Ramucirumab is a monoclonal antibody that targets the vascular endothelial growth factor receptor 2 (VEGFR-2) and has been shown to improve survival of patients with advanced gastric cancer. It has been reported that sustained VEGF blockade beyond progression had a survival benefit in various cancers. This is a multicenter, open-label, randomized phase III study that enrolled patients with unresectable gastric cancer who had received previously ramucirumab containing chemotherapy. Patients were randomly allocated to either irinotecan plus ramucirumab arm or irinotecan alone arm in a 1:1 ratio. Irinotecan was administered at a dose of 150 mg/m2, every two weeks, in both arms, and ramucirumab at a dose of 8 mg/kg was added biweekly. The primary endpoint was overall survival (OS), expecting a hazard ratio (HR) of 0.77 (a power of 80% with significance level of one-sided 0.05) for full analysis set (FAS). Secondary endpoints include progression-free survival (PFS), overall response rate (ORR), and safety. From February 2019 to August 2022, 402 patients from 121 institutions participating 9 Japanese clinical trial groups were recruited. As of the data cutoff, 362 events for OS were observed. Median OS in the combination of irinotecan plus ramucirumab and irinotecan alone were 9.4 months and 8.5 months (adjusted HR 0.909, 95% confidence interval [CI] 0.738 – 1.119; p=0.369). Median PFS were 3.8 months and 2.8 months (HR 0.722, 95% CI 0.590 - 0.884; p=0.001) and ORR were 22.1% (33/149) and 15.0% (25/167), respectively. The safety profile was consistent with the known profiles of both irinotecan and ramucirumab, and there were no new safety findings. This is the first report of the phase III trial to evaluate sustained anti-angiogenic therapy in advanced gastric cancer. In this study, although the addition of ramucirumab to irinotecan after disease progression of ramucirumab improved PFS and ORR with manageable toxicity, the primary endpoint of OS was not met.

Anti-PD-1 antibody in addition to HER2-targeted therapy and chemotherapy may enhance antibody-dependent cell-mediated cytotoxicity and add further chemotherapeutic efficacy for HER2 -positive advanced gastric cancer (AGC). On the other hand, it remains unclear molecular profiles related to efficacy and resistance to this dual targeted therapy. Real-time tracking of these changes of the alteration using ctDNA may contribute to the treatment optimization. We enrolled tissue-confirmed HER2 -positive AGC who received chemotherapy with HER2 and anti-PD-1 dual targeted therapy from phase Ib clinical trial. Genomic profiling of 74 genes of their plasma by next-generation sequencing was carried out using ctDNA panel (Guardant 360®) to compare with their clinical parameters, clinical outcomes of dual targeted therapy and HER2 gene amplifications in matched tissue samples. Twenty-one patients were eligible in this study. HER2 gene amplification and single nucleotide variant (SNV) / Indels were detected in 12 (57.1%), 3 (14.3%) patients, respectively. Maximum mutant allele frequency (mMAF) in diffuse type histology were significantly lower than intestinal type histology (P = 0.01), and mMAF were associated with tumor diameter (r = 0.626, P = 0.0032). Tissue and ctDNA HER2 copy numbers were significantly correlated (r = 0.662, P = 0.019). Patients without HER2 SNV / Indels (n=17) had significantly longer PFS and OS than patients with HER2 SNV / Indels (n=3) (median PFS: 20.8 vs 8.4 months; P = 0.04; HR, 0.24, median OS: NA vs 14.0 months; P = 0.037; HR, 0.18). Moreover, patients with focal HER2 gene amplification (n = 9) had significantly longer PFS and OS than patients with HER2 aneuploidy (n=3) (median PFS: 20.8 vs 8.4 months; P = 0.007; HR, 0.08, median OS: NA vs 14.8 months; P = 0.0046; HR, 0.077). In patients achieving CR or PR (n=16), mMAF 3 weeks after initiation of chemotherapy was significantly lower than those in patients achieving SD (n=4) (P = 0.0087). Our data confirmed that HER2 SNV / Indels and gene amplification status may be predictor of treatment efficacy in patients with HER2- positive AGC who received chemotherapy with HER2 and PD-1 dual targeted therapy.

Recently, we reported safety and efficacy of T-mab plus N-mab with S-1/Capecitabine plus oxaliplatin (UMIN000034222). The aim of this study was to explore a candidate biomarker for this new combination therapy. Patients were treated with S-1 80 mg/m2/day or Capecitabine 2000 mg/m2/day on days 1-14 with oxaliplatin 130 mg/m2, N-mab 360mg, and T-mab 8mg/kg for initial treatment, and subsequently with 6 mg/kg on day 1, repeated every 3 weeks. Pre-treatment primary tumor samples were collected for whole exome sequencing (WES). 42 patients enrolled in this clinical trial, and WES was performed on 23 patients. In the copy number analysis, ERBB2 amp. was observed most frequently in 15 patients (65%). Subsequently, GATA6, MYC and CCNE1 amp. were observed in 8 (35%), 6 (26%), and 5 (22%) patients, respectively. In the mutation analysis, TP53 was observed most frequently in 20 patients (87%). Subsequently, mutations in APC, ERBB3, and PIK3CA were observed in 6 (26%), 3 (13%), and 3 (13%) patients, respectively. Among them, APC mut., MYC, and GATA6 amp. were associated with worse survival. Patients with APC mut. showed significantly shorter PFS (median 5.6 vs 20.8 months, HR 3.47, 95%CI 1.16-10.44, p = 0.018), but not for OS (median 21.0 vs 26.5 months, HR 1.19, 95%CI 0.31-4.60, p = 0.806). Patients with MYC amp. showed significantly shorter PFS (median 4.2 vs 18.0 months, HR 3.48, 95%CI 1.09-11.12, p = 0.024) and OS (median 13.9 months vs not reached, HR 3.97, 95%CI 0.95-16.54, p = 0.042), respectively. Patients with GATA6 amp. showed significantly shorter PFS (median 5.8 vs 32.0 months, HR 3.53, 95%CI 1.25-9.99, p = 0.011) and OS (median 13.9 months vs not reached, HR 3.74, 95%CI 1.04-13.40, p = 0.030). As for objective response rates (ORRs), patients with APC mut. and MYC amp. showed lower response rates (50% vs 82% for APC mut., 67% vs 77% for MYC amp.), whereas comparable ORR was shown for GATA6 amp. (75% vs 73 %). APC mut., MYC, and GATA6 amp. may have negative clinical impacts on the effects of the new combination therapy including T-mab and N-mab.

We conducted a clinical trial evaluating safety and efficacy of T-mab plus N-mab with S-1/Capecitabine plus oxaliplatin (UMIN000034222). The aim of this study was to investigate the clinical significance of ERBB2 amplification (amp.) and TMB-H for this new combination therapy. Patients were treated with S-1 80 mg/m2/day or Capecitabine 2000 mg/m2/day on days 1-14 with oxaliplatin 130 mg/m2, N-mab 360mg, and T-mab 8mg/kg for initial treatment, and subsequently with 6 mg/kg on day, repeated every 3 weeks. Pretreatment primary tumor samples were collected for whole exome sequencing (WES) and immunohistochemistry (IHC). Among 42 patients enrolled in this clinical trial, WES was performed on 23 patients. ERBB2 amp. (≥ 6 copies) was observed in 15 patients (65%). Fourteen (93.3%) of these 15 patients with ERBB2 amp. and 2 (25%) of 8 patients without ERBB2 amp. were IHC3+, respectively (p = 0.002). There was a weak positive correlation between ERBB2 copy number and PFS (r = 0.449, p = 0.032). Patients with ERBB2 amp. showed longer PFS than those without ERBB2 amp. (mPFS: 16.3 vs 5.8 months, HR = 0.70 [95%CI 0.24-2.09], p = 0.522). In particular, 7 patients with high ERBB2 copy number (≥ 50) showed remarkably longer PFS and a higher response rate than 16 patients with < 50 (mPFS: 20.8 vs 6.7 months, HR = 0.40 [95%CI 0.12-1.30], p = 0.117, response rate: 100% vs 63%, p = 0.124). TMB-H (≥ 10 muts/Mb) was observed in 6 patients (26%), and these patients also showed substantially longer PFS than those with TMB-L (mPFS: 16.3 vs 9.2 months, HR = 0.43 [95%CI 0.12-1.51], p = 0.172) with a comparable response rate (83% vs 73%). Eleven patients with ERBB2 copy number ≥ 50 or TMB-H showed significantly longer PFS (mPFS: 20.8 vs 5.8 months, HR = 0.28 [95%CI 0.09-0.88], p = 0.021) and OS (mOS: not reached vs 15.0 months, HR = 0.10 [95%CI 0.01-0.78], p = 0.007) and a higher response rate (91% vs 58%, p = 0.155) than the remaining 12 patients. High ERBB2 copy number and TMB-H may be a candidate biomarker for this new combination therapy including T-mab and N-mab in patients with HER2-positive advanced gastric cancer.

Previous studies showed that angiogenesis-related factors could play a key role in the development of immunosuppressive microenvironment and may serve as predictors for chemotherapy. This biomarker study was focused on the dynamics of angiogenesis-related factors in clinical trial of combination therapy with PTX, RAM plus Nivo for AGC as 2nd-line treatment, with expected antitumor activity [Kadowaki S, et al, Ann Oncol, 2019 Jul;30 Suppl4]. We evaluated plasma concentrations of angiogenesis-related factors in plasma at baseline, 4 weeks after treatment, and progression and the association with clinical outcomes in patients with available samples. PlGF, VEGF-A/D, HGF, IL-6/8, angiopoietin-2, sNeurophilin-1, sICAM-1, sVCAM-1, sVEGFR-1/2/3, and INF-γ were measured by magnetic bead panel Milliplex xMAP kits, Flt3L and sPD-L1 by ELISA. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by the log-rank test. Fisher's exact test was used to compare IL-6 level and response. Forty-one of 43 AGC pts were enrolled: median age, 66 years; male, 82.9%; ECOG PS 1, 48.8%; and diffuse type, 43.9%. Plasma average levels of PlGF, VEGF-A/D, and sVCAM-1 significantly increased after treatment; whereas angiopoietin-2 exhibited a decrease during treatment. When the median value was adopted as cut-off value, high levels of IL-8 and sICAM-1 at baseline were significantly associated with shorter OS [HR 2.69 (95%CI 1.28-5.92), p = 0.009; HR 3.50 (95%CI 1.63-8.16), p = 0.001, respectively]; whereas, comparable PFS. The elevation of IL-6 level at 4 weeks were detected in 8 (35%) of 23 responders and in only 2 (15%) of 13 non-responders (P = 0.21). Moreover, it was significantly associated with favorable OS [HR 0.20 (95%CI 0.05-0.60), p = 0.002], but not PFS. This study identified baseline plasma levels of IL-8 and sVCAM-1 as potential prognostic markers corresponding to favorable OS for combination therapy of PTX, RAM plus Nivo in patients with AGC. In addition, the increase in IL-6 level at 4 weeks may predict clinical benefit from the combination therapy.

We previously reported that trastuzumab (Tmab) combined with S-1 plus oxaliplatin (SOX) exhibited promising activity with well-tolerated toxicities in patients (pts) with human epidermal growth factor receptor type 2 (HER2)-positive advanced gastric cancer (AGC) (Gastric Cancer 2019). Here, we report the results of a follow-up extension, including exploratory analyses performed to investigate predictive factors for treatment effects. We conducted an open-label, phase II trial in pts with chemo-naïve, HER2-positive AGC. Pts received S-1 (40 mg/m2) BID orally on days 1–14, oxaliplatin (130 mg/m2) intravenously on day 1, and Tmab (course 1, 8 mg/kg; course 2, 6 mg/kg) intravenously on day 1 of a 21-day cycle. The primary endpoint was objective response rate (ORR); secondary end points included overall survival (OS), progression-free survival (PFS), and adverse events. A sample of 75 provided the study with 90% power to test a hypothesis of threshold RR of 50% and an expected RR of 65% at a one-sided significance level of 0.05 using the binomial test. Seventy-five patients were enrolled from June 2015 to January 2018. Pts characteristics were previously reported. In the full analysis set of 75 pts with a median follow up of 20.6 months, ORR was 70.7% (95% confidence interval (CI): 59.0–80.6) and the disease control rate was 93.3% (95% CI: 85.1–97.8). OS and PFS (median) were 20.6 (95% CI: 15.9–29.2) and 8.8 (95% CI: 7.3–11.8) months, respectively. In the exploratory analyses, both OS and PFS were longer in pts with HER2 3+ (n=55) than in pts with 2+ (n=20) [OS, 25.9 vs.16.3 months; hazard ratio (HR), 0.59; 95% CI: 0.329–1.053; P=0.07; PFS, 9.8 vs. 7.0 months; HR, 0.72; 95% CI: 0.421–1.229; P=0.23]. Pts who underwent conversion surgery (n=8) exhibited dramatically prolonged survival [OS, not reached; 3-year survival rate, 85.7% (95% CI: 33.4–97.9), PFS, 34.5 months (95% CI: 6.9–not reached)]. Tmab in combination with SOX exhibited promising therapeutic effects in pts with HER2-positive AGC. Efficacy was enhanced in pts with HER2 3+ and in those who underwent conversion surgery.

The first-in-human phase I study of E7090 consists of dose-escalation (Part 1) and expansion (Part 2) cohorts, which has been conducted in Japan. The interim analysis results of Part 2, as of 31 July 2019, were reported (ASCO-GI 2020 #538). The interim analysis indicated that E7090 had a manageable safety profile and the promising clinical activity in cholangiocarcinoma subjects with FGFR2 rearrangements. In this study, we analyzed tumor tissue and plasma samples with NGS panels to assess baseline tumor gene characteristics and evolution of the ctDNA profile during E7090 treatment. In part 2, subjects with cholangiocarcinoma harboring FGFR2 gene rearrangements (cholangiocarcinoma [CCA] cohort) and gastric cancer harboring FGFR2 gene amplification or FGFR2 protein high expression (GC cohort) were enrolled. Archival tumor tissue samples were analyzed with PGDx elio tissue complete NGS panel (PGDx; Personal Genome Diagnostics, Inc.). Plasma sample was collected at pre-treatment, every day 1 of odd cycle on-treatment and at discontinuation visit for ctDNA analysis with PGDx elio plasma resolve NGS panel. As of cutoff date, 3 June 2020, 6 subjects harboring FGFR2 rearrangements identified with break-apart fluorescence in situ hybridization were enrolled in the CCA cohort. Among six tumor tissue samples, one was failed in quality-check of NGS assay. Fusion gene partner in FGFR2 rearrangements was identified in 4 of the 5 tumor tissues as BICC1, CCDC6, POC1B, and SLMAP (n=1, each). FGFR2 rearrangements were also detected in baseline blood samples from 3 of the 6 subjects. In those three cases, the number of mutant reads for FGFR2 rearrangements in ctDNA assay decreased during treatment. ctDNA for FGFR2 (L617F, M537I) were detected in blood from 2 subjects at discontinuation visit. The updated efficacy and safety results in Part 2 will also be presented as of a new cutoff date. The NGS assay illuminated FGFR2 fusion partners in archival tumor tissues. Besides, ctDNA analysis indicated ctDNA for FGFR2 rearrangements were decreased during E7090 treatments, and the potential clonal changes occurred as detections of ctDNA with FGFR2 mutations.

For clinical stage I submucosal (cT1b-SM) thoracic esophageal squamous cell carcinoma (ESCC), surgery is the standard treatment and chemoradiotherapy (CRT) is optional. We conducted a single-arm confirmatory study of diagnostic endoscopic resection (ER) plus selective CRT for cT1bN0M0 ESCC and reported that the 5-year overall survival (OS) ASCO Annual Meeting. In the current study, we analyzed the regional lymph-node (LN) failure patterns at the final follow-up for patients (pts) who received CRT to explore the way to further improvement of this strategy. The eligibility criteria of JCOG0508 included: histologically proven thoracic ESCC, T1b diagnosed by endoscopic ultrasound, cN0M0, primary tumor size ≤ 5 cm and esophageal lumen circularity ≤ 3/4, and age 20-75 years. After ER, additional CRT was indicated by pathological (p) findings: Group B, pT1b with negative resection margin and pT1a with vascular invasion -prophylactic CRT; Group C, pT1b with positive resection margin -definitive CRT. In Group A (pT1a with no vascular invasion), no treatment was added. CRT consisted of 2 courses of chemotherapy (5-fluorouracil and cisplatin with 4-week interval), and radiation therapy (RT) of 41.4 Gy/23 fr delivered to the loco-regional LN area (Group B) or 50.4 Gy/28 fr with a boost to the primary site (Group C). Of 177 pts registered in 2006-2012, 102 pts were classified into Group B/C (87/15) after ER. At the final follow-up, pts who experienced regional LN failure as the first site were extracted from Group B/C. Diagnostic radiographs and RT planning data were collected for central review to verify relationship between failure site and irradiation field. Among 102 pts, 96 actually received CRT to the loco-regional LN area (Group B/C: 83/13). At the final follow-up, 11 pts (Group B/C: 9/2) experienced regional LN failure as the first site (11.5%). Median time to failures and OS after registration was 498 days (232 - 1632) and 917 days (392 - 2200) in these pts. Clinico-pathological findings of primary lesions were as follows; Ut/Mt/Lt: 0/9/2, pM3/pSM1/pSM2: 1/2/8, ly0/1: 3/8, v0/1: 5/6. The number of LN failures was solitary in 8 pts. With regard to relationship between failure site and RT field, in-field/out-of-field/both/marginal failures were observed in 8/0/2/1, respectively. All out-of-field failures occurred in abdominal para-aortic LN area. All pts received second line chemotherapy and/or salvage surgery for LN failures. Although the diagnostic ER plus selective CRT for T1b ESCC was shown to have comparable efficacy to surgery as a minimally invasive option, in-field regional LN failure was observed in 11.5% among pts who received CRT. There may be still room to improve in radiation field and/or dose.

Abstract Background Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated. Patients and methods Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. Results Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0–78.2) with nivolumab plus SOX and 76.5% (50.1–93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8–NR) and 10.6 months (5.6–12.5), respectively. Conclusion Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX. Clinicaltrials.gov ID NCT02746796.

Background: Nivolumab (Nivo) monotherapy has demonstrated clinical activity and safety for esophageal cancer refractory or intolerant to standard chemotherapy (Lancet oncology, online March 14, 2017, http://doi.org/10.1016/S1470-2045(17)30181-X). We report updated results base on a minimum follow-up of 2-years. Methods: Patients aged ≥ 20 years with ECOG PS 0-1 were enrolled and treated with Nivo (3 mg/kg, IV, Q2W) until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) evaluated by independent review committee according to RECIST 1.1. Other endpoints included safety, overall survival (OS), progression-free survival (PFS) and duration of response (DOR). Results: Between February 25, 2014 and November 14, 2014, 65 patients with esophageal squamous-cell carcinoma were enrolled; median age of 62 years (range 49-80); male/female, 54/11; ECOG PS 0/1, 29/36; median number of 3.0 (range 1-8) prior regimens. The primary endpoint of ORR was 17.2% (11/64 patients, CR/PR: 1/10, 95% confidence interval [CI] 9.9, 28.2) as of May 17, 2015. Median OS and PFS were 10.8 and 1.5 months. With a minimum follow-up of 2-years (cutoff date November 17, 2016), 6 patients remained on treatment with Nivo. The ORR was 17.2% (CR/PR: 3/8) and median DOR was 11.17 months (95% CI 3.02, -). The Kaplan-Meier estimated 1-, 1.5- and 2-years OS rate were 45.3% (95% CI 32.9, 56.9), 25.0% (15.2, 36.0) and 17.2% (9.2, 27.3). One, 1.5- and 2-years PFS rate were 10.3% (95% CI: 4.2, 19.4), 8.6% (3.2, 17.3) and 8.6% (3.2, 17.3). Adverse events (AEs) were reported in 56 (86.2%) of 65 patients including grade 3 − 4 AEs reported in 19 patients (29.2%). The most common AEs were diarrhea (21.5%), decreased appetite (18.5%), lung infection (13.8%) and cough (12.3%). Seven patients (10.8%) discontinued the study treatment due to drug-related AEs, while no treatment-related death was reported. Conclusions: Nivo suggest a durable, long-term survival benefit with 17.2% of patients alive at 2-years. These data support ongoing phase III study (NCT 02569242) assessing Nivo monotherapy compared with docetaxel or paclitaxel. Clinical trial identification: JapicCTI-No.142422 Legal entity responsible for the study: Ono Pharmaceutical Co., Ltd Funding: Ono Pharmaceutical Co., Ltd, Bristol-Myers Squibb Disclosure: Y. Kitagawa: Ono Pharmaceutical Co.,Ltd. and Bristol-Myers Squibb (Honoraria, Grants, research supports). Y. Doki: Ono Pharmaceutical Co.,Ltd. (advisory doard), Ono Pharmaceutical Co.,Ltd. (Honoraria, Grants, research supports). K. Kato: Ono Pharmaceutical Co.,Ltd., Shionogi, MSD. T. Kojima: Institution (Ono Pharmaceutical Co.,Ltd., Shionog, MSD, Taiho, Merck Serono, AstraZeneca) S. Hironaka: Advisory Board (MBL), Honoraria (Yakult Honsha, Eli lilly). H. Hara: Advisory role (Ono, Chugai Pharma), “Honoraria (Chugai, Taiho, Merck Serono, Yakult Honsha, Lilly) Reserch funding (AstraZeneca, Chugai, Merck Serono, MSD, Ono, Taiho, Takeda, Boehringer Ingelheim, Dainippon Sumitomo, Daiichi Sankyo, Lilly). T. Kudo: Bayer (research supports). S. Iwasa: corporate-sponsored research (Novartis, Merck Serono, Lilly, Daiichi Sankyo, Bristol-Myers Squibb). K. Muro: Shionogi, MSD, Daiichi Sankyo, Kyowa Hakko Kirin, Gilead Sciences, honoraria for lectures. (Chugai, Takeda, Eli Lilly Japan, Merck Serono, Taiho, Yakult honsha). K. Yamaguchi: Ono Pharmaceutical Co., Ltd (research supports). All other authors have declared no conflicts of interest.

Background: Nivo monotherapy demonstrated its efficacy with manageable safety for G/GEJ cancer refractory or intolerant to standard chemotherapy at the primary analysis (ATTRACTION-02[ONO-4538-12]: ASCO-GI 2017, Kang YK et al. J Clin Oncol. 2017; 35 [suppl 4S abstract 2]). This randomized phase 2/3 trial is to evaluate the efficacy and safety of Nivo in combination with 1st line chemotherapy in unresectable advanced or recurrent G/GEJ cancer (NCT02746796). Methods: This trial includes previously untreated pts aged ≥ 20 years with ECOG PS 0-1 and had measurable, unresectable advanced or recurrent HER2 (-) G/GEJ cancer. It consists of 2 parts. Part 1 is a randomized, open-label trial to evaluate the feasibility of Nivo (360 mg, Q3W) in combination with oxaliplatin (130 mg/m2, Q3W) plus either S-1 (40 mg/m2 twice daily, day 1-14, SOX) or capecitabine (1000 mg/m2 twice daily, day 1-14, CapeOX) in terms of activity and safety. Part 2 is a randomized, double-blind, placebo-controlled trial comparing Nivo to placebo in combination with SOX/CapeOX in terms of overall survival and progression free survival (PFS). Results: A total of 40 pts were included into part 1, 21 pts were randomized to Nivo+SOX and 19 to Nivo+CapeOX. The median age was 62.5 years, 27 pts (67.5%) were male, 20 pts (50.0%) had ECOG PS 1. Median duration of treatment was 7.03 months (range 0.1-9.9) as of 24 Feb 2017. Both treatments were well tolerated. Grade 3-4 treatment-related adverse events (AEs) were reported 23 pts (57.5%). No Nivo-related AEs leading to discontinuation were reported. Overall response rate was 68.4% (26/38, CR10, PR16) and disease control rate was 86.8%. Median PFS was not reached. 18 pts (46.2%) remain on treatment at the time of the data cut off. There were no significant differences in activity and safety between the 2 treatments. Conclusions: Nivo+SOX/CapeOX were feasible with promising activity as the 1st-line chemotherapy in pts with previously untreated unresectable advanced or recurrent G/GEJ cancer. Part 2 of the study is ongoing. Clinical trial identification: NCT02746796 Legal entity responsible for the study: Ono Pharmaceutical Co., ltd. Funding: Ono Pharmaceutical Co., ltd., Bristol-Myers Squibb Disclosure: Y-K. Kang: Ono, Bristol-Myers Squibb, Lilly/ImClone, Taiho Pharmaceutical, Roche/Genentech, Novartis, Bayer. K. Kato: Ono Pharmaceutical Co., Ltd., Shionogi, MSD. H.C. Chung: Lilly, GSK, MSD, Merck-Serono, BMS/Ono, Taiho, Celltrion, Quintiles, BMS. K-W. Lee, K. Yamaguchi: Ono. Y. Komatsu: Taiho, Lilly, MSD, Ono, Novartis, Bayer, Chugai, Yakult, Pfizer, Merck. H. Hara: Chugai Pharma, Taiho Pharmaceutical, Merck Serono, Yakult Honsha, Lilly, AstraZeneca, MSD, Ono Pharmaceutical, Takeda, Boehringer Ingelheim, Dainippon Sumitomo Pharma, Daiichi Sankyo. N. Boku: Ono, Taiho, Chugai, Eli-Lily. L-T. Chen: Novartis, GSK, Merck Serono, TTY, Polaris, ONO, Eli Lilly, MSD, PharmaEngine, Merrimack, Syncore, Five Prime, anti-alpha enolase (ENO-1) monoclonal antibody/HuniLife. All other authors have declared no conflicts of interest.