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Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4).

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.

SUBMITTER: Boku N

PROVIDER: S-EPMC6386029 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4).

Boku N N Ryu M-H MH Kato K K Chung H C HC Minashi K K Lee K-W KW Cho H H Kang W K WK Komatsu Y Y Tsuda M M Yamaguchi K K Hara H H Fumita S S Azuma M M Chen L-T LT Kang Y-K YK

Annals of oncology : official journal of the European Society for Medical Oncology 20190201 2

<h4>Background</h4>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 ther ...[more]

PMID: 30566590

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Project description:BackgroundEGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma.MethodsIn this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785.FindingsBetween June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]).InterpretationAddition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma.FundingAmgen, UK National Institute for Health Research Biomedical Research Centre.

Project description:Lessons learnedAdding docetaxel to the modified FOLFOX7 backbone (DOF) is a feasible three-drug combination therapy for advanced gastric cancer with high activity, providing evidence that leucovorin is not necessary in this setting.The DOF regimen represents an alternative to the FLOT (5-FU 2,600 mg/m2 as 24-hour infusion with leucovorin 200 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2) regimen that can be considered in select patients with advanced gastric cancer and is a potential choice in the curative setting.BackgroundThe combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) demonstrates high response rates in advanced gastric cancer, albeit with increased toxicity. Given the efficacy of platinum-taxane-fluoropyrimidine regimens, this phase II study evaluated the efficacy and toxicity of docetaxel, oxaliplatin, and 5-FU (DOF) for the treatment of metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma.MethodsPatients with metastatic or unresectable gastric or GEJ adenocarcinoma with no prior therapy for metastatic disease received docetaxel 50 mg/m2 on day 1, oxaliplatin 85 mg/m2 on day 1, and 5-FU 2,400 mg/m2 continuous intravenous infusion over 46 hours; cycles were repeated every 2 weeks. The primary endpoint was overall response rate (ORR).ResultsForty-four patients were enrolled. Assessment of treatment response and toxicity was feasible in 41 and 43 patients, respectively. ORR was 73.2% (68.3% partial response; 4.9% complete response). Therapy was discontinued for progressive disease in 53%, toxicity in 26%, and death on treatment in 16%. Two patients underwent surgical resection. Thirty-three patients (76.7%) received at least seven cycles (7-34). Grade 3-4 toxicities occurred in 31 patients (72.1%), including neutropenia (23.3%), neurologic (20.9%), and diarrhea (14.0%). Median overall survival was 10.3 months.ConclusionDOF demonstrates a high response rate, expected safety profile, and prolonged survival and remains an option for select patients with unresectable or metastatic gastric or GEJ adenocarcinoma.

Project description:BackgroundAdding anti-angiogenics to neoadjuvant chemotherapy for localized gastric cancer is recognized as a promising strategy, but its clinical value remains to be defined.MethodsThis single-center, single-arm, phase 2 trial included patients with locally advanced (cT3/4aN+M0) adenocarcinoma of the stomach or gastroesophageal junction (GEJ) who received three cycles of intravenous oxaliplatin (135 mg/m2 on day 1), oral capecitabine (1000 mg/m2 twice daily on days 1 to 14), and oral apatinib for 21 days (250 mg once daily in the first two cycles, and further increased to 500 mg daily in the third cycle based on whether any adverse event of grade 3 or worse occurred), and an additional cycle of oxaliplatin plus capecitabine, followed by gastrectomy with D2 lymphadenectomy. The primary endpoint was the proportion of patients who achieved an objective response according to RECIST version 1.1.ResultsBetween April 28, 2017, and October 23, 2019, 37 patients were screened and 35 participants were included. Of the 32 patients assessable for efficacy and safety, objective responses were achieved in 25 (78.1%; 95% confidence interval [CI], 60.0% to 90.7%) patients. Thirty-one (96.9%) patients received R0 resection, two (6.3%) patients achieved pathological complete response, and 11 (34.4%) patients achieved pathological response. At the data cutoff date (September 30, 2021), the median event-free survival was 42.6 (95% CI, 16.2 to not reached) months, and the median overall survival was not reached. The most common grade 3 or 4 treatment-emergent adverse events were hypertension (9/32, 28.1%), thrombocytopenia (7/32, 21.9%), and neutropenia (5/32, 15.6%). Seven (21.9%) patients developed surgical complications, and the most common one was intra-abdominal abscess (4/32, 12.5%).ConclusionsThe concomitant use of apatinib, oxaliplatin, and capecitabine as neoadjuvant therapy showed promising efficacy and manageable safety profile in patients with locally advanced adenocarcinoma of the stomach or GEJ, and further phase 3 study is warranted.Trial registrationThis study was registered with ClinicalTrial.gov ( NCT03229096 ).

Dataset Information

Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4).

Publications

Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4).

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