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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.

Background FOLFIRINOX (FFX) and Gemcitabine with nab-Paclitaxel (GN) are both proven to be superior to Gemcitabine in first line treatment for advanced pancreatic cancer (APC). However, there has been no phase 3 randomized controlled trials to prove FFX is superior to GN in APC. This population-based cohort study was conducted to compare efficacy and safety profiles of the two standard regimens in APC. Methods In this retrospective cohort study, we evaluated all newly diagnosed patients (pts) with APC who received either FFX or GN as first line therapy during 2010-2018 at three Canadian institutions. The primary objective was to assess survival. Secondary objective was to compare safety profile of the two regimens. Kaplan Meier method and log-rank test were used for survival curves. Results There were 231 eligible pts identified: 143 received FFX and 88 received GN. FFX pts were slightly younger than GN (median age: 62 (IQR: 56-67) vs 66 (IQR: 58-73) respectively). There were predominantly more males: FFX 89 (62.2%) vs GN 46 (52.3%). WHO performance status (PS) of 0 were 38 (28.4%) vs 14 (16.5%) and 1 were 90 (67.2%) vs 65 (76.5%) respectively. The median progression-free survival (PFS) of FFX was 5.5 months (mts) (95% CI: 5.0-6.7) vs 5.1 mts (95% CI: 3.8-7.1) with GN (p = 0.37). The median overall survival (OS) with FFX was 9.3 mts (95% CI: 7.5 – 11.1) vs. 10.2 mts (95% CI: 6.8-11.3) with GN (p = 0.81). On multivariate analysis chemotherapy regimen was not correlated with PFS or OS. There were more grade 3-4 toxicity in FFX vs GN group: diarrhea – 22 (15.4%) vs 3 (3.4%) (p = 0.004), nausea – 20 (14%) vs 6 (6.8%), vomiting – 13 (9.1%) vs 6 (6.8%), peripheral sensory neuropathy (PSN) – 8 (5.6%) vs 3 (3.4%), thrombocytopenia – 28 (19.6%) vs 5 (5.7%) (p = 0.003) respectively. Gr 3-4 neutropenia rates were similar in both regimens: 23 (16%) in FFX vs 15 (17%) in GN. Conclusions Our results revealed that FFX or GN had comparable survival and safety profiles. Given lower Gr 3-4 toxicity profile of GN regimen, GN is likely preferable choice for majority of pts. FFX could be reserved for young high performance pts. Legal entity responsible for the study Segal Cancer Centre Jewish General Hospital. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Aim: Use of bevacizumab in the management of glioblastoma multiforme (GMB) remains controversial. Currently in Canada, it is approved for recurrent GBM treatment. We describe the use of bevacizumab and analyses the efficacy across treatment lines in GBM. Methods: Patients (pts) diagnosed GBM (primary or secondary) from 2008-2014 and treated with bevacizumab were identified at McGill University Hospitals; demographics, diagnosis, and treatment pattern were collected via chart review. Primary endpoints were median progression-free survival (PFS) and overall survival (OS) estimated via Kaplan-Meier method. Secondary endpoint was toxicity. Grading of adverse events (AEs) were in accordance to CTCAE 4.0 criteria. Results: 64 pts were identified and their files were analyzed (40 males; median age at diagnosis 54 years, range 26-83). Majority had KPS score ≥70 (n = 56, 87.5%). 49 (76.6%) pts had primary and 15 (23.4%) had secondary GBM. Available MGMT testing was performed in 24 pts (methylated n = 10, 15.6%; unmethylated n = 14, 21.9%). 30 (46.9%) received bevacizumab in 1st line and 34 (53.1%) 2nd line and beyond (2L+). The median duration of bevacizumab in 1st line 36.6 weeks and 2L+ 14.21 weeks (overall 24.4 weeks; range Conclusions: Our results show bevacizumab treatment may be more efficient after a recurrence than when used in the beginning of treatment and are in line with reported registration trials data. Disclosure: All authors have declared no conflicts of interest.

One of the standard approach for the locally advanced rectal cancer patients is neoadjuvant chemoradiation therapy (CRT), followed by total mesorectal excision (TME) and adjuvant chemotherapy (ACT). ACT compliance has been a major concern for these patients. In this study we assessed the possible impact of neoadjuvant radiation therapy (RT) modality on ACT compliance. Methods We, retrospectively, analyzed the data of 114 locally advanced rectal cancer patients, after neoadjuvant RT and referred for consideration of ACT, at McGill University hospitals. ACT compliance was defined as pts who received at least 6 cycles of ACT and optimal dose compliance (ODC) was defined as pts who received at least 85% of the recommended chemotherapy dose. Neoadjuvant RT modalities included high dose rate endorectal brachytherapy (HDREBT) alone with no chemotherapy; conformal external beam RT (3D-CRT) with chemotherapy and intensity-modulated RT (IMRT) with chemotherapy. We applied a chi-square test for 2-way categorical associations and multivariable logistic regression with compliance as the outcome. Results The data of 114 consecutive locally advanced rectal cancer patients, mean age 64y (range:32-85), were analyzed. 41 patients (36%) were treated with neoadjuvant HDREBT alone, 33 (29%) with 3D-CRT and chemotherapy, and 40 (35%) with IMRT and chemotherapy. The HDREBT dose was 26 Gy in 4 consecutive fractions alone and that of 3D-CRT and IMRT was 50 Gy in 25 fractions, Monday to Friday with concurrent 5-FU. 41 pts (36%) received FOLFOX, 13 (11%) XELOX, 11 (10%) 5-FU, 7 (6%) Xeloda and 9 (8%) received other chemotherapy, while 33 pts refused the ACT. ACT compliance after HDREBT, 3D-CRT and IMRT were respectively: 70.7%, 45.5%, 37.5% (p = 0.008). Age was a negative factor (p Conclusion Our data suggests that neoadjuvant HDREBT yields significantly higher rates of ACT compliance and ODC compared to 3D-CRT with chemotherapy and IMRT with chemotherapy. Disclosure All authors have declared no conflicts of interest.

Background Adolescent and young adult (AYA) cancer patients are confronted with obstacles and challenges related to their diagnosis and treatment compared to children and older adults. The aim of this study is to compare patient-related and health care system-related delays, from cancer symptom onset to diagnosis and treatment, between the AYA brain tumor patients and older adult brain tumor patients. Material and methods This study is based on a questionnaire conducted in 2010-2012 completed by AYA brain tumor patients diagnosed at the ages between 16 and 39 years and older adult brain tumor patients diagnosed at an average age of 59 years. Total delay (time from cancer symptom onset to treatment start) was calculated and divided into three stages (1) Patient delay: time from patient symptom onset until first health care contact date; (2) Health care system delay: time from first health care contact until diagnosis date; (3) Treatment delay: time from diagnosis date until first treatment. Median delay in days with interquartile interval (IQI) is the main outcome measure. Results For AYA brain tumor patients, we identify a median total delay of 169 (IQI 72-395) days, a median patient delay of 1 (0-78) days, a median health care system delay of 42 (5-203) days and a median treatment delay of 60 (35-92) days. For older adult brain tumor patients, we identify a median total delay of 76 (58-175) days, a median patient delay of 0 (0-14) days, a median health care system delay of 25 (14-42) days and a median treatment delay of 35 (21-63) days. Delays of all stages are longer in AYA brain tumor patients as compared to older adult brain tumor patients, and the findings of total delay and treatment delay are statistically significant (p = 0.013 and p = 0.048, respectively). Conclusions Health care system delay and treatment delay account for much of the delay from symptom onset to first treatment in both groups which indicates professional characteristics of frontline medical personnel may contribute to delay. Also, we have longer delays in AYA brain tumor patients. This suggests that AYA cancer patients as underserved patient population need to get more attention from healthcare professionals and the general community. Disclosure All authors have declared no conflicts of interest.

Background Tumor EGFR and KRas mutations are both predictive and prognostic biomarkers in patients with advanced NSCLC. We analyzed the correlation between these biomarkers and treatment outcomes in a phase III trial of 3rd/4th line sorafenib in patients with NSCLC. Methods The global, randomized, placebo-controlled MISSION trial enrolled 703 patients with advanced relapsed/refractory NSCLC of predominantly non-squamous histology. The primary study endpoint was overall survival (OS). EGFR and KRas mutations were analyzed in archival tumor samples and in circulating tumor DNA isolated from plasma. Results Tumor and/or plasma mutation data were available from 347 patients (49%). EGFR and KRas mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were well balanced between treatment arms. Analysis of the interaction between EGFR mutation status and treatment effect on survival suggested that patients with EGFR mutations (mEGFR) benefitted from sorafenib, while those with wild-type EGFR (wtEGFR) did not (p = 0.023). Median OS was two-fold longer in mEGFR patients receiving sorafenib versus placebo (423 vs 197 days, HR 0.48, p = 0.002). There was no significant difference in OS between patients with wtEGFR receiving sorafenib or placebo (253 vs 256 days, HR 0.92, p = 0.559). An interaction was also seen between EGFR mutation status and the sorafenib effect on PFS (p = 0.015). Patients with mEGFR treated with sorafenib had better outcomes compared to placebo based on Cox regression analysis (HR 0.27, p Conclusion Post-hoc analyses of efficacy outcomes in MISSION suggest that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving 3rd/4th line sorafenib. These results must be interpreted with caution due to the small, non-representative nature of the genetic biomarker subpopulation analyzed in this trial. Further prospective investigation may be warranted. Disclosure T.S.K. Mok: Honoraria: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, and GSK Biologicals Speaker: Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, and Merck Serono Research funding: Astrazeneca. L. Paz-Ares: Dr. Paz-Ares has received honoraria from Bayer HealthCare Pharmaceuticals, Lilly, Roche and Pfizer. Y. Wu: Dr. Wu has received lecture fees from Roche, AstraZeneca, Eli Lilly, and Pfizer. V. Hirsh: Member of the steering committee for the MISSION trial. C. Lathia: Dr. Lathia is an employee of Bayer HealthCare. T.J. Ong: Dr. Ong is an employee of, and owns shares in, Bayer HealthCare. C. Pena: Dr. Pena is an employee of Bayer HealthCare. All other authors have declared no conflicts of interest.

Introduction Personalized medicine in oncology relies on translational research efforts to identify biomarkers that will influence clinical management. This is a concerted effort requiring an organizational framework that is often underestimated. The Quebec Clinical Research Organization in Cancer (Q-CROC) consortium is a multi-disciplinary and multi-institutional group of scientists and clinicians devoted to integrating and enhancing translational and clinical research capacity in Quebec. We describe here the organizational framework driving a multicenter, prospective study to identify biomarkers of clinical resistance to first-line therapy in metastatic colorectal cancer (NCT00984048, Q-CROC-01). Results The Q-CROC consortium has put in place an organizational infrastructure to support the activities and operations of its translational projects. We identified and addressed several critical issues during the course of the Q-CROC-01 translational project that were also common to our subsequent biomarker-driven trial in lymphoma (Q-CROC-02, NCT01238692) and breast cancer (Q-CROC-03, NCT01276899). Examples of these issues include: (i) feasibility and burden of tissue collection at participating sites, (ii) limiting pre-analytical variability in blood and tissue specimens for functional downstream applications, (iii) verification of tumor content on biopsy specimens, (iv) tracking sample flow, (v) integration of clinical data with discovery platforms, and (vi) engaging participation throughout all steps of the project. A critical element in these projects was a scientific project management team to ensure that objectives were aligned and deliverables were met. This academic framework for translational research may be comparable to that of multicenter clinical trials undertaken by industry, but some challenges, including financial and time constraints, data sharing and IP agreements, and engagement of its members, may be more palpable in the academic setting. Conclusion Infrastructure science is underestimated and under-reported in translational cancer research and is crucial to the success of any large-scale biomarker discovery effort. Our experience with three multi-institutional biomarker-driven trials is that progress hinges upon the availability of an infrastructure that provides a concrete link between each component. The Q-CROC-01 project is funded by a Pfizer-FRSQ Innovation Fund award and by Sanofi-Aventis. Q-CROC-02 is funded by Novartis and Roche, and Q-CROC-03 is funded by a Genome Quebec grant.