Summary Background Nivolumab is a human monoclonal IgG4 antibody that inhibits programmed cell death protein 1 (PD-1) expressed on activated T cells. We investigated the safety and activity of ...nivolumab in patients with treatment-refractory oesophageal cancer. Methods We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. The primary endpoint was centrally assessed objective response (the proportion of patients whose best response was complete or partial response), according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related adverse events (defined as events for which a causal relation to nivolumab could not be ruled out) were monitored throughout the study. The safety analysis was done in patients who received at least one dose of nivolumab, and drug activity was assessed in patients who received at least one dose of nivolumab and had at least one central assessment of tumour response. This study is registered with clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients is ongoing. Findings Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10·8 months (IQR 4·9–14·3). 11 (17%, 95% CI 10–28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one 2%) patient each), grade 3 lung infection (five 8% patients), grade 3 decreased appetite (two 3% patients), grade 3 increased blood creatinine phosphokinase (two 3% patients), and grade 3 dehydration (two 3% patients). Serious adverse events that occurred during the study were lung infection (four 6% patients), dehydration (two 3%), interstitial lung disease (two 3%), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one 2% patient each). There were no treatment-related deaths. Interpretation Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma. Funding Ono Pharmaceutical, Bristol-Myers Squibb.
Summary Background Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line ...treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. Methods ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov , number NCT01041404. Findings 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18·6 months (IQR 11–25) in the trastuzumab plus chemotherapy group and 17·1 months (9–25) in the chemotherapy alone group. Median overall survival was 13·8 months (95% CI 12–16) in those assigned to trastuzumab plus chemotherapy compared with 11·1 months (10–13) in those assigned to chemotherapy alone (hazard ratio 0·74; 95% CI 0·60–0·91; p=0·0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 67% vs chemotherapy alone, 184 63%), vomiting (147 50% vs 134 46%), and neutropenia (157 53% vs 165 57%). Rates of overall grade 3 or 4 adverse events (201 68% vs 198 68%) and cardiac adverse events (17 6% vs 18 6%) did not differ between groups. Interpretation Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. Funding F Hoffmann-La Roche.
Summary Background Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish ...whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer. Methods We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20–80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m2 oxaliplatin, 200 mg/m2 l -leucovorin, 400 mg/m2 bolus fluorouracil, and 2400 mg/m2 infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m2 intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699. Findings Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7–13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7–12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86–1·27; less than non-inferiority margin of 1·33, pnon-inferiority =0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 8% of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six 2% of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 34% vs 22 9%; p<0·0001). Grade 3 or higher anorexia (13 5% vs three 1%; p=0·019) and diarrhoea (23 9% vs seven 3%; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab). Interpretation SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations. Funding Taiho.
Summary Background Fluorouracil and folinic acid with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are widely used as first-line or second-line chemotherapy for metastatic colorectal cancer. ...However, infusional fluorouracil-based regimens, requiring continuous infusion and implantation of an intravenous port system, are inconvenient. We therefore planned an open-label randomised controlled trial to verify the non-inferiority of irinotecan plus oral S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; IRIS) to FOLFIRI as second-line chemotherapy for metastatic colorectal cancer. Methods Between Jan 30, 2006, and Jan 29, 2008, 426 patients with metastatic colorectal cancer needing second-line chemotherapy from 40 institutions in Japan were randomly assigned by a computer-based minimisation method to receive either FOLFIRI (n=213) or IRIS (n=213). In the FOLFIRI group, patients received folinic acid (200 mg/m2 ) and irinotecan (150 mg/m2 ) and then a bolus injection of fluorouracil (400 mg/m2 ) on day 1 and a continuous infusion of fluorouracil (2400 mg/m2 ) over 46 h, repeated every 2 weeks. In the IRIS group, patients received irinotecan (125 mg/m2 ) on days 1 and 15 and S-1 (40–60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was progression-free survival, with a non-inferiority margin of 1·333. Statistical analysis was on the basis of initially randomised participants. This study is registered with ClinicalTrials.gov , number NCT00284258. Findings All randomised patients were included in the primary analysis. After a median follow-up of 12·9 months (IQR 11·5–18·2), median progression-free survival was 5·1 months in the FOLFIRI group and 5·8 months in the IRIS group (hazard ratio 1·077, 95% CI 0·879–1·319, non-inferiority test p=0·039). The most common grade three or four adverse drug reactions were neutropenia (110 52·1% of 211 patients in the FOLFIRI group and 76 36·2% of 210 patients in the IRIS group; p=0·0012), leucopenia (33 15·6% in the FOLFIRI group and 38 18·1% in the IRIS group; p=0·5178), and diarrhoea (ten 4·7% in the FOLFIRI group and 43 20·5% in the IRIS group; p<0·0001). One treatment-related death from hypotension due to shock was reported in the FOLFIRI group within 28 days after the end of treatment; no treatment-related deaths were reported in the IRIS group. Interpretation Progression-free survival with IRIS is not inferior to that with FOLFIRI in patients receiving second-line chemotherapy for metastatic colorectal cancer. Treatment with IRIS could be an additional therapeutic option for second-line chemotherapy in metastatic colorectal cancer. Funding Taiho Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd.