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Chemotherapy followed by margin-negative resection (R0) is the treatment of choice for patients with localized pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant multiagent chemotherapy (MAC) or MAC then radiotherapy (RT) may optimize surgical candidacy. The purpose of this study was to compare pathologic outcomes of MAC followed by conventionally fractionated radiotherapy (CRT) versus stereotactic body radiotherapy (SBRT) for patients with resected PDAC.Patients diagnosed with nonmetastatic PDAC between 2012 and 2017 and who received preoperative MAC or MAC+RT were identified in the National Cancer Database. Variables associated with R0 and overall survival were identified with logistic regression and Cox analysis (P0.05).A total of 5273 patients were identified (MAC: 3900, MAC+CRT: 955, MAC+SBRT: 418). The median RT dose/fraction (fx) in the MAC+CRT and MAC+SBRT cohorts was 50.4 Gy/28 fx and 33 Gy/5 fx. Patients receiving MAC+CRT versus MAC+SBRT had similar rates of ypT3-T4 disease (54% vs. 58%, P=0.187), R0 (87% vs. 84%, P=0.168), and pathologic complete response (pathologic complete response; 6% vs. 4%, P=0.052), however, MAC+CRT was associated with less regional lymphatic disease (ypN+: 28% vs. 41%, P0.001). The median overall survival of patients receiving MAC+CRT versus MAC+SBRT was 24.6 versus 29.5 months (P=0.045).For patients with resected PDAC, MAC+CRT, and MAC+SBRT had similar rates of R0 and pathologic complete response, although MAC+CRT was associated with lower ypN+. Prospective evaluation of neoadjuvant RT regimens with attention to radiation therapy design is warranted.

Introduction: Many patients do not benefit from immunotherapies targeting immune checkpoints such as PD(L)-1 due to a variety of resistance mechanisms. The AhR pathway is downstream of the Trp-IDO/TDO-Kyn axis. High levels of immune-suppressive AhR-activating ligands, such as kynurenine derived from IDO1/TDO2-expressing tumors, have been implicated as a potential resistance mechanism and are associated with poor responses to PD-1 therapies. Compared with inhibition of IDO1/TDO2 alone, direct AhR inhibition can block the activation of this transcription factor and may better counteract immune suppression. BAY2416964 is a novel, oral AhR inhibitor currently in a Phase I clinical trial in patients with solid tumors. Preclinically, BAY2416964 can block the activation of AhR by kynurenine and relieve its immune-suppressive effects, thereby restoring anti-tumor T-cell activity, reducing the level of inhibitory myeloid-derived suppressor cells and regulatory T cells, and improving the effectiveness of PD-1 blockade. We have analyzed PK and biomarker data from the ongoing monotherapy dose-escalation study to explore a potential optimal dose and schedule for effective AhR inhibition. Methods: PK data were intensely sampled from patients in 10 different groups with different dosing regimens (once and twice daily) and various food-intake scenarios. AhR downstream target gene expression after ex vivo kynurenic acid stimulation of patients’ peripheral blood mononuclear cells (PBMCs) was assessed. A population PK (popPK) model was developed and calibrated to characterize the PK of BAY2416964 across treatment groups. This model accounts for the non-linear relationship between dose and bioavailability as well as the effect of food intake. Results: The preliminary popPK model identified a non-linear relationship between the BAY2416964 dose and its (relative) bioavailability which was dependent on the respective food condition. The popPK model was able to describe the clinical BAY2416964 plasma exposures from all dose groups, including the effect of food intake. Ex vivo analysis of PBMCs showed inhibition of kynurenic acid-induced AhR downstream gene expression (such as CYP1A1, CYP1B1), suggesting effective in vivo target engagement in the doses tested. Conclusion: This modeling-based PK analysis along with target engagement in peripheral blood informed the posology to be tested in the dose-expansion part of the ongoing clinical trial. Citation Format: Kyriakos Papadopoulos, Michael Cecchini, Juanita S. Lopez, Dirk Jäger, Ki Young Chung, Michael Platten, Florian Prinz, Yuko Ishii, David Schaer, Ilona Gutcher, Gabriele Leder, Radost Pencheva, Thomas Wagener, Christian Scheerans, Carsten Zieschang, Andrea Wagner, Spyros Stamatelos, Ecaterina Dumbrava. Preliminary analysis of pharmacokinetic (PK) and target engagement biomarkers from a first in human phase 1 study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT276.

Introduction: ATRi and PARPi combinations kill tumor cells via synergistic modulation of complementary DDR pathways but clinical utility is limited by overlapping toxicities. A genome-wide CRISPR-Cas9 screen identified DDR alterations that sensitize tumors to the ATRi camonsertib (cam) plus PARPi. Based on preclinical models, tolerability and efficacy of cam plus PARPi given intermittently at low doses in pts with solid tumors with DDR alterations, including BRCA-mutated PARPi-resistant cancers, was evaluated. Methods: Pts (≥ 18 yrs) with relapsed/refractory (r/r) solid tumors with DDR alterations were treated with cam plus talazoparib (tala), niraparib (nira), or olaparib (ola) in 2 phase I trials (NCT04497116, NCT04972110). An adaptive BOIN design was used to optimize dose/schedule. Endpoints were safety, recommended phase II dose (RP2D), pharmacokinetics (PK), response (RECIST v1.1 [confirmed/unconfirmed], CA 125, or PSA), clinical benefit rate (CBR; RECIST/tumor marker response or treatment duration ≥ 16 wk), and ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency [mVAF] ≥ 50%). Results: As of Nov 2022, 99 pts were enrolled (61 with ≥ 3 prior lines of therapy, 36 PARPi-pretreated); 43, 27, 29 pts in tala, nira, and ola combinations, respectively. Tumors included ovarian (n=20), prostate (n=13), breast (n=17), bile duct (n=3); most common genotypes were ATM (n=26), BRCA1 (n=19), and BRCA2 (n=33). Grade 3+ toxicities included reversible myelosuppression (neutropenia, anemia, and thrombocytopenia in 35%, 28%, and 14% of pts overall; 33%, 16%, and 11% at preliminary RP2Ds), fatigue (3%), and alkaline phosphatase increase (2%). Two pts discontinued treatment due to drug-related toxicity. Forty pts remain on therapy, up to 63 wks. Preliminary RP2Ds: cam 80 mg QD (d 5-7) + tala 0.25 mg QD, 1 wk on/1 wk off; cam 80 mg QD + nira 100 mg QD, 2 d on/5 d off; cam 50 mg QD + ola 100 mg BID, 3 d on/4 d off. As of abstract submission, response rate was 13% in 85 evaluable pts; CBR was 49%. Responders included pts with ovarian (n=6), bile duct (n=2), and breast, pancreatic, and carcinoma of unknown primary (n=1 each) cancers harboring alterations in BRCA1/2 (n=9), IDH1 (n=1), and ATM (n=1). Of 30 evaluable PARPi-pretreated pts, response rate was 23% and CBR was 52%. MRR was 64% (14/22 evaluable); change in mVAF correlated with a change in target lesion size (r=0.63, P=0.001). PK of each drug in the combination was consistent with respective monotherapy PK. Conclusion: Combination of cam plus PARPi at low doses on intermittent schedules was generally well-tolerated with clinical activity in DDR-aberrant tumors, including those pretreated with PARPi. RP2D optimization and translational correlative studies are ongoing. Citation Format: Timothy A. Yap, Siddhartha Yadav, Benjamin Herzberg, Benedito A. Carneiro, Elisa Fontana, Martin Højgaard, Michael J. Pishvaian, Ruth Plummer, Theresa L. Werner, Vaibhav Sahai, Stephanie Lheureux, Elizabeth K. Lee, Niharika B. Mettu, Gregory M. Cote, Joseph D. Schonhoft, Victoria Rimkunas, Ian M. Silverman, Marisa Wainszelbaum, Gerson Peltz, Adrian J. Fretland, Kezhen Fei, Danielle Ulanet, Insil Kim, Maria Koehler, Ezra Rosen, Michael Cecchini. Safety and efficacy of three PARP inhibitors (PARPi) combined with the ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in patients (pts) with solid tumors harboring DNA damage response (DDR) alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT018.

Background TAS-102, a novel antimetabolite, is approved for treatment of refractory metastatic colorectal cancer (CRC). This study sought to determine whether the addition of TAS-102 to oxaliplatin (TAS-OX) was safe and effective in metastatic CRC previously treated with oxaliplatin. Methods This investigator-initiated, open-label, single-arm phase 1b study enrolled patients with metastatic CRC previously treated with 5-fluorouracil, irinotecan, and oxaliplatin. In dose escalation, TAS-102 was given at 3 dose levels: 25, 30, and 35 mg/m2 twice daily on day 1 to day 5 with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. The primary endpoint of dose escalation was the recommended dose for expansion, and in dose expansion, the primary endpoint was overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Results Forty-one patients were treated with TAS-OX. No dose-limiting toxicities were observed in the 11 patients treated in escalation. The recommended dose for expansion was 35 mg/m2 TAS-102 twice daily on day 1 to day 5 in combination with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. In the intention-to-treat population, the ORR was 2.4% (95% CI, 0%-12.9%) with 1 of 41 patients having a partial response, although 12 (29%) had tumor shrinkage. The median progression-free survival was 2.7 months (95% CI, 2.4-4.8 months) and median overall survival was 6.8 months (95% CI, 5.7-10 months). Conclusions TAS-OX is safe with no unexpected toxicities at standard doses of each agent. The combination did not result in a clinically meaningful ORR, although progression-free survival and overall survival were encouraging in this heavily pretreated population. Lay summary For metastatic colorectal cancer, the treatment combination of TAS-102 and oxaliplatin was found to be well-tolerated and revealed no unexpected side effects. Twelve of 41 patients had reductions in the size of their tumor, and the study treatment delayed the time to tumor growth as opposed to what would be expected.

BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.

29 Background: Brain metastases (BM) are rare in colorectal cancer (CRC) with 1-3% of patients developing BM over their lifetime. There are no screening recommendations for BM in patients with CRC and most are diagnosed after a patient develops symptoms. Identifying the clinical characteristics for patients with CRC and BM may aid clinicians to consider BM early in symptom onset and potentially screen appropriate patients. Methods: We performed a retrospective chart review of patients >18 years diagnosed with CRC and BM at Yale New Haven Hospital from 1/2012-9/2021. Clinical characteristics were analyzed by descriptive statistics, time intervals were compared using the Mann-Whitney test, and survival analysis was done using the Kaplan-Meier method. Results: We identified 93 patients with CRC and BM. Median age at diagnosis was 56 years, 55% were male, 75% of patients had a left sided primary tumor and 47% were rectal primary. At initial diagnosis, 38% and 39% were stage III and IV respectively. RAS/RAF mutations were present in 45% of patients and all were mismatch repair proficient. The median time from CRC diagnosis to BM was 3.81 years (95% CI 3.09, 4.41) and median time from metastatic CRC to BM was 2.21 years (95% CI 1.48, 2.75). Median overall survival after developing BM was 0.49 years (95% CI 0.24, 0.70). Patients with RAS/RAF mutations had a decreased median time from CRC diagnosis to BM of 3.33 years (95% CI 2.69, 4.37) compared to RAS/RAF wildtype at 5.09 years (95% CI 4.44, 7.97) (p 0.0028). Median time to BM from CRC diagnosis was also decreased in females (p 0.01). The location of primary tumor did not significantly decrease time to BM. Prior to BM diagnosis, 76% of patients had lung metastasis. 84% of patients received treatment for BM while 14% had no BM treatment and 2% were unknown. For treatment 50% had Gamma Knife Radiosurgery, 22% underwent surgical excision +/- adjuvant radiation, and 12% underwent whole brain radiotherapy. After BM treatment, 43% of patients received additional chemotherapy. Conclusions: Although BM in CRC is uncommon, early diagnosis in those at risk is critical given the urgent nature of BM. Patients with CRC that develop BM frequently have tumors that originate in the left side of the colon and preexisting lung metastasis. In patients with CRC and BM, the majority develop BM > 3 years after initial CRC diagnosis, and BM onset is significantly shorter in females and patients with tumors harboring a RAS/RAF mutation. After BM diagnosis and treatment, less than half of patients are able to receive subsequent therapy, and median survival is < 6 months. [Table: see text]

115 Background: BI 905711 is a tetravalent bispecific antibody that cross-links TRAILR2 with CDH17. This cross-linking drives CDH17-dependent TRAILR2 oligomerization, leading to caspase activation and eventual apoptosis, inhibiting tumor growth in preclinical models of GI cancer. Methods: This Phase Ia/b study of BI 905711 in patients (pts) with advanced GI cancers (NCT04137289) aimed to determine the maximum tolerated dose (MTD) based on the proportion of pts with dose-limiting toxicities (DLT) and explore preliminary antitumor activity. In Phase Ia, pts received BI 905711 every 14 days. One pt with colorectal cancer (CRC) was enrolled at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 pts with CRC were enrolled at each subsequent level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). Up to 4 pts with non-CRC GI cancers were included at the dose level below the CRC cohort. Dose escalation was guided by a Bayesian logistic regression model. Results: As of 01 August 2022, 48 pts (CRC: n = 26; non-CRC: n = 22, including 13 with pancreatic ductal adenocarcinoma [PDAC]) had received BI 905711 (dose range 0.02–4.8 mg/kg); pts had a median age of 61 years (range 27–78) and had received a median of 3 (range 1–11) prior lines of treatment. No DLTs were observed and the MTD was not reached. 41 pts had AEs (grade [G] 3–5: 14 pts; serious: 13 pts). 17 pts had treatment-related AEs (TRAEs); 4 TRAEs were G3: AST increased (2 pts), fatigue and ALT increased (1 pt each). 1 pt had serious TRAEs: G2 decreased appetite and G3 fatigue. 2 pts had G1/2 infusion-related reactions that resolved and did not prevent resumption of treatment. PD biomarker modulation on the level of plasma caspase-3/7 activity was most common at 0.6 mg/kg (4/7 pts) or 1.2 mg/kg (2/6 pts). 13 pts achieved stable disease (SD) and 8 pts were progression-free for ≥4 months (PFS4). In pts with CRC, 6 pts achieved SD and 3 had PFS4. Among non-CRC pts, 7 pts achieved SD (PDAC: n = 6) and 5 had PFS4 (PDAC: n = 4). Median duration of treatment was 30.5 days (range 15–246) overall and 71 days (range 15–211) in the 0.6 mg/kg group (n = 8, predicted therapeutic dose; of whom 3 pts had PFS4: CRC: n = 1/4 [all CDH17+]; non-CRC: n = 2/4). Conclusions: In heavily pretreated pts, BI 905711 was associated with a tolerable safety profile and early signs of disease control. BI 905711 will be further assessed in Phase Ib in 4 dose groups: 0.6/1.2/2.4 mg/kg every 14 days, and 0.6 mg/kg weekly. Clinical trial information: NCT04137289 .

Background: Ramucirumab is a monoclonal antibody that binds to the vascular endothelial growth factor receptor 2, increasing hypoxia in the tumor microenvironment. In advanced gastric cancer, single agent ramucirumab is well tolerated and improves overall survival (OS) compared to placebo although it is largely cytostatic with a response rate ≤3%. Preclinical in vitro and in vivo experiments reveal that hypoxia induces homologous recombination deficiency (HRD) in tumors, which may be exploited by the addition of inhibitors of poly (ADP-ribose) polymerase (PARPi). We thus designed NCI10066 for metastatic gastric cancer with the hypothesis that ramucirumab would sensitize tumors to the PARPi olaparib. Methods: NCI 10066 (NCT03008278) was a phase 1/2, multicenter, open-label clinical trial sponsored by the Cancer Therapy Evaluation Program. Eligible patients had histologically confirmed metastatic gastric or GEJ adenocarcinoma with measurable disease refractory to ≥ 1 prior therapy that did not contain ramucirumab. Patients were treated with escalating doses of olaparib with ramucirumab 8 mg/kg every 2 weeks in a 3+3 design. Dose escalation evaluated two dose levels: olaparib 200 mg twice daily with ramucirumab 8 mg/kg every 2 weeks (dose level 1) and olaparib 300 mg twice daily with ramucirumab 8 mg/kg every 2 weeks (dose level 2). The primary objective of dose escalation was to assess safety and measure dose limiting toxicities (DLT) to determine the recommended phase 2 dose (RP2D). The primary objective in phase 2 was to evaluate clinical activity at the RP2D in a 40-patient expansion cohort. Results: From 2/8/18 - 9/17/21, 51 patients were enrolled at 10 centers throughout the Experimental Therapeutics Clinical Trials Network and 28/51 (55%) patients had ≥2 prior lines of therapy. In dose escalation 3 patients were treated at dose level 1 and 8 at dose level 2. No DLTs were observed at dose level 1 and at dose level 2 there was 1 DLT (fatigue) in 6 evaluable patients. The RP2D was determined to be olaparib 300 mg twice daily and ramucirumab 8 mg/kg every 2 weeks. Forty patients were treated in dose expansion at the RP2D. Of 46 patients evaluable for a response there were 5/46 (11%) partial responses (PR) and the disease control rate (PR/SD) was 29/46 (63%) at 6 weeks. The median progression free survival (PFS) was 2.8 months (95% CI 2.3 - 4.2) and the median OS was 7.3 months (95% CI 5.6 - 13.0). Grade ≥ 3 treatment related adverse events were seen in 13 (25%) of patients and there were no treatment related deaths. Conclusions: The combination of olaparib and ramucirumab is well tolerated with a RP2D of olaparib 300 mg twice daily and ramucirumab 8 mg/kg every 2 weeks. The ORR, PFS, and OS exceed the historical control with ramucirumab monotherapy, suggesting that the combination is clinically active. Biomarkers are critical to defining patient subsets more likely to benefit from the combination and HRD biomarker analysis is ongoing. Citation Format: Michael Cecchini, Joseph Chao, Yu Shyr, James Cleary, Nataliya Uboha, May Cho, Anthony Shields, Shubham Pant, Laura Goff, Kristin Spencer, Edward Kim, Chih-Yuan Hsu, Stacey Stein, Jaykumar Thumar, Jeremy Kortmansky, John Kunstman, Patricia LoRusso, Percy Ivy, Jill Lacy. A phase 1/2 study of olaparib in combination with ramucirumab in metastatic gastric and gastroesophageal junction adenocarcinoma (GEJ) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT170.

3535 Background: Approximately 20% of colorectal cancer (CRC) has an activating mutation in the PIK3CA oncogene. PIK3CA codes for the catalytic subunit of phosphoinositide 3-kinase alpha (PI3Kα), which ultimately activates the AKT and mammalian target of rapamycin (mTOR) pathway. The PI3Kα inhibitor alpelisib has been approved for breast cancer where a single PIK3CA activating mutation is sufficient for response. However, two activating mutations (multi-hit) in the PIK3CA allele substantially increases PI3Kα signaling compared to single hot spot mutations and results in exceptional response to PI3Kα inhibition. We aimed to identify the prevalence of PIK3CA multi-hit mutations in CRC to identify patients potentially susceptible to PI3K inhibitors. Methods: Tissue-based comprehensive genomic profiling (CGP) was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified, CAP (College of American Pathologists)-accredited laboratory (Foundation Medicine Inc., Cambridge, MA, USA) on all-comers during the course of routine clinical care from 2013-2021. Approval was obtained from the Western Institutional Review Board (Protocol No. 20152817). Hybrid capture was carried out for at least 324 cancer-related genes, including PIK3CA. Results: We identified 48,836 patients with advanced CRC who underwent Foundation Medicine testing and 846 (1.7%) patients with multi-hit PIK3CA mutations. Additional clinical and molecular data was available for 41,154 of these patients of which 710 (1.7%) had multi-hit PIK3CA and 7627 (19%) had any deleterious PIK3CA mutation . The local colon tumor was used for sequencing in 70% of cases and a separate site in 30% of cases. Patients with PIK3CA multi-hit mutations were 53% male with a median age of 60 (interquartile range 50-70). The microsatellite status was available for 697 of 710 patients with multi-hit PIK3CA and 123/697 (18%) were microsatellite instability-high. The Table outlines the genes with cooccurring mutations of >10% prevalence for multi-hit PIK3CA CRC, including the clinically relevant mutations in KRAS (65%) and BRAF (13%). The four most common PIK3CA variants were H1047R (9.8%), E545K (9.2%), E542K (9.0%) and R88Q (7.1%). The most common variant pair was E542K with E545K in 4.7% of multi-hit cases. Conclusions: Double-hit mutations in PIK3CA are seen in 1.7% of advanced CRC patients and may represent a subset of patients that may have enhanced sensitivity to PI3K inhibitors. Given the high prevalence of CRC in the United States and worldwide this represents a clinically meaningful prevalence of multi-hit PIK3CA. Future investigation on the clinical utility of PI3K inhibitors may be warranted in multi-hit PIK3CA CRC.[Table: see text]

Background Expert knowledge is often shared among multidisciplinary academic teams at tumor boards (TBs) across the country, but these conversations exist in silos and do not reach the wider oncology community. Objective Using an oncologist-only question and answer (Q&A) website, we sought to document expert insights from TBs at National Cancer Institute–designated Comprehensive Cancer Centers (NCI-CCCs) to provide educational benefits to the oncology community. Methods We designed a process with the NCI-CCCs to document and share discussions from the TBs focused on areas of practice variation on theMednet, an interactive Q&A website of over 13,000 US oncologists. The faculty translated the TB discussions into concise, non–case-based Q&As on theMednet. Answers were peer reviewed and disseminated in email newsletters to registered oncologists. Reach and engagement were measured. Following each Q&A, a survey question asked how the TB Q&As impacted the readers’ practice. Results A total of 23 breast, thoracic, gastrointestinal, and genitourinary programs from 16 NCI-CCC sites participated. Between December 2016 and July 2021, the faculty highlighted 368 questions from their TBs. Q&As were viewed 147,661 times by 7381 oncologists at 3515 institutions from all 50 states. A total of 277 (75%) Q&As were viewed every month. Of the 1063 responses to a survey question on how the Q&A affected clinicians’ practices, 646 (61%) reported that it confirmed their current practice, 163 (20%) indicated that a Q&A would change their future practice, and 214 (15%) reported learning something new. Conclusions Through an online Q&A platform, academics at the NCI-CCCs share knowledge outside the walls of academia with oncologists across the United States. Access to up-to-date expert knowledge can reassure clinicians’ practices, significantly impact patient care in community practices, and be a source of new knowledge and education.

Background Randomized controlled trials (RCTs) are the gold standard for evidence-based practice, but their development and implementation is resource intensive. We aimed to describe modern RCTs in gastrointestinal (GI) cancer and identify predictors of successful accrual and publication. Materials and Methods ClinicalTrials.gov was queried for phase III GI cancer RCTs opened between 2010 and 2019 and divided into two cohorts: past and recruiting. Past trials were analyzed for predictors of successful accrual and the subset with ≥3 years follow-up were analyzed for predictors of publication. Univariate and multivariable (MVA) logistic regression were used to identify covariates associated with complete accrual and publication status. Results A total of 533 GI RCTs were opened from 2010 to 2019, 244 of which are still recruiting. In the “past” trials cohort (235/533) MVA, Asian continent of enrollment was a predictor for successful accrual, whereas trials with prolonged enrollment (duration longer than median of 960 days) trended to failed accrual. Predictors for publication on MVA included international enrollment and accrual completion. Sponsorship was not associated with accrual or publication. Notably, 33% of past trials remain unpublished, and 60% of trials that were closed early remain unpublished. Conclusion Accrual rate and the primary continent of enrollment drive both trial completion and publication in GI oncology. Accrual must be streamlined to enhance the impact of RCTs on clinical management. A large portion of trials remain unpublished, underscoring the need to encourage dissemination of all trials to, at a minimum, inform future trial design. Implications for Practice Two-thirds of gastrointestinal (GI) oncology phase III randomized controlled trials successfully accrue; however, one third of these trials are unpublished and more than half of trials that close early are unpublished. The strongest predictors for publication are successful accrual and international collaborations. Initiatives to optimize the trial enrollment process need to be explored to maximize the potential for trials to engender progress in clinical practice. Moreover, this study identified a significant publication bias in the realm of GI oncology, and the field should promote reporting of all trials in order to better inform future trial questions and design.

136 Background: O6-methylguanine DNA methyltransferase (MGMT) is the principal repair mechanism of DNA damage created by alkylating agents. Approximately 40% of colorectal cancers (CRC) exhibit MGMT promoter hypermethylation, expected to result in gene silencing. The role of MGMT as a biomarker is poorly understood, and quantitative measurement of MGMT protein has not been performed in CRC. We hypothesized that altered tumor MGMT would affect DNA damage response, modulate adaptive anti-tumor immune responses, and influence survival in CRC. Methods: We used multiplexed quantitative immunofluorescence (QIF) to study 4 clinically annotated retrospective patient cohorts treated from 2000 to 2017 at Yale, consisting of 400 formalin-fixed paraffin-embedded CRC cases represented in tissue microarray format. These included paired tumors and adjacent non-tumor colonic mucosa (n = 112 pairs in Cohort 1), paired primary CRC and lymph node metastases (n = 31 pairs in Cohort 2), and 2 cohorts with primary stage I-IV tumors (n = 250 in Cohort 3; n = 150 in Cohort 4). We established a QIF panel for simultaneous, localized measurement of DAPI (all cells), cytokeratin (CK; tumor epithelial cells), MGMT, γH2AX (DNA damage response), and CD8. The measurement of fluorescent signals in CK-positive tumor cells or CK-negative stromal cells was achieved using co-localization strategies and the AQUA QIF platform. Results: We identified lower MGMT protein levels in CRC cells than in non-tumor colonic epithelium (p < 0.0001), and in lymph node metastases compared to paired primary CRC tumors (p = 0.0411). Using the visual detection threshold, tumor selective MGMT protein downregulation was identified in 20% of cases in Cohorts 3 and 4. Microsatellite instability-high (MSI-H) cases showed decreased tumoral MGMT protein compared to microsatellite stable (MSS) cases (p = 0.002). In Cohorts 3 and 4, low tumoral MGMT was consistently associated with increased CD8+ tumor infiltrating lymphocytes (p = 0.0472; p = 0.0002). The association between MGMT and γH2AX was inconsistent. The association between MGMT and CD8 was significant only in MSS cases (p = 0.0001) but not in MSI-H cases (p = 0.0979), supporting that the effect is not driven by MSI-H status. Tumor-selective MGMT downregulation evidenced by a low tumor-to-stroma ratio was associated with improved progression-free survival and overall survival in both Cohorts 3 and 4, but statistical significance was only seen in Cohort 3. Conclusions: MGMT protein downregulation occurs in 20% of CRCs and is associated with increased adaptive anti-tumor immune responses, mismatch repair (MMR) deficiency and better prognosis. MGMT deficiency may alter DNA repair in tumor cells and mediate the accumulation of antigenic mutations or neopeptides, independent from MMR status. Our results support a biomarker role of MGMT protein and suggest a role for immunotherapy combinations in MGMT deficient tumors.

TPS375 Background: In normal conditions, Claudin (CLDN)18.2 is a tight junction protein with expression strictly confined to differentiated epithelial cells in gastric mucosa. CLDN18.2 has been found to be upregulated, and involved in tumor development and progression in a variety of tumor types such as gastric, pancreatic, and bile duct cancer (BTC). The biological characteristics of CLDN18.2 suggest it is an ideal therapeutic target for cancer drug development. IMAB362 is the first anti-CLDN18.2 monoclonal antibody (mAb) of high potency to have been tested in humans and it revealed clinical efficacy in gastric cancer in a phase II study. TST001, a humanized IgG1 mAb, binds to a distinct epitope of CLDN18.2 with higher affinity and mediates CLDN18.2 expressing cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) in comparison with IMAB362; Furthermore, TST001 is produced using an optimized glycoengineering process to increase affinity to FcR. The enhanced binding to CLDN18.2 on tumor cells and FcR on NK cells results in more efficient engagement of the tumor cells with NK cells and antibody mediated cellular cytotoxicity. In preclinical xenograft studies, TST001 displayed potent anti-tumor activities in the tumor models with medium to high level of CLDN18.2 expression and synergy anti-cancer effect with checkpoint inhibitor. A mAb specific for CLDN18.2 was also developed as an IHC based biomarker for patient enrollment in the clinical trials. Methods: This is an open-label, multi-center, phase I clinical trial to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK) profile and preliminary anti-cancer effect of TST001 in patients with locally advanced or metastatic solid tumors. (NCT04396821) The study consists of two parts: Part A is a 3+3 dose escalation design with sequential dose cohorts of 1, 3, 6, 10mg/kg in Q2W and Q3W schedules. Based on the emerging safety data, higher doses may be proposed for testing. About 27-54 patients will be enrolled. Dose expansion (Part B) will utilize doses of TST001 based on the emerging data from Part A. In Part B, up to 20 patients with CLDN18.2 overexpression per tumor specific cohort will be enrolled to 3 cohorts: A: TST001 single agent in gastric/gastroesophageal junction (G/GEJ) cancer; B: TST001 + nivolumab in G/GEJ cancer; C: TST001 single agent in pancreatic cancer or BTC. All patients in Part B will be selected by CLDN18.2 expression by central lab testing. The safety, anti-tumor activity, and PK will be further assessed in Part B. Enrolment began in July 2020 in the USA and is ongoing in multiple sites. As of 20 September, 2021, 23 subjects were dosed in Part A and the dose of 10mg/kg is being tested. Another phase I study of TST001 single agent and in combination with chemotherapy in patients with metastatic solid tumor is also ongoing in China (NCT04495296).

TPS222 Background: Activation of the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) induces apoptosis via caspase activation. Targeting TRAILR2 is an attractive therapeutic strategy, but some early TRAILR2 agonists were associated with severe hepatotoxicity. Cadherin 17 (CDH17), a membrane protein highly expressed in GI cancers, is not expressed in normal hepatocytes so using CDH17 as a liver-sparing anchor may avoid hepatotoxicity. BI 905711 is a tetravalent bispecific antibody that cross-links TRAILR2 with CDH17 to induce CDH17-dependent TRAILR2 oligomerisation. In preclinical assays, BI 905711 demonstrated a potency shift of ̃1000 fold versus the 1st-generation TRAILR2 agonist lexatumumab. BI 905711 induced apoptosis in CDH17-positive tumor cells in vitro, impaired tumor growth in pt-derived colorectal cancer (CRC) xenografts, and no hepatotoxicity was observed. Methods: This phase Ia/Ib study (NCT04137289) aims to determine the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of BI 905711 in pts with advanced, refractory GI cancers. Up to 140 adult pts with histologically confirmed, advanced unresectable/metastatic colorectal, gastric, esophageal or pancreatic adenocarcinoma, cholangiocarcinoma, or gallbladder or small intestine carcinoma, who have progressed on standard-of-care therapies, will be enrolled. In phase Ia, pts will receive intravenous BI 905711 at escalating doses (range 0.02–4.8 mg/kg) every 14 days, until disease progression or unacceptable toxicities. Dose escalation will be guided by a Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) in the first 28 days. In phase Ia, a minimum number of CRC pts will be enrolled to each cohort: ≥1 CRC pt at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 pts at each subsequent dose level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). In parallel to dose escalation in CRC pts, up to 4 pts with non-CRC GI cancers will be included at the dose level below that of the CRC cohort. If an objective response (OR) per RECIST v1.1 is observed in CRC or non-CRC GI pts at a safe dose level, up to 10 additional pts with the same tumor type will be recruited at that dose level. In phase Ib, CRC pts will be randomized into up to 4 dose cohorts (as determined in phase Ia; n=20 each) to define the recommended phase II dose. The primary endpoints are determination of the MTD based on the proportion of pts with DLTs (phase Ia) and OR rate based on RECIST v1.1 (phase Ib). Secondary endpoints include PK parameters and OR in pts with measurable disease (phase Ia), and disease control, tumor shrinkage, duration of response, and progression-free survival (phase Ib). Trial enrollment is ongoing, with 33 pts enrolled to date. Clinical trial information: NCT04137289.

Purpose/objective(s) Following presentation of the CALGB 80803 trial, which demonstrated notably high pathologic complete response (pCR) rates with induction FOLFOX followed by chemoradiotherapy (CRT), our institution more routinely incorporated induction chemotherapy (IC) into the management of LA-EC patients. However, improvements in progression-free (PFS) or overall survival (OS) with this regimen compared to pre-operative CRT alone have not yet been shown. We hypothesized IC-CRT would lead to an improvement in OS and PFS when compared to CRT. Materials/methods Patients with operable LA-EC were eligible for analysis if they received CRT between 2013-2019. The cohort was stratified into two groups, IC-CRT vs. CRT. The Kaplan-Meier method was used to estimate OS and PFS. The cumulative incidences of local recurrence (LR), locoregional recurrence (LRR), and distant metastasis (DM) were reported. The impact of treatment group on pathologic response and surgical outcomes were assessed by Chi-square. Results 95 patients were included for analysis (IC-CRT n = 58; CRT n = 37). Baseline characteristics included median Karnofsky Performance Status 80, median weight loss 5% (IQR 0-9%), with the majority being adenocarcinoma histology (81%), T3-T4 (60%), N+ (79%), located in the distal esophagus or gastroesophageal junction (89%). Patients receiving IC-CRT were more likely to have been treated after 2016 (64% vs 38%, P = 0.021). IC was most commonly FOLFOX (74%) for a median of 3 (IQR 1-3) cycles. CRT was delivered to a median dose of 50 Gy in 25-28 fractions. Surgery was attempted in 60% and 68% of the IC-CRT and CRT cohorts, respectively. Median follow-up was 26 months. ICRT and CRT were associated with similar 2-year OS (66% [95% CI 51-78%] vs 70% [95% CI 52-83%]) and PFS (47% [95% CI 33-59%] vs 48% [95% CI 30-63%]). In the adenocarcinoma subset (n = 77), 2-year OS was 69% (95% CI 52-81%) in the IC-CRT cohort vs 61% (95% CI 40-77%) with CRT. 2-year PFS was 46% (95% CI 31-60%) and 38% (95% CI 20-56%), respectively. IC-CRT was not associated with an OS or PFS benefit among any patient subgroup. Recurrence rates were similar between the cohorts (47%) and first recurrence was most commonly DM (61% IC-CRT vs 65% CRT). Patients receiving IC-CRT compared to CRT had numeric but not statistically significant improvement in pCR (45% vs 29%, P = 0.24) and N-stage regression (72% vs 58%, P = 0.28). There was no difference in the rate of R0 resection, hospitalization, surgical complications, or treatment-related death with use of IC-CRT. Conclusion IC-CRT was not associated with improved OS or PFS in this small and perhaps underpowered cohort study. Further investigations are needed to explore the impact of IC-CRT on quality of life, symptom burden, and to see if meaningful trends develop with time.

Background: The release of ATP from dying cancer cells in response to platinum-based chemotherapy increases immunosuppressive extracellular adenosine, which can bind and activate the A2a and A2b receptors on immune cells, diminishing the effectiveness of the anti-tumor immune response. Concomitant dual adenosine receptor blockade may therefore enhance the therapeutic efficacy of some chemotherapeutic agents. Etrumadenant (etruma, AB928) is the first clinical-stage small-molecule, selective dual antagonist of A2aR and A2bR for which combination data with mFOLFOX-6 in mCRC were previously presented1,2. Here we present updated results for safety in all patients (pts) and efficacy in 3L+ pts. Methods: ARC-3 (NCT03720678) was a phase 1/1b, multicenter, open-label study to evaluate etruma + mFOLFOX-6 in pts with mCRC. Eligible pts had histologically confirmed mCRC with ≥1 measurable lesion. Pts received 75 mg (phase 1 only) or 150 mg etruma orally once daily (QD) + mFOLFOX-6. The primary objective was to assess the safety of the combination; secondary objectives included evaluation of clinical activity. Results: As of 20Nov2020, 44 pts were enrolled and received etruma (75mg: n=4; 150mg: n=40) + mFOLFOX-6. Etruma-related AEs were reported in 34 pts and were mostly Grade 1 or 2; those reported in >30% of pts were fatigue and nausea. One pt had an etruma-related Grade 3 acute kidney injury and there were no Grade 4-5 etruma-related SAEs. There were 22 efficacy-evaluable 3L+ subjects, all of which had received prior FOLFOX and/or FOLFIRI. In this subgroup, the ORR was 9.1% and the median PFS and OS were 3.9 and 15.7 mos respectively. Conclusions: Updated results confirm etruma + mFOLFOX-6 was well tolerated in pts with mCRC without significant additive toxicity and was associated with disease control in heavily pretreated pts. Based on these encouraging data, a platform study (ARC-9) has been initiated to further explore this and other combinations in mCRC pts. References 1. Cecchini M, et.al. AACR Annual Meeting 2020, Abstract# 99532. Udyavar A, et.al. SITC Annual Meeting 2020, Abstract# 338 Citation Format: Michael Cecchini, Cheng Quah, Shiyao Liu, Rachel Woloski, Akshata Udyavar, Marios Giannakis. ARC-3: Updated results of etrumadenant (AB928) + modified FOLFOX-6 (mFOLFOX-6) in metastatic colorectal cancer (mCRC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT129.

The prognosis of metastatic pancreatic cancer remains poor despite recent advances in treatment with multidrug chemotherapy regimens. Use of immune checkpoint inhibitors and molecular targeted therapies has so far been disappointing. This report describes a patient with chemotherapy-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) whose tumor was characterized by an activating mutation in exon 19 of the epidermal growth factor receptor (EGFR). He experienced response to erlotinib for 10 months, and then developed disease progression in association with emergence of the T790M mutation. Activating EGFR mutations in cancers other than lung are uncommon, but when present may predict response to EGFR tyrosine kinase inhibitors (TKIs). Development of the T790M mutation in this case suggests that EGFR-targeted TKIs may follow similar patterns of resistance regardless of tumor type. Although actionable mutations are detected infrequently in PDAC, this case illustrates the potential benefit of offering genomic analysis to all patients with advanced disease.

e18584 Background: Cancer progression rates following diagnosis are readily measured. However, the progression rate of cancer during the preclinical sojourn time is generally unobserved. Understanding the duration of preclinical stages (“dwell time”) would allow clinicians to better identify appropriate screening intervals for cancer. We therefore elicited estimates of progression rate during the preclinical sojourn time for a wide variety of malignancies from a panel of clinical experts. Methods: We used a validated consensus methodology (RAND/UCLA modified Delphi panel method) to elicit per-stage dwell time estimates for 20 solid cancers and lymphoma from experts. Eleven experienced oncologists (general and subspecialists) from community and academic centers reviewed literature on the natural history of disease and estimated in number of years (

2624 Background: KY1044, is a fully human IgG1 anti ICOS antibody designed to stimulate Teffs and to deplete ICOS high Tregs in the tumor microenvironment. Methods: Patients with advanced/metastatic malignancies received escalating doses of KY1044 as a single agent and in combination with atezolizumab 1200 mg by IV infusion every 3 weeks until disease progression or unacceptable toxicity. Dose escalation was guided by a modified toxicity probability interval design. The primary objective was to determine safety, tolerability, and maximum tolerated dose. Cohorts that were tolerated were later enriched with more subjects. AEs were classified according to CTCAE v5 and efficacy measures performed according to RECIST v1.1 every 8 weeks for the first 16 weeks and then every 12 weeks. Results: As of 16-Dec-2020, a total of 103 patients have been enrolled in the study (38 patients as monotherapy in 6 cohorts at doses ranging from 0.8 to 240 mg and 65 in combination with atezolizumab in 5 cohorts at doses 0.8 – 80 mg). 63% and 55% of patients received ≥4 prior anti-cancer therapies in the single agent and combination cohorts, respectively. All cohorts were completed without DLTs during the first 21 days of treatment. In the KY1044 single agent cohorts, 47.4% of patients experienced treatment-related AEs (TRAEs), all were grades 1 or 2. In the combination cohorts, TRAEs were observed in 58% of patients. Most of the TRAEs were grade 1 or 2 apart from 8 TRAEs that were ≥grade 3 occurring in 43 weeks (range 45 to 66 weeks). Conclusions: KY1044 is well tolerated as single agent and in combination with atezolizumab. Objective responses have been observed in this phase 1 part of the study. The phase 1 expansion and phase 2 part of the study is ongoing. Clinical trial information: NCT03829501.

TPS150 Background: ATP release from dying cancer cells in response to platinum-based chemotherapy increases extracellular immunosuppressive adenosine, which binds and activates the A2a and A2b receptors on immune cells. Adenosine-mediated signaling impairs activation, proliferation, and cytotoxic activity of effector T cells, resulting in inhibition of antitumor activity. Concomitant adenosine receptor blockade may therefore enhance the therapeutic efficacy of chemo/immunotherapy regimens. Etrumadenant (AB928), the first clinical-stage, small-molecule, dual adenosine receptor antagonist, is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Recently, results were reported for the ARC-3 phase 1/1b study of etrumadenant + modified 5-fluorouracil + oxaliplatin (mFOLFOX-6) in patients (pts) with mCRC. In this study, etrumadenant + mFOLFOX-6 was well tolerated without significant additive toxicity. Disease control was observed in patients with RAS/BRAF mutated mCRC, as well as 3L+ disease previously treated with FOLFOX and/or FOLFIRI (PR and/or SD >4 mo). Due to deep responses in 1L-3L+ pts, 6 pts had the opportunity to pursue surgery and radiotherapy with curative intent. The encouraging results from ARC-3 warrant further evaluation of etrumadenant-based combination therapy for mCRC. Methods: ARC-9 is a phase 1b/2, multicohort, open-label, randomized platform study designed to evaluate safety and clinical activity of etrumadenant (150 mg orally once daily [QD]) in combination with standard-of-care (SOC) regimens or novel therapeutics in pts with mCRC (Table). Cohort eligibility is based on prior anticancer treatment history. Pts enrolled in Cohorts A and B will be randomized (2:1) into the experimental vs SOC arms. Cohort C consists of a single arm to allow inclusion of novel agents as they become available with built in early stopping rules for futility. Pts who progress on the SOC arm of Cohort A can enroll in Cohort B; pts who progress on the SOC arm of Cohort B can crossover to the experimental arm. Primary endpoints across cohorts are shown in Table. Safety monitoring will occur throughout the trial, disease assessments will occur every 8 weeks, and correlative study pre- and on-treatment biopsies will be performed. [Table: see text]

82 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy signals and safety of treatment (tx) combinations across tumor types. Isatuximab (isa; anti-CD38) targets CD38 receptors expressed on immunosuppressive cells in the tumor microenvironment. We hypothesized atezolizumab (atezo; anti–PD-L1) + isa would induce an anti-tumor response beyond that of regorafenib (rego), a multi-kinase inhibitor, in patients (pts) with tx-refractory metastatic colorectal cancer (mCRC). Methods: This randomized Phase Ib/II trial (NCT03555149) enrolled pts with microsatellite stable/mismatched repair proficient mCRC who had received ≤ 2 prior tx lines (fluoropyrimidine-, oxaliplatin- or irinotecan-containing chemotherapy plus a biologic agent). Pts received atezo (1200 mg intravenously [IV] every 3 weeks [q3w]) + isa (10 mg/kg IV q3w) or control tx with rego (160 mg orally days 1–21; dose escalation to 160 mg during Cycle 1 allowed per institutional guidelines). The primary endpoint was objective response rate (ORR; investigator-assessed RECIST 1.1); secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: Data cutoff date was March 3, 2020. Fifteen pts received atezo + isa and 13 pts received rego. Fourteen atezo + isa pts (93.3%) and 11 control arm pts (84.6%) had received 2 prior lines of tx; 9 atezo + isa pts (60.0%) and 9 control pts (69.2%) had liver metastases at enrollment. No responses were seen in either arm; 3 pts receiving atezo + isa (20.0%) and 8 control pts (61.5%) had stable disease as their best response. DCR (response and/or stable disease ≥ 12 weeks) was 6.7% with atezo + isa and 15.4% with control. One pt treated with atezo + isa beyond progression had prolonged disease stabilization. Median PFS was 1.4 mo (95% CI: 1.4, 1.8) with atezo + isa and 2.8 mo (95% CI: 1.6, 3.1) in the control arm; median OS was 5.1 mo (95% CI: 3.1, 7.8) with atezo + isa and 10.2 mo (95% CI: 4.8, not reached) with control. Tx-related adverse events (AEs, Grade 1-4) occurred in 13 atezo + isa pts (86.7%), and 12 control pts (92.3%). The most common tx-related AEs with atezo + isa were infusion-related reaction (73.3%), nausea (26.7%) and fatigue (20.0%). No Grade 5 AEs occurred in the atezo + isa arm, 1 (7.7%) was reported in the control arm (sepsis, considered unrelated to study tx). No atezo + isa pts and 1 control-arm pt (7.7%) withdrew from treatment due to a tx-related AE. Biomarker analyses did not identify any significant trends related to efficacy. Conclusions: In this trial, superior efficacy of atezo + isa vs rego was not shown. However, the atezo + isa combination was well tolerated, with a manageable safety profile. Clinical trial information: NCT03555149.

462 Background: To evaluate epidemiology, treatment and outcomes of stage 4 gastrointestinal stromal tumors (GIST). Methods: The 2010-2016 United States National Cancer Database was queried for adult patients diagnosed with invasive GIST (ICD code 8936) at AJCC stage 4, without prior malignant disease. Overall survival (OS) was evaluated using Cox proportional hazards regression, accounting for potential confounders in multivariable models. Results: A total of 1,578 stage 4 GIST were included (13.3% of all GIST) with a male:female ratio of 1.38:1. The most common cancer site was the stomach (55.4%) and small intestine (40% of stage 4 GIST). At diagnosis, median age was 62 years and median tumor diameter 10 cm. Distant organ metastases were reported in 58.7%, the most frequent being hepatic (n = 801, 50.8% of stage 4 GIST). The majority of stage 4 GIST patients received systemic therapy (78.6%), either alone (35.4%) or combined surgery+systemic therapy (43.3%). Systemic therapy was administered neoadjuvant in 6.9%, adjuvant in 32%, and neoadjuvant+adjuvant in 5.1% of surgically resected patients. Another n = 204 patients (12.9% of all stage 4 GIST) were treated with surgical resection alone. GIST overall survival rates were 88%, 77%, 67% and 51% at 1, 2, 3, and 5 years, respectively. On multivariable Cox proportional hazard models, primary GIST treatment independently affected OS: compared to combined surgery+systemic therapy, OS was shorter for patients receiving systemic therapy alone (HR = 2.77 (95% CI: 2.12-3.61, p < 0.001)) and no treatment (HR = 4.2 (95% CI: 2.75-6.43, p < 0.001)). No significant OS difference was evident comparing surgery+systemic therapy and surgery alone (HR = 1.23 (95% CI: 0.88-1.72, p = 0.227)). In subgroup analyses of patients undergoing surgical resection, no statistically significant OS difference was evident comparing neoadjuvant, adjuvant and combined neoadjuvant+adjuvant systemic therapy on multivariable analyses. Treatment at non-academic vs. academic centers was associated with shorter OS (multivariable HR = 1.36 (95% CI: 1.1-1.69, p = 0.005)). Further independent OS predictors were male sex (vs. female HR = 1.28 (95% CI: 1.03-1.59, p = 0.023)), older age, higher comorbidities, higher cancer grade, and larger cancer diameter. Conclusions: Stage 4 GIST is a rare gastrointestinal malignancy that most commonly manifests in the stomach and small intestine in male patients, with frequent hepatic metastases and excellent 5-year OS rates of up to 51%. Combined surgery+systemic therapy demonstrates best outcomes, although surgical resection alone might yield comparable results in selected patients.

Background: The release of ATP from dying cancer cells in response to platinum-based chemotherapy increases extracellular immunosuppressive adenosine (A), which binds to and activates the A2a and A2b receptors on immune cells resulting in an ineffective anti-tumor immune response. Concomitant adenosine receptor blockade may therefore enhance the therapeutic efficacy of some chemotherapeutic agents. AB928, the first clinical-stage small molecule dual adenosine receptor antagonist, is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Methods: ARC-3 (NCT03720678) is a Phase 1/1b, open-label study in participants (pts) with advanced CRC. Phase 1 escalation identified AB928 150 mg orally once daily as the recommended dose in combination with standard mFOLFOX-6. Phase 1b expansion is ongoing and includes at least 15 and up to 40 pts. Eligible pts must have unresectable or mCRC, ECOG performance status 0-1, and at least one RECIST measurable lesion. Phase 1 eligibility included up to 5 lines of prior therapy; Phase 1b is similarly scoped. Exploratory biomarker analyses include immunohistochemistry of the adenosine axis, tumoral next gene sequencing, and tumor/blood immune correlates. Results: As of 27Dec19, 21 pts received AB928 150 mg + mFOLFOX-6: 7 in Phase 1 and 14 in Phase 1b. All previously treated pts (n=12) were FOLFOX- and/or FOLFIRI-experienced. Prior metastatic therapies range from 3 to 5 in Phase 1 escalation and 0 to 3 in Phase 1b expansion. Adverse events (AEs) reported in >30% of pts included fatigue, diarrhea, and thrombocytopenia. AEs related to AB928 occurred in 13 pts and were mostly mild to moderate. AB928-related Grade 3 AEs reported by 3 pts were diarrhea, AST increase, and neutropenia; there were no Grade 4-5 AB928-related AEs. Out of 15 evaluable pts, by investigator assessment, the disease control rate was 100% with 2 partial responses (13%; 1 confirmed, 1 pending confirmation) and 13 stable disease (87%). Of pts with stable disease, 6/13 (46%) had tumor shrinkage >15%. Median time on treatment was 15.4 (range: 1.7 - 40.6+) and 11.9 (range: 2.7 - 15.7+) weeks for Phase 1 and Phase 1b, respectively, with initiation of Phase 1b dosing on 09Sep19. Enrollment up to 40 pts is proceeding based on early efficacy gates; 15 pts are currently receiving study treatment. Conclusions: AB928 with mFOLFOX-6 has been well tolerated without significant evidence of additive toxicity in pts with mCRC. Combination treatment was associated with disease control in all evaluable pts, including those with microsatellite stable and RAS/BRAF mutated mCRC. Additional updates on the safety, clinical activity, and correlative biomarker results for all escalation/expansion pts will be presented. Citation Format: Michael Cecchini, Manuel Modiano, Fadi Braiteh, Olivia S. Gardner, Houston N. Gilbert, Daniel DiRenzo, Lisa Seitz, Matt J. Walters, Fangfang Yin, Rachel Woloski, Melissa C. Paoloni, Ki Y. Chung. Efficacy and safety of AB928 plus modified FOLFOX-6 (mFOLFOX-6) in participants with metastatic colorectal cancer (mCRC): Initial results at the recommended dose for expansion (ARC-3) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-387.

Background: Gut microbiome composition affects response to PD-1 blockade; and recent proof of concept studies suggest that gut microbiome manipulation is effective in reversing resistance to PD-1 blockade. VE800 is an oral live biotherapeutic consisting of 11 distinct non-pathogenic, non-toxigenic, commensal bacterial strains manufactured in lyophilized form. VE800 induces CD8+ T cell infiltrate into tumors; and significantly enhances anti-tumor activity of PD-1 blockade preclinically in multiple tumor models in a CD103+ dendritic cell and major histocompatibility (MHC) class I dependent fashion (Tanoue et al., 2019). Retrospective analysis of cancer patient's (pt) samples also suggests that greater VE800 strain abundance is associated with improved response to PD-1 blockade. The objective of this phase I study is to evaluate the safety, tolerability, and clinical activity of VE800 administered orally in combination with nivolumab in pts with select cancers. Methods: CONSORTIUM-IO (NCT04208958) is an open-label, first-in-human study evaluating VE800 and nivolumab combination in pts with anti-PD-1/PD-L1 relapsed/refractory melanoma, anti-PD-1/PD-L1 naïve gastric/gastroesophageal junction (GEJ) adenocarcinoma and anti-PD-1/PD-L1 naïve microsatellite-stable (MSS) colorectal cancer. Following a 5-day course of oral vancomycin 125mg QID, VE800 will be administered daily along with nivolumab (480mg Q4W). A single dose level of VE800 will be evaluated. In the interests of maximizing safety, a Simon 2-stage design will be used for each disease cohort. Although no dose-limiting toxicities (DLT) are expected, the first 3 pts will be enrolled serially 1 week apart; and safety data of the first 6 pts will be reviewed prior to further accrual. Pts will continue to receive VE800/nivolumab combination until disease progression or unacceptable toxicity. Primary endpoints include safety, tolerability; and clinical activity by objective response rate (ORR) per RECIST v1.1. Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS); and metagenomic strain-level analysis of degree/duration of VE800 strain colonization. Exploratory endpoints include tumor and blood immunophenotyping, serum/stool metabolomics and global changes in fecal microbiome composition. CONSORTIUM-IO is currently actively enrolling pts. Citation Format: Diwakar Davar, Judy S. Wang, Michael Cecchini, Zev Wainberg, Martin Gutierrez, Anita Turk, Rose Szabady, Jason Norman, Bernat Olle, Bruce Roberts, Dmitri Bobilev. Consortium-IO: A safety and efficacy study of VE800 in combination with nivolumab in previously treated patients with select advanced metastatic cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT246.

e16052 Background: To assess microsatellite instability (MSI) and KRAS mutation prevalence, discrepancies and their impact on outcome in AJCC stage IV colorectal adenocarcinoma (colorectal cancer; CRC). Methods: The 2010-2016 United States National Cancer Database was queried for stage IV CRC patients > 18yo and information on MSI and KRAS mutation. Microsatellite status was stratified as stable microsatellites (MSS, including low instability) and microsatellite instability high (MSI-H). KRAS status was stratified as mutation and wildtype. Prevalence and discrepancies were evaluated according to patient demographics, US geography and CRC factors. Overall survival (OS) was assessed using Cox proportional hazards models adjusting for age, gender, race, comorbidities, metastatic burden, CRC treatment, treatment center type, and year of CRC diagnosis. A priori, a statistical interaction test between microsatellite status, KRAS status and primary CRC site was planned. Results: Microsatellite/KRAS status was available for n = 10,844/n = 25,712 patients, respectively. OS was assessed in n = 5,904 patients with data on both microsatellite and KRAS status, and follow-up. Overall prevalence of MSI-H was 3.1% and KRAS mutation 42.4%. Microsatellite and KRAS status varied according to primary CR site, as presented in Table. Further variation was evident according to US-geography, with MSI-H rates ranging from 1.6% to 4.1%, and KRAS mutation rates ranging from 41.1% to 44%. On multivariable analyses, longer OS was observed in patients with KRAS wildtype versus mutation (HR = 0.91, 95% CI: 0.85-0.97 p = 0.004), MSS versus MSI-H (HR = 0.75, 95% CI: 0.62-0.9, p = 0.003), and left-sided versus right-sided CRC (HR = 0.65, 95% CI: 0.6-0.7, p < 0.001). The effect of KRAS mutation further varied with CRC site and microsatellite status (interaction p = 0.002). Conclusions: Depending on its primary site and US geography, stage IV CRC shows distinct mutational behavior. KRAS mutation, MSI-H, MSI-H and primary CRC sidedness independently affect overall survival and interact with distinct prognostic profiles. Generically classifying adenocarcinomas of different site as “CRC” might deprecate this diversity. [Table: see text]

770 Background: Patients (pts) receiving treatment for metastatic pancreatic cancer (MPC) experience significant symptoms, treatment related side effects and psychosocial burdens. The ASCO guidelines recommend early palliative care consultation (PCC) to improve quality of life and survival. However, limited real-world data is available regarding the timing of PCC, hospice enrollment and location of death (LOD) in pts with MPC. Methods: We conducted a retrospective observational analysis of pts treated with chemotherapy for MPC at the Yale Smilow Cancer Hospital and affiliated community care centers (CCC) from January 2011 to April 2019. Patient demographics, treatment dates, initial PCC, enrollment of hospice at the time of death and LOD were manually abstracted from the electronic medical record. Univariate and multivariable logistic regression analyses were conducted to predict for PCC and death outside the hospital. Results: Of 363 pts identified with MPC who received chemotherapy, 38% (138) had a PCC. 67% (93) of patients’ initial PCC was in the hospital versus 33% (45) in the outpatient setting. The median time from the start of first-line chemotherapy to the first PCC was 5.2 months (interquartile range [IQR] 1.2 – 12.9). The median time from the first PCC to death was 1.5 months (IQR 0.5 – 4.42). At the time of our analysis, 300 pts had died and of those 76% (229) were enrolled on hospice at the time of death while 24% (71) were not. With respect to LOD, 47% (139) of pts died at home with hospice, 31% (94) at an inpatient hospice facility and 22% (67) died in the hospital. Female gender was associated with an increased likelihood of a PCC (HR 1.78, 95% CI 1.07-2.94, P = 0.026). Pts treated at a CCC were less likely to have a PCC (HR 0.21, 95% CI 0.12-0.36, P < 0.001). A PCC was not associated with a higher likelihood of death outside the hospital (HR 1.31, 95% CI 0.75-2.29, P = 0.346). Conclusions: Although most pts with MPC enroll in hospice, PCC is generally underutilized. In fact, many pts receive PCC near the end of life and in the hospital. Further studies are warranted to determine how best to incorporate early PCC to maximize supportive care for pts with MPC.

609 Background: While carcinoid and neuroendocrine tumors (NET) can manifest throughout the human body, approximately 2/3 of these tumors arise in the gastrointestinal (GI) tract. Methods: The 2019 version of the National Cancer Database was searched for adult patients with carcinoid or neuroendocrine tumors of the GI tract. Tumor incidence, patient demographics, treatment and cancer variables of GI carcinoid/NETs were compared to other GI cancers. Cox proportional hazards models were used to evaluate overall survival (OS). Results: A total of 101,744 patients were included. Carcinoid/NET incidence varied with primary location, with highest proportion in the small intestine (55.7% of all small intestinal cancers). Compared to other histologies, carcinoid/NETs were more common in younger patients (median age 60 vs. 68years, p < 0.001) and African Americans (18 vs 12%, p < 0.001). Median carcinoid/NET diameter 15mm vs. 40mm for other cancers (p < 0.001). Carcinoid/NETs were diagnosed at lower stages than other histologies (AJCC stage 3/4, 30% vs. 47%, p < 0.001), with most metastases in the liver (8.9%). Stage 1/2 carcinoid/NETs were most often treated by surgical resection with or without concurrent chemotherapy (65%; 22%), whereas stage 3/4 patients received chemotherapy alone or in combination with surgical resection more commonly (39%; 25%). After multivariable adjustment, primary cancer site emerged as an independent prognosticator: longest OS was observed in patients with carcinoid/NET of the small intestines (vs. colonic frame HR = 0.40, 95% CI: 0.37-0.44, p < 0.001). Comparable results were evident in patients with hepatic metastases (small intestines vs. colonic frame carcinoid/NETs; HR = 0.20, 95% CI: 0.17-0.24, p < 0.001). Other independent OS prognosticators were patient age, gender, race and comorbidities, as well as tumor size, stage and treatment. Conclusions: Compared to other GI-associated tumors, carcinoid/NETs are more common in younger patients, African Americans, diagnosed with smaller diameter at low stage. Carcinoid/NETs of the small intestines are associated with improved overall survival compared to other primary disease sites.

769 Background: FOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GN) are established first line (1L) therapies for metastatic pancreatic cancer (MPC) but real-world data on their comparative effectiveness is limited. Methods: All cases of MPC treated with 1L FFX or GN at Yale Smilow Cancer Hospital and the affiliated community care centers (CCC) from January 2011 – April 2019 were reviewed. Patient (pt) demographics, prior therapy, initial and subsequent dose reductions (DR), time to treatment discontinuation (TTD), overall survival (OS), and second line (2L) treatment data were manually abstracted from the electronic medical record. Categorical and continuous variables were compared between 1L FFX and GN cohorts via the Chi-squared and Wilcoxon rank-sum tests. Median OS was calculated by the Kaplan-Meier method. Results: We identified 363 MPC pts treated with 1L FFX or GN; 269 (74%) pts were treated with FFX and 94 (26%) with GN as 1L therapy. 204 (56%) pts were treated at the main campus and 159 (44%) at a CCC. Demographics and baseline characteristics (FFX/GN) were as follows: gender (male) 55% / 41%; race (white) 82% / 77%; age < 76 90% / 71% ( P < 0.001). 332 (91%) of pts received no prior therapy; 21 (6%) had prior surgery plus adjuvant gemcitabine and 10 (3%) had surgery alone. 98% of FFX-treated pts were treated with upfront DR, compared to 78% of GN-treated pts ( P= 0.003). 78% and 53% of FFX-treated and GN-treated pts, respectively, had subsequent DR ( P< 0.001). Median TTD was 4.8 months with FFX and 3.4 months with GN ( P= 0.0029) and the median OS was 11.3 months with FFX versus 7.2 months with GN ( P < 0.0001). After 1L, 33% and 61% of FFX- and GN-treated pts, respectively, received no further chemotherapy ( P< 0.001). Conclusions: In the largest manually abstracted retrospective analysis to date, MPC pts treated with 1L FFX were younger, more likely to receive 2L therapy, and had increased survival compared to pts treated with GN. The OS of pts treated with FFX was similar to the OS reported by Conroy et al despite upfront dose attenuations in 98% of pts. A randomized trial is needed to confirm optimal sequencing of chemotherapy in MPC.

The 2018 Accelerating Anticancer Agent Development (AAADV) Workshop assembled a panel of experts for an in-depth discussion session to present “Challenges with Novel Clinical Trial Designs.” This panel offered assessments of the challenges faced by industry, the FDA, investigators, institutional review boards, and patients. The panel focused on master protocols, which include umbrella trials, platform trials, and basket trials. Umbrella trials and platform trials share many commonalities, whereas basket trials are more distinct. Umbrella and platform trials are generally designed with multiple arms where patients of the same histology or other unifying characteristics are enrolled into different arms and multiple investigational agents are evaluated in a single protocol. In contrast, basket studies generally enroll patients with different tumor types based on the presence of a specific mutation or biomarker regardless of histology; these trials may include expansion cohorts. These novel designs offer the promise of expedited drug assessment and approval, but they also place new challenges on all the stakeholders involved in the drug development process. Only by identifying the challenges of these complex, innovative clinical trial designs and highlighting challenges from each perspective can we begin to address these challenges. The 2018 AAADV Workshop convened a panel of experts from relevant disciplines to highlight the challenges that are created by master protocols, and, where appropriate, offer strategies to address these challenges.

Background: Hyperclustering of death receptor 5 (DR5) and subsequent induction of apoptosis, which normally occurs upon binding of its ligand TRAIL, can be mimicked by agonistic antibodies (Abs). However, clinical efficacy of conventional DR5 Abs has been disappointing. To improve antibody-mediated DR5 clustering on cancer cells, we utilized the HexaBody® antibody technology. This antibody platform is based on the discovery that IgG molecules can organize into hexamers through intermolecular Fc-Fc interactions upon binding to membrane-bound targets. HexaBody molecules are IgG1 Abs with a single point mutation in the Fc domain that enhances hexamerization. HexaBody-DR5/DR5 is a 1:1 mixture of two non-competing anti-DR5 HexaBody molecules that induces potent caspase-dependent apoptosis through hexamer-dependent hyperclustering of DR5 on the cell surface. We previously showed that HexaBody-DR5/DR5 induced superior potency compared to conventional DR5 antibodies in vitro and in vivo. Methods: To obtain preclinical proof-of-concept for targeting specific solid tumors using HexaBody-DR5/DR5, we performed a patient-derived xenograft (PDX) mouse clinical trial (1 mouse per group design) using a large number of colorectal (CRC) (100), gastric (19), urothelial (13), non-small cell lung cancer (NSCLC) (90), and triple-negative breast cancer (TNBC) (20) PDX models. Results: HexaBody-DR5/DR5 showed potent anti-tumor activity (tumor stasis or tumor regression) in a substantial proportion of the CRC (36%), gastric (42%) and urothelial (54%) models. Additional in vivo studies comparing single vs multiple dosing demonstrated that maximal anti-tumor activity was already achieved after a single dose of HexaBody-DR5/DR5. A Phase 1/2 clinical trial to determine the RP2D and assess clinical safety of HexaBody-DR5/DR5 in cancer patients is currently ongoing (NCT03576131), from which a case study will be presented. Conclusions: Potent anti-tumor activity of HexaBody-DR5/DR5 was observed in large and diverse panels of CRC, gastric and urothelial PDX models, providing preclinical rationale for the clinical evaluation of HexaBody-DR5/DR5 in these indications. Citation Format: Marije B Overdijk, Michael Cecchini, Kristin Strumane, Marcel Brandhorst, Andreas Lingnau, Paul W.H.I. Parren, Merete Ellekilde-Pedersen, Ulf Forssmann, Tahamtan Ahmadi, A. Kate Sasser, Janine Schuurman, Esther C.W. Breij, Patricia LoRusso. HexaBody-DR5/DR5 (GEN1029) shows potent preclinical antitumor activity in a variety of patient-derived xenograft (PDX) tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C025. doi:10.1158/1535-7163.TARG-19-C025

272 Background: Expert knowledge is often shared among academic oncologists at tumor boards (TBs) at National Cancer Institute Designated Cancer Centers (NCI-CCs), but not documented or made accessible to community oncologists. Using an oncologist-only question and answer (Q&A) website, we sought to disseminate expert insights from TBs at NCI-CCs to provide educational benefit to the oncology community. Methods: A process was designed with faculty at 11 NCI-CCs to document and share discussions from TBs focused on areas of clinical complexity and practice variation on theMednet.org, an interactive Q&A website of over 8,700 US oncologists. One faculty member from each TB was selected as a site leader. She or he distilled discussions about patient management from the TB into a question that addressed the clinical situation being discussed. After the question was posted, faculty at the participating NCI-CCs were asked to answer the question on theMednet. Answers were peer reviewed, indexed, stored and disseminated via email newsletters to registered oncologists. Community engagement was measured by Q&A page views, upvotes of Q&A, and poll participation. Results: A total of 15 Breast, Thoracic, and Gastrointestinal programs from 11 NCI-CCs participated. Between 12/2016 and 5/2019, faculty highlighted 146 questions from their TBs. Q&A were viewed 43,291 times by 3,585 oncologists including 2,264 community oncologists. One hundred and eighty-four answers are posted by 56 academic physicians and peer reviewed by 76 academic physicians. One hundred and eighty-five publications were cited. Community oncologists upvoted Q&A 808 times and voted in 45 polls related to the questions 1,667 times. Viewership of NCI-CC Q&A increased by 419% over time. Q&A were repeatedly searched and viewed, with 90% of all TB Q&A viewed every month. Conclusions: Via the online Q&A theMednet platform, NCI-CC providers effectively made expert knowledge easily accessible to community oncologists across the US. Timely access to evidence based recommendations from expert faculty can inform future practice choices in the community. [Table: see text]

437 Background: Induction FFX for PC deemed either BR or LA at diagnosis provides an opportunity to downstage pts with the aim of an R0 surgery. The addition of RT after induction FFX may further downstage. However, there is a paucity of data regarding long-term survival for BR and LA patients successfully downstaged and resected. We performed a retrospective review of BR and LA PC treated with induction FFX +/- RT followed by surgery or consolidative RT at the Yale Cancer Center (YCC) to assess survival in these two cohorts. Methods: Clinical data was abstracted for pts with BR or LA PC who had surgery or received consolidative RT without surgery after induction FFX +/- RT at the YCC from 2010-2018. Surgical pts were re-reviewed by a radiologist to assess vascular involvement (BR vs. LA) using NCCN criteria. PFS and OS for surgery and consolidative RT were analyzed by the Kaplan-Meier method. Survival was compared via the log rank test. Results: 102 pts met inclusion criteria (BR=47, LA=55), 41 pts had surgery [BR=29/47 (62%) LA=12/55 (22%)] and 61 pts had consolidative RT [(BR= 18/47 (38%), LA= 43/55 (78%)] after induction FFX. 18 surgery pts received RT prior to resection and all surgery pts had R0 resection. Median follow up was 25 mo (range 5 – 97). Median PFS with surgery was 22 mo (95% CI 15 – 59) vs 14 mo (95% CI 10.9 – 20.1) with consolidative RT (p

630 Background: TAS-102 is an oral combination of the anti-metabolite 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI), preventing the degradation of FTD. It is approved as mCRC monotherapy with improved survival. Oxaliplatin is often reintroduced in mCRC after progressive disease (PD) on maintenance 5-FU although response is poor. The decreased efficacy may be related to acquired 5-FU resistance. We therefore explored the safety and efficacy of oxaliplatin in combination with an alternative and non cross-resistant anti-metabolite, TAS-102. Methods: Phase 1 of TAS-OX is a 3+3 dose-escalating study at a starting dose of TAS-102 25 mg/m2 and oxaliplatin 85 mg/m2 with three dose levels (table). TAS-102 is administered days 1-5 and oxaliplatin day 1, every 2 weeks. Eligible patients previously received 5FU, oxaliplatin, irinotecan, appropriate biologics, had measurable disease, usual laboratory parameters, and ECOG PS 0-1. The primary objective was to determine the recommended phase II dose (RP2D). Results: Twelve patients were evaluable for dose limiting toxicity (DLT). No DLTs were observed. Treatment related grade ≥ 3 AEs were neutropenia (n = 4) and thrombocytopenia (n = 1). No AEs resulted in treatment discontinuation. Two patients (dose levels 2 and 3) required dose reductions for prolonged neutropenia. Median number of cycles for all treated patients was 6 ± 4. The disease control rate (DCR) at 8 weeks was 67%. Best response in all evaluable patients was 1 PR (8%) 7 (59%) SD and 4 (33%) PD. Conclusions: The RP2D of TAS-102 is 35 mg/m2 in combination with oxaliplatin 85 mg/m2. No DLTs were observed and no unexpected AEs were seen. The DCR in this heavily pretreated patient population is encouraging. Phase II is now enrolling at this dose (NCT 02848079). Clinical trial information: NCT02848079. [Table: see text]

Background TAS-102 (trifluridine and tipiracil hydrochloride; a novel combination oral nucleoside anti-tumor agent) has recently received regulatory approval for patients with refractory metastatic colorectal cancer (mCRC). Internal review of data at a single-institution showed a trend towards better overall survival (OS) for patients who experienced chemotherapy-induced neutropenia at 1-month (CIN-1-month). To explore this finding further, a cohort study was designed based on outcome data from three centers in United States and one from Japan. Methods CIN-1-month after starting TAS-102 was defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 as a neutrophil count decrease of ≥ grade 2 (absolute neutrophil count

TPS4137Background: Gastric cancer remains a significant health problem in the US and globally with more than 951,600 annual cases worldwide. Moreover, the incidence of GEJ-centered adenocarcinoma i...

61 Background: Early results from recent studies using immune checkpoint blockade targeting programmed death 1 (PD-1) have suggested that pleomorphic undifferentiated sarcomas may have response rates of over 40%. As of now predictive biomarkers for response and resistance have been incompletely characterized. Methods: A 58-year-old man who received radiation for a head and neck squamous cell cancer, developed a radiation-induced undifferentiated pleomorphic sarcoma (UPS) in his neck in 2014. His sarcoma was resected but recurred in 2015. He received adjuvant radiation after surgical debulking in September 2015 and was found on radiation simulation scan to have new widespread metastatic disease involving liver, lung, and bone. He started treatment on nivolumab in November 2015 and has had a sustained near complete response in all lesions. Results: All sites had a near complete response to nivolumab treatment. Pre treatment tissue analysis revealed no mutations or amplifications in 134 cancer-related genes, on the Oncomine Assay (Life Technologies, Inc.). Normal tissue was noted to be heterozygous for BRCA2 N372H, while the allelic fraction of the 372H variant in the tumor was found to be 85%. Programmed death ligand-1 (PDL-1) immunohistochemistry staining of the tumor tissue was negative. Tumor infiltrating lymphocytes were not noted in the tumor tissue specimen. Conclusions: This patient exhibited a near complete response to all sites of disease, with remaining PET avidity in a single hilar node. The role of the BRCA2 variant and radiation just prior to starting nivolumab is unknown. BRCA2 N372H is a common single nucleotide polymorphism (SNP) in the population with a minor allele frequency of 0.25. Although the effect of the 372H variant on BRCA2 protein structure is predicted to be minimal, population studies have suggested a slightly increased risk of breast and ovarian cancer in homozygotes. It is possible that the radiation treatment to the site of recurrence in the head and neck, resulted in an abscopal effect enhancing the therapeutic effect of nivolumab therapy. Additional testing on his tissue is being done to further investigate the response.

e15124Background: TAS-102 (tri-fluoro-thymidine and tipiracil hydrochloride; a novel combination oral nucleoside anti-tumour agent) was recently approved for patients with refractory metastatic col...

e18188Background: Multidisciplinary tumor board (MTB) meetings have become a standard for evidence based decision making at medical centers worldwide. We believe that the expertise at subspecialty ...

Metastatic melanoma is frequently treated with immune activating therapy, which poses a theoretical risk of inducing graft versus host disease (GVHD) in those who have received allogeneic stem cell transplantation. The literature reporting the safety of immunotherapy in post transplant patients is limited. We report two patients with metastatic melanoma who received treatment with immunotherapy after allogeneic stem cell transplantation that did not result in GVHD.