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Purpose Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab is a fully human IgG2 antibody that inhibits Notch2/3 receptors. Patients and methods Aphase 2, randomized, placebo-controlled, multicenter trial evaluated the activity of tarextumab in combination with nab-paclitaxel and gemcitabine in patients with metastatic PDAC. Patients were stratified based on ECOG performance score and Ca 19-9 level and randomized 1:1 to nab-paclitaxel, gemcitabine with either tarextumab or placebo. Based on preclinical and phase Ib results suggesting a positive correlation between Notch3 gene expression and tarextumab anti-tumor activity, patients were also divided into subgroups of low, intermediate, and high Notch3 gene expression. Primary endpoint was overall survival (OS) in all and in patients with the three Notch3 gene expression subgroups (≥25th, ≥50% and ≥75% percentiles); secondary end points included progression-free survival (PFS), 12-month OS, overall response rate (ORR), and safety and biomarker investigation. Results Median OS was 6.4 months in the tarextumab group vs 7.9 months in the placebo group (HR = 1.34 [95% CI = 0.95, 1.89], P = .0985). No difference observed in OS in the Notch3 gene expression subgroups. PFS in the tarextumab-treated group (3.7 months) was significantly shorter compared with the placebo group (5.5 months) (hazard ratio was 1.43 [95% CI = 1.01, 2.01]; P = .04). Grade 3 diarrhea and thrombocytopenia were more common in the tarextumab group. Conclusions The addition of tarextumab to nab-paclitaxel and gemcitabine did not improve OS, PFS, or ORR in first-line metastatic PDAC, and PFS was specifically statistically worse in the tarextumab-treated patients. Clinical trial registry no NCT01647828.

Background:18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) imaging is not routine in patients with localized pancreatic cancer (PC). We evaluated the prognostic value of PET/CT in patients who received neoadjuvant therapy.Methods: Patients with localized PC underwent pretreatment PET/CT with or without posttreatment (preop) PET/CT. Maximum standardized uptake values (SUV) were classified as high or low based on a cut point of 7.5 at diagnosis (SUVdx) and 3.5 after neoadjuvant therapy (preoperative; SUVpreop). Preop carbohydrate antigen 19-9 (CA19-9) was classified as normal ( ≤ 35 U/mL) or elevated.Results: Pretreatment PET/CT imaging was performed on 201 consecutive patients; SUVdx was high in 98 (49%) and low in 103 (51%). Preop PET/CT was available in 104 (52%) of the 201 patients; SUVpreop was high in 60 (58%) and low in 44 (42%). Following neoadjuvant therapy, preop CA19-9 was normal in 90 (45%) patients and elevated in 111 (55%). Median overall survival (OS) of all patients was 27 months; 33 months for the 103 patients with a low SUVdx and 22 months for the 98 patients with a high SUVdx (p = 0.03). Median OS for patients with low SUVdx/normal preop CA19-9, high SUVdx/normal preop CA19-9, low SUVdx/elevated preop CA19-9, and high SUVdx/elevated preop CA19-9 were 66, 34, 23, and 17 months, respectively (p < 0.0001). OS was 44 months for the 148 (74%) patients who completed all intended neoadjuvant therapy and surgery and 13 months for the 53 (26%) who did not undergo surgery (p < 0.001).Conclusion: Pretreatment PET/CT avidity and preop CA19-9 are clinically significant prognostic markers in patients with PC.

Background More than 70% of patients with localized pancreatic cancer treated with upfront surgery develop disease recurrence. Herein we describe the radiographic patterns and timing of disease recurrence after neoadjuvant therapy and surgery in patients with pancreatic cancer. Methods Radiographic patterns of first disease recurrence were examined in patients with localized pancreatic cancer who completed neoadjuvant therapy and surgery. Disease recurrence was classified as local (pancreas, resection bed, or peripancreatic vasculature); regional (peritoneum or abdominal wall); or distant (liver, lung, bone). Progression-free survival was calculated from the date of diagnosis to the date of recurrence. Results Of 306 consecutive patients who completed neoadjuvant therapy and surgery, 149 (49%) had resectable pancreatic cancer and 157 (51%) had borderline resectable disease. Neoadjuvant therapy consisted of chemoradiation (32%), chemotherapy (14%), or both therapies (54%). Overall, primary therapy (including preoperative and postoperative therapy) consisted of chemoradiation alone in 29 (9%), chemotherapy alone in 14 (5%), and both therapies in 263 (86%) patients. At a median follow-up of 27 months, 186 (61%) of the 306 patients had recurrent pancreatic cancer. Sites of first recurrence were local-only in 29 (9%), regional-only in 19 (6%), distant-only in 87 (28%), and multisite in 51 (17%). The overall median progression-free survival for all patients was 24 months. Neoadjuvant chemoradiation reduced the odds of local-only recurrence (odds ratio: 0.21; 95% confidence interval: 0.06–0.77; P = .02). Conclusion After neoadjuvant therapy and surgery, 9% of patients were found to have local-only recurrence. Treatment sequencing that incorporates neoadjuvant chemoradiation may improve local disease control.

576 Background: Stromal HA poses a physical barrier and protects tumor cells from immune surveillance. PEGPH20 is a pegylated, human recombinant PH20 hyaluronidase that remodels tumor stroma. Preclinical studies of PEGPH20 showed improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies. This study aimed to evaluate the efficacy, safety, and translational biomarkers of PEGPH20 plus pembrolizumab in pts with HA-high refractory mPC. Methods: mPC pts with HA-high expression, ECOG PS 0-1, ≤ 2 prior therapies for metastatic disease, life expectancy ≥ 12 weeks were treated with PEGPH20 3 µg/kg iv on D1, D8, D15 and pembrolizumab 200 mg iv on D1 in 21-day cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, overall survival (OS), and objective response rate (ORR). Blood and tumor biopsies were collected at baseline and on-study. Translational endpoints included flow cytometry and IHC for immune subsets, T-cell receptor sequencing, immune transcriptome, circulating cytokines, and plasma and tumor HA levels. Assuming a one-sided α-level of 0.05 and power of 80%, 31 evaluable pts were needed to detect an improvement of median PFS from 3 to 6 months. Results: Between May 2019 to Nov 2019, 38 pts were screened for HA expression, and 8 pts were enrolled, with median age 68 years (range 60-73), 7 males, and median 2 prior therapies (range 1-4). The accrual was stopped early by Halozyme Pharmaceuticals due to lack of benefit from PEGPH20 added to chemotherapy in the HALO-301 study. Treatment exposure median was 2 cycles (range 1-6). Reasons for study discontinuation were disease progression (n = 4), termination by sponsor (n = 3), patient withdrawal to enroll in hospice (n = 1). Treatment related toxicities were musculoskeletal (n = 6, grade 1/2), edema (n = 2, grade 1), fatigue (n = 1, grade 3), dyspnea (n = 1, grade 2), hypothyroidism (n = 1, grade 2). Median OS was 7.2 months (95% CI 1.2-11.8), and median PFS was 1.5 months (95% CI 0.9-4.4). Best response was stable disease (n = 2, 25%) lasting 2.2 and 9 months, respectively, and no responses were noted. Patients with available molecular sequencing data had MSS tumors. Translational biomarkers will be presented. Conclusions: Pembrolizumab and PEGPH20 did not increase PFS compared to historical data among heavily pretreated mPC pts, but the median OS of 7.2 months is encouraging. Translational analyses will provide insights into immune modulatory effects from PEGPH20 that could inform future studies with stroma targeted therapies and immune checkpoint blockade in mPC. Clinical trial information: NCT03634332.

Background Patients with locally advanced pancreatic cancer have historically been considered inoperable. The purpose of this report was to determine resectability rates for patients with locally advanced pancreatic cancer based on our recently described definitions of type A and type B locally advanced pancreatic cancer. Methods An institutional prospective pancreas cancer database was queried for consecutive patients with locally advanced pancreatic cancer treated between January 2009 and June 2017. All pretreatment imaging was re-reviewed and patients were categorized as locally advanced pancreatic cancer type A or type B. Demographics, induction therapy, resection type, and outcomes were reviewed. Results We identified 108 consecutive patients; 12 were excluded from analysis due to the absence of available pretreatment imaging or they had not yet completed all intended neoadjuvant therapy. Of the remaining 96 patients (45 type A, 51 type B), disease progression occurred in 19 (20%) during induction therapy and 30 (31%) were deemed inoperable at final preoperative restaging. Therefore, 47 (49%) of 96 patients were taken to surgery and 40 (42%) underwent successful resection (28 [62%] of 45 type A and 12 [24%] of 51 type B); an RO resection was achieved in 32 (80%). Metastatic disease was found intraoperatively (6 at laparoscopy, 1 at laparotomy) in 7 (15%) of 47 patients. There were no mortalities; 6 (15%) patients experienced major postoperative complications. Resected patients had a median overall survival of 38.9 months. Conclusion Locally advanced pancreatic cancer can be dichotomized into type A and B with distinctly different probabilities of completing all therapy to include surgery; thereby allowing goals of therapy to be established at the time of diagnosis. Multimodality therapy that includes surgery can be accomplished in selected patients with locally advanced pancreatic cancer and is associated with a median overall survival that approximates earlier stages of disease. (Surgery 2017;160:XXX-XXX.)

Background Current guidelines recommend genetic testing for all patients with pancreatic cancer (PC). Methods Patients with localized PC who received neoadjuvant therapy between 2009 and 2018 were identified. Genetic consultation (including personal and family history of cancer), genetic testing, and variant data were abstracted. Results Of 510 patients identified, 163 (32%) underwent genetic counseling and genetic testing was performed in 127 (25%). Patients who underwent genetic testing were younger (median age: 63 vs. 67, p = 0.01). Multi-gene testing was performed in 114 (90%) of 127 patients, targeted gene testing was performed in 8 (6%), and not specified in 5 (4%). Of 127 patients who underwent genetic testing, 20 (16%) had pathogenic (P)/likely pathogenic (LP) variants, observed in ATM (n = 7/105,7%), CHEK2 (n = 3/98, 3%), BRCA1 (n = 2/117, 2%), BRCA2 (n = 2/122, 2%), PALB2 (n = 1/115, 1%), MUTYH (n = 1/98, 1%), CDKN2A (n = 1/94, 1%), STK11 (n = 1/97, 1%), NBN (n = 1/98, 1%), and MSH6 (n = 1/97, 1%). Of 20 patients with either a P/LP variant, nine (45%) had a prior cancer, three (15%) had a first-degree relative with PC, and six (30%) had an any-degree relative with PC. Conclusion Pathogenic/likely pathogenic variants were identified in 16% of patients who underwent genetic testing, 60% of which occurred in the homologous recombination pathway.

Tumor profiling can improve the selection of oncologic therapies in patients with pancreatic cancer (PC). The impact of neoadjuvant therapy on tumor testing is unknown. Molecular profiling using commercially available 53-, 315-, or 472-gene next generation sequencing (NGS) panels was performed on surgical specimens following neoadjuvant therapy. All specimens with 472-gene sequencing also had immunohistochemical (IHC) testing. Treatment recommendations were based on somatic variants and IHC staining. NGS was performed on 74 patient specimens: 42 (57%) with a 472-gene panel, 28 (38%) with a 315-gene panel, 3 (4%) had 472- and 315-gene panels, and 1 (1%) patient had 53- and 472-gene panels (78 total tests). Likely pathogenic/pathogenic variants were identified in 73 (94%) of the 78 tests. Of the 73 samples with variants identified, 13 (18%) variants were associated with an actionable treatment: ATM (n = 10), BRCA1 (n = 1), PIK3CA (n = 1), and BRCA2 (n = 1). No patient had more than one actionable variant. Based on NGS results, the most commonly recommended therapy was a platinum agent (n = 12/78, 15%). Of the 46 specimens that underwent IHC analysis, overlapping chemotherapeutic treatment recommendations were identified in 40 (87%) specimens. Using current multigene NGS panels, actionable variants were identified in 13 (18%) of 74 surgical specimens and primarily involved genes of the DNA repair pathway. Anecdotal reproducibility of test concordance was low.

Background It is difficult to successfully deliver multimodality therapy to patients with operable pancreatic cancer. Data on the natural history of such efforts are necessary for physicians to guide shared decision-making with patients and families. We report the survival of consecutive patients with borderline resectable pancreatic cancer who received neoadjuvant therapy before surgery. Methods Data regarding demographics, neoadjuvant therapy, surgery, pathology, and survival duration were abstracted on consecutive patients with borderline resectable pancreatic cancer diagnosed between 2009 and 2017 and not treated on available clinical trials. Borderline resectable pancreatic cancer was defined based on ≥1 of the following: local tumor anatomy, pretreatment serum carbohydrate antigen 19-9 >2,000 U/mL, and the presence of radiographic lesions indeterminate for metastases. Results Neoadjuvant therapy was delivered to 185 patients with borderline resectable pancreatic cancer who were not enrolled in competing clinical trials; 13 (7%) patients received chemoradiation, 12 (7%) received chemotherapy, and 160 (86%) received both. Of the 185 patients, 115 (62%) completed all intended neoadjuvant therapy and surgery; 81 (70%) of 115 underwent pancreaticoduodenectomy; and vascular reconstruction was performed in 51 (44%). A margin negative resection was achieved in 111 (97%) of 115 patients, and 83 (72%) were node negative. Median overall survival for all 185 patients was 20 months; 31 months for the 115 patients who completed all neoadjuvant therapy and surgery as compared to 13 months for the 70 patients who were not resected ( P 0001). Conclusion After neoadjuvant therapy, surgical resection was performed in 62% of patients with borderline resectable pancreatic cancer. Those who normalized preoperative serum carbohydrate antigen 19-9 and had node negative pathology achieved the longest survival. To further improve median survival for all patients, we are incorporating adaptive approaches to neoadjuvant therapy sequencing based on objective assessments of response.

Background Enthusiasm for neoadjuvant therapy is growing from the emerging consensus that pancreatic cancer is a systemic disease at the time of diagnosis. Those who remain in favor of upfront surgery often cite the lack of reported data to support alternative treatment sequencing. We therefore report the results of all patients treated outside of a clinical trial under the direction of a multidisciplinary pancreatic cancer working group. Methods We reviewed all patients with resectable pancreatic cancer treated with neoadjuvant therapy (NeoTx) from 2009 to 2013; we excluded those patients treated on prospective clinical trials as they will be the subject of subsequent reports. Data regarding demographics, NeoTx, operative outcomes, pathology, and survival data were abstracted from a prospective database. Results NeoTx was initiated in 69 patients; median age was 65 years (interquartile range [IQR]: 11) and median carbohydrate antigen 19-9 at diagnosis was 96.5 (IQR 210). NeoTx consisted of chemotherapy alone ( n = 10, 14%), chemotherapy and radiation (chemoradiation, n = 53, 77%), or both ( n = 6, 9%). Median carbohydrate antigen 19-9 after NeoTx was 39 (IQR 104) corresponding to a median decrease of 60%. Operative resection was completed in 60 (87%) of the 69 patients. At restaging after NeoTx, 5 (7%) of 69 patients were not considered candidates for surgery because of the development of metastatic disease ( n = 4) or an inadequate performance status ( n = 1). At the time of surgery, 4 (6%) of 64 patients had metastatic disease found at laparoscopy. Of the 60 patients who underwent surgical resection, a complete pathologic response was observed in 2 (3%) patients; 20 (33%) had positive lymph nodes, and the median number of positive lymph nodes was 2 (IQR 3). R0 resections were achieved in 58 (97%) of the 60 patients. Additional postoperative adjuvant therapy was administered to 37 (62%) of the 60 patients. Median survival of all 69 patients was 31.5 months; 44.9 months for the 60 patients who completed all NeoTx and resection compared with 8.1 months for the 9 patients who were not resected (log rank P Conclusion NeoTx for resectable pancreatic cancer was associated with a median overall survival of 32 months; something not reported for patients treated with surgery first if based on intent-to-treat analysis. Treatment sequencing may provide an oncologic benefit beyond that of the selection bias afforded surgery after a period of induction therapy.

The majority of patients with localized pancreatic cancer (PC) who undergo surgery followed by adjuvant therapy will develop metastatic disease, suggesting that surgery alone is not sufficient for cure and micrometastases are present even when are not clinically detected. As such, the delivery of early systemic therapy may be a rational alternative to a surgery-first approach, in an effort to provide oncologic therapies which are commensurate with the disease stage, and improve surgical selection. This review details the rationale for a neoadjuvant approach to localized PC and provides specific recommendations for both pretreatment staging and treatment sequencing for patients with resectable and borderline resectable PC.

Treatment sequencing in older patients is difficult because of concomitant comorbidities and often decreasing performance status. The present study sought to examine the effect of neoadjuvant therapy and pancreatic surgery in older patients with resectable or borderline-resectable (BLR pancreatic cancer (PC).Patients with resectable or BLR PC treated with neoadjuvant therapy were classified as older (≥ 75 years) or younger (75 years).Neoadjuvant therapy was initiated in 246 patients; 210 (85%) younger than 75 years and 36 (15%) older. Older patients had a greater median Charlson comorbidity index (CCI): 6 vs 4 (P.01). Completion of all intended therapy (neoadjuvant therapy and surgery) occurred in 177 (72%) of the 246 patients; 153 (73%) of the 210 younger and 24 (67%) of the 36 older patients (P = .43). Failure to complete all therapy was associated with BLR clinical stage (odds ratio [OR] 0.26, P = .001), increased posttreatment/preoperative serum levels of CA19-9 (OR 0.27, 95% confidence interval 0.14-0.53), and CCI ≥ 6 (OR 0.44, 95% confidence interval 0.22-0.86). Median overall survival for all study patients was 26.1 and 19.7 months (P = .13) for younger and older patients, respectively. Of the 177 patients who completed all therapy, the difference in survival between younger and older patients was not statistically significant (36.5 months vs 27.2 months, P = .47).Failure to complete neoadjuvant therapy and eventual pancreatic resection is associated with BLR stage, increased posttreatment/preoperative CA19-9, and CCI ≥ 6, but not older age. Older patients who completed neoadjuvant therapy and underwent resection experienced a survival benefit compared with those who did not complete all intended therapy. Balancing the toxicity of sequential therapies with their cumulative effect on tolerance and risk for pancreatic surgery will be the key to developing optimal treatment sequencing in older patients with PC.

4050 Background: Somatic mutations in KRAS, HRAS, NRAS (extended RAS) and BRAF have prognostic and predictive impact in pts with mCRC. We analyzed the prognostic impact of specific somatic mutations in extended RAS and BRAF. Methods: We retrospectively reviewed the electronic medical records of pts with mCRC at our institution who underwent comprehensive genomic profiling (CGP) utilizing the Foundation One assay. DNA was extracted from clinical specimens and CGP was performed on hybrid-capture, adaptor ligation-based libraries for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. BRAF mutations were classified as class I, II and III according to accepted nomenclature. Fisher’s exact test and Kaplan Meier estimates were used for statistical analyses. This project was approved by the Medical College of Wisconsin Institutional Review Board. Results: 273 pts were identified - median age at diagnosis was 57, 48% were male. Somatic mutations in extended RAS were found in 138 (50%) pts, majority being mutations in KRAS (46%). Among pts with KRAS mutations, codon 12, 13, 61 and 146 mutations accounted for 73%, 11%, 4% and 6% respectively while KRAS G12C mutations accounted for 9%. BRAF mutations were detected in 22 (8%) pts - BRAF V600E and non–V600E mutations accounting for 4.4% and 3.6% respectively. Among pts with BRAF mutations, 17 (77%) were kinase domain mutations, 16 of which could be further classified as class I (12/16), II (1/16) and III (3/16). Median overall survival (mOS) for the entire cohort was 26.4 months (mo). KRAS mutated pts had a mOS of 25.8 mo; pts with KRAS G12C mutation had a mOS of 23 mo compared to 27.1 mo for pts with other KRAS mutations (p < 0.001).Pts with BRAF mutation had a mOS of 26.2 mo; pts with BRAF V600E mutation had a mOS of 14.1 mo compared to 30.6 mo for pts with BRAF non-V600E mutations (p = 0.1). Conclusions: The poor prognosis of pts with KRAS G12C and BRAF V600E mutations compared to pts with other KRAS and BRAF mutations merit further biologic characterization with functional assays. Individualized therapeutic strategies must be conceptualized for mCRC pts with specific RAS/BRAF mutations, considering their widely disparate prognosis and putative downstream signaling mechanisms. Dynamic molecular simulation to understand conformational changes in proteins associated with specific mutations will be pivotal to optimizing precision therapeutic strategies.

TPS785 Background: PDA is characterized by invasiveness and therapeutic resistance in part due to a desmoplastic stroma and an immunosuppressive microenvironment ( Provenzano PP, Hingorani S. Br J Cancer 2013). PD1/PD-L1 inhibitors have no single agent activity in PDA, except for pts with mismatch repair defects. There is high need to overcome resistance to immune targeted therapies and develop biomarkers for pts selection. Stromal HA poses a physical barrier and protects tumor cells from immune surveillance ( Kultti A, et al Biomed Res Int 2014). By remodeling the tumor stroma, PEGPH20 allows infiltration of cytotoxic T lymphocytes, and improves delivery of chemotherapy and PD1/PD-L1 antibodies ( Singha NC, et al Mol Cancer Ther 2015). mPDA pts refractory to 1st line therapy have median overall survival (OS) of 6 mos. We hypothesize that stroma remodeling with PEGPH20 sensitizes PDA to immune therapy, and stroma and immunologic biomarkers will identify pts most likely to benefit. In this trial we will evaluate the efficacy, safety and translational biomarkers of PEGPH20 plus pembrolizumab in HA-high refractory mPDA. Methods: Eligible pts have ECOG PS 0-1, ≤ 2 prior therapies for mPDA, life expectancy ≥ 12 wks, able/willing to have tumor biopsies at baseline and after 6 wks of treatment. PEGPH20 dosing is 3 µg/kg iv QW and pembrolizumab 200 mg iv Q3W (2-4 hrs after PEGPH20 on wk 1) in 3-wk cycles. All pts receive prophylactic low molecular weight heparin. Primary endpoint: progression-free survival (PFS). Secondary endpoints: safety, OS, response rates. Translational endpoints: flow cytometry of peripheral and intratumoral immune cells, T-cell receptor sequencing, immune transcriptome, immune subsets IHC, circulating cytokines, serial plasma and tumor HA levels. For the primary endpoint of PFS, with a sample size of 31 evaluable pts, a one-sided α-level of 0.05, assuming 12 mos of accrual and 6 mos of follow-up, this study has 80% power to detect a difference between the null hypothesis median PFS 3 mos, versus the alternative hypothesis median PFS 6 mos. The study was activated in May 2019 and is open to accrual; 6 pts were enrolled as of 24Sept 2019. Clinical trial information: NCT03634332.

759 Background: PC is a lethal disease with limited treatment options. We utilized Comprehensive Genomic Profiling (CGP) to identify putative prognostic and/or predictive biomarkers. Methods: We retrospectively reviewed PC patients (pts) at our institution who underwent CGP utilizing the Foundation One assay. CGP was performed on hybrid-capture, adaptor ligation-based libraries for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. PC pts were categorized by clinical stage – localized (resectable and borderline resectable PC; LPC), locally advanced (LAPC) and metastatic (mPC). Effect of gene alterations (GAs) with at least 10% prevalence were analyzed. The marginal effect of each gene on radiographic response and survival outcomes was estimated using proportional odds and multivariate Cox regression analysis, respectively, adjusting for stage. Results: Ninety-three pts were identified - median age was 63, 55% were male, and 50% were smokers. Clinical stage at diagnosis was LPC, LAPC and mPC in 42 (45%), 23 (25%) and 28 (30%) pts, respectively. The most commonly altered genes were KRAS (94%), TP53 (75%), CDKN2A (41.2%) and SMAD4 (32.9%). All patients were microsatellite stable and the median tumor mutational burden was 1.7. 5-FU (52%) or Gemcitabine (46%) based chemotherapy combinations were utilized as the first systemic therapy. Median overall survival for patients with LPC, LAPC and mPC were 30.7, 28.8 and 9.6 months respectively. Thirty-eight (91%) pts with LPC underwent curative intent surgery compared to 15 (65%) pts with LAPC (p = 0.019). Thirty-five (95%) pts with wild type (WT) CDKN2A and 47 (94%) pts with WT CDKN2B underwent curative intent surgery compared to 13 (65%) and 1(14%) pt(s) with GAs in CDKN2A and CDKN2B respectively (p = 0.003 and p < 0.0001 respectively). The response to chemotherapy was statistically significantly higher in pts with WT CDKN2A (53%) and CDKN2B (48%) compared to pts with GAs in CDKN2A (19%) and CDKN2B (12%) (p = 0.03 and p = 0.05, respectively). Conclusions: GAs in CDKN2A/B may have a predictive and possibly a prognostic impact. The clinical validity and biological relevance of these findings need to be further explored in larger studies.

Objectives One facet of precision medicine is the use of tumor molecular profiling to guide chemotherapeutic selection. We conducted the first prospective clinical trial of molecular profiling to guide neoadjuvant therapy in patients with operable pancreatic ductal adenocarcinoma (PDAC). We hypothesized that more effective systemic therapy would prevent disease progression during neoadjuvant therapy and, therefore, allow more patients to undergo surgery. Methods In patients with resectable and borderline resectable (BLR) PDAC, molecular profiling consisted of immunocytochemical staining of pretreatment endoscopic ultrasound-guided fine needle aspiration tumor biopsies using 6 biomarkers. Neoadjuvant systemic therapy was selected based on the molecular profiling results. The primary endpoint was the completion of all intended neoadjuvant therapy and surgery. Results The trial enrolled 130 patients; 61 (47%) resectable and 69 (53%) BLR. Molecular profiling was reported within a median of 5 business days (IQR: 3). Of the 130 patient samples, 95 (73%) had adequate cellularity for molecular profiling and 92 (71%) patients received molecular profile-directed therapy. Of the 92 patients who had predictive profiling, 74 (80%) received fluoropyrimidine-based therapy and 18 (20%) received gemcitabine-based therapies. Of the 130 patients, 107 (82%) completed all intended neoadjuvant therapy and surgery; 56 (92%) of the 61 with resectable PDAC and 51 (74%) of 69 with BLR PDAC. Conclusions We report the first prospective clinical trial that utilized molecular profiling to select neoadjuvant therapy in patients with operable PDAC. Such high resectability rates have not been observed in prior neoadjuvant trials, suggesting that molecular profiling may improve the efficacy of chemotherapy in these patients.

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

Purpose Docetaxel, cisplatin, and fluorouracil (DCF) is a standard first-line three-drug chemotherapy regimen for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and is associated with significant toxicity. We examined the safety and efficacy of a modified DCF (mDCF) regimen in a randomized multicenter phase II study. Patients and Methods Previously untreated patients with metastatic gastric or GEJ adenocarcinoma were randomly assigned to receive either mDCF (fluorouracil 2,000 mg/m2 intravenously [IV] over 48 hours, docetaxel 40 mg/m2 IV on day 1, cisplatin 40 mg/m2 IV on day 3, every 2 weeks) or parent DCF (docetaxel 75 mg/m2, cisplatin 75 mg/m2, and fluorouracil 750 mg/m2 IV over 5 days with granulocyte colony-stimulating factor, every 3 weeks). The study had 90% power to differentiate between 6-month progression-free survival of 26% and 43%, with type I and II error rates of 10% each. An early stopping rule for toxicity was included, defined as grade 3 to 4 adverse event rate > 70% in the first 3 months. Results From November 2006 to June 2010, 85 evaluable patients were enrolled (male, n = 61; female, n = 24; median age, 58 years; Karnofsky performance status, 90%; GEJ, n = 28; gastric, 57). mDCF (n = 54) toxicity rates included 54% grade 3 to 4 toxicity (22% hospitalized) within the first 3 months and 76% grade 3 to 4 toxicity over the course of treatment. The DCF arm (n = 31) closed early because of toxicity, with rates of 71% grade 3 to 4 toxicity (52% hospitalized) within 3 months and 90% grade 3 to 4 toxicity over the course of treatment. Six-month PFS was 63% (95% CI, 48% to 75%) for mDCF and 53% (95% CI, 34% to 69%) for DCF. Median overall survival was improved for mDCF (18.8 v 12.6 months; P = .007). Conclusion mDCF is less toxic than parent DCF, even when supported with growth factors, and is associated with improved efficacy. mDCF should be considered a standard first-line option for patients with metastatic gastric or GEJ adenocarcinoma.

Among patients with localized pancreatic cancer (PC), the benefit of adjuvant therapy after neoadjuvant therapy and surgery is unknown. Patients with localized PC who completed all intended neoadjuvant therapy and surgery were categorized based on the receipt of adjuvant therapy and by pathologic lymph node status (LN−/LN+). Data was available from 234 consecutive patients, 121 (52%) with resectable and 113 (48%) with borderline resectable PC. Of the 234 patients, 92 (39%) were LN+ and 142 (61%) were LN−. The median overall survival (OS) for the 234 patients was 39 months, 42.3 months for patients who received any adjuvant therapy and 34.1 months for those who did not (p = 0.29). Of the 92 LN+ patients, the median OS with and without adjuvant therapy was 29.5 and 23.2 months, respectively (p = 0.02). Of the142 LN− patients, the median OS was 45 months with or without adjuvant therapy (p = 0.86). In an adjusted hazard model, additional adjuvant therapy had a significant protective effect among LN+ patients (HR 0.39; 95% CI 0.21–0.70; p = 0.002) but not in LN− patients (HR 0.89; 95% CI 0.53–1.52; p = 0.68). Among patients with localized PC who received neoadjuvant therapy and surgery, the benefit of adjuvant therapy was limited to those with node-positive disease.

Upper abdominal irradiation for pancreatic cancer is administered in close proximity to the radiation-sensitive kidneys. There is difficulty in defining dose-volume parameters to predict late renal toxicity after partial kidney irradiation. Less than 10% of the general population is estimated to have asymmetrical kidney function; however, there are no studies that examine this in patients with pancreatic cancer. The primary purpose of this study was to determine the prevalence of asymmetrical kidney function in patients with pancreatic cancer. A secondary aim was to determine if asymmetrical kidney function was associated with abnormal laboratory values or kidney size on computed tomography scans. Finally, we aimed to develop recommendations for when a functional renal scan in patients with pancreatic cancer should be ordered.We performed a retrospective review of patients with resectable, borderline resectable, and locally advanced pancreatic cancer who received abdominal radiation therapy and had preradiation functional renal scans between 2009 and 2015. Asymmetrical kidney function was defined as a difference between the 2 kidneys that was ≥60%/40% on a functional renal scan. Serum studies (blood urea nitrogen [BUN], creatinine [Cr], and glomerular filtration rate [GFR]) and abdominal computed tomography scans were routinely obtained before simulation.Of the 204 patients examined, 23 (11.2%) had asymmetrical kidney function that was identified on preradiation functional renal scans. Elevated Cr or BUN, a GFR60, or a medical history that suggested abnormal renal function were not significantly associated with asymmetrical kidney function. Only 6 of 23 patients (26%) with asymmetrical kidney function had a notable difference in kidney size.In our series, approximately 11% of patients with pancreatic cancer have asymmetrical kidney function that was not identified by kidney size, serum BUN, Cr, GFR, or a significant medical history. These data suggest that in cases in which renal radiation doses exceed a V18 of 20% to 30% or there is concern about baseline renal function, a functional renal scan should be considered.

Introduction: Systemic chemotherapy plays a pivotal role in the treatment of localized and metastatic GEJ CA patients (pts), however, there are no reliable predictive biomarkers. CGP is increasingly used to guide selection of targeted therapies, but its role in personalizing cytotoxic chemotherapy is not clear. We investigated the correlation between somatic alterations (SAs) and clinical outcome in pts with GEJ CA treated with cytotoxic chemotherapy. Methods: Medical records of all patients with GEJ CA who had CGP data available were retrospectively reviewed under an IRB approved protocol. DNA was extracted from formalin fixed paraffin embedded clinical specimens and CGP was performed on hybrid-capture, adaptor ligation-based libraries to a mean coverage depth of >600 unique reads utilizing the Foundation Medicine platform (315 gene panel). The effect of the SAs and clinical covariates on response and survival outcomes were modeled using logistic and Cox regression analyses, respectively. Lasso was used for model selection, with the penalty parameter chosen as providing the lowest error-rate via 5-fold cross-validation. Results: Fifty-six patients were identified; median age was 62.5, 51(91%) were male, 39 (70%) had metastatic disease, histology was adenocarcinoma in 41 (73%) and ERBB2 amplification was detected in 11 pts (22%). Median tumor mutational burden (TMB) was 6.1 (0.9-75.7) and one patient had a microsatellite unstable tumor. 46 (82%) pts received a platinum-based combination as first line therapy, mfolfox6 was the most commonly utilized regimen (30%). Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) were noted in 3 (5.6%), 34 (63.0%), 5 (9.3%) and 12 (22.2%) pts, respectively. Median progression free survival (PFS) and OS was 31.3 and 72.8 months, respectively for patients with localized GEJ CA, while median PFS and OS were 6.3 and 18.7 months, respectively for patients with metastatic GEJ CA. On multivariate analysis, in addition to stage, SA in SPTA1 correlated with improved response (p=0.0026, OR=0.052, 95% CI 0.002-0.378), while SAs in PIK3CG (p = 0.016; HR=-6.7, 95% CI 1.26-30.46) and EGFR (p = 0.041; HR=3.6; 95% CI 0.9-11.8) correlated with worse overall survival (OS). Conclusion: We were able to identify SAs that correlated with objective response and survival, however, confirmatory analyses in larger datasets and prospective validation is necessary. The negative prognostic effect of SAs in PIK3CG and EGFR merit further exploration, considering their viability as therapeutic targets. Robust, quantitative and systematic somatic analysis of pre-treatment biopsies, pathway-network analysis and correlation with clinical outcome are essential to gaining mechanistic insights and maximizing therapeutic impact. Citation Format: Vidya Kollu, Arun Singhavi, Paul S. Ritch, James P. Thomas, Aniko Szabo, Ben George. Not all tumors are created equal: Evaluating the impact of comprehensive genomic profiling (CGP) on clinical outcomes in esophageal/gastroesophageal cancer (GEJ CA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4931.

Background Vascular resection/reconstruction at the time of pancreatectomy is performed when limited vascular involvement is the only barrier to complete resection. Splenic vein (SV) ligation facilitates resection/reconstruction of the superior mesenteric vein (SMV)–portal vein (PV) confluence and widely exposes the superior mesenteric artery and celiac origin. If the inferior mesenteric vein does not provide for retrograde decompression, SV ligation may result in sinistral portal hypertension; creation of a distal splenorenal shunt (DSRS) can prevent this complication. Additional complexity occurs in the setting of cavernous transformation of the PV. A mesocaval shunt (MCS) can be utilized to temporarily divert portal flow allowing for a safe portal dissection. Herein we report our initial experience utilizing DSRS and MCS at the time of pancreatectomy for cancer. Methods We reviewed all patients who underwent pancreatic resection for cancer and had either a DSRS and/or MCS performed between January 1, 2009 and February 1, 2012. Results Of 11 patients identified, 10 had adenocarcinoma, 9 underwent standard or extended pancreaticoduodenectomy, and 2 underwent total pancreatectomy. Median operative time was 9.5 hours, median blood loss was 1,000 mL and median duration of stay was 10 days. There were no mortalities. There was 1 Clavien grade III complication during the index admission and 3 others were readmitted. No patient required reoperation. Conclusion We provide proof of concept that extended pancreatic resection in the setting of limited vascular involvement can be safely performed. This is the first report utilizing MCS and DSRS to facilitate resection of the SMV-PV confluence in the setting of cavernous transformation of the PV.

Historically, the clinical staging of pancreatic cancer has centered on the surgical management of the primary tumor, because few effective chemotherapeutic agents were available and long-term survival was only achieved in the context of surgical resection. Such a strategy of complete oncologic surgical care is reasonable when surgery is both the principal therapy and highly effective. However, complex surgery for pancreatic cancer—often performed in older patients after a lengthy period of induction therapy—can be associated with significant morbidity and mortality. The majority of patients with pancreatic cancer present either locally advanced or metastatic disease at the time of diagnosis. In this article, we will discuss the role of multimodality management of patients with borderline resectable and locally advanced pancreatic cancer. Considering that surgery has a modest impact on the natural history of pancreatic cancer in most patients, a neoadjuvant approach to treatment sequencing is favored for patients with borderline resectable pancreatic cancer, and this same rationale has been extended to select patients with locally advanced disease who demonstrate an exceptional response to induction therapy.

In pancreatic cancer, as with many other solid tumors, a commonly held surgical adage—a chance to cut is a chance to cure—has been promulgated throughout the years. Following such reasoning, surgical extirpation of a localized tumor would prevent tumor dissemination and metastatic tumor progression. However, decades of surgical experience have demonstrated that surgical resection alone provides a limited median survival benefit. Despite the optimization of surgical technique and perioperative management over the past three decades, little progress has been made to improve the limited survival of patients with localized pancreatic cancer who receive surgery. In this article, we discuss the rationale for a novel management strategy for patients with resectable pancreatic cancer, which may improve patient selection and the delivery of multimodality therapy.

The impact of glycemic control in patients with pancreatic cancer treated with neoadjuvant therapy is unclear. Glycated hemoglobin (HbA1c) values were measured in patients with localized pancreatic cancer prior to any therapy (pretreatment) and after neoadjuvant therapy prior to surgery (preoperative). HbA1c levels greater than 6.5% were classified as abnormal. Patients were categorized based on the change in HbA1c levels from pretreatment to preoperative: GrpA, always normal; Gr B, worsened; GrpC, improved; and GrpD, always abnormal. Pretreatment HbA1c levels were evaluable in 123 patients; there were 67 (55%) patients in GrpA, 8 (6%) in GrpB, 22 (18%) in GrpC, and 26 (21%) in GrpD. Of the 123 patients, 92 (75%) completed all intended therapy to include surgery; 57 (85%) patients in GrpA, 4 (50%) patients in GrpB, 16 (72%) patients in GrpC, and 15 (58%) patients in GrpD (p = 0.01). Elevated preoperative carbohydrate antigen 19-9 (CA19-9) (OR 0.22;[0.07–0.66]), borderline resectable (BLR) disease stage (OR 0.20;[0.01–0.45]) and abnormal preoperative HbA1c (OR 0.30;[0.11–0.90]) were negatively associated with completion of all intended therapy. Abnormal preoperative HbA1c was associated with a 2.74-fold increased odds of metastatic progression during neoadjuvant therapy (p = 0.08). Elevated preoperative HbA1c is associated with failure to complete neoadjuvant therapy and surgery and a trend for increased risk of metastatic progression.

Purpose To assess safety and efficacy of folinic acid, 5-fluorouracil, gemcitabine (FFG) and folinic acid, fluorouracil, oxaliplatin (FOLFOX4) regimens with added bevacizumab as first-line treatment in patients with advanced colorectal cancer (CRC). Patients and Methods Patients with Stage III unresectable or Stage IV adenocarcinoma of the colon or rectum were randomly assigned to either FFG weekly for 6 weeks of an 8-week cycle or FOLFOX4 every 2 weeks. After FDA approval, bevacizumab 5 mg/kg was added every 2 weeks. Treatment continued until disease progression. Planned enrollment was 190 patients. Primary endpoint was overall response rate (ORR); secondary endpoints included evaluation of adverse events, time to progression (TTP), and overall survival (OS). Disease Control Rate (DCR; % of patients with complete or partial responses or stable disease) was a post hoc analysis. Results The trial was stopped prematurely due to low enrollment. Of 84 enrolled patients (42 to each arm), 36 patients (18 in each arm) received bevacizumab. ORR was greater (P = .002) for FOLFOX4 (17/42; 40.5%) than for FFG (4/42; 9.5%); however, TTP, OS, and DCR results were not statistically different comparing FOLFOX4 and FFG. Peripheral neuropathy was more frequent (P =

Introduction : Immune check point inhibitors(ICIs) are widely used to treat various solid tumors, but there is a paucity of biomarkers that reliably predict response to such therapy. We sought to identify somatic alterations (SAs) that can predict response to ICI. Further, we investigated the effect of these SAs on clinical outcome. Methods: We retrospectively reviewed medical records of all patients (pts) that received ICI at our institution (2012-2017) and had CGP performed on pre-treatment biopsies. DNA was extracted from formalin fixed paraffin embedded clinical specimens and CGP was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of >600 unique reads utilizing the Foundation Medicine platform (315 gene panel). Twenty-four SAs, occurring in at least 5% of the pts were correlated with response using the Wilcoxon-Mann-Whitney test and p-values were adjusted for multiple testing using Benjamini-Hochberg's false-discovery rate (FDR) method. Cox proportional hazards regression was used to investigate the effect of baseline covariates on progression-free survival (PFS); The effect of SAs was analyzed using the exact log rank test. The effect of response on progression and death was investigated using a 4-state model with “ICI therapy”, “response”, “progression”, and “death” as possible states. Results: Among the 76 pts that met criteria, 71 (lung-25, urothelial-6, esophageal-6, gynecologic-6, renal-5, sarcoma-5, melanoma-4, colorectal-4, prostate-3, head and neck-3, other-4) had an evaluable response and were included in the analyses. Median age was 62 years, 6 (8.5%) pts received ICI as first line therapy, while 65 (91.5%) pts received a median of 1 line of therapy prior to ICI; median of 5 doses of ICI therapy were administered. Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) were noted in 3 (4.2%), 11 (15.5%), 10 (14.1%) and 47 (66.2%) pts respectively. SAs in RBM10 (p = 0.0024), PIK3CA (p = 0.0027), ARID1A (p = 0.0039), and SMARCA4 (p = 0.0047) correlated with response in a statistically significant fashion (adjusted p value = 0.028). PFS and overall survival (OS) of the entire cohort was 3.7 and 11.4 months respectively. Pts with SAs in RBM10 (p = 0.0011), ARID1A (p = 0.0102), and PIK3CA (p = 0.0013) demonstrated a statistically significant improvement in PFS (median not met, not met, and 9.3 months, respectively). Response to ICI significantly reduced the hazard of progression (HR=0.11, p=0.0006), but not the hazard of non-relapse mortality (NRM) (HR=0.41, p=0.53). Conclusion: CGP was able to identify SAs predictive of response to ICI and improved PFS. The significant reduction in the hazard of progression with response to ICI emphasizes the predictive value of the identified biomarkers. The validity and putative mechanistic relevance of these predictive SAs need further elucidation. Citation Format: Ravi K Narra, Arun K Singavi, Jonathan Thompson, Smitha Menon, James Thomas Thomas, Carolyn Oxencis, Mathew Riese, Paul Ritch, Deepak Kilari, Aniko Szabo, Ben George. Application of comprehensive genomic profiling (CGP) to predict therapeutic response to immune checkpoint inhibitors (ICI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 654.

271 Background: Mutations in oncogenic KRAS have been widely accepted as the signature genomic alteration (GA) in sporadic PDAC, but therapeutic efforts aimed at targeting constitutively activated KRAS have been disappointing. We examined somatic GAs in KRAS WT PDAC utilizing a CGP platform to identify actionable targets. Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) PDAC clinical specimens and CGP was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 unique reads. Alterations in the RAS/ RAF/ MEK pathway genes ( KRAS, NRAS, HRAS, ARF, BRAF, EGFR, MAP2K2, MAP2K1, MAPK1) and DNA Damage Repair (DDR) pathway genes ( BRCA1/2, ATM, ATR, BRIP1, RAD50, RAD51, RAD52, PALB2, CHEK1, CHEK2) were examined. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. TMB was categorized based on mutations(m)/Mbp of DNA - high (H; > 20), Intermediate (I; 8-20) and low (L; < 8). Results: CGP was performed on 3426 PDAC specimens; 1815 (53%) were male, 390 (11.3%) were KRAS WT. GAs in the RAS/ RAF/ MEK pathway were identified in 90.6% of all cases, while 68 (17.4%) KRAS WT cases had one or more GAs in RAS/ RAF/ MEK pathway genes. DDR pathway GAs were identified in 1405 (41%) cases for a total of 2050 GAs, and 180 (46%) KRAS WT cases for a total of 285 GAs. DDR pathway alterations were common in KRAS WT PDAC compared to KRAS mutated PDAC (p = 0.028). Among the 842 (24.6%) cases with available TMB data, 5 (0.6%), 104 (12.3%) and 733 (87.1%) pts had H, I and L, TMB respectively. Among 88 (22.6%) KRAS WT cases with available TMB data, 2 (2.3%), 12 (13.6%) and 74 (84.1%) pts had H, I and L, TMB, respectively. MSI status was available in 2314 (67.5%) cases, 13 (0.6%) were MSI-high (MSI-H); among the KRAS WT cases, 222 (57%) had MSI status available, 3 (1.3%) were MSI-H. Conclusions: MSI-H status and high TMB are rare in PDAC, regardless of KRAS mutation status. GAs in the DDR pathway are relatively common in PDAC and may serve as predictive biomarkers for platinum chemotherapeutic agents and/or PARP inhibitors. Prospective validation of such predictive gene signatures will improve therapeutic efficacy and minimize toxicities.

677 Background: Intact HRR pathway genes play a critical role in repairing double-stranded DNA breaks. Genomic alterations (GA) in several HRR pathway genes have been well characterized, demonstrating prognostic and predictive significance. However, there are many variants of unknown significance (VUS) in the HRR pathway genes that need better characterization. Methods: Patients (pts) with mCRC that harbored VUSs in HRR pathway genes (HRR- VUS; BRCA1/2, ATM, ATR, RAD50, RAD51, PALB2, CHEK1, CHEK2) and treated with front line platinum therapy were identified by review of our institutional molecular data base (MDB) and EMR. Time to 2nd line therapy (TT2L) and Overall Survival (OS) were calculated. DNA was extracted from formalin fixed paraffin embedded clinical specimens and Next Generation Sequencing (NGS) was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 unique reads utilizing the Foundation Medicine NGS platform. Results: Among the 873 pts in our institutional MDB, 96 (11%) had mCRC, 20 (21%) harbored HRR pathway GAs, 15 (16%) were categorized as VUSs. HRR-VUS pts had a median age of 57 at diagnosis, 5 (33%) were male, 3 (20%) were right-sided. Distribution of HRR-VUSs in this cohort is summarized in table 1. All pts with HRR-VUSs were micro-satellite stable (MSS), median TMB was 4.5 (range 0 – 8.1). Median TT2L and OS in mCRC pts with HRR-VUSs were 8.0 and 43 months (m) respectively. Two pts with HRR-VUSs had TT2L > 24 m and OS > 40 m; one of them had a BRCA1P1464A mutation, while the other had a BRCA2 amplification. Conclusions: BRCA2, ATM and BRCA1 were the HRR genes that harbored VUSs most frequently in pts with mCRC. Majority with HRR-VUSs had left sided primaries, were MSS and had low TMB. BRCA1P1464A mutation in the ATM binding domain needs further characterization on account of prolonged TT2L with platinum based chemotherapy. Patients with HRR-VUSs that are predictive of benefit with platinum based chemotherapies could be considered for maintenance therapy with PARP inhibitors [Table: see text]

TPS543 Background: Cholangiocarcinoma (CCA) is treated with CIS and GEM (CISGEM), but prognosis is poor. Hyaluronan (HA) accumulation in solid tumors may impede drug and immune cell access. PEGPH20 targets tumors that accumulate HA (HA-high). This study (NCT03267940) plans to enroll 70 subjects to evaluate the safety and activity of PEGPH20 + programmed cell death-ligand 1 (PD-L1) agent atezolizumab, (PEGCISGEMATEZO), & PEGPH20 + CISGEM (PEGCISGEM) in HA-high subjects with CCA and gallbladder cancer. Study will comprise initial run-in and expansion portions. Primary endpoints include incidence of AEs and other laboratory/safety parameters and ORR (RECIST v1.1). Secondary endpoints include PK parameters; DOR, DCR, PFS, and ORR (RECIST v1.1 and immune-modified RECIST); and OS and OS by PD-L1 expression. Methods: ~6 HA-high subjects will be enrolled in PEGCISGEM arm run-in portion and undergo at ≥1 cycle; subsequently, 6 HA-high subjects will enter the PEGCISGEMATEZO arm. Treatment period will be 21-day cycles. In the expansion portion, ~50 HA-high subjects will be enrolled and randomized in a 2:2:1 ratio into PEGCISGEMATEZO, PEGCISGEM, and CISGEM arms. PEGPH20 is planned to be administered at 3.0 μg/kg on Days 1, 8 and 15 of all cycles in both portions. ATEZO will be administered at 1200 mg 1–3 hours after PEGPH20 on Day 1 of each 21-day cycle in the PEGCISGEMATEZO arm in both portions. In the PEGCISGEM & PEGCISGEMATEZO arms, dosing schedule for CISGEM is the same during both portions, with administration of 25 mg/m2 CIS and 1000 mg/m2 GEM on Days 2 and 9 of each cycle. In CISGEM control arm (expansion only), dosing schedule will be on Days 1 and 8 of each cycle. Treatment will continue until death, withdrawal of consent, disease progression, or unacceptable toxicity. Tumor response will be evaluated using RECIST v1.1. AEs will be graded per NCI CTCAE v4.03. Tumor samples will be tested retrospectively for PD-L1 expression. Safety data will be periodically monitored by an independent data monitoring committee. Clinical trial information: NCT03267940.

383 Background: 80% of HCC pts present with advanced disease, treatment for such pts is palliative in nature. It is important to ascertain cost associated with such palliative therapy, considering modest survival benefit afforded by these treatments. Methods: Utilizing a non-Medicare national claims database (MarketScan), we analyzed a cohort of pts with HCC diagnosis (Dx). Consistent with literature, pts selected had at least two claims with HCC code (155.0) between 1/1/2010 and 12/31/2013, at least 2 claims with chronic liver condition within 1 year of the HCC Dx, no claims for other malignancies for 1 year before HCC Dx, and excluded hepatectomy or transplant. Follow up was from date of first HCC claim to end of continuous insurance coverage (EOC) with prescription drug claim tracking, or 12/31/2015. Pts were divided into 4 groups based on receipt of S, LDT, combined therapy (LDT+S), or best supportive care (BSC) after HCC Dx. Costs obtained by adding payment (Pmt) amounts for all inpatient, outpatient, and drug claims over follow-up period. Demographics and costs were summarized using means for continuous and frequencies for categorical variables. No adjustment for censoring was done, as no reason available for EOC. Average monthly cost was computed for each pt, and then averaged over pts. Results: Data were available for 6,987 patients over specified period, 67% were males, mean age was 60.2 years. Cost data by therapy received are summarized in the table below. Conclusions: Majority of HCC pts in this database were treated with BSC. Time to EOC tracked was significantly shorter for pts treated with S, compared to other 3 groups. Monthly cost associated with LDT, LDT+S, and S were not substantially different, but higher than cost associated with BSC. Prospectively collected survival, quality of life and cost data are important to ascertain true impact of palliative therapy in pts with advanced HCC. [Table: see text]

To describe venous thromboembolism (VTE) rates in patients with pancreatic cancer (PC) during neoadjuvant therapy.Factors associated with VTE were evaluated using multivariable logistic regression modeling in patients with resectable and BLR PC treated with neoadjuvant therapy between 2009 and 2014.Prevalent VTEs were detected in 13 (5%) of the 260 patients. Incident VTEs were detected in 26 patients (10%); 9 (8%) of the 109 resectable and 17 (11%) of the 151 BLR patients (P = 0.53). Of the 26 incident events, 9 (35%) were PEs, 9 (35%) were extremity DVTs, and 8 (31%) involved the SMV/PV. VTEs were catheter-related in 7 (27%) of the 26 patients. Rh(D) antigen positivity was associated with a decreased risk of incident VTE (OR:0.32, 95%CI:0.11-0.85, P = 0.02). Completion of neoadjuvant therapy to include surgery occurred in 176 (75%) of the 234 patients without incident VTE as compared to 14 (54%) of the 26 patients with incident VTE (P = 0.02). The median survival for all 260 patients was 24.3 months: 17.0 months versus 24.6 months for patients who did and did not develop incident VTE during neoadjuvant therapy (P = 0.11).Patients with localized PC who receive neoadjuvant therapy are at significant risk of VTE and thromboprophylaxis may be warranted. J. Surg. Oncol. 2016;114:581-586. © 2016 Wiley Periodicals, Inc.

The management of localized pancreatic cancer (PC) remains controversial. Historically, patients with localized disease have been treated with surgery followed by adjuvant therapy (surgery-first approach) under the assumption that surgical resection is necessary, even if not sufficient for cure. However, a surgery-first approach is associated with a median overall survival of only 22-24 months, suggesting that a large proportion of patients with localized PC have clinically occult metastatic disease. As a result, adjuvant therapy has been recommended for all patients with localized PC, but in actuality, it is often not received due to the high rates of perioperative complications associated with pancreatic resections. Recognizing that surgery may be necessary but usually not sufficient for cure, there has been growing interest in neoadjuvant treatment sequencing, which benefits patients with both localized and metastatic PC by ensuring the delivery of oncologic therapies which are commensurate with the stage of disease. For patients who have clinically occult metastatic disease, neoadjuvant therapy allows for the early delivery of systemic therapy and avoids the morbidity and mortality of a surgical resection which would provide no oncologic benefit. For patients with truly localized disease, neoadjuvant therapy ensures the delivery of all components of the multimodality treatment. This review details the rationale for a neoadjuvant approach to localized PC and provides specific recommendations for both pretreatment staging and treatment sequencing for patients with resectable and borderline resectable (BLR) disease.

The antisense oligonucleotide aprinocarsen specifically inhibits the transcription of protein kinase C-alpha. This study evaluated the response rate of the combination therapy of aprinocarsen, gemcitabine, and carboplatin in previously untreated patients with advanced non-small cell lung cancer (NSCLC). Secondary objectives included the measurement of time-to-event efficacy parameters and toxicity. Patients with stage IV or stage IIIB disease (N(3) and/or pleural/pericardial effusion) were treated with gemcitabine 1,250 mg/m(2) on days 1 and 8 and carboplatin AUC 5 on day 1 every 21 days. Aprinocarsen was administered as 2mg/kg/day continuous iv infusion on the first 14 days of each cycle, following the carboplatin treatment. A total of 36 patients received a median of 3 treatment cycles, with 10 patients completing 6 cycles. No complete response was observed, while partial response was seen in 25% of patients. Stable disease and progressive disease was observed in 36.1% and 22.2% of patients. The median overall survival was 8.3 months, and the median duration of progression-free survival was 5.7 months (95% CI, 3.2-7.1 months). Thrombocytopenia (78%) and neutropenia (50%) were the major grade 3/4 toxicities. Enrollment for this study was stopped and the study was terminated in March 2003 due to the results of a large phase III study, which suggested that aprinocarsen did not improve response or add survival benefit to chemotherapy in advanced NSCLC. The addition of aprinocarsen to gemcitabine+carboplatin therapy in patients with NSCLC showed moderate activity. However, this combination resulted in severe thrombocytopenia in the majority of patients.

Background: Although currently available 5-hydroxytryptamine type 3 receptor (5-HT3) antagonists are effective, not all patients receiving these agents achieve adequate control of chemotherapy-induced nausea and vomiting (CINV). Palonosetron, a potent and highly selective 5-HT3 antagonist with a strong affinity for 5-HT3 and a prolonged plasma elimination half-life, may provide a longer duration of action than other approved agents. Patients and methods: One hundred and sixty-one patients were randomly assigned to receive a single intravenous bolus dose of palonosetron (0.3, 1, 3, 10, 30 or 90 µg/kg) before administration of highly emetogenic chemotherapy, with no pretreatment with corticosteroids. Results: The four highest doses of palonosetron were similarly effective during the first 24 h, producing clearly higher complete response (CR) (no emesis, no rescue medication) rates in the 3, 10, 30 and 90 µg/kg groups (46%, 40%, 50% and 46%, respectively) than in the 0.3–1 µg/kg group (24%) of evaluable patients (n = 148). The 3 µg/kg dose was identified as the lowest effective dose. A single dose of palonosetron showed prolonged efficacy in preventing delayed emesis, with approximately one-third of patients who received palonosetron 10 or 30 µg/kg maintaining a CR throughout the 7-day period following chemotherapy administration. Dose-proportional increases in pharmacokinetic parameters and a long plasma half-life (43.7–128 h) were observed. Palonosetron was well-tolerated, with no dose–response effect evident for the incidence or intensity of adverse events. Conclusions: Palonosetron is an effective and well-tolerated agent for the prevention of CINV following highly emetogenic chemotherapy, with 3 and 10 µg/kg identified as the lowest effective palonosetron doses.

This randomized study of previously untreated patients with extensive disease small cell lung cancer was designed (a) to compare the survival of patients treated with either effective standard chemotherapy or an investigational anti-cancer drug as initial therapy and (b) to evaluate response rates and toxic effects of such therapies. One hundred and thirty-five patients were randomly assigned to receive as initial therapy, either the standard CAV regimen--cyclophosphamide (1000 mg/m(2)), doxorubicin (50 mg/m(2)) and vincristine (1.4 mg/m(2)) every 3 weeks--or the phase II drugs ifosfamide (1.5 gm/m(2)/days 1-5) with mesna (300 mg/m(2)) dose at 0, 4 and 8 h after IV daily ifosfamide every 3 weeks or teniposide (60 mg/m(2)/days 1-5) every 3 weeks. Nonresponders received salvage chemotherapy-etoposide (120 mg/m(2) on days 1, 2 and 3) and cisplatin (60 mg/m(2) on day 1), repeated every 3 weeks. Among the 46 patients on CAV, there were two complete and 24 partial responses (56%). Among the 43 patients on ifosfamide, there were three complete and 18 partial responses (49%), while among the 46 patients on teniposide, there were two complete and 18 partial responses (43%). Eighty-three of the patients proceeded onto salvage regimen, of which 81 were analyzable for response and toxicity. Among the 81 patients who continued on salvage therapy and were evaluable for response, the overall best response rate was 61% for CAV+salvage, 54% for ifosfamide+salvage, and 53% for teniposide+salvage. These rates were not significantly different (P=0.962). Of the 135 analyzable patients, 130 (96%) have died. The estimated median survival time was 42 weeks for CAV patients, 43 weeks for ifosfamide, and 38 weeks for teniposide. Seven patients survived longer than 2 years (four on CAV, one on ifosfamide and two on teniposide). There were 29 life-threatening complications to the induction regimen (22 (48%) on CAV, four (9%) on ifosfamide and three (7%) on teniposide) and seven lethal complications (two on CAV, four on ifosfamide and one on teniposide). The treatments were significantly different with respect to the overall degree of toxicity (P0.0001) with CAV being more toxic. The data of this study, like the previous ECOG study suggests that the administration of a new agent followed by effective salvage chemotherapy in the treatment of extensive disease small cell lung cancer may have no adverse effect on survival.

e15766 Background: The role of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging of pancreatic cancer (PC) has not been well defined. We evaluated the prognostic value of FDG-PET imaging in patients with localized PC enrolled in a prospective trial of personalized molecular-directed neoadjuvant therapy. Methods: Pretreatment FDG-PET was classified as high or low based on a standardized uptake value (SUV) cutpoint of 7.2 (population median). Carbohydrate antigen 19-9 (CA19-9) was measured after the completion of neoadjuvant therapy (preoperative) and classified as normal (≤35 U/mL) or elevated. Results: Pretreatment FDG-PET imaging was performed on 100 consecutive patients; SUV was high in 50 and low in 50. Preoperative CA19-9 values were available in 99 of 100 patients; 54 (55%) were elevated and 45 (45%) were normal. Of the 100 patients, 81 completed neoadjuvant therapy and surgery, and 19 were not resected. Among the 81 resected patients, SUV was high in 37 (46%) and low in 44 (54%); preoperative CA19-9 was elevated in 40 (49%) and normal in 41 (51%). The median overall survival (OS) for all patients was 39 months; 45 months for who completed all intended neoadjuvant therapy and surgery and 9 months for patients who were not resected. The median OS for patients with normal CA19-9/low SUV, normal CA19-9/high SUV, elevated CA19-9/low SUV, and elevated CA19-9/high SUV were not reached, 35, 24, and 18 months, respectively (p = 0.0001). Conclusions: Pretreatment FDG-PET avidity and preoperative CA19-9 are important prognostic markers and may be used to estimate the anticipated benefit of surgery; information of immediate clinical significance for both treatment sequencing and the application of surgery to patients who are frequently of advanced age or high-risk.