Reactive cutaneous capillary endothelial proliferation following camrelizumab monotherapy or combination therapy for multi-cancers: a large-scale pooled analysis of 10 studies in China.

Background: Skin toxicities are the most common adverse events related to immunotherapy, such as reactive cutaneous capillary endothelial proliferation (RCCEP) following treatment with the anti-programmed cell death-1 antibody camrelizumab. Objective: This study aimed to comprehensively analyze the clinical features and prognostic value of RCCEP in patients with malignancies who received camrelizumab alone (Camre) or in combination with the angiogenesis-targeted agent apatinib (Camre-Apa) or chemotherapy (Camre-Chemo). Design: A large-scale pooled analysis. Methods: Individual patient-level data were derived from 10 clinical trials of camrelizumab monotherapy, camrelizumab plus apatinib, or camrelizumab plus chemotherapy (n = 1305). Results: RCCEP occurred in 77.0% (516/670) of patients with Camre, 23.6% (70/296) with Camre-Apa, and 67.8% (230/339) with Camre-Chemo. Most RCCEP lesions were grade 1 or 2 in severity. The median time to onset was 0.8 months [interquartile range (IQR), 0.6-1.2] with Camre, 5.0 months (IQR, 2.7-8.0) with Camre-Apa, and 1.6 months (IQR, 1.0-4.2) with Camre-Chemo; and the median duration was 4.8 months (IQR, 2.6-8.8), 4.4 months (IQR, 1.7-8.9), and 7.2 months (IQR, 4.1-14.3), respectively. In all the three groups, patients with RCCEP showed significantly better clinical outcomes compared with those without [objective response rate: 23.8% versus 1.9% with Camre, 48.6% versus 21.2% with Camre-Apa, and 78.7% versus 54.1% with Camre-Chemo; median progression-free survival: 3.2 versus 1.7 months (hazard ratio (HR) = 0.36), 10.2 versus 4.5 months (HR = 0.39), and 12.7 versus 7.3 months (HR = 0.38); median overall survival: 13.3 versus 3.8 months (HR = 0.34), 29.2 versus 13.5 months (HR = 0.46), and not reached versus 12.8 months (HR = 0.19); all p < 0.0001]. Conclusion: Although RCCEP occurred frequently with camrelizumab, most lesions were mild and self-limiting. The occurrence of RCCEP was strongly associated with the antitumor activity and survival of camrelizumab, both as monotherapy and in combination therapy.

A phase IV study to evaluate the safety of fruquintinib in Chinese patients in real-world clinical practice.

INTRODUCTION: Fruquintinib is approved in China for patients with metastatic colorectal cancer (CRC) who progressed after 2 lines of chemotherapy. This postmarketing study was conducted to evaluate the safety of fruquintinib in the Chinese population, including previously treated patients with advanced CRC and other solid tumors. METHODS: Patients in the first cycle of fruquintinib or expected to start fruquintinib within a week were enrolled. Fruquintinib was administrated according to the label or per physicians' discretion. Patient characteristics and safety information were collected at baseline, 1 month, and 6 months after consent (or 30 days after the last dose). RESULTS: Overall, 3005 patients enrolled between April 24, 2019 and September 27, 2022. All enrolled patients received at least one dose of fruquintinib. Most patients had metastases at baseline. The median age was 60 years. More than half (64.0%) of the patients started fruquintinib at 5 mg, and the median treatment exposure was 2.7 months. Nearly one-third (32.5%) of patients with CRC received fruquintinib with concomitant antineoplastic agents. Treatment-emergent adverse events (TEAEs) leading to dose modification were reported in 626 (20.8%) patients, and 469 (15.6%) patients experienced TEAEs leading to treatment discontinuation. The most common grade ≥ 3 TEAEs were hypertension (6.6%), palmar-plantar erythrodysesthesia syndrome (2.2%), and platelet count decreased (1.0%). Combination therapy did not lead to excessive toxicities. CONCLUSIONS: The safety profile of fruquintinib in the real world was generally consistent with that in clinical studies, and the incidence of TEAEs was numerically lower than known VEGF/VEGFR inhibitor-related AEs. Fruquintinib exhibited manageable safety and tolerability in Chinese patients in the real-world setting.

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): final results of a randomised phase 3 study.

BACKGROUND: The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up. METHODS: COSMIC-312 was an open-label, randomised, phase 3 study done across 178 centres in 32 countries. Patients aged 18 years or older with previously untreated advanced hepatocellular carcinoma were eligible. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), and adequate marrow and organ function, including Child-Pugh class A liver function; those with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were ineligible. Patients were randomly assigned (2:1:1) using a web-based interactive response system to a combination of oral cabozantinib 40 mg once daily plus intravenous atezolizumab 1200 mg every 3 weeks, oral sorafenib 400 mg twice daily, or oral single-agent cabozantinib 60 mg once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were for cabozantinib plus atezolizumab versus sorafenib: progression-free survival per RECIST 1.1, as assessed by a blinded independent radiology committee, in the first 372 randomly assigned patients (previously reported) and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib. The secondary endpoint was progression-free survival in all patients randomly assigned to cabozantinib versus sorafenib. Outcomes in all randomly assigned patients, including final overall survival, are presented. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03755791. FINDINGS: Between Dec 7, 2018, and Aug 27, 2020, 432 patients were randomly assigned to combination treatment, 217 to sorafenib, and 188 to single-agent cabozantinib, and included in all efficacy analyses. 704 (84%) patients were male and 133 (16%) were female. 824 of these patients received at least one dose of study treatment and were included in the safety population. Median follow-up was 22·1 months (IQR 19·3-24·8). Median overall survival was 16·5 months (96% CI 14·5-18·7) for the combination treatment group and 15·5 months (12·2-20·0) for the sorafenib group (hazard ratio [HR] 0·98 [0·78-1·24]; stratified log-rank p=0·87). Median progression-free survival was 6·9 months (99% CI 5·7-8·2) for the combination treatment group, 4·3 months (2·9-6·1) for the sorafenib group, and 5·8 months (99% CI 5·4-8·2) for the single-agent cabozantinib group (HR 0·74 [0·56-0·97] for combination treatment vs sorafenib; HR 0·78 [99% CI 0·56-1·09], p=0·05, for single-agent cabozantinib vs sorafenib). Grade 3 or 4 adverse events occurred in 281 (66%) of 429 patients in the combination treatment group, 100 (48%) of 207 patients in the sorafenib group, and 108 (57%) of 188 patients in the single-agent cabozantinib group; the most common were hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), palmar-plantar erythrodysaesthesia (36 [8%] vs 18 [9%] vs 16 [9%]), aspartate aminotransferase increased (42 [10%] vs eight [4%] vs 17 [9%]), and alanine aminotransferase increased (40 [9%] vs six [3%] vs 13 [7%]). Serious adverse events occurred in 223 (52%) patients in the combination treatment group, 84 (41%) patients in the sorafenib group, and 87 (46%) patients in the single agent cabozantinib group. Treatment-related deaths occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) in the sorafenib group (general physical health deterioration), and four (2%) in the single-agent cabozantinib group (asthenia, gastrointestinal haemorrhage, sepsis, and gastric perforation). INTERPRETATION: First-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals. FUNDING: Exelixis and Ipsen.

Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: final analysis of the randomized phase 2 FIGHT trial.

BACKGROUND: We report the final results of the randomized phase 2 FIGHT trial that evaluated bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 in patients with FGFR2b-positive (2 + /3 + membranous staining by immunohistochemistry), HER-2-negative gastric or gastroesophageal junction cancer (GC). METHODS: Patients received bemarituzumab (15 mg/kg) or placebo once every 2 weeks with an additional bemarituzumab (7.5 mg/kg) or placebo dose on cycle 1 day 8. All patients received mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months. RESULTS: In the bemarituzumab-mFOLFOX6 (N = 77) and placebo-mFOLFOX6 (N = 78) arms, respectively, 59.7% and 66.7% of patients were FGFR2b-positive in ≥ 10% of tumor cells. The median PFS (95% confidence interval [CI]) was 9.5 months (7.3-13.7) with bemarituzumab-mFOLFOX6 and 7.4 months (5.7-8.4) with placebo-mFOLFOX6 (hazard ratio [HR], 0.72; 95% CI 0.49-1.08); median OS (95% CI) was 19.2 (13.6-24.2) and 13.5 (9.3-15.9) months, respectively (HR 0.77; 95% CI 0.52-1.14). Observed efficacy in FGFR2b-positive GC in ≥ 10% of tumor cells was: PFS: HR 0.43 (95% CI 0.26-0.73); OS: HR 0.52 (95% CI 0.31-0.85). No new safety findings were reported. CONCLUSIONS: In FGFR2b-positive advanced GC, the combination of bemarituzumab-mFOLFOX6 led to numerically longer median PFS and OS compared with mFOLFOX6 alone. Efficacy was more pronounced with FGFR2b overexpression in ≥ 10% of tumor cells. Confirmatory phase 3 trials are ongoing (NCT05052801, NCT05111626). CLINICAL TRIAL REGISTRATION: NCT03694522.

Activity of Tepotinib in Hepatocellular Carcinoma With High-Level MET Amplification: Preclinical and Clinical Evidence.

PURPOSE: MET amplification (METamp) has been reported in 1%-5% of patients with hepatocellular carcinoma (HCC) and may be sensitive to MET inhibition. Tepotinib, a selective MET inhibitor, has shown promising activity in HCC with MET overexpression. We investigated the preclinical and clinical activity of tepotinib in HCC with METamp (MET gene copy number [GCN] ≥5), including high-level METamp (MET GCN ≥10). METHODS: Preclinical antitumor activity of tepotinib 100 mg/kg (orally, days 1-5, every 7 days, 3-5 weeks; 3-12 replicates) was evaluated according to METamp status, as determined using the nCounter platform (NanoString), in 37 HCC patient-derived xenografts (PDXs) in immunodeficient mice. Clinical outcomes were evaluated in patients with METamp by fluorescence in situ hybridization who received tepotinib 500 mg (450 mg active moiety) in two phase Ib/II trials in HCC with MET overexpression. RESULTS: Across the PDX models, tepotinib induced complete or near-complete tumor regression in the only two models with high-level METamp. Median tumor volume reductions were 100% and 99.8% in models with MET GCN 47.1 and 44.0, respectively. Across the two clinical trials, 15/121 patients had METamp. Disease control was achieved by 11/15 patients with METamp (complete response [CR], n = 1; partial response [PR], n = 4; stable disease [SD], n = 6) and 4/4 with high-level METamp (CR, n = 1; PR, n = 2; SD, n = 1). All three patients with high-level METamp and objective response received treatment for >1 year, including one patient who received first-line tepotinib for >6 years. CONCLUSION: High-level METamp may be an oncogenic driver in HCC that is sensitive to MET inhibitors such as tepotinib.

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

BACKGROUND: 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. METHODS: 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. FINDINGS: 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]). INTERPRETATION: 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. FUNDING: Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck.

Baseline radiologic features as predictors of efficacy in patients with pancreatic neuroendocrine tumors with liver metastases receiving surufatinib.

Objective: Currently, pre-treatment prediction of patients with pancreatic neuroendocrine tumors with liver metastases (PNELM) receiving surufatinib treatment was unsatisfying. Our objective was to examine the association between radiological characteristics and efficacy/prognosis. Methods: We enrolled patients with liver metastases in the phase III, SANET-p trial (NCT02589821) and obtained contrast-enhanced computed tomography (CECT) images. Qualitative and quantitative parameters including hepatic tumor margins, lesion volumes, enhancement pattern, localization types, and enhancement ratios were evaluated. The progression-free survival (PFS) and hazard ratio (HR) were calculated using Cox's proportional hazard model. Efficacy was analyzed by logistic-regression models. Results: Among 152 patients who had baseline CECT assessments and were included in this analysis, the surufatinib group showed statistically superior efficacy in terms of median PFS compared to placebo across various qualitative and quantitative parameters. In the multivariable analysis of patients receiving surufatinib (N=100), those with higher arterial phase standardized enhancement ratio-peri-lesion (ASER-peri) exhibited longer PFS [HR=0.039; 95% confidence interval (95% CI): 0.003-0.483; P=0.012]. Furthermore, patients with a high enhancement pattern experienced an improvement in the objective response ratio [31.3% vs. 14.7%, odds ratio (OR)=3.488; 95% CI: 1.024-11.875; P=0.046], and well-defined tumor margins were associated with a higher disease control rate (DCR) (89.3% vs. 68.2%, OR=4.535; 95% CI: 1.285-16.011; P=0.019) compared to poorly-defined margins. Conclusions: These pre-treatment radiological features, namely high ASER-peri, high enhancement pattern, and well-defined tumor margins, have the potential to serve as predictive markers of efficacy in patients with PNELM receiving surufatinib.

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

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Merck Sharp and Dohme.

Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial.

BACKGROUND: Evidence for the efficacy of combined PD-1 and HER2 blockade with chemotherapy on progression-free and overall survival in HER2-positive gastro-oesophageal cancer is scarce. The first interim analysis of the randomised, phase 3 KEYNOTE-811 study showed a superior objective response with pembrolizumab compared with placebo when added to trastuzumab plus fluoropyrimidine and platinum-based chemotherapy. Here, we report results from protocol-specified subsequent interim analyses of KEYNOTE-811. METHODS: The randomised, phase 3 KEYNOTE-811 trial involved 168 medical centres in 20 countries worldwide. Patients aged 18 years or older with locally advanced or metastatic HER2-positive gastro-oesophageal junction adenocarcinoma, without previous first-line treatment, were randomly assigned (1:1) by an integrated interactive voice-response and web-response system to intravenous pembrolizumab 200 mg or placebo, both to be combined with standard chemotherapy (fluoropyrimidine and platinum-based therapy) plus trastuzumab every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxic effects, or investigator or participant-initiated withdrawal. Randomisation used a block size of four and was stratified by region, PD-L1 status, and chemotherapy. Dual primary endpoints were progression-free and overall survival, analysed by intention to treat. Safety was assessed in all randomly assigned patients who received at least one dose of study treatment according to the treatment received. KEYNOTE-811 is registered with ClinicalTrials.gov (NCT03615326) and is active but not recruiting. FINDINGS: Between Oct 5, 2018, and Aug 6, 2021, 698 patients were assigned to pembrolizumab (n=350) or placebo (n=348). 564 (81%) were male and 134 (19%) were female. At the third interim analysis, 286 (82%) of 350 patients in the pembrolizumab group and 304 (88%) of 346 in the placebo group who received treatment had discontinued treatment, mostly due to disease progression. At the second interim analysis (median follow-up 28·3 months [IQR 19·4-34·3] in the pembrolizumab group and 28·5 months [20·1-34·3] in the placebo group), median progression-free survival was 10·0 months (95% CI 8·6-11·7) in the pembrolizumab group versus 8·1 months (7·0-8·5) in the placebo group (hazard ratio [HR] 0·72, 95% CI 0·60-0·87; p=0·0002). Median overall survival was 20·0 months (17·8-23·2) versus 16·9 months (15·0-19·8; HR 0·87 [0·72-1·06]; p=0·084). At the third interim analysis (median follow-up 38·4 months [IQR 29·5-44·4] in the pembrolizumab group and 38·6 months [30·2-44·4] in the placebo group), median progression-free survival was 10·0 months (8·6-12·2) versus 8·1 months (7·1-8·6; HR 0·73 [0·61-0·87]), and median overall survival was 20·0 months (17·8-22·1) versus 16·8 months (15·0-18·7; HR 0·84 [0·70-1·01]), but did not meet prespecified criteria for significance and will continue to final analysis. Grade 3 or worse treatment-related adverse events occurred in 204 (58%) of 350 patients in the pembrolizumab group versus 176 (51%) of 346 patients in the placebo group. Treatment-related adverse events that led to death occurred in four (1%) patients in the pembrolizumab group and three (1%) in the placebo group. The most common treatment-related adverse events of any grade were diarrhoea (165 [47%] in the pembrolizumab group vs 145 [42%] in the placebo group), nausea (154 [44%] vs 152 [44%]), and anaemia (109 [31%] vs 113 [33%]). INTERPRETATION: Compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumours with a PD-L1 combined positive score of 1 or more. Overall survival follow-up is ongoing and will be reported at the final analysis. FUNDING: Merck Sharp & Dohme.

Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma. METHODS: In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice-web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098. FINDINGS: The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9-22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 22·1-NE]) compared with active surveillance (median, NE [21·4-NE]; hazard ratio, 0·72 [adjusted 95% CI 0·53-0·98]; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab. INTERPRETATION: Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit-risk profile more fully. FUNDING: F Hoffmann-La Roche/Genentech.

Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial.

Importance: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment. Objective: To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC. Design, Setting, and Participants: The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy-naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022. Intervention: Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily. Main Outcomes and Measures: The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety. Results: A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib. Conclusions and Relevance: In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib. Trial Registration: ClinicalTrials.gov Identifier: NCT03412773.

Plain language summary of the TOPAZ-1 study: durvalumab and chemotherapy for advanced biliary tract cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary describing the results of a Phase III study called TOPAZ-1. The study looked at treatment with durvalumab (a type of immunotherapy) and chemotherapy to treat participants with advanced biliary tract cancer (BTC). Advanced BTC is usually diagnosed at late stages of disease, when it cannot be cured by surgery. This study included participants with advanced BTC who had not received previous treatment, or had their cancer come back at least 6 months after receiving treatment or surgery that aimed to cure their disease. Participants received treatment with durvalumab and chemotherapy or placebo and chemotherapy. The aim of this study was to find out if treatment with durvalumab and chemotherapy could increase the length of time that participants with advanced BTC lived, compared with placebo and chemotherapy. WHAT WERE THE RESULTS OF THE STUDY?: Participants who took durvalumab and chemotherapy had a 20% lower chance of experiencing death at any point in the study compared with participants who received placebo and chemotherapy. The side effects experienced by participants were similar across treatment groups, and less than 12% of participants in either treatment group had to stop treatment due to treatment-related side effects. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, these results support durvalumab and chemotherapy as a new treatment option for people with advanced BTCs. Based on the results of this study, durvalumab is now approved for the treatment of adults with advanced BTCs in combination with chemotherapy by government organizations in Europe, the United States and several other countries.

Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer).

WHAT IS THIS SUMMARY ABOUT?: This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer. WHAT WERE THE RESULTS OF THE STUDY?: Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, STRIDE is more effective than sorafenib for people with unresectable HCC.

Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study.

BACKGROUND: FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. METHODS: The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1-4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0-1 (or equivalent for adolescents aged 12-17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. FINDINGS: Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%) were male. The data cutoff was Aug 15, 2022. At a median follow-up of 17·9 months (IQR 13·6-23·9), an objective response was observed in 64 (30% [95% CI 24-36]) of 217 patients across 16 distinct tumour types. The most common grade 3 or higher treatment-emergent adverse events related to erdafitinib were stomatitis (25 [12%]), palmar-plantar erythrodysaesthesia syndrome (12 [6%]), and hyperphosphataemia (11 [5%]). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis in four (2%) patients and diarrhoea in two (1%). There were no treatment-related deaths. INTERPRETATION: RAGNAR results show clinical benefit for erdafitinib in the tumour-agnostic setting in patients with advanced solid tumours with susceptible FGFR alterations who have exhausted other treatment options. These results support the continued development of FGFR inhibitors in patients with advanced solid tumours. FUNDING: Janssen Research & Development.

Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer.

PURPOSE: In a phase IIb trial of nimotuzumab plus gemcitabine, substantial clinical benefits were observed in patients with locally advanced or metastatic pancreatic cancer (PC). Therefore, we conducted a phase III clinical study to verify the efficacy and safety of this combination regimen in patients with K-Ras wild-type tumors (ClinicalTrials.gov identifier: NCT02395016). PATIENTS AND METHODS: Eligible patients were randomly assigned to receive nimotuzumab (400 mg once per week) or placebo followed by gemcitabine (1,000 mg/m2 on days 1, 8, and 15, once every 4 weeks) until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) and the secondary end points were progression-free survival (PFS), response rates, and safety. RESULTS: A total of 480 patients were screened; 92 patients were enrolled and 82 patients with K-Ras wild-type tumors were eligible. In the full analysis set, the median OS was 10.9 versus 8.5 months, while the restricted mean survival time (RMST) was 18.05 versus 11.14 months for the investigational versus control arm (ratio of control v investigation = 0.62 [0.40-0.97]; P = .036). Median PFS was 4.2 versus 3.6 months in the investigational versus control arm (log-rank P = .04; hazard ratio, 0.60 [0.37-0.99]) and the restricted mean PFS time was 8.08 versus 4.76 months (RMST ratio, 0.58 [0.38-0.90]; P = .036). Both OS and PFS were longer in the nimotuzumab group than in the placebo group. The objective response rates and disease control rates were 7% versus 10% and 68% versus 63% for the investigational and control groups, respectively. The incidence of adverse events were comparable between the two groups. CONCLUSION: In patients with locally advanced or metastatic K-Ras wild-type PC, nimotuzumab plus gemcitabine significantly improved OS and PFS with a good safety profile.

Chinese expert consensus recommendations for the administration of immune checkpoint inhibitors to special cancer patient populations.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte-associated antigen-4 have shown significantly durable clinical benefits and tolerable toxicities and have improved the survival of patients with various types of cancer. Since 2018, the National Medical Products Administration of China has approved 17 ICIs as the standard treatment for certain advanced or metastatic solid tumors. As ICIs represent a broad-spectrum antitumor strategy, the populations eligible for cancer immunotherapy are rapidly expanding. However, the clinical applications of ICIs in cancer patient populations with special issues, a term that refers to complex subgroups of patients with comorbidities, special clinical conditions, or concomitant medications who are routinely excluded from prospective clinical trials of ICIs or are underrepresented in these trials, represent a great real-world challenge. Although the Chinese Society of Clinical Oncology (CSCO) has provided recommendations for screening before the use of ICIs in special populations, the recommendations for full-course management remain insufficient. The CSCO Expert Committee on Immunotherapy organized leading medical oncology and multidisciplinary experts to develop a consensus that will serve as an important reference for clinicians to guide the proper application of ICIs in special patient populations. This article is a translation of a study first published in Chinese in The Chinese Clinical Oncology (ISSN 1009-0460, CN 32-1577/R) in May 2022 (27(5):442-454). The publisher of the original paper has provided written confirmation of permission to publish this translation in Therapeutic Advances in Medical Oncology.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Safety and efficacy of apatinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma after the failure of two or more lines of chemotherapy (AHEAD): a prospective, single-arm, multicenter, phase IV study.

BACKGROUND: Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. METHODS: Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan-Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. RESULTS: Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6-5.4%), and DCR was 35.8% (95% CI, 33.7-38.0%). The median PFS was 2.7 months (95% CI 2.2-2.8), and the median OS was 5.8 months (95% CI 5.4-6.1). CONCLUSIONS: The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.

A novel AKR1C3 specific prodrug AST-3424 and its combination therapy in hepatocellular carcinoma.

OBJECTIVE: AST-3424 is a novel specific aldo-keto reductase 1C3 (AKR1C3) prodrug that releases a DNA alkylating reagent upon reduction by AKR1C3. This study aimed to evaluate the efficacy and safety of AST-3424 in patient-derived tumor xenograft (PDTX) model and orthotopic model against hepatocellular carcinoma (HCC). MATERIALS AND METHOD: PDTX models derived from three HCC patients and orthotopic mice models using HepG2 cells were developed. The mice were treated with AST-3424 alone or combined with other drugs (oxaliplatin, apatinib, sorafenib and elemene in PDTX models, oxaliplatin and 5- fluorouracil in orthotopic models). The tumor volume and weight, as well as the mice weight were assessed. The liver tumor and transplanted tumor were removed for histological, immunohistochemical and Western blot detection in orthotopic model experiments. RESULTS: AST-3424 could inhibit tumor growth in HCC PDTX models and orthotopic models, with no difference in safety compared with other marketed drugs, and the drug combination did not increase toxicity. The inhibitory effect of combination treatment was more obvious than which used alone. The reduction of AKR1C3 expression was negatively correlated with AST-3424 dose. CONCLUSION: AST-3424 had a promising effect against HCC in PDTX model and orthotopic model with good safety. It could promote the sensitivity of other drugs without increasing toxicity. Clinical trials are warranted to further certify its antitumor effect and safety.