Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): final report of a rando

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.

Zhang X ，Liang H ，Li Z ，Xue Y ，Wang Y ，Zhou Z ，Yu J ，Bu Z ，Chen L ，Du Y ，Wang X ，Wu A ，Li G ，Su X ，Xiao G ，Cui M ，Wu D ，Chen L ，Wu X ，Zhou Y ，Zhang L ，Dang C ，He Y ，Zhang Z ，Sun Y ，Li Y ，Chen H ，Bai Y ，Wang Y ，Yu P ，Zhu G ，Suo J ，Jia B ，Li L ，Huang C ，Li F ，Ye Y ，Xu H ，Wang X ，Yuan Y ，E J ，Ying X ，Yao C ，Shen L ，Ji J ... -  《-》

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superior

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, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX 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.

Zhang X ，Liang H ，Li Z ，Xue Y ，Wang Y ，Zhou Z ，Yu J ，Bu Z ，Chen L ，Du Y ，Wang X ，Wu A ，Li G ，Su X ，Xiao G ，Cui M ，Wu D ，Chen L ，Wu X ，Zhou Y ，Zhang L ，Dang C ，He Y ，Zhang Z ，Sun Y ，Li Y ，Chen H ，Bai Y ，Qi C ，Yu P ，Zhu G ，Suo J ，Jia B ，Li L ，Huang C ，Li F ，Ye Y ，Xu H ，Wang X ，Yuan Y ，E JY ，Ying X ，Yao C ，Shen L ，Ji J ，RESOLVE study group ... -  《-》

Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial.

The optimum curative approach to adenocarcinoma of the oesophagus and oesophagogastric junction is unknown. We aimed to compare trimodality therapy (preoperative radiotherapy with carboplatin plus paclitaxel [CROSS regimen]) with optimum contemporaneous perioperative chemotherapy regimens (epirubicin plus cisplatin or oxaliplatin plus fluorouracil or capecitabine [a modified MAGIC regimen] before 2018 and fluorouracil, leucovorin, oxaliplatin, and docetaxel [FLOT] subsequently). Neo-AEGIS (CTRIAL-IE 10-14) was an open-label, randomised, phase 3 trial done at 24 centres in Europe. Patients aged 18 years or older with clinical tumour stage T2-3, nodal stage N0-3, and M0 adenocarcinoma of the oesophagus and oesophagogastric junction were randomly assigned to perioperative chemotherapy (three preoperative and three postoperative 3-week cycles of intravenous 50 mg/m2 epirubicin on day 1 plus intravenous 60 mg/m2 cisplatin or intravenous 130 mg/m2 oxaliplatin on day 1 plus continuous infusion of 200 mg/m2 fluorouracil daily or oral 625 mg/m2 capecitabine twice daily up to 2018, with four preoperative and four postoperative 2-week cycles of 2600 mg/m2 fluorouracil, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin, and 50 mg/m2 docetaxel intravenously on day 1 as an option from 2018) or trimodality therapy (41·4 Gy in 23 fractions on days 1-5, 8-12, 15-19, 22-26, and 29-31 with intravenous area under the curve 2 mg/mL per min carboplatin plus intravenous 50 mg/m2 paclitaxel on days 1, 8, 15, 22, and 29). The primary endpoint was overall survival, assessed in all randomly assigned patients who received at least one dose of study drug, regardless of which study drug they received, by intention to treat. Secondary endpoints were disease-free survival, site of treatment failure, operative complications, toxicity, pathological response (complete [ypT0N0] and major [tumour regression grade 1 and 2]), margin-free resection (R0), and health-related quality of life. Toxicity and safety data were analysed in the safety population, defined as patients who took at least one dose of study drug, according to treatment actually received. The initial power calculation was based on superiority of trimodality therapy (n=366 patients); it was adjusted after FLOT became an option to a non-inferiority design with a margin of 5% for perioperative chemotherapy (n=540). This study is registered with ClinicalTrials.gov, NCT01726452. Between Jan 24, 2013, and Dec 23, 2020, 377 patients were randomly assigned, of whom 362 were included in the intention-to treat population (327 [90%] male and 360 [99%] White): 184 in the perioperative chemotherapy group and 178 in the trimodality therapy group. The trial closed prematurely in December, 2020, after the second interim futility analysis (143 deaths), on the basis of similar survival metrics and the impact of the COVID-19 pandemic. At a median follow-up of 38·8 months (IQR 16·3-55·1), median overall survival was 48·0 months (95% CI 33·6-64·8) in the perioperative chemotherapy group and 49·2 months (34·8-74·4) in the trimodality therapy group (3-year overall survival 55% [95% CI 47-62] vs 57% [49-64]; hazard ratio 1·03 [95% CI 0·77-1·38]; log-rank p=0·82). Median disease-free survival was 32·4 months (95% CI 22·8-64·8) in the perioperative chemotherapy group and 24·0 months (18·0-40·8) in the trimodality therapy group [hazard ratio 0·89 [95% CI 0·68-1·17]; log-rank p=0·41). The pattern of recurrence, locoregional or systemic, was not significantly different (odds ratio 1·35 [95% CI 0·63-2·91], p=0·44). Pathological complete response (odds ratio 0·33 [95% CI 0·14-0·81], p=0·012), major pathological response (0·21 [0·12-0·38], p<0·0001), and R0 rates (0·21 [0·08-0·53], p=0·0003) favoured trimodality therapy. The most common grade 3-4 adverse event was neutropenia (49 [27%] of 183 patients in the perioperative chemotherapy group vs 11 [6%] of 178 patients in the trimodality therapy group), followed by diarrhoea (20 [11%] vs none), and pulmonary embolism (ten [5%] vs nine [5%]). One (1%) patient in the perioperative chemotherapy group and three (2%) patients in the trimodality therapy group died from serious adverse events, two (one in each group) of which were possibly related to treatment. No differences were seen in operative mortality (five [3%] deaths in the perioperative chemotherapy group vs four [2%] in the trimodality therapy group), major morbidity, or in global health status at 1 and 3 years. Although underpowered and incomplete, Neo-AEGIS provides the largest comprehensive randomised dataset for patients with adenocarcinoma of the oesophagus and oesophagogastric junction treated with perioperative chemotherapy (predominantly the modified MAGIC regimen), and CROSS trimodality therapy, and reports similar 3-year survival and no major differences in operative and health-related quality of life outcomes. We suggest that these data support continued clinical equipoise. Health Research Board, Cancer Research UK, Irish Cancer Society, Oesophageal Cancer Fund, and French National Cancer Institute.

Reynolds JV ，Preston SR ，O'Neill B ，Lowery MA ，Baeksgaard L ，Crosby T ，Cunningham M ，Cuffe S ，Griffiths GO ，Parker I ，Risumlund SL ，Roy R ，Falk S ，Hanna GB ，Bartlett FR ，Alvarez-Iglesias A ，Achiam MP ，Nilsson M ，Piessen G ，Ravi N ，O'Toole D ，Johnston C ，McDermott RS ，Turkington RC ，Wahed S ，Sothi S ，Ford H ，Wadley MS ，Power D ，Neo-AEGIS Investigators and Trial Group ... -  《The Lancet Gastroenterology &amp; Hepatology》

Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line oxaliplatin-based chemotherapy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer (ARMANI): a randomised, open-label, multicentre, phase

Paclitaxel plus ramucirumab is recommended as a second-line treatment regimen in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer. We aimed to assess whether switch maintenance or early second-line therapy with paclitaxel plus ramucirumab improved outcomes compared with continuation of oxaliplatin and fluoropyrimidine doublet chemotherapy as a first-line strategy. ARMANI was a multicentre, open-label, randomised, phase 3 trial done in 31 hospitals in Italy. We enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction cancer, who had disease control after 3 months of FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). Patients were randomly assigned (1:1) to either paclitaxel 80 mg/m2 on days 1, 8, and 15 plus ramucirumab at 8 mg/kg on days 1 and 15 every 28 days intravenously (switch maintenance group) or continuation of oxaliplatin-based doublet chemotherapy (FOLFOX or CAPOX) for an additional 12 weeks, followed by fluoropyrimidine monotherapy maintenance (control group). Randomisation was stratified by previous gastrectomy (no vs yes), peritoneal carcinomatosis (yes vs no), and primary tumour location (gastro-oesophageal junction vs gastric). Treatment group allocation was done using a web-based system with a minimisation algorithm implementing a random component. The primary endpoint was progression-free survival, analysed on an intention-to-treat basis. The safety population included patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov, NCT02934464, and is complete. Between Jan 1, 2017, and Oct 2, 2023, 280 patients were randomly assigned to receive paclitaxel plus ramucirumab (switch maintenance group; n=144) or to continue FOLFOX or CAPOX (control group; n=136). All patients were White. 180 (64%) of 280 patients were male and 100 (36%) were female. At a median follow-up of 43·7 months (IQR 24·0-57·9), 253 (90%) of 280 patients had a progression-free survival event: 131 (91%) of 144 patients in the switch maintenance group and 122 (90%) of 136 patients in the control group. Median progression-free survival was 6·6 months (95% CI 5·9-7·8) in the switch maintenance group and 3·5 months (2·8-4·2) in the control group (HR 0·61, 95% CI 0·48-0·79; p=0·0002). The assumption of proportional hazards was violated; in an analysis of 24-month restricted mean survival time, restricted mean progression-free survival was 8·8 months (95% CI 7·7-9·9) in the switch maintenance group and 6·1 months (5·0-7·2) in the control group (p=0·0010). The most frequent grade 3-4 treatment-related adverse events were neutropenia (37 [26%] patients in the switch maintenance group vs 13 [10%] patients in the control group), peripheral neuropathy (eight [6%] vs nine [7%]) and arterial hypertension (nine [6%] vs none). Serious adverse events occurred in 28 (20%) of 141 patients in the experimental group and 15 (11%) of 135 patients in the control group; these events were treatment-related in two (1%) patients in the switch maintenance group (pulmonary embolism) and two (1%) patients in the control group (mucositis and anaemia). No treatment-related deaths occurred. Paclitaxel and ramucirumab switch maintenance could be a potential treatment strategy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer who are not eligible for immunotherapy or targeted agents. Partly funded by Eli Lilly.

Randon G ，Lonardi S ，Fassan M ，Palermo F ，Tamberi S ，Giommoni E ，Ceccon C ，Di Donato S ，Fornaro L ，Brunetti O ，De Vita F ，Bittoni A ，Chini C ，Spallanzani A ，Nappo F ，Bethaz V ，Strippoli A ，Latiano T ，Cardellino GG ，Giuliani F ，Morano F ，Niger M ，Raimondi A ，Prisciandaro M ，Pircher CC ，Sciortino C ，Marchesi S ，Garattini SK ，Airò G ，Miceli R ，Di Bartolomeo M ，Pietrantonio F ... -  《-》

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial.

PD-1 inhibitors combined with chemotherapy have shown efficacy in gastric or gastro-esophageal junction cancer. We compared the efficacy and safety of pembrolizumab plus chemotherapy with placebo plus chemotherapy in participants with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. KEYNOTE-859 is a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial, done at 207 medical centres across 33 countries. Eligible participants were aged 18 years and older with previously untreated histologically or cytologically confirmed locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to receive pembrolizumab or placebo 200 mg, administered intravenously every 3 weeks for up to 35 cycles. All participants received investigator's choice of fluorouracil (intravenous, 800 mg/m2 per day) administered continuously on days 1-5 of each 3-week cycle plus cisplatin (intravenous, 80 mg/m2) administered on day 1 of each 3-week cycle or capecitabine (oral, 1000 mg/m2) administered twice daily on days 1-14 of each 3-week cycle plus oxaliplatin (intravenous, 130 mg/m2) administered on day 1 of each 3-week cycle. Randomisation was done using a central interactive voice-response system and stratified by geographical region, PD-L1 status, and chemotherapy in permuted block sizes of four. The primary endpoint was overall survival, assessed in the intention-to-treat (ITT) population, and the populations with a PD-L1 combined positive score (CPS) of 1 or higher, and PD-L1 CPS of 10 or higher. Safety was assessed in the as-treated population, which included all randomly assigned participants who received at least one dose of study intervention. Here, we report the results of the interim analysis. This study is registered with ClinicalTrials.gov, NCT03675737, and recruitment is complete. Between Nov 8, 2018, and June 11, 2021, 1579 (66%) of 2409 screened participants were randomly assigned to receive pembrolizumab plus chemotherapy (pembrolizumab group; n=790) or placebo plus chemotherapy (placebo group; n=789). Most participants were male (527 [67%] of 790 participants in the pembrolizumab plus chemotherapy group; 544 [69%] of 789 participants in the placebo plus chemotherapy group) and White (426 [54%]; 435 [55%]). Median follow-up at the data cutoff was 31·0 months (IQR 23·0-38·3). Median overall survival was longer in the pembrolizumab group than in the placebo group in the ITT population (12·9 months [95% CI 11·9-14·0] vs 11·5 months [10·6-12·1]; hazard ratio [HR] 0·78 [95% CI 0·70-0·87]; p<0·0001), in participants with a PD-L1 CPS of 1 or higher (13·0 months [11·6-14·2] vs 11·4 months [10·5-12·0]; 0·74 [0·65-0·84]; p<0·0001), and in participants with a PD-L1 CPS of 10 or higher (15·7 months [13·8-19·3] vs 11·8 months [10·3-12·7]; 0·65 [0·53-0·79]; p<0·0001). The most common grade 3-5 adverse events of any cause were anaemia (95 [12%] of 785 participants in the pembrolizumab group vs 76 [10%] of 787 participants in the placebo group) and decreased neutrophil count (77 [10%] vs 64 [8%]). Serious treatment-related adverse events occurred in 184 (23%) participants in the pembrolizumab group and 146 (19%) participants in the placebo group. Treatment-related deaths occurred in eight (1%) participants in the pembrolizumab group and 16 (2%) participants in the placebo group. No new safety signals were identified. Participants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group. Therefore, pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. Merck Sharp and Dohme.

Rha SY ，Oh DY ，Yañez P ，Bai Y ，Ryu MH ，Lee J ，Rivera F ，Alves GV ，Garrido M ，Shiu KK ，Fernández MG ，Li J ，Lowery MA ，Çil T ，Cruz FM ，Qin S ，Luo S ，Pan H ，Wainberg ZA ，Yin L ，Bordia S ，Bhagia P ，Wyrwicz LS ，KEYNOTE-859 investigators ... -  《-》