG/PEMBRO dose reductions or interruptions in 71%/57% of pts on REG 120 mg and 59%/45% on REG 80 mg. Median treatment duration (range) was 3.0 months (mo; 0.2–20.5) for REG 120 mg and 3.5 mo (0.03–24.4) for PEMBRO, and 3.5 mo (0.7–10.8) for REG 80 mg and 3.5 mo (0.8–11.3) for PEMBRO. Of 32 evaluable pts on REG 120 mg, 10 (31%) had a partial response (PR) and 18 (56%) had stable disease (SD); disease control rate (DCR) was 88% (RECIST v1.1). Of 22 pts on REG 80 mg, 4 (18%) had a PR and 16 (73%) had SD; DCR was 91%. As of 17 Dec 2020, 16 pts remain on treatment (REG 120 mg n = 5; REG 80 mg n = 11); median follow up was 11.7 mo and 6.9 mo, respectively. REG pharmacokinetic exposure was as expected for 80 mg and 120 mg doses. Flow cytometry analysis of sequential peripheral blood showed changes in subsets of T-cells and monocytes, which may contribute to clinical benefit. Conclusions: First-line REG plus PEMBRO in advanced HCC showed no new safety signals and encouraging anti-tumor activity (DCR ̃90%). The REG 80 mg cohort appeared to have lower rates of dose reductions and interruptions due to TEAE vs REG 120 mg. Efficacy data for the REG 80 mg cohort are preliminary due to short follow-up. Clinical trial information: NCT03347292. [Table: see text]
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- 2021
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17. A phase 1 study of TAK-164, an anti-guanylyl cyclase C (GCC) antibody-drug conjugate (ADC), in patients (pts) with advanced gastrointestinal (GI) cancers expressing GCC
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Johanna C. Bendell, Harry H. Miao, Aaron Moss, Richard D. Kim, Neeraj Gupta, James M. Cleary, Aparna Raj Parikh, Shining Wang, Alexis D. Leal, Joanna Pye, David P. Ryan, and Brittany Bahamon
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Drug ,chemistry.chemical_classification ,Cancer Research ,medicine.drug_class ,business.industry ,media_common.quotation_subject ,Peptide ,Guanylate cyclase 2C ,Monoclonal antibody ,Oncology ,chemistry ,medicine ,Cancer research ,In patient ,business ,Linker ,GCC Antibody ,media_common ,Conjugate - Abstract
3050 Background: TAK-164 is a second-generation ADC comprising a human IgG1 monoclonal antibody targeting GCC conjugated to a DNA-damaging alkylating agent by a peptide linker. TAK-164 demonstrated cytotoxic and antitumor activity in GCC-expressing cells and xenograft mouse models. This first-in-human study investigated the safety, pharmacokinetics (PK), and preliminary efficacy of TAK-164. Methods: Adult pts with GCC-positive, advanced/metastatic GI cancers received TAK-164 intravenously on day 1 of a 21-day cycle (Q3W). Dose escalation proceeded based on cycle 1 safety data via a Bayesian model of modified toxicity probability interval starting at 0.004 mg/kg. Results: Thirty-one pts were enrolled. Median age was 58 years (range 32–72), 58.1% of pts were female and 64.5% had colon carcinoma. The median number of prior lines of therapy was 4 (range 2–9). TAK-164 was given at 0.004 (n = 1), 0.008 (n = 1), 0.016 (n = 1), 0.032 (n = 5), 0.064 (n = 7), 0.12 (n = 7), 0.16 (n = 2), 0.19 (n = 3), 0.25 (n = 3) and 0.32 mg/kg (n = 1). No pts had dose-limiting toxicities (DLT) in cycle 1 up to 0.32 mg/kg. Three pts had adverse events (AEs) after cycle 1 considered to be DLTs: 1 pt receiving 0.19 mg/kg (grade 3 pyrexia and grade 5 hepatic failure) and 2 pts receiving 0.25 mg/kg (1 pt had grade 3 nausea, and grade 4 platelet count decrease and neutrophil count decrease; 1 pt had grade 4 hepatic failure and grade 4 platelet count decrease). Dosing was capped at 0.19 mg/kg due to hepatic toxicity and the recommended phase 2 dose (RP2D) was determined as 0.064 mg/kg based on safety and tolerability beyond cycle 1. Overall, pts received a median of 2 (range 1–8) treatment cycles. TAK-164-related treatment-emergent AEs (TEAEs) reported in 77.4% of pts included platelet count decrease (58.1%), fatigue (38.7%), and anemia (32.3%). TAK-164-related grade ≥3 TEAEs reported in 32.3% of pts included platelet count decrease (12.9%), alanine aminotransferase increase, aspartate aminotransferase increase, fatigue, and anemia (all 9.7%). Three pts discontinued due to TAK-164-related TEAEs. There was a dose-dependent increase in TAK-164 maximum plasma concentration and exposure over the range 0.016–0.32 mg/kg, with no meaningful accumulation in PK with repeat Q3W dosing. One pt receiving TAK-164 0.19 mg/kg showed γH2AX induction via immunohistochemistry in a post-treatment biopsy, demonstrating target engagement. One pt with low baseline GCC expression who received 5 cycles of TAK-164 0.008 mg/kg had an unconfirmed partial response at cycle 4; 11 of 25 (44.0%) evaluable pts had a best overall response of stable disease. Conclusions: TAK-164 appeared to have a manageable safety profile up to 0.064 mg/kg in pts with advanced GI cancers; hepatic toxicity was identified as a potential risk. The RP2D was determined as 0.064 mg/kg but was considered insufficient to derive significant clinical benefit. Clinical trial information: NCT03449030.
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- 2021
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18. Efficacy of olaparib therapy in metastatic pancreatic ductal adenocarcinoma (PDAC) with homologous recombination deficiency (HRD)
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Richard D. Kim, Estrella M. Carballido, James Kevin Hicks, Kirsten Blue, Dae Won Kim, and Elaine Tan
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Cancer Research ,Pancreatic ductal adenocarcinoma ,business.industry ,medicine.disease ,Olaparib ,chemistry.chemical_compound ,Oncology ,chemistry ,Pancreatic cancer ,Mutation (genetic algorithm) ,medicine ,Cancer research ,Homologous Recombination Deficiency ,business - Abstract
e16266 Background: Pancreatic cancer is one of the deadliest malignancies, with a 5 year OS of around 3%. Up to 3% of unselected patients (pts) with (PDAC) have the BRCA 1/2 mutation, while up to 15% possess HRD (ARID1A, ATM, BAP1, BARD1, BRIP1, CHEK1/2, FANCA, PALB2, RAD50, RAD51). PARP inhibitors, like olaparib, demonstrate clinical benefit in metastatic PDAC with BRCA mutations (mBRCA) and may have a role in those with HRD. The objective of this study is to determine the role of PARP inhibition in PDAC with HRD. Methods: This was a retrospective chart review of metastatic PDAC pts with germline (g) or somatic (s) mBRCA or HRD who received olaparib. An analysis of PFS and OS was performed for PDAC pts with mBRCA vs. HRD. Results: Forty-six pts with metastatic pancreatic cancer were identified to have mBRCA (n = 13) or HRD (n = 23) and received olaparib in our database. Median age was 73 years for mBRCA and 66 years for HRD. Five pts received olaparib as maintenance therapy after disease control with platinum: 2 mBRCA and 3 HRD pts. Six pts with mBRCA and 7 pts with HRD were platinum naïve prior to olaparib. Zero pts with mBRCA and 3 pts with HRD received olaparib after disease progression on platinum. The median (med)PFS for mBRCA vs. HRD was 6.1 months vs. 2.8 months (HR 0.5, 95% CI: 0.2-1.1, p = 0.07). The medOS for mBRCA vs. HRD was 7.7 vs. 5.3 months (HR 0.7, 95% CI: 0.2-1.9, p = 0.4). Of those with mBRCA who received olaparib, prior cisplatin exposure (n = 8) vs. cisplatin naïve (n = 5) led to medPFS of 6.1 vs. 7.8 months (HR 1.8, 95% CI 0.5-6.7, p = 0.3) and medOS of 6.8 months vs. 9.5 months (HR 1.5, 95% 0.3-6.4, p = 0.6). Six pts with HRD including gCHEK2 c.407T > C, gCHEK2 c.1461+1 G > A, gPALB2 gain (exon 11), sFANCI p.N1252S, sATM p.V2716A, sARID1A Q944fs*14 were noted to have disease control of at least 3 months on olaparib. Only one of these pts received olaparib as maintenance therapy after platinum. The medPFS was 6.1 months and medOS was not reached. One pt with HRD (sFANCI N1252S) had progressive disease on platinum prior to olaparib, but had stable disease > 5 months with olaparib. Conclusions: Our study suggests olaparib may have anticancer activity in PDAC with certain HRD. In addition, olaparib may have a role outside maintenance therapy in PDAC with mBRCA. Prospective studies are needed to confirm these findings.
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- 2021
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19. Investigate the efficacy of immunotherapy for treatment of pancreatic adenocarcinoma (PDAC) with mismatch repair deficiency (dMMR)
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Richard D. Kim, Estrella M. Carballido, Kirsten Blue, Arish Noor, Trenton Avriett, Dae Won Kim, and Luis E. Aguirre
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Cancer Research ,Oncology ,business.industry ,medicine.medical_treatment ,Immune checkpoint inhibitors ,medicine ,Cancer research ,MISMATCH REPAIR DEFICIENCY ,Adenocarcinoma ,Immunotherapy ,medicine.disease ,business - Abstract
415 Background: Immune checkpoint inhibitors (ICI) have been approved in solid tumors with dMMR. However, only limited data are available for PDAC with dMMR given the rarity of dMMR in PDAC. We evaluated efficacy of ICIs in PDAC with dMMR. Methods: Retrospective clinical and pathologic data were collected for patients (pts) with pancreatic adenocarcinoma from May 2017 to June 2020 at Moffitt cancer center. Results: We identified 10 pts with dMMR PDAC. The median age was 64.5 years (range: 42-86) and 4 pts were male. 4 pts had resectable disease, 3 had locally advanced and 3 had metastatic disease at initial diagnosis. MSH6 deficiency (def) was found in 2 cases, PMS2 def in 2, MLH/PMS2 def in 5, and MSH2/MSH6 in 1. 7 pts were treated with ICIs. 3 pts had locally advanced and 4 had metastatic disease when they started ICIs. 5 received Pembrolizumab (pem), 1 received ipilimumab/ nivolumab (ipi/nivo), and 1 received pem then ipi/nivo after progressive disease (PD) on pem. The median number of prior lines of chemotherapy was 1 (range 0-2). 6 pts were evaluable, and 1 had rapid disease progression after 1 dose of pem. Among 6 evaluable pts, 3 had an objective response (1: complete response and 2: partial response), and 2 had stable disease (SD). Median progression-free survival was 8.2 mo, and median overall survival was not reached with median follow-up (FU) of 6.8 mo. The median duration of response was not reached with a median FU of 22.6 mo. The pt with CR remained disease-free for up to 22 months. The pt whose treatment was switched to ipi/nivo after PD on pem achieved SD > 4mo on ipi/nivo. While on immunotherapy, one patient with ipi/nivo developed immunotherapy associated rash requiring systemic steroids, and another on pem developed hypothyroidism requiring levothyroxine. Conclusions: This series suggest ICIs can provide durable clinical efficacy in pts with dMMR PDAC.
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- 2021
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20. A phase II study of atezolizumab (ATEZO) and bevacizumab (Bev) in combination with Y90 TARE in patients (Pts) with hepatocellular carcinoma (HCC)
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Kevin Kim, Yixing Jiang, Lipika Goyal, Beau M Toskich, Laura W. Goff, Thomas A. Abrams, Alexander Y. Kim, Stacey Stein, Kabir Mody, Aiwu Ruth He, Smitha S. Krishnamurthi, Daniel H. Johnson, Daniel B. Brown, T. Sandow, Nabeel Akhter, Nainesh Parikh, Charles Martin, Richard D. Kim, Renuka Iyer, and Michael Petroziello
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Cancer Research ,Bevacizumab ,Tare weight ,biology ,business.industry ,T cell ,Phases of clinical research ,Dendritic cell ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Atezolizumab ,Hepatocellular carcinoma ,Cancer research ,biology.protein ,Medicine ,Antibody ,business ,medicine.drug - Abstract
TPS358 Background: The anti–PD-L1 antibody ATEZO prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF BEV can increase dendritic cell maturation, enhance T cell infiltration, and reduce myeloid-derived suppressor cells and regulatory T-cells in tumors. This combination has been FDA approved for first-line treatment of advanced HCC based on the IMbrave 150 study. On the other hand, locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire. It is the standard of care for pts with intermediate-stage HCC (iHCC). Based on preclinical and clinical data, we hypothesize that the combination of Y90 TARE, BEV, and ATEZO induces synergistic tumor-killing. Methods: This is an open-label, multicenter, randomized phase II study of Y90 TARE and BEV plus ATEZO compared with Y90 TARE alone in pts with unresectable IHCC. The primary study objective is to assess and compare the progression-free survival (PFS) (per mRECIST 1.1) of pts in each arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of TARE combined with ATEZO and BEV in pts with HCC. Exploratory objectives are to assess the role of the immunoscore and PD-L1 expression levels in the prediction of improved clinical outcome in pts receiving Y-90 TARE and BEV plus ATEZO; the composition of tumor-infiltrating immune cell subtypes in predicting response to a chosen therapy; how Y90 therapy affects the proportion of antigen-presenting cells in the tumor; and symptoms experienced by pts receiving TARE and BEV plus ATEZO treatment, using patient-reported outcomes. Eligible pts have either HCC that is not amenable to surgical resection, confirmed by pathology review, or at least BCLC stage B HCC outside of downstaging criteria. Other standard eligibility criteria apply. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE followed by ATEZO and BEV (Arm B). Pts will have TARE mapping during week (wk) 1 and TARE treatment during wk 2. In Arm B, pts will start BEV plus ATEZO 4 wks (±1 wk) after TARE treatment. Pts will have abdominal MRI or CT scans every 12 weeks, CT scans of the chest every 24 wks, and a second tumor biopsy at 4 wks. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of TARE with BEV and ATEZO in the first 10 pts randomized to Arm B for two cycles. If there are no grade ≥ 3 unexpected toxicities possibly, probably or definitely related to combined TARE plus BEV plus ATEZO, the study will continue to accrue 128 pts in total. Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Enrollment began in September 2020. Clinical trial information: NCT04541173.
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- 2021
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21. Results of a phase Ib study of regorafenib (REG) 80 mg/day plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC)
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Richard D. Kim, Dirk Waldschmidt, Flavia Menezes, Tatiane Ishida, Roniel Cabrera, Max W. Sung, Udo Mueller, William P. Harris, Anthony B. El-Khoueiry, and Peter R. Galle
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Pembrolizumab ,medicine.disease ,First line treatment ,chemistry.chemical_compound ,chemistry ,Regorafenib ,Hepatocellular carcinoma ,Internal medicine ,Medicine ,business - Abstract
323 Background: In a phase Ib study, REG 120 mg/day plus PEMBRO for first-line treatment of advanced HCC showed no unexpected safety signals and encouraging anti-tumor activity. At the maximum tolerated dose (MTD) of REG (120 mg/day), approximately three-quarters of patients (pts) had a REG dose reduction or interruption due to a treatment-emergent adverse event (TEAE). Here, we present preliminary data for the REG 80 mg/day cohort. Methods: This is an ongoing, dose-finding study in pts who had no prior systemic therapy. In the first cohort, pts received REG 120 mg/day orally for 3 weeks on/1 week off plus PEMBRO 200 mg intravenously q 3 weeks. In later cohorts, the REG dose could be escalated (160 mg/day) or reduced (80 mg/day); the PEMBRO dose is fixed. The primary objective is safety and tolerability. Secondary objectives are to define the MTD and recommended phase II dose and assess anti-tumor activity. Results: By July 24, 2020, 16 pts were treated with REG 80 mg/day. Median age was 67 years (range 56–79), 25%/75% were Barcelona Clinic Liver Cancer stage B/C, 100% Child–Pugh A, and 69%/31% had Eastern Cooperative Oncology Group performance status 0/1. Grade (Gr) 3 TEAEs occurred in 8/16 pts (50%) and there were no Gr 4 TEAEs (Table); one pt experienced Gr 5 pneumonitis (not drug related). There were no reports of Gr 3 hand–foot skin reaction or Gr 3 maculopapular rash, and one report (6%) of Gr 3 rash. TEAEs led to a REG dose reduction or interruption in 50% of pts and to a PEMBRO dose interruption in 25% of pts. Median treatment duration (range) including pts ongoing was 4.1 months (0.4–7.1) for REG and 3.8 months (0.03–7.2) for PEMBRO. Of 13 evaluable pts, 2 (15%) had a partial response and 9 (69%) had stable disease (Response Evaluation Criteria in Solid Tumors v1.1); disease control rate was 85%. Conclusions: These preliminary results for the combination of REG 80 mg/day plus PEMBRO for first-line treatment of advanced HCC were consistent with the REG 120 mg/day cohort. The combination showed no unexpected safety signals and encouraging anti-tumor activity. Assessment of REG 80 mg/day plus PEMBRO is ongoing. Clinical trial information: NCT03347292. [Table: see text]
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- 2021
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22. Results of biomarker analysis from phase II trial of nivolumab in refractory biliary tract cancer
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Richard D. Kim, Olatunji B. Alese, Dae Won Kim, Michael J. Schell, Elaine Tan, Vincent Chung, and Jun-Min Zhou
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Cancer Research ,medicine.medical_specialty ,Biliary tract cancer ,business.industry ,Phases of clinical research ,Gastroenterology ,Oncology ,Refractory ,Internal medicine ,medicine ,In patient ,Biomarker Analysis ,Clinical efficacy ,Nivolumab ,business - Abstract
338 Background: Our previous phase II study demonstrated that nivolumab provides modest but durable clinical efficacy in patients (pts) with refractory biliary tract cancer (BTC), suggesting the significant clinical benefit of nivolumab in selected pts and identification of potential predictive biomarkers. Here, we report outcomes from the biomarker analysis. Methods: Pre-treatment tumor samples were obtained and assessed for immunohistochemistry (IHC) with PD-1 and PDL-1 antibodies, mRNA sequencing (RNAseq), and whole exome sequencing (WES). Clinical efficacy was correlated with the molecular analysis. Prior cisplatin exposure was reviewed to evaluate the impact of cisplatin on the tumor mutational burden (TMB) and clinical outcome. Results: Among 46 pts who had tumor response evaluation, 31 pts received cisplatin prior to nivolumab, and 15 were cisplatin-naive. Pre-treatment tumor samples were assessed for IHC (n = 42), RNAseq (n = 11), and WES (n = 11) based on tissue availability. There was no statistically significant correlation between prior cisplatin exposure and clinical outcome. Among 42 available tumor samples, 18 (43%) expressed PD-L1 positivity ( > 1%), which was associated with a statistically significant prolonged progression free survival (PFS). Median PFS was 10.4 months for PD-L1 positive vs 2.4 months for PD-L1 negative (HR 0.23, 95% CI 0.10-0.51; P < 0.001), while there was no statistically significant correlation between PD-1 expressing tumor infiltrating lymphocytes and clinical outcome. There was also no statistically significant difference in TMB of cisplatin-exposed (n = 8) vs. cisplatin-naïve tumor samples (n = 3) (9162, SD = 150 vs. 8898, SD = 806, p = 0.62). In comparing the group with prolonged disease control of at least 16 weeks (n = 4) to those with rapid disease progression (n = 7) who had mRNA sequencing performed, levels of AC005609.1, FAT3, TMEM151A, ADARB2, FAM153A were all significantly upregulated (p < 0.01), while levels of CLCA1, MUC2, IGHV3-43, SWORA6, and CRISP3 were all significantly downregulated (p < 0.01). Conclusions: Prior cisplatin exposure did not lead to statistically significant differences in clinical outcome or TMB in advanced BTC pts treated with nivolumab. However, PD-L1 expression > 1% correlated with improved PFS, and variations in level of certain mRNA sequences were noted when comparing pts who had rapid disease progression vs. prolonged disease control with nivolumab. This suggests that BTC pts with positive PD-L1 expression and a particular mRNA profile may have a favorable response to nivolumab. Further studies are needed to confirm these findings. Clinical trial information: NCT02829918.
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- 2021
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23. Association between post-treatment (tx) alpha-fetoprotein (AFP) reduction and outcomes in real-world (rw) U.S. patients (pts) with advanced HCC (aHCC)
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Richard D. Kim, Xiaoliang Wang, Anala Gossai, Christina M. Parrinello, Rebecca A. Miksad, Kelly Magee, and Ghassan K. Abou-Alfa
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Clinical trial ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Post treatment ,Alpha-fetoprotein ,business ,Tyrosine kinase - Abstract
341 Background: A decrease in post-tx AFP may be associated with improved outcomes in clinical trials. However, the impact of AFP reduction after initiation of a first-line (1L) tyrosine kinase inhibitor (TKI) therapy on outcomes is unclear among pts with aHCC treated in routine clinical practice. Methods: This analysis utilized data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database and included pts with aHCC with ≥2 visits between 1/1/2011-7/31/2019 who received 1L TKI. Pts with a baseline serum AFP value (closest to 1L initiation within -30 to +7 days) and a post-tx AFP value (closest to 8 weeks after 1L initiation within ±2 weeks) were included. Post-tx AFP reduction was defined as a ≥20% decrease from baseline AFP, and no reduction as a
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- 2021
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24. Outcomes of Lynch syndrome (LS) patients treated with immune checkpoint inhibitors (ICI)
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Xia Wang, Jameel Muzaffar, Shahla Bari, Richard D. Kim, and Marco Matejcic
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Cancer Research ,business.industry ,medicine.disease ,MLH1 ,digestive system diseases ,Lynch syndrome ,MSH6 ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Oncology ,MSH2 ,030220 oncology & carcinogenesis ,medicine ,PMS2 ,Cancer research ,DNA mismatch repair ,business ,Gene ,030215 immunology - Abstract
1548 Background: LS is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2 (d-MMR). A minority of LS patients have MMR proficient tumors (p-MMR). ICI therapy has dramatically changed outcome of d-MMR (majority of LS patients. However, data about response to ICI in LS patients, irrespective of their tumor MMR status is scarce. The aim of this study was to evaluate outcomes of ICI therapy in all LS associated Cancer. Methods: This was a retrospective analysis of LS associated cancers treated with one of the 6 ICIs at our center. We also looked at age, sex, microsatellite status, response and survival. Results: Out of 262 LS patients analyzed, 194 had cancer and 22 received ICIs. Among the patients analyzed, the mean age at diagnosis of 1st cancer was 51 yrs. There were 10 females (47%). 10 patients had colorectal (45%), 3 urothelial (14%), 2 renal cell, 2 cholangiocarcinoma and one each of esophageal, ovarian, uterine, glioblastoma multiforme and pancreatic cancer. One patient died from progressive disease after receiving a single dose and was not included in the analysis. 17 patients (80%) received Pembrolizumab, 11 patients were microsatellite unstable (MSI), 3 were microsatellite stable (MSS) while 7 were unknown. 2 patients achieved complete response (CR) (10%), 1 patient had partial response (PR) (5%), 13 had stable disease (62%) while 5 had progressive disease (23%) leading to a disease control rate (DCR) of 76%. Of the 3 known MSS Lynch syndrome patients, 2 did not respond while the 3rd continues to respond at 9 months of therapy. Of the 5 patients who had PD, 2 were MSS, 2 unknown and 1 MSI. Among the 16 patients who responded, 15 of 16 (94%) had sustained response and have not experienced disease progression or relapse. 3 of these patients have been off therapy (1 due to immune related adverse evet) and have had no relapse. One responder progressed after 18 cycles of therapy. The DCR was 71% at 12 months as well as 48 months of follow up. Median progression survival has not been reached. Similarly, median overall survival has not been reached. Conclusions: Our study is the one of the largest reported analysis of LS associated cancer patients treated with ICIs and included LS patients with both MSI and MSS tumors. Though small, our data suggests robust DCR and prolonged responses in Lynch associated MSS tumors treated with ICI. This encouraging response in MSS tumors along with higher response rates in LS associated cancers as compared to non-LS MSI tumors, suggests that there may be additional drivers of response to ICI in LS patients leading to superior responses.
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- 2020
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25. Phase Ib study of regorafenib (REG) plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC)
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Xiaojing (Amily) Zhang, Peter R. Galle, Anthony B. El-Khoueiry, Dirk Waldschmidt, William P. Harris, Syma Iqbal, Max W. Sung, Richard D. Kim, and K. Nakajima
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Cancer Research ,business.industry ,medicine.drug_class ,Pembrolizumab ,medicine.disease ,Monoclonal antibody ,Multikinase inhibitor ,First line treatment ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Regorafenib ,Hepatocellular carcinoma ,Cancer research ,Medicine ,business ,030215 immunology - Abstract
564 Background: REG is a multikinase inhibitor with immunomodulatory activity and PEMBRO is an anti-PD-1 monoclonal antibody. Both are approved as monotherapy for patients (pts) with HCC previously treated with sorafenib. Based on their potential synergistic effects, we conducted a phase 1b study of REG plus PEMBRO for first-line treatment of advanced HCC. Methods: This is an ongoing, open-label, dose-escalation study in pts with advanced HCC who had no prior systemic therapy. In the first cohort, pts received REG 120 mg/day PO for 3 weeks on/1 week off plus PEMBRO 200 mg IV q 3 weeks. In later cohorts, the REG dose could be escalated (160 mg) or reduced (80 mg) based on the modified toxicity probability interval design; the PEMBRO dose is fixed. The primary objective is safety and tolerability. Secondary objectives are to define the maximum tolerated dose (MTD) and recommended phase 2 dose, and to assess antitumor activity. Results: As of August 23, 2019, 29 pts have been treated at the REG 120 mg level. Median age is 65 years (range 32–81); 41%/55% of pts are BCLC stage B/C; 100% are Child–Pugh A; ECOG status 0/1 is 72%/28%. Dose-limiting toxicities occurred in 4/18 evaluable pts: grade (Gr) 3 increased ALT/AST with Gr 2 increased bilirubin (n = 2); Gr 3 rash (n = 2). The MTD of REG in the combination was 120 mg. Most common Gr 3 or 4 treatment-emergent adverse events (TEAEs) are shown (n = 29). There were no Gr 5 TEAEs. 59%/31% of pts had REG/PEMRO-related Gr 3 or 4 TEAEs. Dose modifications (reductions or interruptions) of REG/PEMBRO for drug-related TEAEs occurred in 59%/31% of pts. Of 23 evaluable pts, 7 (30%) had a partial response (PR) and 14 (61%) had stable disease (RECIST v1.1); 1 additional pt had PR by mRECIST. Conclusions: The combination of REG plus PEMBRO for first-line treatment of advanced HCC showed no unexpected safety signals and encouraging antitumor activity. Accrual is continuing at REG 120 mg dose and an expansion cohort evaluating REG 80 mg plus PEMBRO is planned. Clinical trial information: NCT03347292. [Table: see text]
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- 2020
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26. Phase II study of copanlisib in combination with gemcitabine and cisplatin in advanced cholangiocarcinoma
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Richard D. Kim, Dae Won Kim, Barbara A. Centeno, Jongphil Kim, Rutika Mehta, Biwei Cao, Elaine Tan, and Angel Meroni
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Oncology ,Cisplatin ,Cancer Research ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,Gemcitabine ,Regimen ,chemistry.chemical_compound ,First line therapy ,chemistry ,Internal medicine ,medicine ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway ,medicine.drug ,Copanlisib - Abstract
556 Background: First line therapy for advanced cholangiocarcinoma (CCA) is currently gemcitabine and cisplatin. However, survival rarely exceeds one year with this regimen. PI3K/AKT activation has been shown to increase resistance to chemotherapy in CCA; therefore, inhibiting this pathway may improve chemotherapy’s efficacy. This phase II study evaluated the safety and efficacy of copanlisib, a potent and reversible pan-class I PI3K inhibitor, with gemcitabine and cisplatin in advanced CCA. Methods: Between July 2016 and April 2019, pts with histologically confirmed advanced/unresectable CCA received cisplatin (25 mg/m2), gemcitabine (1000mg/m2), and copanlisib 60mg on day 1 and 8, every 21 days as first line treatment. The primary endpoint was PFS at 6 months. Secondary endpoints were RR, median OS and PFS, and safety profile. A single-arm Simon’s two-stage minimax design with one-sided 10% type I error and 80% power was used. Based on ABC-01 and ABC-02 studies, PFS6 for gemcitabine and cisplatin were 57.1% and 59.3%, respectively. Therefore, PFS6 of 57% was considered not to warrant further study and ≥72% to warrant further investigation. Results: Twenty-four pts received at least one dose of the study drug (62.5% female, median age 64 years), with 70.8% intrahepatic, 16.7% extrahepatic, and 12.5% gallbladder cancer. For all pts, median OS was 13.9 months (95% CI: 6.8-17.9) and median PFS was 6.2 months (95% CI: 1.3-11.1). PFS at 6 and 12 months was 57.0% and 42.2%, and 6 and 12-month OS was 73.9% and 53.2%, respectively. Only 19 pts were considered evaluable for RR. Five pts were either lost to follow up, withdrew consent, or died before a second scan was done. Six pts achieved PR (31.5%) and 11 (57.9%) had SD. Grade 3 or higher adverse events (AE) occurred in 75% of pts. The most common grade 3/4 AEs were decreased neutrophil count (40%) and increased lipase (20%). Treated related AEs led to drug discontinuation for 3 pts (12.5%) and dose modification for 7 pts (29.2%). Conclusions: Gemcitabine, cisplatin, and copanlisib in combination did not meet the primary endpoint of 6-month PFS. However, additional correlative work is ongoing to identify a possible biomarker for copanlisib. Clinical trial information: NCT02631590.
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- 2020
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27. Comparative efficacy of second-line treatments for advanced hepatocellular carcinoma: A network meta-analysis
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Jing Zhao, Jinlin Song, Rachel Savidge, Alexander Marshall, Neehar D. Parikh, Keith D. Huff, Muhan Yuan, Richard D. Kim, and Keith A. Betts
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Malignancy ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Second line ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,Meta-analysis ,Hepatocellular carcinoma ,medicine ,business ,030215 immunology - Abstract
545 Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and is often advanced at the time of diagnosis. This study conducted a network meta-analysis (NMA) to assess the comparative efficacy of second-line (2L) immunotherapy and tyrosine kinase inhibitors (TKIs) without biomarker selection for advanced HCC (aHCC), including nivolumab (NIVO) + ipilimumab (IPI), cabozantinib (CABO), regorafenib (REG), and placebo (PBO). Methods: Randomized trials for CABO and REG (CELESTIAL and RESORCE) were identified through a literature review and included in the NMA. NIVO (1mg/kg) + IPI (3mg/kg) (from CHECKMATE-040) was linked into the evidence network through a matching-adjusted indirect comparison (MAIC) vs. the PBO arm of the CELESTIAL trial. The CELESTIAL trial was chosen due to the similar study design and patient population as the CHECKMATE-040 trial. Clinically relevant characteristics were matched, which included age, sex, Barcelona clinic liver cancer stage, Eastern Cooperative Oncology Group status, α-fetoprotein level, and prior treatments. The NMA included CELESTIAL, RESORCE, and the MAIC results. Investigator-assessed ORR and hazard ratio (HR) of overall survival (OS) were compared in the NMA. Results: After matching the baseline characteristics in the MAIC, the ORR of NIVO+IPI was 30.4% and the HR vs. PBO was 0.35. In the NMA, NIVO+IPI had significantly higher ORR (31.2%) compared to TKIs and PBO (REG: 4.8%; CABO: 4.2%; PBO: 1.0%, differences are presented in Table). In addition, NIVO+IPI was associated with significantly prolonged OS vs. TKIs and PBO (HR: NIVO+IPI vs. REG: 0.56; NIVO+IPI vs. CABO: 0.46; NIVO+IPI vs. PBO: 0.35). Conclusions: The NMA showed that NIVO+IPI was associated with significantly higher ORR and prolonged OS compared to TKIs as 2L treatments for aHCC. [Table: see text]
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- 2020
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28. Phase I study of preoperative capecitabine and lenvatinib with external radiation therapy in locally advanced rectal adenocarcinoma
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Sophie Dessureault, Sarah E. Hoffe, Rutika Mehta, Seth Felder, Julian Sanchez, Jessica M. Frakes, Mokenge P. Malafa, Maria E. Martinez Jimenez, Richard D. Kim, Ankita Tandon, and Iman Imanirad
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Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,business.industry ,Locally advanced ,External Radiation Therapy ,medicine.disease ,Phase i study ,Capecitabine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,medicine ,Rectal Adenocarcinoma ,Radiology ,Lenvatinib ,business ,Complete response ,030215 immunology ,medicine.drug - Abstract
125 Background: Neoadjuvant chemo-radiation is a standard of care for locally advanced rectal cancer. Patients with pathologic complete response (pCR) have improved outcomes with less local and systemic failure. Dual targeting with platelet derived growth factor (PDGF) and vascular endothelial growth factor receptor (VEGFR) in combination with radiation can escalate tumor response with radiation. Lenvatinib is an oral multi-kinase inhibitor and had shown potent anti-tumor activity in xenograft models cultured with human colorectal cancer (CRC) lines. Methods: Patients with stage II or III rectal cancer, confirmed by endoscopic ultrasound or MRI, were recruited in 3 cohorts of 3 patients per dose level, with an expansion cohort at the MTD. Lenvatinib oral daily dose started at 14 mg (cohort 1) and was escalated to 20 mg (cohort 2) followed by 24 mg (cohort 3). In this 3+3 design, patients received dose escalation of lenvatinib with standard doses of capecitabine (850 mg/m2 PO BID) concurrent with external beam radiation on days 1-5 weekly for 28 treatments. Following completion patients underwent surgery in 6-10 weeks. Results: Twenty patients with median age of 55 were enrolled in 3 cohorts (1 patient was ineligible). There were no dose limiting toxicity at the maximum tested dose of lenvatinib (24 mg). Two patients are still awaiting surgery. 12 patients have undergone low anterior resection and 5 patients have had abdominoperineal resection. Therefore, out of 17 patients, 29.4% (5/17) showed pCR, and downstaging was observed in 71% of the patients (12/17). The mean neoadjuvant rectal cancer score (NAR) was 11.4 and median NAR was 8.43. Six patients had grade 3 adverse events (AEs) (1 rectal pain,1 transaminitis, 2 lymphopenia, 1 HTN, 1 with both leukocytosis and hyponatremia). No grade 4 AEs were noted. Most common AEs were hypertension, rectal pain, nausea, diarrhea, fatigue and dermatitis. No peri operative complications were observed. Conclusions: The study shows that the combination of lenvatinib and capecitabine with radiation is well tolerated in locally advanced rectal cancer with promising mean NAR score. The encouraging results will need to be validated in a randomized study. Clinical trial information: NCT02935309.
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- 2020
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29. A phase II study of TAS-102 in combination with ramucirumab in advanced, refractory gastric or gastroesophageal junction (GEJ) adenocarcinoma
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Iman Imanirad, Young-Chul Kim, Neal Shah, Estrella M. Carballido, Rutika Mehta, Dae Won Kim, and Richard D. Kim
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Oncology ,Cancer Research ,medicine.medical_specialty ,5 year survival rate ,business.industry ,Phases of clinical research ,Multimodality Therapy ,Gastroesophageal Junction ,medicine.disease ,Unmet needs ,Ramucirumab ,Refractory ,Internal medicine ,medicine ,Adenocarcinoma ,business - Abstract
TPS4149 Background: Patients with advanced gastric cancer experience a 5 year survival rate 2 twice daily. Each cycle length will be 28 days. The primary endpoint is 6 month OS and secondary endpoints are safety, objective response rate and PFS. Fifteen patients will be enrolled in the first stage. If ≥ 7 of the 15 are alive at 6 months, an additional 10 patients will be enrolled in the second phase. Enrollment is currently ongoing. Clinical trial information: NCT03686488.
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- 2019
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30. Final analysis of phase II trial of regorafenib (REG) in refractory advanced biliary cancers (BC)
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Hanna K. Sanoff, Dae Won Kim, Fatima Tariq, Yingmiao Liu, Andrew B. Nixon, Richard D. Kim, and Andrew Poklepovic
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Antitumor activity ,Cisplatin ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Biliary cancer ,Gemcitabine ,chemistry.chemical_compound ,Refractory ,chemistry ,Internal medicine ,Regorafenib ,medicine ,Effective treatment ,business ,medicine.drug - Abstract
4083 Background: While gemcitabine plus cisplatin has demonstrated significant antitumor activity as 1st line therapy of BC, there is no effective treatment after failure of gemcitabine-based therapy. REG is an oral multi-kinase inhibitor that targets angiogenesis, oncogenesis and cancer proliferation/metastasis. We evaluated the efficacy of REG in BC. Methods: Patients (pts) with histologically proven BC who progressed on at least one line of systemic therapy received REG 160 mg daily 21 days on 7 days off, in 28 day cycles. The primary endpoint was 6-month (mo) overall survival (OS) and the secondary endpoints were median OS, progression free survival (PFS) and response rates (RR). Pre and post-treatment plasma were collected for cytokine evaluation. Results: A total of 39 pts received at least 1 dose of REG; 32 pts were evaluable for efficacy. Median age was 62 (range: 27-88) years and the primary sites of tumor were intrahepatic cholangiocarcinoma (68.8%), extrahepatic (18.8%), and gallbladder (12.5%). Pts were considered evaluable for efficacy if patients received more than 1 cycle of REG. For 32 evaluable pts, 6 mo OS was 52% with median PFS of 2.8 mo (95% CI: 1.1-4.5) and median OS of 7.9 mo (95% CI: 0-18.7). Median PFS and OS of the pts (n=20) failed 1 line of therapy were 3.7 mo (95% CI: 3.2-4.1) and 13.8 mo (95% CI: 1.8-25.8), respectively. Median PFS and OS of the pts (n=12) failed 2 lines were 1.8 mo (95% CI: 1.63-1.97) and 4.5 mo (95% CI: 2.6-6.3), respectively. RR was 9.4% (2 PR and 1 unconfirmed PR) and DCR was 62.5%. Total 71.8% of grade 3/4 adverse events (AE) were observed, and the most common AE were fatigue (56.4%) and hypertension (53.8%). Dose modification was required in 49% of the pts. Among the 23 cytokines analyzed, elevated baseline VEGF-A was associated with good prognosis (HR 0.62, p=0.01). Elevated baseline TIMP-1 (HR 1.79, p=0.04) and IL-6 (HR 1.33, p=0.05) were associated with poor prognosis. REG treatment decreased BMP-9, GP130, VEGF-R2 and VEGF-R3 and increased IL-6, PIGF, TIMP-1, VCAM-1 and VEGF-A significantly. Conclusions: The primary endpoint was met in this study. VEGF-A may be further evaluated as a predictive biomarker for REG in BC. Further randomized trials are warranted to confirm the efficacy and the correlative data. Clinical trial information: NCT02115542.
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- 2019
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31. A phase II study of nivolumab in patients with advanced refractory biliary tract cancers (BTC)
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Jun-Min Zhou, Neal Shah, Daneng Li, Dae Won Kim, Michael J. Schell, Vincent Chung, Richard D. Kim, and Olatunji B. Alese
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Cancer Research ,medicine.medical_specialty ,business.industry ,Advanced stage ,Phases of clinical research ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Second line ,Oncology ,Refractory ,Biliary tract ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,In patient ,Nivolumab ,business ,030215 immunology - Abstract
4097 Background: Biliary tract cancers (BTC) are often typically diagnosed at an advanced stage. There is no established second line option for patients with advanced BTC who have failed one prior systemic therapy. The phase II study evaluated safety and efficacy of nivolumab, anti PD-1 antibody in refractory BTC patients. Methods: Pts with histologically proven BTC who progressed on at least one line but no more than three lines of systemic therapy received nivolumab 240mg IV q2weeks for 16 weeks and then 480 mg IV every 4 weeks until disease progression or unacceptable toxicity. The primary endpoint of the study was objective response rate (ORR) by RECIST 1.1 every 8 weeks. The Simon two staged design was used to assess ORR.18 patients were accrued and if one response was seen, the plan was to accrue additional 34 patients. Secondary endpoints were PFS, OS and safety profile. Results: At data cutoff (Jan 14, 2018), 54 patients with BTC (female: 50%, Median age: 65 years) were enrolled. The primary sites of tumor were intrahepatic cholangiocarcinoma (63%) extrahepatic (11%), and gallbladder (26%). 30 pts (56%) failed 1 line of therapy and 24 (44%) failed more than one line of therapy. 45 pts (1 pt withdrew consent, 1pt just enrolled prior to data cutoff and 7 pts came off the study due to clinical progression) were evaluable for response rate. Out of 45 pts, 10 pts (22%) achieved PR (1 unconfirmed PR) and 17 pts (37.8%) achieved SD. DCR was 60%. All patients who responded were microsatellite stable. For evaluable 45 pts with median follow up of 13.34 months, median PFS was 3.98 months (95% CI: 2.33-5.98) and the median OS was 14.22 months (95% CI: 6.64-NA). 6 and 12month OS was 71.4 and 52.3% and 6 and 12 month PFS was 35.2% and 24.1% respectively. Most common treatment related AEs (TRAE) was alkaline phosphatase increased (24.5%). Grade III/IV TRAEs were seen in 11 pts (20.4%); most common were hyponatremia (3 pts) and elevated alkaline phosphatase (2 pts). No treatment related AEs led to discontinuation of the study drug. Tissue samples were collected in all pts with planned correlative studies underway including the PDL 1 status. Conclusions: Nivolumab was well tolerated and has shown promising efficacy in refractory BTC including durable responses lasting 2 years. Further randomized trial is warranted in refractory BTC. Clinical trial information: NCT02829918.
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- 2019
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32. Determining optimal follow up for patients with anal cancer following chemoradiation
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Jessica M. Frakes, Estrella Carballido, Sarah E. Hoffe, Sophie Dessureault, Marissa Frazer, Iman Imanirad, Seth Felder, Julian Sanchez, Richard D. Kim, and George Yang
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Cancer Research ,medicine.medical_specialty ,Oncology ,business.industry ,Health care ,medicine ,Anal cancer ,medicine.disease ,Intensive care medicine ,business ,Inefficiency - Abstract
689 Background: U.S. health care is increasingly defined by over expenditure and inefficiency. Optimizing patient follow-up is critical especially in cancers treated with high control rates. The objective of this study was to assess time to disease recurrence or toxicity in a cohort of patients with anal carcinoma in order to optimize patient care. Methods: 140 patients diagnosed with biopsy-proven, non-metastatic anal carcinoma, treated with chemoradiation utilizing IMRT, were identified from an institutional database at our high volume center. After IRB approval, a retrospective study was conducted that evaluated local recurrence (LR), distant metastasis (DM), overall survival (OS), and late ≥ grade three toxicity (LG3T) based on National Cancer Institute Common Terminology for Adverse Events version 4. Patients were followed post-treatment every three months for two years, every six months in years 3-5 then yearly thereafter with imaging per National Comprehensive Cancer Network recommendations. Results: Median age and follow up is 58 years and 27 months, respectively. Patients were staged based on AJCC 8th edition and 24 patients were stage I (17%), 55 stage II (39%) and 61 stage III (44%). The median radiation dose was 54 Gy (range: 40-62.5), and 11% of patients required a radiation break. The two year LC, DMFS, and OS were 93%, 94% and 89% and 5-year LC, DMFS, OS were 92%, 87% and 85% respectively. In total, there were 29 disease or treatment related events: LR occurred in nine patients, DM in 11 patients, and LG3T in nine patients. Overall, 62% of events occurred within year one and 77 % within two years. Stratified by event type, at two years 79% of LR, 64% of DM and 89% LG3T were identified. At the remaining follow-up points after 2 years there was an event incidence rate of 1.4%. Conclusions: The majority of recurrences/toxicities in patients diagnosed with non-metastatic anal carcinoma after chemoradiation occur within the first year, with 77% of any event occurring before year two. The data from individual time points suggest a reduction in follow-up during years 3-5 may provide adequate surveillance. Considering revisions of the current follow-up recommendations could maximize health care resources while also improving patient quality of life.
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- 2019
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33. Dose intensity of nab-paclitaxel and gemcitabine chemotherapy in metastatic pancreatic cancer
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Alexander Lim, Salvatore Michael Bottiglieri, Kunhwa Kim, Richard D. Kim, and Dae-Won Kim
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Oncology ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,Standard of care ,business.industry ,medicine.medical_treatment ,Combination chemotherapy ,Dose intensity ,Gemcitabine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Paclitaxel ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,Metastatic pancreatic cancer ,Medicine ,business ,030215 immunology ,Nab-paclitaxel ,medicine.drug - Abstract
251 Background: Combination chemotherapy with nab-paclitaxel/gemcitabine is a standard of care option in metastatic pancreatic cancer management with increasing use due to an improvement in median overall survival of 1.8 months compared to gemcitabine alone. It is also used in practice in the second and third-line settings for patients that have progressed on fluorouracil based regimens. As the utility of this combination chemotherapy has grown, dose intensity (DI) in relation to survival outcome is an important measure for real world application. Methods: Fifty-six patients that were 18 years or older with metastatic pancreatic cancer treated with nab-paclitaxel/gemcitabine as first-line therapy from January 1, 2013 to December 31, 2014 at Moffitt Cancer Center were identified through medical records. The subjects were retrospectively reviewed, and demographic, treatment outcomes (survival and progression), and DI were collected. Overall survival was calculated with Kaplan Meier survival curves. Multi-Cox regression models estimated multivariable-adjusted hazard ratio with 95% confidence intervals. Results: There was no significant relationship between receiving a DI > 85% regimen in relation to independent variables of age > 65, sex, primary site, and known distant metastasis; however DI > 85% was significant for patients that received additional chemotherapy following nab-paclitaxel/gemcitabine (p = 0.044). The DI > 85% group compared to the < 85% group had a hazard ratio (HR) for all-cause mortality of 0.285 (0.106-0.764, p = 0.013). Six and 12-month survival were higher in the DI > 85% group (p = 0.009, p = 0.02 respectively). Conclusions: DI > 85% for nab-paclitaxel/gemcitabine compared to DI < 85% may have a lower all-cause mortality and higher 6 and 12-month survival.
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- 2019
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34. Phase I study of preoperative capecitabine and lenvatinib with external radiation therapy in locally advanced rectal adenocarcinoma
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Jessica Frakes, Rutika Mehta, Sarah E. Hoffe, Iman Imanirad, Maria E Martinez Jimenez, Julian Sanchez, Mokenge Peter Malafa, Seth Felder, Sophie Dessureault, and Richard D. Kim
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Cancer Research ,Oncology - Abstract
694 Background: Despite routine use of neoadjuvant chemoradiation, patients with advanced rectal tumors experience significant rates of treatment failure and recurrence. Radiation resistance is a particular problem. Dual targeting of PDGF and VEGFR (Vascular endothelial cell growth factor receptor) in combination with radiation can enhance tumor response. Lenvatinib inhibits the kinase activities of VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET and in vivo results show that it effectively delays the growth of human colorectal xenografts. Methods: This is a phase I clinical trial of lenvatinib in combination with capecitabine administered with radiation. Patients with stage II or III rectal cancer confirmed by endoscopic ultrasound or MRI were eligible for the study. In this 3+3 phase I study with 3 cohorts, patients were treated with escalating doses of lenvatinib administered in combination with standard doses of capecitabine (850 mg/m2 PO BID D1-5 weekly for 5 ½ to 6 weeks) and external beam radiation therapy (180 cGY on D1-5 weekly for 5 ½ to 6 weeks). Patients underwent surgery 6-10 weeks after neoadjuvant therapy. Results: Nine patients have been enrolled in the 3 cohorts with the median age of 51 years. Lenvatinib dosing started at 14 mg PO daily (cohort 1) and was safely escalated to 20 mg PO daily (cohort 2) followed by 24 mg PO daily (cohort 3). There were no DLTs at the maximum tested dose of lenvantinib (24 mg). 5 patients have undergone low anterior resection and 4 have had abdominoperineal resection. The pathological complete response (pCR) rate was 33.33%, and downstaging was observed in 100% of patients. Median neoadjuvant rectal cancer score (NAR) was 8.7. Three pts had grade 3 events (2 hypertension (HTN), 1 lymphopenia) without any grade 4 events. Most common AEs were HTN and fatigue. No perioperative complications were observed. Tissues for all pts have been collected for planned correlative studies. Conclusions: This study shows that the combination of lenvatinib with capecitabine, and EBRT is well tolerated. NAR score and downstaging rates are encouraging. Currently we are enrolling 10 additional pts at the maximum tested dose of lenvatinib to further evaluate efficacy and safety. Clinical trial information: NCT02935309.
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- 2019
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35. Impact of sarcopenia on outcomes in patients with rectal carcinoma treated with trimodality therapy
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Seth Felder, Sophie Dessureault, Richard D. Kim, Jessica M. Frakes, Iman Imanirad, G. Daniel Grass, Julian Sanchez, Sarah E. Hoffe, Maria L. Sandoval, and Zhigang Yuan
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Oncology ,Cancer Research ,medicine.medical_specialty ,Prognostic factor ,business.industry ,Internal medicine ,Sarcopenia ,Rectal carcinoma ,medicine ,In patient ,business ,medicine.disease - Abstract
687 Background: Sarcopenia has been identified as a negative prognostic factor in several gastrointestinal malignancies. We sought to evaluate whether total psoas area (TPA) was predictive of grade ≥ 3 toxicity, recurrence and overall survival in patients with rectal carcinoma who received tri-modality therapy. Methods: After IRB approval, a retrospective analysis of 112 patients with biopsy-proven rectal cancer treated with neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy was performed. The L4 vertebra was identified on pre-treatment axial CT and the bilateral psoas muscles were manually contoured to determine the skeletal muscle index, which was normalized by height. Sarcopenia was defined as TPA less than the median of the cohort. (< 1463 mm3/m). Acute toxicity was defined as within 3 months of radiation based on Common Terminology Criteria for Adverse Events version 4. Chi-square was used to assess differences between groups. Time to event analysis was estimated by Kaplan-Meier methods followed by log rank comparison. Predictor variables for outcomes were assessed with Cox regression. Results: Median follow-up was 31 months. Female gender was strongly associated with being sarcopenic (P < 0.001) otherwise no other differences in clinical or treatment characteristics were found. 20 patients (17.8%) developed recurrence (95% distant). Patients with sarcopenia had a decreased risk of recurrence (P = 0.048) as well as a longer time to recurrence from radiation (50 vs. 21.4 months, P = 0.006) and surgery (47.2 vs. 17.9 months, P = 0.006). Gender was not associated with risk of recurrence (p = 0.131). On multivariable analysis, absence of sarcopenia was predictive of time to recurrence following radiation (HR 4.7, 95% CI: 1.2-18.8; P = 0.03). The presence of sarcopenia was not associated with overall survival (P = 0.12) or grade ≥ 3 acute toxicity (P = 0.242). Conclusions: In our cohort, patients with sarcopenia appear to have better tumor control when compared to patients without sarcopenia independent of gender, suggesting this may be a predictor of treatment response. However, sarcopenia was not associated with overall survival or probability of having grade ≥ 3 acute toxicity.
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- 2019
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36. Phase I study of tramatinib combined with sorafenib in patients (pts) with advanced hepatocellular cancer (HCC)
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Biwei Cao, Dae Won Kim, Fadzai Masawi, Richard D. Kim, Dung-Tsa Chen, Emilie Wang, and Amit Mahipal
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MAPK/ERK pathway ,Sorafenib ,Cancer Research ,Hepatocellular cancer ,business.industry ,Preclinical data ,digestive system diseases ,Phase i study ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,In patient ,Signal transduction ,business ,neoplasms ,030215 immunology ,medicine.drug - Abstract
431 Background: RAS/RAF/MEK/ERK (MAPK) signaling pathway is associated with proliferation, progression, and survival of HCC. Preclinical data suggests that activation of MAPK pathway may be one of resistant mechanisms of sorafenib, and the combination of MEK inhibitor and sorafenib can induce synergistic anticancer activity in HCC. We evaluated the safety and efficacy of trametinib (MEK inhibitor) combined with sorafenib in HCC. Methods: This was a phase I single center study with standard 3+3 design for pts with treatment naïve advanced HCC. The primary endpoints are determining dose limiting toxicities (DLT) and maximum tolerated dose (MTD). Secondary endpoints include overall survival (OS), progression free survival (PFS), and disease control rate (DCR). Initial plan was to enroll pts in 4 escalating dose levels (dl)—trametinib 1mg daily (qd)/sorafenib 200mg twice daily (bid)(dl 1), trametinib 1.5mg qd/sorafenib 200mg bid (dl 2), trametinib 1.5mg qd/sorafenib 400mg bid (dl 3), trametinib 2mg qd/sorafenib 400mg bid (dl 4). Eligible pts had advanced unresectable HCC, ECOG PS 1, Child-Pugh Score 6, and adequate organ function. Results: 17 pts were treated in 3 different dl of trametinib and sorafenib (3 in dl 1, 8 in dl 2, and 6 in dl 3). Median age was 65 years (range 40-80) with 64.7% male. All pts were evaluated for toxicity, but only 15 were evaluable for DLT. 2 pts were replaced as they came off of study within 1 month (1 pt in dl 3 due to varices unrelated to the study drug, 1 pt in dl 2 for voluntary withdrawal due to side effects). DLT was noted in dl 3 with 2 pts (grade 4 hypertension (HTN) and grade 3 elevated (elev) of bilirubin/AST/ALT > 7 days). Most common grade 3/4 treatment related adverse events were elev AST (47.1%), HTN (23.5%), elev Alk Phos (17.6%), elev ALT (5.9%), elev bilirubin (5.9%), and diarrhea (5.9%). The median PFS was 4.0 months (mo), and median OS was 5.8 mo. 11 pts were evaluable for response after cycle 2 (8 stable disease (SD), 2 disease progression (PD), 1 partial response). 3 pts were evaluable for response after cycle 4 (1 SD, 2 PD). DCR was 63.6%. Conclusions: Trametinib and sorafenib can be safely administered up to trametinib 1.5mg qd and sorafenib 200mg bid for pts with advanced HCC. Clinical trial information: NCT02292173.
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- 2019
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37. Pathologic outcomes of systemic therapy followed by stereotactic body radiation therapy (SBRT) for pancreatic cancer (PC) in a novel lateral decubitus treatment position
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Jose M. Pimiento, Richard D. Kim, Pamela J. Hodul, Kujtim Latifi, Dae Won Kim, Sarah E. Hoffe, Mokenge P. Malafa, Ethan Song, and Jessica M. Frakes
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Cancer Research ,medicine.medical_specialty ,business.industry ,Stereotactic body radiation therapy ,LATERAL DECUBITUS ,medicine.disease ,Systemic therapy ,Position (obstetrics) ,Oncology ,Pancreatic cancer ,Medicine ,Radiology ,business ,Stereotactic body radiotherapy - Abstract
415 Background: Outcomes of multi-fraction stereotactic body radiotherapy (SBRT) for PC report low rates of toxicity and high local control, improving feasibility for combination with more aggressive systemic therapy regimens. However, SBRT in the ablative range poses risk to adjacent normal structures, excluding this option for tumors within 1 cm of a mucosal organ. In this study, we report our initial experience with treatment in the lateral decubitus position. Methods: An IRB retrospective query identified patients with pancreatic body adenocarcinoma treated with systemic chemotherapy followed by SBRT in the lateral decubitis position. SBRT was delivered to the entire gross disease with 30 Gy in 5 fractions with focal dose escalation up to 40 Gy to the tumor/vessel interface (TVI) as long as constraints were met. Patients were explored for resection if no metastasis or progression on restaging scans. The primary endpoints were pathologic response and margin status. Descriptive analysis was performed with SPSS 24. Results: The median age of the cohort was 68.6 (range, 50-83 yrs), with a white (94%) and male (59%) predominance. Initial staging of the 17 patients who met criteria included 10 (59%) patients diagnosed with borderline resectable disease (BRPC) and 7 (41%) with locally advanced disease (LAPC). 7 (41%) patients were treated with FOLFIRINOX, 5 (29%) with gemcitabine/nab-paclitaxel, 4 (24%) with gemcitabine/capecitabine/docetaxel, and 1 (6%) with gemcitabine/paclitaxel preceding SBRT. A median dose of 40 Gy (range, 33-40 Gy) was delivered to the TVI for all patients. 5 BRCP (29%) and 2 LAPC (12%) patients went to surgery, with 6 of these patients undergoing an R0 resection (86%) and 1 BRPC patient with an R1 resection. Pathologic tumor regression grades by the College of American Pathologists guidelines were 14% Grade 1, 71% Grade 2, and 14% Grade 3. Conclusions: Lateral decubitus treatment expands inclusion of pancreatic body patients for SBRT with focal TVI dose escalation leading to margin negative resection and significant partial tumor response, warranting future studies exploring ablative dosing in this position.
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- 2019
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38. Integrated profiling the patterns of pathologic response to neoadjuvant chemoradiation and the genomic-based radiation sensitivity in rectal cancer
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Sarah E. Hoffe, Sophie Dessureault, Jessica M. Frakes, Syeda Mahrukh Hussnain Naqvi, Richard D. Kim, Michael J. Schell, Kamran Ahmed, Seth Felder, Javier F. Torres-Roca, Iman Imanirad, Julian Sanchez, and Zhigang Yuan
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Oncology ,Cancer Research ,medicine.medical_specialty ,Radiation sensitivity ,business.industry ,Colorectal cancer ,Internal medicine ,medicine ,Pathologic Response ,business ,medicine.disease ,Complete response - Abstract
573 Background: Given the lack of biomarkers to predict a pathologic complete response (pCR) after neoadjuvant chemoradiation (NACRT) for rectal cancer, selection for non-operative management (NOM) mandates complete clinical response. We have previously developed/validated a model to assess genomic-based tumor radiosensitivity: the radiosensitivity index (RSI), which formulates a clinically actionable model to calculate genomic-adjusted radiation dose (GARD). We determined the profiles of RSI and GARD for rectal cancer and correlated these findings with the pathologic response patterns. Methods: One hundred seventeen rectal cancer patients treated from 2009 to 2018 with NACRT were assessed for the tumor regression grade (TRG) (0 = pCR; 1 = moderate response; 2 = partial response; 3 = poor response). RSI was analyzed in an independent tissue cohort of 113 resected rectal cancer samples. GARD was derived as described before, which shows a high GARD value indicated a superior therapeutic effect of radiation. Results: Median follow-up from completion of NACRT was 26 months. The primary tumor stages were 7% T2, 84% T3, and 9% T4. The majority of patients (82%) received concurrent 5-FU or Capecitabine and (83%) received RT dose of 50.4 Gy (range 45-56 Gy). Median time from end of NACRT to surgery was 61 days (range 36-105 days). The patterns of pathological response were TRG 0 (n = 24; 21%), 1 (n = 62; 53%), 2 (n = 25; 21%), and 3 (n = 6; 5%), suggesting heterogeneous sensitivity to treatment with similar tumor stage and treatment regimens. The median RSI for the tissue cohort was 0.46 (range 0.19-0.81) with 37% of the samples considered radiosensitive based on prior data. GARD values ranged from 5.17 to 41.79 (median 19.24), suggesting heterogeneous RT therapeutic effects. Conclusions: The findings from the clinical cohort were consistent with the tissue cohort showing significant heterogeneity in the individual tumor radiosensitivity and GARD-based RT therapeutic effects. With the development of GARD-based prospective trials, we anticipate more biology-based customized RT dosing which could optimize patient selection for NOM and individualize the most appropriate dose for each patient.
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- 2019
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39. Multi institutional phase II trial of single agent regorafenib in refractory advanced biliary cancers
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Richard D. Kim, Andrew Stewart Poklepovic, Andrew B. Nixon, Dae Won Kim, Heloisa P. Soares, Jongphil Kim, Jun Min Zhou, Fatima Tariq, Natalie Burgess, and Hanna Kelly Sanoff
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Cancer Research ,Oncology - Published
- 2018
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40. Phase II study of copanlisib (BAY 80-6946) in combination with gemcitabine and cisplatin in advanced cholangiocarcinoma
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Heloisa P. Soares, Richard D. Kim, Rutika Mehta, Dae-Won Kim, and Jongphil Kim
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0301 basic medicine ,Oncology ,Cisplatin ,Cancer Research ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,Gemcitabine ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Overall survival ,Progression-free survival ,business ,medicine.drug ,Copanlisib - Abstract
TPS525 Background: The current standard of treatment for cholangiocarcinoma (CCA) is gemcitabine and cisplatin that favored both overall survival (OS) and progression free survival (PFS) when compared to gemcitabine alone. The survival however remains less than than 1 year. Predominant activation of PI3K/AKT signaling pathway is seen in cell line and human tumors of CCA promoting tumorigenesis and increased resistance to radiation and chemotherapy. Inhibition of this pathway sensitizes CCA cells to therapies. Copanlisib is a selective and reversible pan-class I PI3K inhibitor. In preclinical studies, copanlisib demonstrated anti-tumor activity in PIK3CA mutated cells particularly in BC. In a Phase I study, 4 treatment naïve patients with CCA showed response, including 1 complete response. The maximum tolerated dose of copanlisib was determined to be 0.8 mg/kg in this study. We hypothesize that the addition of copanlisib to gemcitabine + cisplatin will enhance the efficacy of the current standard regimen in advanced CCA. Tumor tissue will be collected on every patient for PTEN immunohistochemical staining and NGS analysis using a 26-genes panel. Methods: This is a single institution phase II single arm two-stage design trial using copanlisib in combination with gemcitabine and cisplatin in patients with advanced CCA. Eligible patients include those diagnosed with advanced, unresectable CCA that are treatment naïve or should have received adjuvant treatment more than 6 months prior to initiating the trial. Patients will be treated with Cisplatin (25 mg/m2) plus Gemcitabine (1000 mg/m2) and Copanlisib (60 mg) on days 1 and 8 on a 21 days cycle. Primary objective of the study is PFS at 6 months with secondary objectives being response rate, median PFS, OS, safety and tolerability. Accrual began on June 28, 2016, with planned enrollment for 25 patients. 14 eligible patients will be enrolled in the first stage. If 8 or more patients (≥57%) are alive and progression free at 6 months, an additional 11 patients will be enrolled in the second stage. 11 patients have been enrolled until now. After 3 cycles, response and progression will be evaluated using RECIST v1.1. Clinical trial information: NCT02631590.
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- 2018
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41. Relationship between tumor-infiltrating lymphocytes (TIL) and absolute lymphocyte count (ALC) or lymphocyte to neutrophil ratio (LTN) in cholangiocarcinoma (CCA)
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Alexander Lim, Daniel A. Anaya, Dae-Won Kim, Richard D. Kim, Domenico Coppola, and Young Doo Chang
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0301 basic medicine ,Cancer Research ,Tumor microenvironment ,Tumor-infiltrating lymphocytes ,business.industry ,Lymphocyte ,medicine.medical_treatment ,Absolute lymphocyte count ,hemic and immune systems ,chemical and pharmacologic phenomena ,Immunotherapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,business ,CD8 - Abstract
343 Background: Tumor microenvironment is potentially a powerful predictive and prognostic marker of immunotherapy. The presence of CD8 TIL has been suggested as a predictive and prognostic marker of PD-1 inhibitor therapy in several malignancies. However, evaluation of TIL is not always feasible especially during or after immunotherapy. Therefore, easily accessible markers are needed for immune monitoring. In CCA, ALC and LTN in peripheral blood have been reported as prognostic factors. We evaluate the relationship between ALC or LTN and CD8 TILs in CCA. Methods: Formalin-fixed paraffin-embedded tumor samples from 41 patients with resected and histologically verified CCA between 1990 and 2015 were identified and immunohistochemically (IHC) stained with anti-CD8. Absolute lymphocyte and neutrophil count of the patients was obtained within 1 week before surgery. The association between ALC, LTN and CD8+ TIL status was investigated using unpaired Student t test and Spearman rank correlation. Results: The median age was 64 (41-85) with 53% male. 22%, 41% and 37% were stage I, II, and III respectively. In CD8 TIL positive, the average ALC was 1764 and in CD8 TIL negative, the average ALC was 2072. There was no significant difference between the two groups (p = 0.38). No difference of LTN was observed between CD8 TIL positive and negative tumors (0.39 vs 0.38, p = 0.69). The correlation between density of CD8 TILs and ALC or LTN was evaluated. No correlation was observed between CD8 TIL density and ALC (R = 0.02, P = 0.3) or LTN (R = 0.02, P = 0.8). Conclusions: ALC or LTN in peripheral blood may not predict CD8 TIL status in patients with CCA.
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- 2018
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42. Final report: A phase I trial of BYL719 in combination with gemcitabine and nab-paclitaxel in locally advanced and metastatic pancreatic cancer
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Taymeyah Al-Toubah, Amit Mahipal, Jongphil Kim, Richard D. Kim, Heloisa P. Soares, and Neron K Lewis
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0301 basic medicine ,Gene isoform ,Cancer Research ,business.industry ,Locally advanced ,P110α ,Gemcitabine ,03 medical and health sciences ,030104 developmental biology ,Oncology ,Metastatic pancreatic cancer ,Cancer research ,Medicine ,business ,PI3K/AKT/mTOR pathway ,medicine.drug ,Nab-paclitaxel - Abstract
398 Background: The PI3K/mTOR pathway has emerged as a potential target for anticancer therapy. Considerable evidence suggests that targeting a single isoform of PI3K (p110α) would have sufficient antitumor activity and improved therapeutic window. Further, PI3KCA mutations, gene encoding isoform p110α, are described in pancreatic adenocarcinoma (PAC). BYL719 is an oral class I α-specific PI3K inhibitor that showed preclinical anti-tumor activity. The first in human phase 1 trial of BYL719 defined the maximum tolerated dose (MTD) at 400mg QD. Methods: This was a phase I, single center study (standard 3+3 design). The primary objective was to determine the MTD of BYL719 in combination with gemcitabine (G) and nab-paclitaxel (nabP) as frontline therapy in locally advanced or metastatic PAC. BYL719 was given orally daily (Table). Patients (pts) were restaged q2 cycles. The study was closed prematurely due to slow accrual. Results: Fifteen pts were enrolled (median age was 58 years). Three pts each participated in cohorts 1 and 2. Nine pts were enrolled in cohort 3, but 4 were replaced (3 pts withdrew consent prior to evaluation and 1 missed > 10 days of treatment). One pt in cohort 3 had DLT related to grade 3 nausea and vomiting. A total of 19 grade 3 and 4 adverse events were records as probably or possibly associated with BYL719. The most common ones were hyperglycemia, anemia, and neutrophil count decreased. One pt developed Posterior reversible encephalopathy syndrome (PRES) during cycle 7. Although we could not completely exclude BYL719 as a cause, PRES was attributed to G. One pt had sudden death during cycle 4 that was attributed to progression. Only 8 pts were evaluable for response. Two had stable disease, 5 had partial responses and 1 had progression. The median progression-free survival and overall survival were 5.36 months (1.6 to 10 months) and 8.74 months (3.8 to 21.2 months) respectively. Conclusions: The combination of full doses of G + nabP and BYL719 can be safely administered up to BYL dose of 250 mg/day. Clinical trial information: NCT02155088. [Table: see text]
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- 2018
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43. Ensituximab (E) in patients (pts) with refractory metastatic colorectal cancer (mCRC): Results of a phase I/II clinical trial
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Kwong Y. Tsang, Michael A. Morse, Anjum Zaki, Muhammad Shaalan Beg, Richard D. Kim, Benjamin R. Tan, Karen Cui, Sharon Mavroukakis, Philip M. Arlen, Elizabeth Poplin, and Nilofer S. Azad
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0301 basic medicine ,Cancer Research ,biology ,Colorectal cancer ,business.industry ,medicine.disease ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,Phase i ii ,Oncology ,Refractory ,Monoclonal ,Cancer research ,medicine ,biology.protein ,In patient ,Ensituximab ,Antibody ,business ,medicine.drug - Abstract
3081 Background: E is an investigational, novel, chimeric monoclonal IgG1 antibody derived from an immunogenic neoantigen with sequence homology to MUC5AC that is preferentially expressed with exquisite specificity to pancreatic cancer and CRC. Its mechanism of action is via antibody-dependent cellular cytotoxicity (ADCC). The efficacy and safety of E was evaluated in a single-arm, open-label, phase 1/2 clinical trial of adult pts with refractory mCRC. Methods: Pts were selected based on > 20% expression of tumor antigen, as measured by immunohistochemistry. Based on phase 1 results, E was administered 3 mg/kg IV every 2 weeks until unacceptable toxicity or disease progression. Primary endpoint was overall survival (OS). Serum cytokine levels were analyzed at baseline, day 4, and day 15. E-mediated ADCC of CD16 genotype V/V, V/F, and F/F pt PBMCs was measured with an IN-111 release assay using the E target-expressing ASPC-1 pancreatic cancer cell line. Results: Fifty-seven and 63 pts were evaluable for OS and safety, respectively. Median OS was significantly longer than historical control: 6.8 vs 5.0 months (mo); p = 0.007; 95% CI: 5.39,8.02. Three pts were alive at end of study (21, 21, and 24 mo); 21 pts survived ≥ 12 mo. Pts had a median of 4 prior therapies (range 2-9); 25% had received regorafenib. Forty-seven pts were evaluable by RECIST, and 20 (43%) had stable disease of target lesions at end of first course (day 57). E was well tolerated, with < 2% grade 3 and no grade 4 toxicities. There were no trends in serum cytokine and chemokine levels. Analysis of 56 samples (8 V/V, 26 V/F, 17 F/F, and 5 undetermined) showed that V/V PBMCs had significantly higher E-mediated ADCC than PBMCs harboring other genotypes. No correlation between CD16 polymorphism and pt outcome was observed. Conclusions: E demonstrated excellent tolerability and encouraging OS in this heavily pretreated population. Correlative in vitro data suggest that E can mediate higher levels of ADCC activity in individuals with a V/V versus other genotypes. The lack of correlation between CD16 polymorphism and pt outcomes in this study suggests that other immune-related factors (under investigation) may impact the efficacy of E in vivo. Clinical trial information: NCT01040000.
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- 2017
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44. SWOG S1310: Randomized phase II trial of single agent MEK inhibitor trametinib vs. 5-fluorouracil or capecitabine in refractory advanced biliary cancer
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Shannon McDonough, Tanios Bekaii-Saab, Abby B. Siegel, Edward J. Kim, Afsaneh Barzi, Ari David Baron, Richard D. Kim, Milind Javle, Katherine A. Guthrie, Stacey Stein, Anthony B. El-Khoueiry, Howard S. Hochster, George P. Keogh, and Vaibhav Sahai
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Oncology ,Trametinib ,Cancer Research ,medicine.medical_specialty ,business.industry ,Standard treatment ,MEK inhibitor ,Gemcitabine ,Capecitabine ,Refractory ,Fluorouracil ,Internal medicine ,medicine ,Single agent ,business ,medicine.drug - Abstract
4016 Background: No standard treatment options are available for patients with advanced BC who fail gemcitabine/platinum therapy. The rationale for evaluation of trametinib was based on the presence of MAPK alterations and on earlier promising results with other MEK inhibitors in BC. Methods: Pts with histologically proven BC who progressed on gemcitabine/platinum were randomized to trametinib (2mg qd) (Arm A) vs infusional 5FU at 2400 mg/m2 over 46 hours or capecitabine (1000 mg/m2PO days 1-14 BID) (Arm B). Patients were stratified by planned chemotherapy 5FU/LV vs capecitabine; and disease site: cholangiocarcinoma vs gallbladder. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS) and response rate (RR). 80 eligible patients (40 for each arm) were needed to detect an improvement in median OS from 5 months to 8.25 months (1.65 HR). A planned interim futility analysis of objective response was performed on the first 14 pts registered to the trametinib arm. Results: The study was stopped early based on the lack of measurable response in the trametinib arm. 53 pts were randomized (27 pts in Arm A vs 26 pts in Arm B). Median age was 62 years and the primary sites of tumor were cholangiocarcinoma (77%) and gallbladder (23%). Median OS was 4.3 months (95% CI 3.1-5.1) for Arm A, and 8.0 months (95% CI 3.2-14.6) for Arm B with a HR of 2.02 (95% CI 1.01-4.03, p=0.05). The median PFS was 1.3 months (95% CI 1.2-1.5) for arm A and 2.8 months (95% CI 1.4-6.9) for arm B with a HR of 2.95 (95% CI 1.38-6.30, p=0.01). Overall RR was 8% (95% CI 0%, 19%) in Arm A vs 10% (95% CI 0%, 23%) in Arm B (p>0.99), and 8% vs 45% had stable disease. Eight pts in Arm A experienced treatment-related ≥ grade 3 toxicities, including one death due to vomiting/dehydration. Seven pts in Arm B experienced treatment-related grade 3 toxicities; no higher grade toxicities were reported. Conclusions: To our knowledge, this is the first prospective randomized study of a targeted agent versus chemotherapy for the second line treatment of BC. In this unselected population, the lack of response to trametinib resulted in early closure. The PFS and OS for trametinib were inferior to 5FU. Clinical trial information: 02042443.
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- 2017
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45. Phase II study of first-line radioembolization with yttrium-90 glass microspheres for intrahepatic cholangiocarcinoma
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Junsung Choi, Richard D. Kim, Ravi Shridhar, Bulent Arslan, Sarah E. Hoffe, Jessica M. Frakes, Timothy J. Yeatman, Binglin Yue, Bela Kis, Kenneth L Meredith, and Gregory M. Springett
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Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,ECOG Performance Status ,medicine.disease ,Gastroenterology ,Radiation therapy ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Clinical endpoint ,030212 general & internal medicine ,Embolization ,Thrombus ,business ,Intrahepatic Cholangiocarcinoma - Abstract
482 Background: The standard of care for unresectable intrahepatic cholangiocarcinoma (ICC) is systemic chemotherapy. The role of liver directed therapy for ICC is controversial given the lack of level I data. We conducted a phase II study to determine the safety and effectiveness of first-line liver directed therapy with radioembolization with yttrium-90 (Y90) glass microspheres for ICC. Methods: Eligible patients were enrolled on an IRB-approved phase II study (NCT01253148). Patients were included if they had no evidence of extrahepatic metastases, Childs-Pugh A, without main portal vein thrombus, bilirubin < 2 mg/dL, ECOG performance status of 0-2, and no prior chemotherapy, liver embolization, or radiation therapy for ICC. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and toxicity. Results: Twenty-five patients were enrolled between 2010 and 2013 with a median followup of 13 months (9-20 months). The median age was 76 years. Twenty patients came off study due to progression or death. The overall response rate was 56%. Median PFS was 6 months (95% CI: 4-12 months). This was likely due to tumors appearing larger after treatment due to tumor inflammation despite a decrease in CA19-9 levels. Univariate (UVA) and multivariate analysis (MVA) failed to identify any prognostic factors associated with PFS. Despite the low median PFS, median OS was 22 months (95% CI: 10 months to upper limit not reached). However, UVA and MVA failed to identify and prognostic factors for OS. Treatment was well tolerated with no reported grade 3 gastrointestinal or general disorder toxicities. Grade 3 ALT, AST, and alkaline phosphatase increase were reported in 4%, 4%, and 8%, respectively. Grade 4 hyperbilirubinemia and thrombocytopenia were reported in 4% and 4%, respectively. There were 2 patient who developed sepsis one patient who died within 30 days of treatment. Conclusions: First-line liver directed therapy with radioembolization with Y90 glass microspheres is a safe and effective treatment for ICC. Further prospective clinical trials are needed to identify the proper sequencing of liver directed therapy and systemic chemotherapy. Clinical trial information: NCT01253148.
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- 2017
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46. Prognostic value of CD8+CD45RO+ tumor-infiltrating lymphocytes (TIL) and PD-L1 in cholangiocarcinoma
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Dae Won Kim, Young Doo Chang, Richard D. Kim, and Domenico Coppola
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0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,biology ,business.industry ,Tumor-infiltrating lymphocytes ,Malignancy ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Biliary tract ,030220 oncology & carcinogenesis ,PD-L1 ,biology.protein ,Medicine ,Immunohistochemistry ,Clinical significance ,Stage (cooking) ,Clone (B-cell biology) ,business - Abstract
286 Background: Cholangiocarcinoma is a malignancy arising from the epithelial cells of the biliary tract with poor prognosis. TILs and PD-L1 have a prognostic impact in various solid tumors. We aimed to investigate TILs and PD-L1 expression and their clinical relevance in cholangiocarcinoma. Methods: Formalin-fixed paraffin-embedded tumor samples from 41 patients with resected and histologically verified cholangiocarcinoma between 1990 and 2015 were identified and immunohistochemically (IHC) stained with anti-CD8, anti-CD45RO and the anti-PDL1 mouse IgG1 (clone 5H1; Thompson) antibodies. Stained tumor samples were reviewed and enumerated by a GI pathologist. PD-L1 positivity was defined ≥ 5% of tumor cells with a minimum of 100 evaluable tumor cells. The association between expression of PDL1, CD8 or CD45RO and survival was investigated using Kaplan-Meier survival and COX proportional hazard regression analyses. Results: The median age of patients was 64 (41-85) with 53% male. 22%, 41% and 37% were stage I, II and III, respectively. CD8 was positive in 16 (39%), CD8CD45RO (memory CD8 cells) was positive in 5 (12%), and PD-L1 was positive in 19 (46%). With a median follow-up of 21.4 months, tumors with CD8+CD45RO+ TIL has better cancer specific survival (median: unreached vs 41.2mo, HR = 0.27, 95% CI: 0.09-0.83, P = 0.023) and overall survival (median: unreached vs 21.4mo, HR = 0.34, 95%CI: 0.14-0.82, P = 0.016) than CD45RO-. The expression of CD8 alone or PD-L1 in tumor was not associated with prognosis. Multivariate analysis showed that CD8+CD45RO+ TIL (HR = 0.13, 95% CI: 0.02-0.99, P = 0.049) as well as stage, adjuvant treatment and R0 resection (microscopically margin-negative) were independent predictors of OS. Conclusions: Presence of CD8 memory T cells (CD8+CD45RO+) in tumor microenvironment was associated with significant better clinical outcome, and the expression of PD-L1 on cholangiocarcinoma cells may suggest a potential therapeutic target of antiPD-L1 antibody therapy in cholangiocarcinoma.
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- 2017
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47. Survival analysis of yttrium-90 radioembolization for unresectable intrahepatic cholangiocarcinoma
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Mokenge P. Malafa, Jessica M. Frakes, Richard D. Kim, Benjamin Biebel, Ambuj Kumar, Gregory M. Springett, Daniel A. Anaya, Bela Kis, Ravi Shridhar, Ghassan El-Haddad, Jehan Shah, Junsung Choi, Jennifer Sweeney, Alexandra Gangi, and Sarah E. Hoffe
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Cancer Research ,medicine.medical_specialty ,Tare weight ,Medical treatment ,business.industry ,Advanced stage ,Malignancy ,medicine.disease ,Surgery ,Oncology ,Clinical endpoint ,medicine ,Single institution ,business ,Survival analysis ,Intrahepatic Cholangiocarcinoma - Abstract
383 Background: Intrahepatic cholangiocarcinoma (ICC) is a rapidly progressing malignancy that frequently presents at an advanced stage and is often chemorefractory. The median overall survival (OS) with best medical treatment is approximately 12 months. The current study examines survival and characterizes predictors of mortality for ICC patients treated with transarterial yttrium-90 radioembolization (TARE). Methods: All patients with unresectable ICC who underwent TARE between May 2009 and May 2016 at a single institution were included and clinicopathologic variables reviewed. Primary endpoint was OS from time of TARE. Secondary endpoints included OS from time of diagnosis, post procedure toxicities and predictors of mortality. Results: A total of 134 TARE were performed on 85 patients. Average age at treatment was 73.4 ± 9.3 years and most patients were female (52%). More than one third of patients had an ECOG of 2 and had no significant post procedure sequalae. Thirty-six patients (42%) had extrahepatic disease at time of treatment and 61 patients (72%) were treated with systemic chemotherapy prior to TARE. A majority of patients (92.9%) received treatment to one lobe with an average radiation dose of 180.1±127.1 Gy. The median OS from time of the first TARE was 12 months (95% CI 7.8–16.1). The median OS from time of diagnosis was 21.4 months (95% CI 14.9-27.8). 51.8% and 26% of treated patients were still alive at 1 and 3 years, respectively. On univariate analysis, age at treatment, ECOG score, presence of extrahepatic disease, baseline albumin, alkaline phosphatase and AST correlated with OS. On multivariate analysis only low ECOG score and higher baseline albumin predicted improved OS (p < 0.01). Conclusions: Y90 radioembolization demonstrates a survival benefit for patients with unresectable ICC compared to historic controls of best medical treatment and should be considered an effective therapy in select patients. A multi-institutional randomized control trial should be performed to evaluate efficacy of TARE in select patients as both 1st line and salvage therapy.
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- 2017
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48. Impact of duodenal invasion on outcomes in patients with pancreatic cancer treated with stereotactic body radiotherapy
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Jose M. Pimiento, Mokenge P. Malafa, Jessica M. Frakes, Heloisa P. Soares, W. Jin, Eric A. Mellon, Sarah E. Hoffe, Pamela J. Hodul, Gilbert Murimwa, and Richard D. Kim
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Endoscopic ultrasound ,Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Incidence (epidemiology) ,medicine.disease ,030218 nuclear medicine & medical imaging ,Surgery ,Clinical trial ,03 medical and health sciences ,Exact test ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Pancreatic cancer ,Toxicity ,medicine ,Duodenum ,Adenocarcinoma ,Radiology ,business - Abstract
408 Background: Clinical trials for pancreatic adenocarcinoma patients treated with a uniform SBRT tumor dose prescription exclude tumors invading the duodenum due to potential for increased GI mucosal complications. We analyzed our non-trial patients to determine the impact of SBRT in the setting of known duodenal invasion. Methods: An IRB-approved institutional database was queried identifying all 220 localized borderline resectable or locally advanced pancreatic cancer patients treated with SBRT from 2009 to 2015. Eligibility included patients with head tumors, a minimum of 6 months of follow up, and duodenal invasion on pretreatment endoscopic ultrasound (EUS). Dose painted SBRT delivered 25-30 Gy to tumor abutting the duodenum and up to 50 Gy to focal tumor/vessel abutment. Analysis evaluated whether patients with duodenal invasion had increased incidence of grade ≥ 3 (G3+) toxicity, GI ulceration or bleeding, or worsened overall survival (OS). Fisher’s Exact Test (2-tailed) compared patient characteristics and binary outcomes. Survival estimates by Kaplan-Meier were compared using log-rank test. Results: The study population included 126 patients (median F/U 14.1 months). Of 23 patients with duodenal invasion, 14 (61%) underwent resection, 3 (13%) developed G3+ toxicity and 1 (4%) had acute pre-op G3 GI bleeding that was controlled endoscopically prior to surgery. Of 103 without duodenal invasion, 48 (47%) underwent resection, 9 (9%) suffered G3+ toxicity and 7 (7%) had any GI bleed or ulceration. None of the 7 patients with GI bleeding or ulceration underwent pancreatectomy, and 3 had bleeding from tumor progression into the duodenum. There was no association between duodenal invasion and the incidence of G3+ toxicity (p = 0.76) or GI ulceration/bleeding (p = 1.0). There was no worsened OS (p = 0.17) or G3+ toxicity (p = 0.22) for patients with duodenal invasion on EUS. Patients with a GI bleeding or ulceration event had decreased OS (p = .014). Conclusions: Duodenal invasion on EUS prior to SBRT did not worsen GI bleeding risk or survival. Our data suggests that excluding pancreatic adenocarcinoma patients with duodenal invasion from SBRT when using a dose-painted approach is unnecessary.
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- 2017
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49. Phase 1/2 study of durvalumab and tremelimumab as monotherapy and in combination in patients with unresectable hepatocellular carcinoma (HCC)
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Johanna C. Bendell, Ghassan K. Abou-Alfa, Michael A. Morse, Yoon-Koo Kang, Masatoshi Kudo, Joyce Antal, Ann-Lii Cheng, Feng Xiao, Stephen L. Chan, Andrew X. Zhu, Richard D. Kim, Bruno Sangro, Jillian Boice, and Shannon R. Morris
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Sorafenib ,Oncology ,Cancer Research ,medicine.medical_specialty ,Durvalumab ,business.industry ,Treatment options ,medicine.disease ,digestive system diseases ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Hepatocellular carcinoma ,medicine ,In patient ,business ,neoplasms ,Tremelimumab ,030215 immunology ,medicine.drug - Abstract
TPS3103Background: No approved standard-of-care treatment options exist for patients with unresectable HCC who progress on, are intolerant to, or have refused sorafenib therapy. The PD-1/PD-L1 path...
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- 2016
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50. Clinical outcomes of patients with solid tumor enrolled in phase 1 clinical trials
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TzuHua Juan, Aaron Cleveland Denson, Amit Mahipal, Barbara Bertles, Richard D. Kim, Georgine Wapinsly, Jae K. Lee, and Daniel C. Sullivan
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Cancer Research ,medicine.medical_specialty ,business.industry ,food and beverages ,Phases of clinical research ,humanities ,Surgery ,Clinical trial ,Patient population ,Oncology ,Internal medicine ,medicine ,business ,Solid tumor - Abstract
2541Background: Insufficient prognostic data can hamper patient enrollment into phase one clinical trials. Prior studies were limited by small numbers, selective patient population by tumor or ther...
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- 2016
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