Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study.

Transarterial chemoembolisation (TACE) is standard care for unresectable, non-metastatic hepatocellular carcinoma. We aimed to evaluate the addition of lenvatinib and pembrolizumab to TACE versus dual placebo plus TACE in patients with unresectable, non-metastatic hepatocellular carcinoma. In this multicentre, randomised, double-blind, phase 3 study (LEAP-012), patients were recruited from 137 global sites in 33 countries or regions. Eligible patients were age 18 years or older with unresectable, non-metastatic hepatocellular carcinoma not amenable to curative treatment, but with tumours amenable to TACE, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and Child-Pugh class A disease. Eligible participants were randomly assigned (1:1), stratified by study site, α-fetoprotein level, ECOG performance status, albumin-bilirubin grade, and tumour burden, by a central interactive response system, to receive TACE and either oral lenvatinib (bodyweight ≥60 kg: 12 mg; bodyweight <60 kg: 8 mg; once daily) plus intravenous pembrolizumab (400 mg once every 6 weeks for up to 2 years) or matched dual placebo (oral and intravenous). Primary endpoints were progression-free survival (threshold one-sided p=0·025), per Response Evaluation Criteria in Solid Tumours version 1.1 (modified for the current study to allow for up to five target tumours in the liver and requiring new intrahepatic tumours to meet LI-RADS 5 criteria to be considered progressive disease) by blinded independent central review, and overall survival (threshold one-sided p=0·0012) in the intention-to-treat (ITT) population (ie, all participants randomly assigned to treatment). Safety was assessed in the as-treated population (ie, all participants who were randomly assigned and received at least one dose of any study treatment). Here, we report results from the first interim analysis (final analysis for progression-free survival). This study is registered with ClinicalTrials.gov, NCT04246177, and is active but not recruiting. Between May 22, 2020, and Jan 11, 2023, 847 patients were screened, of whom 480 (57%) were enrolled and randomly assigned to receive TACE plus lenvatinib plus pembrolizumab (n=237) or TACE plus dual placebo (n=243; ITT population). Median age was 66 years (IQR 58-73), 82 (17%) of 480 participants were female, 398 (83%) were male, 98 (20%) were White, 347 (72%) were Asian, four (1%) were Black or African American, and five (1%) were American Indian or Alaska Native. Median follow-up as of data cutoff (Jan 30, 2024) was 25·6 months (IQR 19·5-32·4). Median progression-free survival was 14·6 months (95% CI 12·6-16·7; 132 events [20 deaths and 112 progressions]) with lenvatinib plus pembrolizumab and 10·0 months (8·1-12·2; 154 events [eight deaths and 146 progressions]) with placebo (hazard ratio [HR] 0·66 [95% CI 0·51-0·84]; one-sided p=0·0002). 69 (29%) of 237 in the lenvatinib plus pembrolizumab group and 82 (34%) of 243 from the placebo group died, with a 24-month overall survival rate of 75% (95% CI 68-80) in the lenvatinib plus pembrolizumab group and 69% (62-74) in the placebo group (HR 0·80 [95% CI 0·57-1·11]; one-sided p=0·087). Grade 3 or worse treatment-related adverse events occurred in 169 (71%) of 237 participants in the lenvatinib plus pembrolizumab group and in 76 (32%) of 241 in the placebo group, the most common of which were hypertension (57 [24%] vs 18 [7%]) and platelet count decreased (27 [11%] vs 15 [6%]). Deaths due to treatment-related adverse events occurred in four (2%) participants in the lenvatinib plus pembrolizumab group (n=1 each due to hepatic failure, gastrointestinal haemorrhage, myositis, and immune-mediated hepatitis) and one (<1%) in the placebo group (due to brain stem haemorrhage). TACE plus lenvatinib plus pembrolizumab showed significant, clinically meaningful improvement in progression-free survival in patients with unresectable, non-metastatic hepatocellular carcinoma compared with TACE plus placebo. The numerical improvement in overall survival is encouraging, but longer follow-up is necessary. Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and Eisai, Nutley, NJ, USA.

Kudo M ，Ren Z ，Guo Y ，Han G ，Lin H ，Zheng J ，Ogasawara S ，Kim JH ，Zhao H ，Li C ，Madoff DC ，Ghobrial RM ，Kawaoka T ，Gerolami R ，Ikeda M ，Kumada H ，El-Khoueiry AB ，Vogel A ，Peng X ，Mody K ，Dutcus C ，Dubrovsky L ，Siegel AB ，Finn RS ，Llovet JM ，LEAP-012 investigators ... -  《-》

Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial.

Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0-72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4-35·3). Median overall survival was 21·2 months (95% CI 19·0-23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2-21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71-1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4-8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3-8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73-1·02; stratified log-rank p=0·047). The most common treatment-related grade 3-4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck.

Llovet JM ，Kudo M ，Merle P ，Meyer T ，Qin S ，Ikeda M ，Xu R ，Edeline J ，Ryoo BY ，Ren Z ，Masi G ，Kwiatkowski M ，Lim HY ，Kim JH ，Breder V ，Kumada H ，Cheng AL ，Galle PR ，Kaneko S ，Wang A ，Mody K ，Dutcus C ，Dubrovsky L ，Siegel AB ，Finn RS ，LEAP-002 Investigators ... -  《-》

Durvalumab with or without bevacizumab with transarterial chemoembolisation in hepatocellular carcinoma (EMERALD-1): a multiregional, randomised, double-blind, placebo-controlled, phase 3 study.

Transarterial chemoembolisation (TACE) is standard of care for patients with unresectable hepatocellular carcinoma that is amenable to embolisation; however, median progression-free survival is still approximately 7 months. We aimed to assess whether adding durvalumab, with or without bevacizumab, might improve progression-free survival. In this multiregional, randomised, double-blind, placebo-controlled, phase 3 study (EMERALD-1), adults aged 18 years or older with unresectable hepatocellular carcinoma amenable to embolisation, an Eastern Cooperative Oncology Group performance status of 0 or 1 at enrolment, and at least one measurable intrahepatic lesion per modified Response Evaluation Criteria in Solid Tumours (RECIST) were enrolled at 157 medical sites including research centres and general and specialist hospitals in 18 countries. Eligible patients were randomly assigned (1:1:1), stratified by TACE method, region, and portal vein invasion, using an interactive voice response or web response system, to TACE plus either durvalumab plus bevacizumab (1500 mg intravenous durvalumab once every 4 weeks, then 1120 mg durvalumab plus 15 mg/kg intravenous bevacizumab once every 3 weeks), durvalumab plus placebo (same regimen using placebo instead of bevacizumab), or placebo alone (same regimen using placebo instead of durvalumab and instead of bevacizumab). Participants, investigators, and those assessing outcomes were masked to treatment assignment until data analysis. The primary endpoint was progression-free survival, by blinded independent central review (BICR), and per RECIST version 1.1, with durvalumab plus bevacizumab versus placebo alone in the intention-to-treat population (ITT; ie, all participants assigned to treatment). Key secondary endpoints were progression-free survival by BICR per RECIST version 1.1 with durvalumab plus placebo versus placebo alone, overall survival, and time to deterioration in select patient-reported outcomes. Participants continue to be followed up for overall survival, and overall survival and patient-reported outcomes will be reported in a later publication. Safety was assessed in the safety analysis set, which included all participants assigned to treatment who received any study treatment (ie, any durvalumab, bevacizumab, or placebo) by treatment received. This study is registered with ClinicalTrials.gov, NCT03778957, and is closed to accrual. Between Nov 30, 2018, and July 19, 2021, 887 patients were screened, of whom 616 were randomly assigned to durvalumab plus bevacizumab (n=204), durvalumab plus placebo (n=207), or placebo alone (n=205; ITT population). Median age was 65·0 years (IQR 59·0-72·0), 135 (22%) of 616 participants were female, 481 (78%) were male, 375 (61%) were Asian, 176 (29%) were White, 22 (4%) were American Indian or Alaska Native, nine (1%) were Black or African American, one (<1%) was native Hawaiian or other Pacific Islander, and 33 (5%) were other races. As of data cutoff (Sept 11, 2023) median follow-up for progression-free survival was 27·9 months (95% CI 27·4-30·4), median progression-free survival was 15·0 months (95% CI 11·1-18·9) with durvalumab plus bevacizumab, 10·0 months (9·0-12·7) with durvalumab, and 8·2 months (6·9-11·1) with placebo. Progression-free survival hazard ratio was 0·77 (95% CI 0·61-0·98; two-sided p=0·032) for durvalumab plus bevacizumab versus placebo, and 0·94 (0·75-1·19; two-sided p=0·64) for durvalumab plus placebo versus placebo. The most common maximum grade 3-4 adverse events were hypertension in participants who received durvalumab and bevacizumab (nine [6%] of 154 participants), anaemia in participants who received durvalumab and placebo (ten [4%] of 232 participants), and post-embolisation syndrome in participants who received placebo alone (eight [4%] of 200 participants). Study treatment-related adverse events that led to death occurred in none of 154 participants who received durvalumab and bevacizumab, three (1%) of 232 who received durvalumab and placebo (n=1 for arterial haemorrhage, liver injury, and multiple organ dysfunction syndrome), and three (2%) of 200 who received placebo alone (n=1 for oesophageal varices haemorrhage, upper gastrointestinal haemorrhage, and dermatomyositis). Durvalumab plus bevacizumab plus TACE has the potential to set a new standard of care. With additional follow-up of the EMERALD-1 study, future analyses, including the final overall survival data and patient-reported outcomes, will help to further characterise the potential clinical benefits of durvalumab plus bevacizumab plus TACE in hepatocellular carcinoma amenable to embolisation. AstraZeneca.

Sangro B ，Kudo M ，Erinjeri JP ，Qin S ，Ren Z ，Chan SL ，Arai Y ，Heo J ，Mai A ，Escobar J ，Lopez Chuken YA ，Yoon JH ，Tak WY ，Breder VV ，Suttichaimongkol T ，Bouattour M ，Lin SM ，Peron JM ，Nguyen QT ，Yan L ，Chiu CF ，Santos FA ，Veluvolu A ，Thungappa SC ，Matos M ，Żotkiewicz M ，Udoye SI ，Kurland JF ，Cohen GJ ，Lencioni R ，EMERALD-1 Investigators ... -  《-》

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 ... -  《-》

Lenvatinib plus pembrolizumab for untreated advanced renal cell carcinoma: a systematic review and cost-effectiveness analysis.

Fleeman N ，Houten R ，Nevitt S ，Mahon J ，Beale S ，Boland A ，Greenhalgh J ，Edwards K ，Maden M ，Bhattacharyya D ，Chaplin M ，McEntee J ，Chow S ，Waddell T ... -  《-》