MSD Oncology Research Articles

626PD - Randomized, phase III trial comparing adjuvant gemcitabine (Gem) versus Gem plus chemoradiation (CCRT) in curatively resected pancreatic ductal adenocarcinoma (PDAC): A Taiwan cooperative oncology group study

Background: Adjuvant chemotherapy is the standard of care for PDAC after curative intent surgery. Current study aims to evaluate the role of additional consolidation CCRT to 6-month adjuvant Gem therapy in resectable PDAC. Methods: Patients with R0/R1 resected PDAC, and negative CT finding within 2 weeks and CA-19.9 <2.5x NUL within one week before registration were eligible. Enrolled patients were stratified by section margin, tumor size and lymph node status then randomized to have either 6 cycles of weekly gemcitabine, day 1, 8 and 15 every 28 days (Arm 1) or 3 cycles of weekly Gem followed by Gem-based CCRT and then another 3 cycles of Gem (Arm 2). The treatment should be initiated within 8 weeks after surgery. The primary end-point was recurrence-free survival (RFS). Secondary end points were overall survival (OS), progression pattern, safety profile and quality of life. Results: Between 2009 and 2015, 147 patients were included, 74 in Arm 1 and 73 in Arm 2. With a minimum of 2 years follow-up, the median RFS was similar between Arm 1 and Arm 2: 12.1(95% CI, 9·0-15·8) versus 13.3 (95% CI, 10.0-17.1) months, (hazard ratio 0.96 [95% CI, 0·67-1·37, p = 0.80]); while OS was 23·5 (95% CI, 18·1-30.8) versus 21·5 (95% CI, 16·7-28·1) months, (hazard ratio 1.07 [95% CI, 0·74-1·55, p = 0·73]). Local recurrence rate was marginally less in Arm 2 (17.6% vs 15.1%, p = 0·68). Grade 3/4 toxicity was 66% vs 73% in Arm 1 and 2, respectively, p = 0·34. Patients in Arm 1 had a trend of better global health status, p = 0·12. Conclusions: This is the first randomized trial using survival as primary endpoint to evaluate the role of add-on CCRT for curatively resected PDAC receiving standard, adjuvant Gem therapy. Despite a trend of better loco-regional control, the add-on CCRT did not improve the RFS and OS in such a patient population. Systemic chemotherapy should remain as the standard of care for PDAC after curative-intent surgery. Clinical trial identification: NCT00994721. Legal entity responsible for the study: Taiwan Cooperative Oncology Group. Funding: National Health Research Institutes. Disclosure: J-S. Chen: Research funding: Ono Pharmaceutical, MSD Oncology, MedImmune, Lilly, TTY Biopharm, Daiichi Sankyo, Orient EuroPharma. L-T. Chen: Research funding: Novartis, Merck, Serono, TTY, Polaris, SyncorePharm, Pfizer, BMS; Honoraria: Ono, Eli Lilly, MSD, PharmaEngine, TTY, SyncorePharm, Novartis, Astra Zeneca, Ipsen; Patents & Royalties of ENO-1mAb/HuniLife; Membership on board of directors or advisory committes: PharmaEngine. All other authors have declared no conflicts of interest.

213O Nintedanib + pemetrexed/cisplatin in malignant pleural mesothelioma (MPM): Phase II biomarker data from the LUME Meso study

Background: The randomised Phase II/III LUME-Meso study is evaluating nintedanib + pemetrexed/cisplatin versus placebo + pemetrexed/cisplatin (≤6 cycles), followed by nintedanib or placebo maintenance, in chemonaïve MPM. In the Phase II part, nintedanib treatment led to improved progression-free survival (PFS; hazard ratio [HR] = 0.54; p = 0.010) and a trend for longer overall survival (OS; HR = 0.77; p = 0.319) compared with placebo. Patients with epithelioid tumours derived greatest benefit. Plasma angiogenic factors and genomic markers were explored for potential associations with treatment outcome in the Phase II epithelioid population. Methods: Baseline plasma levels of 58 angiogenic factors were analysed by multiplex immunoassay (Human AngiogenesisMAP®, Myriad RBM). Genes implicated in the nintedanib mode of action and/or mesothelioma pathophysiology (VEGFR1, VEGFR3 and mesothelin) were evaluated for known single-nucleotide polymorphisms (SNPs). Biomarker associations with PFS/OS treatment effects were analysed by Cox regression and interaction tests with false-discovery rate (FDR) adjustment. Analyses were exploratory and hypothesis generating. Results: Angiogenic factor and genomic data were available for 71 and 67 patients, respectively, in the epithelioid population (n = 77). Of the angiogenic factors evaluated, only endoglin showed a possible trend for association with both PFS and OS improvement, with potentially greater benefit in patients with low plasma levels. Major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A) showed weak association with OS effect, while the VEGFR1 SNP rs9582036 A/A genotype was potentially correlated with PFS benefit. However, all biomarker treatment associations were limited by small subgroup size (especially for minor genotypes) and FDR-adjusted interaction tests were not significant. Conclusions: These first biomarker results for nintedanib-treated MPM showed potential signals for greater PFS/OS benefits in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, but no biomarkers showed clear and significant association with nintedanib efficacy. Clinical trial identification: NCT01907100 Legal entity responsible for the study: Boehringer Ingelheim Funding: Boehringer Ingelheim Disclosure: N. Pavlakis: Advisory Boards: Boehringer Ingelheim, MSD, Merck, BMS, Astra Zeneca, Takeda, Bayer, Novartis, Pfizer, Roche, Ipsen Speaking Honoraria: Boehringer Ingelheim, Bayer, Novartis, Pfizer, Roche Travel Support: BMS, Astra Zeneca, Roche. N. Steele: Honoraria: Pfizer, Novartis Consulting/advisory role: MSD, Boehringer Ingelheim, BMS Research funding: Merck Serono, AstraZeneca, Boehringer Ingelheim, BMS, Novartis, Roche Travel, accommodation, expenses: Pfizer, MSD Oncology, Boehringer Ingelheim. A. Nowak: Consulting/Advisory Role: Aduro Biotech, Morphotek, Bayer, AstraZeneca, Sellas Life Sciences, Trizell, Boehringer Ingelheim, Epizyme, Roche Research Funding: Boehringer Ingelheim, AstraZeneca Travel and expenses: Amgen, AstraZeneca, Boehringer Ingelheim. S. Novello: Speakers' Bureau: AstraZeneca, MSD, Bristol-Myers Squibb, Roche, Pfizer, Eli Lilly. S. Popat: Honoraria: Pfizer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Novartis, Roche Consulting/advisory role: Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Roche Research funding: Boehringer Ingelheim, Epizyme, BMS, Clovis Oncology, Eli Lilly, Roche. L. Greillier: Honoraria: Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Pfizer, AstraZeneca, Novartis Pharma, Roche Consulting/advisory role: Boehringer Ingelheim, Bristol-Myers Squibb, Roche Research funding: Roche. M. Reck: Honoraria: Boehringer Ingelheim, Proacta, BMS, MSD, Pfizer, Eli Lilly, AstraZeneca, Merck Inc., Celgene, Novartis Consulting/advisory role: Boehringer Ingelheim, Eli Lilly, BMS, MSD, Pfizer, AstraZeneca, Merck Inc., Celgene, Novartis, Roche Speaker's bureau: Roche, Eli Lilly, MSD Oncology, Merck, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Pfizer, Novartis. T. Kitzing: Employment: Boehringer Ingelheim. G. Scagliotti: Honoraria: Eli Lilly, Pfizer, MSD, AstraZeneca, Roche Consulting/Advisory role: Eli Lilly Speakers' Bureau: Eli Lilly, MSD. All other authors have declared no conflicts of interest.

765P - The nationwide cancer genome screening project in Japan SCRUM-Japan GI-SCREEN: Efficient identification of cancer genome alterations in advanced small intestine cancer

Background: We have conducted the Nationwide Cancer Genome Screening Project in Japan since April 2015 using Next Generation Sequencing in advanced non-colorectal gastrointestinal (GI) cancer (aNon-CRC), called as the SCRUM-Japan GI-SCREEN. Methods: This study is ongoing with 20 major cancer centers. Patients with aNon-CRC, including who plan to or receive chemotherapy were eligible. DNA and RNA were extracted from FFPE tumor samples and were analyzed by the Oncomine Cancer Research Panel (OCP) which allows to detect gene mutations, copy number variants (CNVs) and gene fusions across 143 genes in a CLIA certified CAP accredited laboratory. The detected genomic variant data were classified according to genetic drivers of cancer including gain- and loss-of-function or single nucleotide variant based on the Oncomine Knowledgebase. In this presentation, we show the results of advanced small intestine cancer cohort. Results: As of October 31st in 2016, a total of 36 advanced small intestine cancer samples were analyzed. The sequence was successfully performed in 26 tumors (72.2%). Out of 26 patients, the primary tumors are located in duodenum (n = 15), jejunum (n = 7), and ileum (n = 2), and unknown (n = 2). The frequently detected mutations in 26 samples of which results were available were KRAS (50.0%), TP53 (42.3%), and APC (23.1%). The frequently detected CNVs (≥ 7copies) were MDM2 (7.7%) and CDK6 (3.8%). PIK3CA mutations were identified in 4 cases (15.4%) and BRAF mutations were identified in 2 cases (7.7%). No gene fusion was detected. Conclusions: This nationwide screening system is efficient to detect rare gene alterations in advanced small intestine cancer. This novel knowledge provides an intriguing background to investigate new target approaches and represents a progress toward more precision medicine. Clinical trial identification: UMIN000016344 Legal entity responsible for the study: SCRUM-Japan GI-SCREEN Funding: 15 SCRUM-Japan collaborating pharmaceutical companies, AMED, NCC Disclosure: W. Okamoto: Research Funding from MSD. Y. Honma: Honoraria from Tenjin pharma. Speakers' bureau from Taiho, Nihon kayaku, Daiichi sankyo and Novartis. Research funding from Daiichi Sankyo, Astrazeneca, Merck serono, Novartis and Teijin pharma. T. Kudo: Research funding from Yakult Honsha, Chugai Pharma and Ono Pharma. Y. Komatsu: Honoraria from Novartis, Pfizer and Bayer. Speakers' bureau from Taiho, Lilly, Chugai, Merch, Novartis, Pfizer and Bayer. Research funding from Taiho, Lilly, MSD, Ono, Novartis, Bayer, Chugai and Yakult. H. Hara: Honoraria from Chugai, Taiho, Merck Serono, Yakult and Lilly. Consulting or advisory role from Ono and Chugai. Research funding from AstraZeneca, Chugai, Merck Serono, MSD, Ono, Taiho, Takeda, Boehringer Ingelheim, Daiichi Sankyo, Lilly, etc. D. Naruge: Research funding from Taiho, Ono, Onco Therapy Science, Merck, Zeria, Lilly, Takeda, Chugai, Bayer, Graxo Smith Kline, Yakult, Sumitomo Dainippom, Daiichi Sankyo, Novartis, Bristol-Myers, Sanofy, Kyowa Hakko Kirin, Astellas, Pfizer, Janssen. T. Moriwaki: Honoraria from Bayer, Chugai Pharma, Merck Serono, Novelpharma, Taiho Pharmaceutical, Takeda, and Yakult Honsha. Research funding from Boehringer Ingelheim, Chugai Pharma, MSD Oncology, Sanofi-Aventis, Taiho Pharmaceutical, Takeda, and Yakult Honsha. S. Nomura: An immediate family member has been employed by Asahi-Kasei pharma. K. Shitara: Receipt of grant/research supports from Daiichi Sankyo, Chugai Pharma, Lilly, MSD, Taiho Pharmaceutical and Dainippon Sumitomo Pharma. A. Ohtsu: An immediate family member has been employed from Celgene. Research Funding from Bristol-Myers Squibb. T. Yoshino: Research funding from GlaxoSmithKline K.K. and Boehringer Ingelheim GmbH. All other authors have declared no conflicts of interest.