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Highlights • Complete resection is a potentially curative treatment for pancreatic cancer. • This report studies neoadjuvant chemotherapy with or without radiation. • The addition of radiation was associated with improved complete resection rates. • The addition of radiation was associated with improved pathologic down staging., Purpose Margin-negative (R0) resection is the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC). Pre-operative multi-agent chemotherapy alone (MAC) or MAC followed by pre-operative radiotherapy (MAC + RT) may be used to improve resectability and potentially survival. However, the optimal pre-operative regimen is unknown. Methods Patients with non-metastatic PDAC from 2006 to 2016 who received pre-operative MAC or MAC + RT before oncologic resection were identified in the National Cancer Database. Univariable and multivariable (MVA) associates with R0 resection were identified with logistic regression, and survival was analyzed secondarily with the Kaplan Meier method and Cox regression analysis. Results 4,599 patients were identified (MAC: 3,109, MAC + RT: 1,490). Compared to those receiving MAC, patients receiving MAC + RT were more likely to have cT3-4 disease (76% vs 64%, p

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: Induction FOLFIRINOX is increasingly used for borderline resectable (BR) and locally advanced (LA) unresectable pancreatic ductal adenocarcinoma (PDAC), but the benefit of surgery versus consolidative radiation in the FOLFIRINOX era is not well defined. Single institution experiences have included FOLFIRINOX with gemcitabine-based chemotherapy, lack a uniform comparator group to surgery, or are limited to surgical patients after FOLFIRINOX. No prospective clinical trials have assessed surgery versus radiation. Therefore, our primary objective was to identify the long-term survival impact of surgery versus radiation for BR and LA unresectable PDAC treated with induction FOLFIRINOX. Methods: We performed a single center retrospective review of BR and LA PDAC treated with FOLFIRINOX from 2010 - 2018. Patients were divided into two cohorts based on receipt of surgery versus consolidative radiotherapy. Findings: We identified 101 BR and LA PDAC patients treated with induction FOLFIRINOX; 40 underwent surgery and 61 received consolidative radiotherapy. The surgery group was 28/40 (70%) BR and 12/40 (30%) LA, while consolidative radiotherapy was 18/61 (30%) BR and 43/61 (70%) LA. The R0 resection rate was 100% for surgery and 18/40 (45%) received radiation prior to surgery. Median overall survival (OS) for surgery was 42·3 months (95% CI 24·6 - not reached) compared to a median OS of 19·6 months (95% CI 16·3 - 24·6) with consolidative radiotherapy(p = 0·0001). On multivariate analysis, surgery was associated with improved OS (HR 0·35, 95% CI 0·17 - 0·71, p=0·004). Interpretation: Surgery after induction FOLFIRINOX is feasible and has a clinically meaningful survival benefit in BR and LA PDAC compared to induction FOLFIRINOX followed by consolidative radiotherapy. Funding Statement: This research was not supported by any funding. Declaration of Interests: The authors declare no conflicts of interest relevant to this manuscript. Ethics Approval Statement: This study was approved by the Yale University institutional review board.

Background Pembro, a PD-1 inhibitor, confers durable benefit in many tumor types but has limited efficacy in non–microsatellite instability–high (MSI-high)/pMMR mCRC. Chemotherapies that include 5-fluorouracil (5-FU), oxaliplatin and irinotecan, which are commonly used to treat mCRC, may modulate intrinsic tumor immunogenicity and sensitize tumors to immunotherapy agents. In the phase 1b KEYNOTE-651 study (NCT03374254), pembro + mFOLFOX7 (cohort B) or pembro + FOLFIRI (cohort D) was evaluated in patients with non–MSI-high/pMMR mCRC. Methods Patients were ≥18 years with non–MSI-high/pMMR mCRC, Eastern Cooperative Oncology Group performance status 0/1, and no prior systemic chemotherapy for stage IV mCRC (cohort B) or 1 prior therapy including a fluoropyrimidine + oxaliplatin-based regimen (cohort D). Patients received pembro 200 mg every 3 weeks (Q3W) + mFOLFOX7 (oxaliplatin [85 mg/m2]; leucovorin [400 mg/m2]; 5-FU [2400 mg/m2]) Q2W (cohort B) or pembro 200 mg Q3W + FOLFIRI (irinotecan [180 mg/m2]; leucovorin [400 mg/m2]; 5-FU [2400 mg/m2]) Q2W (cohort D). Primary objectives were safety/tolerability and establishment of the recommended phase 2 dose (RP2D); the secondary objective was objective response rate. Results At data cutoff (Feb 18, 2019), 15 patients in cohort B and 16 in cohort D started treatment; median follow-up was 6.8 months (cohort B) and 5.7 months (cohort D). Treatment was discontinued in 4 patients (27%) in cohort B (adverse event [AE], n = 1 [7%]; PD, n = 3 [20%]) and 9 patients (56%) in cohort D (AEs, PD, patient withdrawal; n = 3 [19%] each). There was 1 dose-limiting toxicity in cohort D: grade 3 small-intestinal obstruction. See RP2Ds for cohorts B and D in the Methods section. All patients had ≥1 treatment-related AE (TRAE). Grade 3 TRAEs occurred in 8 patients each in cohort B (53%) and cohort D (50%), most commonly anemia and neutropenia (13% each) in cohort B and neutropenia, diarrhea, fatigue, and leukopenia (13% each) in cohort D. There were no grade 4-5 TRAEs. Efficacy results will be presented. Conclusions Pembro in combination with mFOLFOX7 or FOLFIRI was safe and tolerable in patients with mCRC. Clinical trial identification NCT03374254; Release date: December 15, 2017. Editorial acknowledgement Jacqueline Kolston, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA); Funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Array BioPharma. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Array BioPharma. Disclosure R. Kim: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Research grant / Funding (institution): Eisai. J. Kortmansky: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche. L. Wong: Research grant / Funding (institution): Astellas Pharma Global Development, Inc./Astellas US, Inc.; Research grant / Funding (institution): BeiGene, Ltd; Research grant / Funding (institution): Exelixis, Inc.; Research grant / Funding (institution): Merck; Research grant / Funding (institution): NovoCure, Inc.; Research grant / Funding (institution): Pierre Fabre Medicament; Research grant / Funding (institution): PledPharma AB; Research grant / Funding (institution): SynCore Biotechnology Co., Ltd.; Research grant / Funding (institution): Halozyme, Inc.; Research grant / Funding (institution): Pharmacyclics, Inc.; Research grant / Funding (institution): TESARO; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Array. M. Tehfe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Celgene; Honoraria (self): Ipsen; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Taisho. J.J. Li: Full / Part-time employment: Merck & Co., Inc. M. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. C. Mayo: Full / Part-time employment: Merck & Co., Inc. P. Marinello: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. E. Chiorean: Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Halozyme; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Array; Advisory / Consultancy: Five Prime; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Halozyme; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Ignyta/Roche; Research grant / Funding (institution): Stemline; Research grant / Funding (institution): Macrogenetics. All other authors have declared no conflicts of interest.

3504Background: While both anti-VEGF(R) and EGFR antibodies have activity in metastatic RAS wild type CRC, the combination of the two appeared to be detrimental when combined with chemotherapy in u...

Pancreatic adenocarcinoma (PC) harbors frequent alterations in p16, resulting in cell cycle dysregulation. A phase I study of docetaxel and flavopiridol, a pan-cyclin-dependent kinase inhibitor, demonstrated encouraging clinical activity in PC. This phase II study was designed to further define the efficacy and toxicity of this regimen in patients with previously treated PC.Patients with gemcitabine-refractory, metastatic PC were treated with docetaxel 35 mg/m(2) followed by flavopiridol 80 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Tumor measurements were performed every two cycles. A Simon two-stage design was used to evaluate the primary endpoint of response.Ten patients were enrolled, and 9 were evaluable for response. No objective responses were observed; however, 3 patients (33%) achieved transient stable disease, with one of these patients achieving a 20% reduction in tumor size. Median survival was 4.2 months, with no patients alive at the time of analysis. Adverse events were significant, with 7 patients (78%) requiringor=1 dose reduction for transaminitis (11%), grade 4 neutropenia (33%), grade 3 fatigue (44%), and grade 3 diarrhea (22%).The combination of flavopiridol and docetaxel has minimal activity and significant toxicity in this patient population. These results reflect the challenges of treating patients with PC in a second-line setting where the risk/benefit equation is tightly balanced.