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The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40–60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40–60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, is 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-CapOx and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5–56·3) in the adjuvant-CapOx group, 56·5% (51·0–61·7) in the adjuvant-SOX group, and 59·4% (53·8–64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61–0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68–1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3–4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. National Key Research and Development Program of China, Beijing Scholars Program 2018–2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. For the Chinese translation of the abstract see Supplementary Materials section.

Although adjuvant chemotherapy with gemcitabine is standard care for resected pancreatic cancer, S-1 has shown non-inferiority to gemcitabine for advanced disease. We aimed to investigate the non-inferiority of S-1 to gemcitabine as adjuvant chemotherapy for pancreatic cancer in terms of overall survival. We did a randomised, open-label, multicentre, non-inferiority phase 3 trial undertaken at 33 hospitals in Japan. Patients who had histologically proven invasive ductal carcinoma of the pancreas, pathologically documented stage I–III, and no local residual or microscopic residual tumour, and were aged 20 years or older were eligible. Patients with resected pancreatic cancer were randomly assigned (in a 1:1 ratio) to receive gemcitabine (1000 mg/m2, intravenously administered on days 1, 8, and 15, every 4 weeks [one cycle], for up to six cycles) or S-1 (40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 day rest, every 6 weeks [one cycle], for up to four cycles) at the data centre by a modified minimisation method, balancing residual tumour status, nodal status, and institutions. The primary outcome was overall survival in the two treatment groups, assessed in the per-protocol population, excluding ineligible patients and those not receiving the allocated treatment. The protocol prespecified that the superiority of S-1 with respect to overall survival was also to be assessed in the per-protocol population by a log-rank test, if the non-inferiority of S-1 was verified. We estimated overall and relapse-free survival using the Kaplan-Meier methods, and assessed non-inferiority of S-1 to gemcitabine using the Cox proportional hazard model. The expected hazard ratio (HR) for mortality was 0·87 with a non-inferiority margin of 1·25 (power 80%; one-sided type I error 2·5%). This trial is registered at UMIN CTR (UMIN000000655). 385 patients were randomly assigned to treatment between April 11, 2007, and June 29, 2010 (193 to the gemcitabine group and 192 to the S-1 group). Of these, three were exlcuded because of ineligibility and five did not receive chemotherapy. The per-protocol population therefore consisted of 190 patients in the gemcitabine group and 187 patients in the S-1 group. On Sept 15, 2012, following the recommendation from the independent data and safety monitoring committee, this study was discontinued because the prespecified criteria for early discontinuation were met at the interim analysis for efficacy, when all the protocol treatments had been finished. Analysis with the follow-up data on Jan 15, 2016, showed HR of mortality was 0·57 (95% CI 0·44–0·72, pnon-inferiority<0·0001, p<0·0001 for superiority), associated with 5-year overall survival of 24·4% (18·6–30·8) in the gemcitabine group and 44·1% (36·9–51·1) in the S-1 group. Grade 3 or 4 leucopenia, neutropenia, aspartate aminotransferase, and alanine aminotransferase were observed more frequently in the gemcitabine group, whereas stomatitis and diarrhoea were more frequently experienced in the S-1 group. Adjuvant chemotherapy with S-1 can be a new standard care for resected pancreatic cancer in Japanese patients. These results should be assessed in non-Asian patients. Pharma Valley Center, Shizuoka Industrial Foundation, Taiho Pharmaceutical.

Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated. In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer (SPIRITS) trial, we aimed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin than with S-1 alone. In this phase III trial, chemotherapy-naive patients with advanced gastric cancer were enrolled betweeen March 26, 2002, and Nov 30, 2004, at 38 centres in Japan, and randomly assigned to S-1 plus cisplatin or S-1 alone. In patients assigned to S-1 plus cisplatin, S-1 (40–60 mg depending on patient's body surface area) was given orally, twice daily for 3 consecutive weeks, and 60 mg/m 2 cisplatin was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks, followed by a 2-week rest period, within a 6-week cycle. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportions of responders, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00150670. 305 patients were enrolled; seven patients were ineligible or withdrew consent, therefore, 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone. Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin (13·0 months [IQR 7·6–21·9]) than in those assigned to S-1 alone (11·0 months [5·6–19·8]; hazard ratio for death, 0·77; 95% CI 0·61–0·98; p=0·04). Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone (median progression-free survival 6·0 months [3·3–12·9] vs 4·0 months [2·1–6·8]; p<0·0001). Additionally, of 87 patients assigned S-1 plus cisplatin who had target tumours, one patient had a complete response and 46 patients had partial responses, ie, a total of 54% (range 43–65). Of 106 patients assigned S-1 alone who had target tumours, one patient had a complete response and 32 had partial responses, ie, a total of 31% (23–41). We recorded more grade 3 or 4 adverse events including leucopenia, neutropenia, anaemia, nausea, and anorexia, in the group assigned to S-1 plus cisplatin than in the group assigned to S-1 alone. There were no treatment-related deaths in either group. S-1 plus cisplatin holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer.

The multicentre RESOLVE trial examined the efficacy of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in gastric or gastro-oesophageal junction cancer. Initial analyses did not encompass overall survival owing to the immature data. This paper provides an updated analysis of the survival data from the RESOLVE trial. In this randomised, open-label, phase 3 study, participants aged 18 years or older with cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma who were feasible for D2 lymphadenectomy and had a Karnofsky performance score of 70 or higher were enrolled. Participants were randomly assigned in a 1:1:1 ratio via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral capecitabine 1000 mg/m2 twice a day on days 1–14, adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral S-1 40–60 mg twice a day on days 1–14), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral S-1 40–60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy. The primary endpoint, assessed in the modified intention-to-treat population, was 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-CapOx and the non-inferiority (hazard ratio [HR] non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx, and has been reported previously. This final report focuses on the secondary endpoint of 5-year overall survival, also assessed in the modified intention-to-treat population. Other secondary endpoints—R0 resection rate and safety—were not updated in this analysis. The study is registered at ClinicalTrials.gov, NCT01534546, and is complete. Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were enrolled and randomly assigned, of whom 1022 participants were included in the modified intention-to-treat population: 345 (259 male, 86 female) in the adjuvant-CapOx group, 340 (238 male, 102 female) in the adjuvant-SOX group, and 337 (271 male, 66 female) in the perioperative-SOX group. As of April 7, 2022, the median duration of follow-up was 62·8 months (IQR 52·0–75·1). The 5-year overall survival rates were 52·1% (95% CI 46·3–57·5) for the adjuvant-CapOx group, 61·0% (55·3–66·2) for the adjuvant-SOX group, and 60·0% (54·2–65·3), for the perioperative-SOX group. Overall survival was significantly prolonged with perioperative-SOX (HR 0·79; 95% CI 0·62–1·00, p=0·049) and adjuvant-SOX (HR 0·77, 0·61–0·98, p=0·033), compared with adjuvant-CapOx. Consistent with the initial analysis of 3-year disease-free survival, the extended 5-year overall survival analysis from the RESOLVE trial confirmed the survival advantage of perioperative-SOX and adjuvant-SOX compared with the standard adjuvant-CapOx regimen. The SOX regimen, given perioperatively or as an adjuvant treatment, emerges as a potential standard treatment modality for locally advanced gastric or gastro-oesophageal junction cancer management in Asian patients. The National Key Research and Development Program of China, the National Natural Science Foundation of China, the Capital's Funds for Health Improvement and Research, the Beijing Natural Science Foundation, National Natural Science Foundation of China, the Beijing Natural Science Foundation, Taiho, Hengrui Pharmaceutical and Sanofi-Aventis. For the Chinese translation of the abstract see Supplementary Materials section.

Background Encouraging antitumor activity of nab-paclitaxel plus S-1 (AS) has been shown in several small-scale studies. This study compared the efficacy and safety of AS versus standard-of-care nab-paclitaxel plus gemcitabine (AG) as a first-line treatment for advanced pancreatic cancer (PC). Methods In this multicenter, randomized, phase II trial, eligible patients with unresectable, locally advanced, or metastatic PC were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 125 mg/m2 on days 1 and 8; S-1 twice daily on days 1 through 14) or AG (nab-paclitaxel 125 mg/m2 on days 1 and 8; gemcitabine 1000 mg/m2 on days 1 and 8) for 6 cycles. The primary endpoint was progression-free survival (PFS). Results Between July 16, 2019, and September 9, 2022, 62 patients (AS, n = 32; AG, n = 30) were treated and evaluated. With a median follow-up of 8.36 months at preplanned interim analysis (data cutoff, March 24, 2023), the median PFS (8.48 vs 4.47 months; hazard ratio [HR], 0.402; P = .002) and overall survival (OS; 13.73 vs 9.59 months; HR, 0.226; P < .001) in the AS group were significantly longer compared to the AG group. More patients had objective response in the AS group than AG group (37.50% vs 6.67%; P = .005). The most common grade 3-4 adverse events were neutropenia and leucopenia in both groups, and gamma glutamyl transferase increase was observed only in the AG group. Conclusion The first-line AS regimen significantly extended both PFS and OS of Chinese patients with advanced PC when compared with the AG regimen, with a comparable safety profile. (ClinicalTrials.gov Identifier: NCT03636308). Encouraging antitumor activity of nab-paclitaxel plus S-1 has been shown in several small-scale studies. This study compared the efficacy and safety of nab-paclitaxel plus S-1 versus standard-of-care nab-paclitaxel plus gemcitabine as a first-line treatment for advanced pancreatic cancer.

SummaryBackgroundOral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer. MethodsWe did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20–75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80–120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969. FindingsBetween Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1–58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49–0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [<1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (<1%) of 970 patients in the endocrine therapy alone group and 23 (2%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis. InterpretationThese data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer. FundingPublic Health Research Foundation (Japan), Taiho Pharmaceutical.

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. 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/m2l-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. 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). 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. Taiho.

Background Nivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited. Methods ATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician’s choice of SOX (oral S-1 [tegafur–gimeracil–oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints—centrally assessed progression-free survival (PFS) and overall survival (OS)—and landmark analyses of OS among patients alive using 3-year follow-up data. Results At the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55–0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75–1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy. Conclusion This 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer. Trial registration NCT02746796

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. 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. 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. 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. Taiho Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd.

Background We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. Methods We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. Results We enrolled 230 patients (anthracycline, n  = 115; S-1, n  = 115). Median overall survival was 30.1 months (95% CI 24.9–35.8) with the S-1 group and 33.7 months (95% CI 25.5–36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80–1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90–1.25); P non-inferiority = 0.0062). Conclusions S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. Clinical trial registration The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.