Background PD-L1 and VEGF blockade with atezolizumab plus bevacizumab has been shown to improve survival in unresectable hepatocellular carcinoma. TIGIT is an immune checkpoint regulator implicated in many cancers, including unresectable hepatocellular carcinoma. Here, we evaluate the clinical activity and safety of the addition of tiragolumab, an anti-TIGIT monoclonal antibody, to atezolizumab plus bevacizumab. Methods This randomised, open-label, phase 1b-2 umbrella study was conducted at 26 centres across China, France, Israel, New Zealand, South Korea, Taiwan, and the USA. Eligible patients were adults aged 18 years old or older with previously untreated locally advanced unresectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, Child-Pugh class A disease, and a life expectancy of at least 3 months. Eligible patients were randomly assigned (2:1) using permuted block randomisation to receive either tiragolumab 600 mg plus atezolizumab 1200 mg plus bevacizumab 15 mg/kg or atezolizumab 1200 mg plus bevacizumab 15 mg/kg, administered via intravenous infusion every 3 weeks on day 1 of each 21-day cycle. Patients received treatment until unacceptable toxic effects or loss of clinical benefit, whichever occurred first. The primary endpoint was objective response rate. Analysis of clinical activity was done in the efficacy-evaluable population (all patients who received at least one dose of each drug for their assigned treatment regimen) and safety was assessed in all patients who received any study treatment. The trial is registered with ClinicalTrials.gov, NCT04524871, and is ongoing. Findings Between Aug 20, 2020, and Feb 10, 2022, we assessed 154 patients for eligibility and 59 eligible patients were randomly assigned to receive tiragolumab plus atezolizumab plus bevacizumab (n=41) or atezolizumab plus bevacizumab (n=18); one patient in the tiragolumab plus atezolizumab plus bevacizumab group experienced an adverse event before receiving any treatment and withdrew from the study. Median age was 650 years (IQR 610-730). 46 (79%) of 58 patients were male and 12 (21%) were female. Most patients were Asian (23 [40%]) or White (21 [36%]). At the time of clinical cutoff (Aug 21, 2023), median follow-up was 206 months (IQR 106-280) in the tiragolumab plus atezolizumab plus bevacizumab group and 140 months (42-185) in the atezolizumab plus bevacizumab group. The confirmed objective response rate was 43% (95% CI 27-59, n=17) in the tiragolumab plus atezolizumab plus bevacizumab group and 11% (1-35, n=2) in the atezolizumab plus bevacizumab group. All patients in both groups experienced an adverse event. The incidence of pruritis (20 [50%] of 40 patients vs three [17%] of 18 patients), arthralgia (13 [33%] vs two [11%]), and diarrhoea (12 [30%] vs one [6%]) was notably higher in the tiragolumab plus atezolizumab plus bevacizumab group than in the atezolizumab plus bevacizumab group, although these were mainly grade 1-2. The most common grade 3-4 adverse events were hypertension (six [15%] of 40 patients in the tiragolumab plus atezolizumab plus bevacizumab group vs two [11%] of 18 patients in the atezolizumab plus bevacizumab group), aspartate aminotransferase increased (three [8%] of 40 patients vs one [6%] of 18 patients), and proteinuria (two [5%] of 40 patients vs two [11%] of 18 patients). Serious adverse events occurred in 21 (53%) of 40 patients in the tiragolumab plus atezolizumab plus bevacizumab group and in ten (56%) of 18 patients in the atezolizumab plus bevacizumab group. Treatment-related deaths occurred in one patient in the tiragolumab plus atezolizumab plus bevacizumab group (due to cholestasis) and two patients in the atezolizumab plus bevacizumab group (due to oesophageal varices haemorrhage and upper gastrointestinal haemorrhage). The addition of tiragolumab to atezolizumab plus bevacizumab did not appear to result in a substantial worsening of treatment-related or immune-mediated adverse events, and no new safety signals were identified. Interpretation This signal-seeking study suggests that the addition of tiragolumab to atezolizumab and bevacizumab might be more clinically active than atezolizumab plus bevacizumab alone in unresectable hepatocellular carcinoma. Based on these data, further study of combination tiragolumab plus atezolizumab plus bevacizumab is warranted. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license.

435 Background: VEGF blockade coupled with cytotoxic chemotherapy can promote an immune-permissive tumor microenvironment that augments response to PD-L1 inhibition. IMbrave151 (NCT04677504) is a randomized, double-blinded, global proof-of-concept Phase II study evaluating atezolizumab (atezo), bevacizumab (bev) and cisplatin and gemcitabine (CisGem) as first-line treatment for advanced biliary tract cancer (aBTC). Here we report updated clinical data and molecular correlates of response and resistance. Methods: Patients (pts) with previously untreated aBTC were randomized 1:1 to receive atezo (1200 mg every 3 weeks [q3w]) + bev (15 mg/kg q3w) or placebo (plb) + CisGem (Cis 25 mg/m 2 and Gem 1000 mg/m 2 on Days 1 and 8 q3w) for up to 8 cycles, followed by atezo (1200 mg q3w) + bev (15 mg/kg q3w) or plb until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety. The final OS analysis was done when ≈90 deaths occurred or when all pts had ≥2 years of follow-up. Transcriptome analysis (n=98) and mutation profiling (n=103) were done on baseline tumor samples. This was a signal-seeking trial to estimate the treatment effect in each arm with no formal hypothesis testing. Results: In total, 162 pts were randomized to either atezo + bev + CisGem (atezo/bev; n=79) or atezo + plb + CisGem (atezo/plb; n=83). The updated PFS HR was 0.67 (95% CI: 0.46, 0.95) in favor of atezo/bev. Updated median PFS was 8.35 mo for atezo/bev and 7.9 mo for atezo/plb, with 6-mo rates of 78% and 63%, respectively. The updated OS HR was 0.97 (95% CI: 0.64, 1.47), with a median of 14.9 mo for atezo/bev and 14.6 mo for atezo/plb. Confirmed ORR was 26.6% for atezo/bev and 26.5% for atezo/plb, with median DORs of 10.28 (95% CI: 6.7, 16.7) and 6.18 mo (95% CI: 4.3, 6.7), respectively. The incidence of Grade 3/4 adverse events was 73% with atezo/bev and 74% with atezo/plb. High VEGFA gene expression was associated with an improved PFS (HR, 0.43; 95% CI: 0.22, 0.83) and OS (HR, 0.66; 95% CI: 0.31, 1.4) in favor of atezo/bev. Hepatocytes high gene signature also was associated with an improved PFS (HR, 0.47; 95% CI: 0.24, 0.92) and OS (HR, 0.66; 95% CI: 0.31, 1.4) in favor of atezo/bev. Pts with PI3k/AKT pathway mutations appeared to have worse OS than pts without mutations (HR, 3.7; 95% CI: 1.5, 9.1) with atezo/bev. Conclusions: Final analysis of the IMbrave151 study indicates a modest PFS benefit in intent-to-treat pts combining atezo with bev and chemotherapy. The trial is limited by small numbers and a non-comparative design. Exploratory analysis of correlative biomarkers suggests that high VEGF-A gene expression and hepatocytes high gene signature may be predictive markers of benefit with atezo/bev, warranting further investigation. Clinical trial information: NCT04677504 .

PURPOSEBiliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti-vascular endothelial growth factor) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition.PATIENTS AND METHODSThis randomized, double-blind, proof-of-concept phase II study enrolled patients (n = 162) with previously untreated advanced BTC (IMbrave151; ClinicalTrials.gov identifier: NCT04677504). Patients were randomly assigned 1:1 to receive cycles of atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo once every 3 weeks until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m2) plus gemcitabine (1,000 mg/m2; cisplatin plus gemcitabine [CisGem]) on days 1 and 8 once every 3 weeks for up to eight cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary end point was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n = 95) and mutation profiling (n = 102) on baseline tumor samples.RESULTSBetween February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo arm (stratified hazard ratio [HR], 0.67 [95% CI, 0.46 to 0.95]). Median overall survival (OS) was 14.9 and 14.6 months in the bevacizumab and placebo arms, respectively (stratified HR, 0.97 [95% CI, 0.64 to 1.47]). The incidence of grade 3 or 4 adverse events was 74% in both arms. High VEGFA gene expression was associated with improved PFS (HR, 0.44 [95% CI, 0.23 to 0.83]) in the bevacizumab arm versus placebo.CONCLUSIONIn unselected patients with advanced BTC, adding bevacizumab to atezolizumab plus CisGem modestly improves PFS but not OS. High VEGFA gene expression may represent a predictive biomarker of benefit from atezolizumab/bevacizumab, warranting further investigation.

491 Background: VEGF blockade coupled with cytotoxic chemotherapy can promote an immune-permissive tumor microenvironment that can augment response to PD-L1 inhibition. IMbrave151 (NCT04677504) is a randomized, double-blind, global Phase II study evaluating the efficacy of atezolizumab (atezo), bevacizumab (bev) and cisplatin and gemcitabine (CisGem) as first-line treatment for patients with advanced biliary tract cancer (aBTC). Methods: Patients with previously untreated aBTC were randomized 1:1 to receive atezo (1200 mg every 3 weeks [q3w]) + bev (15 mg/kg q3w) or placebo + CisGem (cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on Days 1 and 8 q3w) for up to 8 cycles, followed by atezo (1200 mg q3w) + bev (15 mg/kg q3w) or placebo until disease progression or unacceptable toxicity. Patients were stratified by disease status, geographic region and primary tumor location. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate and safety. No formal hypothesis testing was performed. Results: In total, 162 patients were randomized to receive either atezo + bev + CisGem (n=79) or atezo + placebo + CisGem (n=83). Median age 63 years, Asia/Rest of World (43/57%), ECOG PS 0/1 (53/48%), intrahepatic/extrahepatic cholangiocarcinoma and gallbladder (54/19/27%), and metastatic/locally advanced stage (82/18%). The HR for PFS was 0.76 (95% CI: 0.51, 1.14). Median PFS was 8.4 months for atezo + bev + CisGem and 7.9 months for atezo + placebo + CisGem; the 6-month PFS rates were 78% and 63%, respectively. The confirmed ORR was 24% for atezo + bev + CisGem and 25% for atezo + placebo + CisGem. DOR ≥6 months was 89% for atezo + bev + CisGem vs 47% for atezo + placebo + CisGem. The incidence of Grade 3 or 4 adverse events was 73% and 74% with atezo + bev + CisGem and atezo + placebo + CisGem, respectively. Median OS is not reached. Conclusions: Both combinations of IMbrave151 showed a manageable safety profile. The aggregate of data suggests that combining atezo with bev and chemotherapy may provide clinical benefit in a subset of patients with aBTC. Follow-up is ongoing for OS. Clinical trial information: NCT04677504 .

Background: The risk of HCC recurrence after liver resection or ablation with curative intent is 70-80% within 5 years, indicating an unmet need for effective adjuvant therapies. Atezolizumab (atezo) with bevacizumab (bev) is the standard of care for unresectable HCC based on the IMbrave150 study, which demonstrated statistically significant and clinically meaningful improvements in overall survival (OS), progression-free survival, and objective response rate versus sorafenib (Finn NEJM 2020, Cheng J Hepatol 2022). On the basis of the antitumor activity of atezo + bev and its capacity to positively modulate the tumor microenvironment, IMbrave050 was designed to evaluate the efficacy of adjuvant atezo + bev in delaying or preventing recurrence in patients (pts) with high-risk HCC. Methods: IMbrave050 (NCT04102098) enrolled pts with HCC at high risk of recurrence following resection or ablation. High-risk criteria were based on tumor burden (tumor size and number), vascular invasion, and tumor differentiation. Pts were randomized to Arm A (atezo + bev) or Arm B (active surveillance). Stratification factors included geographic region (Asia-Pacific excluding Japan vs rest of world) and a composite factor encompassing the number of high-risk features, curative procedure, and use of optional adjuvant TACE (allowed for one cycle following resection). Pts in Arm A received atezo 1200 mg + bev 15 mg/kg IV q3w for a period of one year or 17 cycles. Pts in Arm B underwent active surveillance for one year and were eligible to crossover to atezo + bev following independent review facility (IRF) confirmation of recurrence. The primary endpoint was IRF-assessed recurrence-free survival (RFS). Secondary efficacy endpoints included OS; investigator-assessed (INV) RFS; RFS and OS according to PD-L1 status; and time to extrahepatic spread and/or macrovascular invasion. Results: The ITT population included 334 pts each in Arms A and B. Baseline demographics were well balanced between arms. At interim analysis, with a median follow-up of 17.4 mo (cut off date: Oct 21, 2022), the primary endpoint was met with an IRF-RFS HR of 0.72 (95% CI, 0.56, 0.93; P=0.0120), and results were generally consistent across clinical subgroups. INV-RFS was similar (HR, 0.70; 95% CI, 0.54, 0.91). The safety of atezo + bev was generally manageable and consistent with the well-established safety profile of each therapeutic agent and with the underlying disease. Conclusions: Atezo + bev is the first adjuvant regimen to demonstrate a statistically significant and clinically meaningful improvement in RFS vs active surveillance in pts at high risk of disease recurrence following resection or ablation. The benefit:risk profile of atezo + bev favors the use of this regimen as an adjuvant therapy and has potential to set a new standard of care in adjuvant HCC. Citation Format: Pierce Chow, Minshan Chen, Ann-Lii Cheng, Ahmed O. Kaseb, Masatoshi Kudo, Han Chu Lee, Adam Yopp, Jian Zhou, Lu Wang, Xiaoyu Wen, Jeong Heo, Won Young Tak, Shinichiro Nakamura, Kazushi Numata, Thomas Uguen, David Hsiehchen, Edward Cha, Stephen P. Hack, Qinshu Lian, Jessica Spahn, Chun Wu, Shukui Qin. IMbrave050: Phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT003.

We assess the longitudinal tumor growth inhibition (TGI) metrics and overall survival (OS) predictions applied to patients with advanced biliary tract cancer (BTC) enrolled in IMbrave151 a multicenter randomized phase II, double-blind, placebo-controlled trial evaluating the efficacy and safety of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine. Tumor growth rate (KG) was estimated for patients in IMbrave151. A pre-existing TGI-OS model for patients with hepatocellular carcinoma in IMbrave150 was modified to include available IMbrave151 study covariates and KG estimates and used to simulate IMbrave151 study outcomes. At the interim progression-free survival (PFS) analysis (98 patients, 27 weeks follow-up), clear separation in tumor dynamic profiles with a faster shrinkage rate and slower KG (0.0103 vs. 0.0117 week(-1); tumor doubling time 67 vs. 59 weeks; KG geometric mean ratio of 0.84) favoring the bevacizumab containing arm was observed. At the first interim analysis for PFS, the simulated OS hazard ratio (HR) 95% prediction interval (PI) of 0.74 (95% PI: 0.58-0.94) offered an early prediction of treatment benefit later confirmed at the final analysis, observed HR of 0.76 based on 159 treated patients and 34 weeks of follow-up. This is the first prospective application of a TGI-OS modeling framework supporting gating of a phase III trial. The findings demonstrate the utility for longitudinal TGI and KG geometric mean ratio as relevant end points in oncology studies to support go/no-go decision making and facilitate interpretation of the IMbrave151 results to support future development efforts for novel therapeutics for patients with advanced BTC.

Abstract Background: The risk of HCC recurrence after liver resection or ablation with curative intent is 70-80% within 5 years, indicating an unmet need for effective adjuvant therapies. Atezolizumab (atezo) with bevacizumab (bev) is the standard of care for unresectable HCC based on the IMbrave150 study, which demonstrated statistically significant and clinically meaningful improvements in overall survival (OS), progression-free survival, and objective response rate versus sorafenib (Finn NEJM 2020, Cheng J Hepatol 2022). On the basis of the antitumor activity of atezo + bev and its capacity to positively modulate the tumor microenvironment, IMbrave050 was designed to evaluate the efficacy of adjuvant atezo + bev in delaying or preventing recurrence in patients (pts) with high-risk HCC. Methods: IMbrave050 (NCT04102098) enrolled pts with HCC at high risk of recurrence following resection or ablation. High-risk criteria were based on tumor burden (tumor size and number), vascular invasion, and tumor differentiation. Pts were randomized to Arm A (atezo + bev) or Arm B (active surveillance). Stratification factors included geographic region (Asia-Pacific excluding Japan vs rest of world) and a composite factor encompassing the number of high-risk features, curative procedure, and use of optional adjuvant TACE (allowed for one cycle following resection). Pts in Arm A received atezo 1200 mg + bev 15 mg/kg IV q3w for a period of one year or 17 cycles. Pts in Arm B underwent active surveillance for one year and were eligible to crossover to atezo + bev following independent review facility (IRF) confirmation of recurrence. The primary endpoint was IRF-assessed recurrence-free survival (RFS). Secondary efficacy endpoints included OS; investigator-assessed (INV) RFS; RFS and OS according to PD-L1 status; and time to extrahepatic spread and/or macrovascular invasion. Results: The ITT population included 334 pts each in Arms A and B. Baseline demographics were well balanced between arms. At interim analysis, with a median follow-up of 17.4 mo (cut off date: Oct 21, 2022), the primary endpoint was met with an IRF-RFS HR of 0.72 (95% CI, 0.56, 0.93; P=0.0120), and results were generally consistent across clinical subgroups. INV-RFS was similar (HR, 0.70; 95% CI, 0.54, 0.91). The safety of atezo + bev was generally manageable and consistent with the well-established safety profile of each therapeutic agent and with the underlying disease. Conclusions: Atezo + bev is the first adjuvant regimen to demonstrate a statistically significant and clinically meaningful improvement in RFS vs active surveillance in pts at high risk of disease recurrence following resection or ablation. The benefit:risk profile of atezo + bev favors the use of this regimen as an adjuvant therapy and has potential to set a new standard of care in adjuvant HCC. Citation Format: Pierce Chow, Minshan Chen, Ann-Lii Cheng, Ahmed O. Kaseb, Masatoshi Kudo, Han Chu Lee, Adam Yopp, Jian Zhou, Lu Wang, Xiaoyu Wen, Jeong Heo, Won Young Tak, Shinichiro Nakamura, Kazushi Numata, Thomas Uguen, David Hsiehchen, Edward Cha, Stephen P. Hack, Qinshu Lian, Jessica Spahn, Chun Wu, Shukui Qin. IMbrave050: Phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT003.

Einleitung Das Risiko eines HCC-Rezidivs nach einer Leberresektion oder -ablation mit kurativer Intention ist hoch, daher bedarf es wirksamer adjuvanter Therapien. Atezolizumab (Atezo)+Bevacizumab (Bev) stellt den Therapiestandard bei nicht resezierbarem HCC dar, da es im Vergleich zu Sorafenib statistisch signifikante und klinisch bedeutsame Verbesserungen hinsichtlich des Gesamtüberlebens (OS), progressionsfreien Überlebens und der objektiven Ansprechrate zeigte (IMbrave150-Studie).

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 174 months (IQR 139-221). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 221-NE]) compared with active surveillance (median, NE [214-NE]; hazard ratio, 072 [adjusted 95% CI 053-098]; p=0012). 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.

Introduction Biliary tract cancers (BTCs) have a dismal prognosis and limited treatment options. The role of immunotherapy in BTC is unclear. BTCs respond poorly to PD-(L)1 blockade, highlighting the need for combination regimens to augment antitumor immunity. Atezolizumab (anti-PD-L1) combined with other therapies is under investigation in advanced BTC.Areas covered This paper provides an overview of the recent progress and future applications of immunotherapy for BTCs and sheds light on the status and therapeutic potential of atezolizumab. We discuss published data for atezolizumab and an examine the rationale and design of ongoing clinical studies. We offer insights and opinions on the future applications and challenges of immunotherapy in BTC.Expert opinion Atezolizumab monotherapy has demonstrated limited antitumor activity in BTC, indicating the need for combination regimens to unlock effective anticancer immunity, and the development of predictive biomarkers to enrich the population. Data for atezolizumab combined with chemotherapy, anti-VEGF agents and other targeted drugs in solid tumors justifies their evaluation in BTC. Several novel atezolizumab-based combinations have been or are currently under investigation in Phase II studies. It is hoped that data from these studies, along with other immunotherapy trials, will provide more effective treatments for patients with BTC.

Hepatocellular carcinoma recurs in 70-80% of cases following potentially curative resection or ablation and the immune component of the liver microenvironment plays a key role in recurrence. Many immunosuppressive mechanisms implicated in HCC recurrence are modulated by VEGF and/or immune checkpoints such as PD-L1. Atezolizumab (PD-L1 inhibitor) plus bevacizumab (VEGF inhibitor) has been shown to significantly improve overall survival, progression-free survival and overall response rate in unresectable HCC. Dual PD-L1/VEGF blockade may be effective in reducing HCC recurrence by creating a more immune-favorable microenvironment. We describe the rationale and design of IMbrave 050 (NCT04102098), a randomized, open-label, Phase III study comparing atezolizumab plus bevacizumab versus active surveillance in HCC patients at high-risk of recurrence following curative resection or ablation. The primary end point is recurrence-free survival. Clinical Trial Registration: NCT04102098.

Cancer immunotherapy (CIT) with antibodies targeting the programmed cell death 1 protein (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis have changed the standard of care in multiple cancers. However, durable antitumor responses have been observed in only a minority of patients, indicating the presence of other inhibitory mechanisms that act to restrain anticancer immunity. Therefore, new therapeutic strategies targeted against other immune suppressive mechanisms are needed to enhance anticancer immunity and maximize the clinical benefit of CIT in patients who are resistant to immune checkpoint inhibition. Preclinical and clinical studies have identified abnormalities in the tumor microenvironment (TME) that can negatively impact the efficacy of PD-1/PD-L1 blockade. Angiogenic factors such as vascular endothelial growth factor (VEGF) drive immunosuppression in the TME by inducing vascular abnormalities, suppressing antigen presentation and immune effector cells, or augmenting the immune suppressive activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. In turn, immunosuppressive cells can drive angiogenesis, thereby creating a vicious cycle of suppressed antitumor immunity. VEGF-mediated immune suppression in the TME and its negative impact on the efficacy of CIT provide a therapeutic rationale to combine PD-1/PD-L1 antibodies with anti-VEGF drugs in order to normalize the TME. A multitude of clinical trials have been initiated to evaluate combinations of a PD-1/PD-L1 antibody with an anti-VEGF in a variety of cancers. Recently, the positive results from five Phase III studies in non-small cell lung cancer (adenocarcinoma), renal cell carcinoma, and hepatocellular carcinoma have shown that combinations of PD-1/PD-L1 antibodies and anti-VEGF agents significantly improved clinical outcomes compared with respective standards of care. Such combinations have been approved by health authorities and are now standard treatment options for renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. A plethora of other randomized studies of similar combinations are currently ongoing. Here, we discuss the principle mechanisms of VEGF-mediated immunosuppression studied in preclinical models or as part of translational clinical studies. We also discuss data from recently reported randomized clinical trials. Finally, we discuss how these concepts and approaches can be further incorporated into clinical practice to improve immunotherapy outcomes for patients with cancer.

Background Dual blockade of PD-L1 and VEGF has enhanced anticancer immunity through multiple mechanisms and augmented antitumour activity in multiple malignancies. We aimed to assess the efficacy and safety of atezolizumab (anti-PD-L1) alone and combined with bevacizumab (anti-VEGF) in patients with unresectable hepatocellular carcinoma. Methods GO30140 is an open-label, multicentre, multiarm, phase 1b study that enrolled patients at 26 academic centres and community oncology practices in seven countries worldwide. The study included five cohorts, and the two hepatocellular carcinoma cohorts, groups A and F, are described here. Inclusion criteria for these two groups included age 18 years and older; histologically, cytologically, or clinically (per American Association for the Study of Liver Diseases criteria) confirmed unresectable hepatocellular carcinoma that was not amenable to curative treatment; no previous systemic treatment; and Eastern Cooperative Oncology Group performance status of 0 or 1. In group A, all patients received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks. In group F, patients were randomly assigned (1:1) to receive intravenous atezolizumab (1200 mg) plus intravenous bevacizumab (15 mg/kg) every 3 weeks or atezolizumab alone by interactive voice-web response system using permuted block randomisation (block size of two) and stratification factors of geographical region; macrovascular invasion, extrahepatic spread, or both; and baseline a-fetoprotein concentration. Primary endpoints were confirmed objective response rate in all patients who received the combination treatment for group A and progression-free survival in the intention-totreat population in group F, both assessed by an independent review facility according to Response Evaluation Criteria in Solid Tumors version 1.1. In both groups, safety was assessed in all patients who received at least one dose of any study treatment. This study is registered with ClinicalTrials.gov, NCT02715531, and is closed to enrolment. Findings In group A, 104 patients were enrolled between July 20,2016, and July 31,2018, and received atezolizumab plus bevacizumab. With a median follow-up of 12.4 months (IQR 8.0-16.2), 37 (36%; 95% CI 26-46) of 104 patients had a confirmed objective response. The most common grade 3-4 treatment-related adverse events were hypertension (13 [13%]) and proteinuria (seven [7%]). Treatment-related serious adverse events occurred in 25 (24%) patients and treatment-related deaths in three (3%) patients (abnormal hepatic function, hepatic cirrhosis, and pneumonitis). In group F, 119 patients were enrolled and randomly assigned (60 to atezolizumab plus bevacizumab; 59 to atezolizumab monotherapy) between May 18,2018, and March 7,2019. With a median follow-up of 6.6 months (IQR 5.5-8.5) for the atezolizumab plus bevacizumab group and 6.7 months (4.2-8.2) for the atezolizumab monotherapy group, median progression-free survival was 5.6 months (95% CI 3.6-7.4) versus 3.4 months (1.9-5.2; hazard ratio 0.55; 80% CI 0.40-0.74; p=0.011). The most common grade 3-4 treatment-related adverse events in group F were hypertension (in three [5%] patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group) and proteinuria (in two [3%] patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group). Treatment-related serious adverse events occurred in seven (12%) patients in the atezolizumab plus bevacizumab group and two (3%) patients in the atezolizumab monotherapy group. There were no treatment-related deaths. Interpretation Our study shows longer progression-free survival with a combination of atezolizumab plus bevacizumab than with atezolizumab alone in patients with unresectable hepatocellular carcinoma not previously treated with systemic therapy. Therefore, atezolizumab plus bevacizumab might become a promising treatment option for these patients. This combination is being compared with standard-of-care sorafenib in a phase 3 trial. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Atezo (anti-PD-L1) + bev (anti–VEGF) statistically significantly prolonged overall survival (OS) and progression-free survival (PFS) vs sorafenib in the phase III IMbrave150 study in patients with unresectable HCC. In the phase Ib study GO30140, atezo + bev statistically significantly increased PFS vs atezo. We present efficacy data from GO30140 patients who crossed over to atezo + bev following progression on atezo. In GO30140 Arm F, 119 patients with unresectable HCC were randomised 1:1 to atezo 1200 mg IV + bev 15 mg/kg IV q3w (Arm F1) or atezo 1200 mg IV q3w (Arm F2). Patients in Arm F2 could cross over to atezo + bev after disease progression (PD) per RECIST 1.1. Investigator-assessed PFS and objective response rate (ORR) following crossover were evaluated. At the data cut on 14 June 2019, 26 of 59 patients in Arm F2 crossed over to atezo + bev following PD after a median 2.5-mo exposure to atezo monotherapy. Crossover patients’ baseline demographics were comparable with those of patients in Arms F2 and F1. With a median follow-up of 4.0 mo post crossover, 1 patient had a partial response (PR) with atezo + bev (ORR 3.8% vs 0% with atezo pre-crossover). The disease control rate was 53.8% with atezo + bev vs 30.8% with atezo pre-crossover. Median (95% CI) PFS post crossover was 5.4 mo (1.9-6.4 mo; 14/26 events) with atezo + bev vs 1.9 mo (1.8-2.1 mo; 26/26 events) with atezo pre-crossover. Best overall response (BOR) before and after crossover are shown in the table. Recognizing the limitations of this exploratory post-hoc analysis, a subset of patients with unresectable HCC with PD on atezo monotherapy may benefit from the addition of bevacizumab. These and other GO30140 data support combination therapyTable: 986PBOR Before vs After Crossover (n = 26)BOR With Atezo Monotherapy Pre- CrossoverBOR With Atezo + Bev Post Crossover, n (%)PRSDPDNE/MissingPD (n = 18)1 (5.6)9 (50.0)6 (33.3)2 (11.1)SD (n = 8)–4 (50.0)–4 (50.0)NE, not evaluable; SD, stable disease. Open table in a new tab .

BACKGROUND Dysregulated hepatocyte growth factor/mesenchymal-epithelial transition (MET) signaling is associated with poor prognosis and resistance to vascular endothelial growth factor inhibition in metastatic colorectal cancer (mCRC). We report outcomes from a double-blind, multicenter phase II trial of the MET inhibitor onartuzumab in combination with mFOLFOX-6 and bevacizumab for mCRC (GO27827; NCT01418222). MATERIALS AND METHODS Patients were randomized 1:1 to receive onartuzumab (10 mg/kg intravenously [IV]) or placebo plus mFOLFOX-6 and bevacizumab (5 mg/kg IV). Oxaliplatin was given for 8-12 cycles; other agents were continued until disease progression, unacceptable toxicity, or death. The primary endpoint was progression-free survival (PFS) in the intent-to-treat (ITT) and MET immunohistochemistry (IHC) expression-positive populations. RESULTS Between September 2011 and November 2012, 194 patients were enrolled. In September 2013, an interim analysis recommended stopping onartuzumab treatment due to lack of efficacy. At the time of the final analysis in February 2014, no significant improvement in PFS was seen with onartuzumab versus placebo in either the ITT or MET IHC-positive populations. An improvement in PFS was noted in the MET IHC-negative population. Neither overall survival nor response rate was improved with onartuzumab. The incidence of fatigue, peripheral edema, and deep vein thrombosis was increased with onartuzumab relative to placebo. CONCLUSION Onartuzumab combined with mFOLFOX-6 and bevacizumab did not significantly improve efficacy outcomes in either the ITT or MET IHC-positive populations. MET expression by IHC was not a predictive biomarker in this setting. The Oncologist 2017;22:264-271 IMPLICATIONS FOR PRACTICE: The addition of onartuzumab to mFOLFOX-6 plus bevacizumab did not improve outcomes in patients with previously untreated metastatic colorectal cancer in this randomized, phase II study. Although initial results with onartuzumab were promising, a number of phase II/III clinical trials have reported a lack of improvement in efficacy with onartuzumab combined with standard-of-care therapies in several tumor types. Furthermore, negative study data have been published for rilotumumab and ficlatuzumab, both of which block hepatocyte growth factor binding to the mesenchymal-epithelial transition (MET) receptor. MET immunohistochemistry was not a predictive biomarker. It remains to be seen if other biomarkers or small molecule inhibitors may be more appropriate for inhibiting this oncogenic pathway.

IMPORTANCE Dysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC.OBJECTIVE To determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC.DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, multicenter trial conducted from November 2012 to March 2014. Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy. Tumor samples were centrally tested for MET expression using Ventana anti-Total c-MET (SP44) rabbit monoclonal antibody, HER2 status, and Lauren histologic subtype. MET-positive tumors were defined as at least 50% of tumor cells showing weak, moderate, and/or strong staining intensity (MET 1+/2+/3+, respectively) by immunohistochemistry.INTERVENTIONS Patients with HER2-negative, MET-positive GEC were enrolled and randomized 1: 1 to receivem FOLFOX6 with or without onartuzumab (10mg/kg).MAIN OUTCOMES AND MEASURES Co-primary end points: overall survival in the intent-to-treat (ITT) population and in patients with MET 2+/3+ GEC. Secondary end points: progression-free survival (PFS), overall response rate (ORR), and safety.RESULTS Enrollment was stopped early due to sponsor decision, which was agreed with an independent data monitoring committee. At the data cutoff (April 25, 2014) there were 562 patients in the ITT population (n = 283 placebo plus mFOLFOX6 [median age, 58 y; 65% male]; n = 279 onartuzumab plus mFOLFOX6 [median age, 60 y; 67% male]); 109 (38.5%) and 105 (37.6%) of the ITT population were MET 2+/3+, respectively. Addition of onartuzumab to mFOLFOX6 did not significantly improve OS, PFS, or ORR vs placebo plus mFOLFOX6 in the ITT (OS hazard ratio [HR], 0.82; 95% CI, 0.59-1.15; P =.24; PFS HR, 0.90; 95% CI, 0.71-1.16; P =.43; ORR, 46.1% vs 40.6%) or MET 2+/3+ populations (OS HR, 0.64; 95% CI, 0.40-1.03; P =.06; PFS HR, 0.79; 95% CI, 0.54-1.15; P =.22; ORR, 53.8% vs 44.6%). Safety was as expected for onartuzumab.CONCLUSIONS AND RELEVANCE Addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3+ populations.

663 Background: In mCRC, MET overexpression has been associated with poor prognosis and resistance to anti-VEGF therapy. We initiated a phase II study to evaluate the combination of onartuzumab (O), a ligand-blocking monoclonal antibody directed against the MET receptor, plus bevacizumab and FOLFOX, in first-line mCRC (GO27827; NCT01418222). Methods: This double-blind, randomized, multicenter phase II study randomized patients 1:1 to receive O (10 mg/kg iv) or placebo (P), plus mFOLFOX6 and bevacizumab (5 mg/kg iv). Stratification was by prior adjuvant therapy. All treatments were given on day 1–3 of a 2-week cycle. Oxaliplatin was given for up to 8–12 cycles; all other agents were continued until progression, unacceptable toxicity or death. Primary endpoint was progression-free survival (PFS) in ITT and MET+ subgroup by immunohistochemistry (IHC). MET status was determined by central laboratory IHC evaluation, with scores of 2+ or 3+ considered MET+. Results: From September 2011 to November 2012, 194 patients were enrolled. A recommendation was made to stop O after an interim efficacy and safety analysis in September 2013, due to lack of efficacy. The final analysis (cut-off Feb 2014) found that O did not improve PFS vs. P in the ITT (HR 0.75 [0.52–1.08]; p=0.12) or MET IHC+ populations (n=79; HR 1.03 [0.56–1.89]; p=0.93), although improvement was noted in the MET IHC− population (n=108; HR 0.60 [0.37–0.97]; p=0.03). Neither overall survival (OS) nor response rate (RR) was improved with O vs. P in any of the groups (OS HR 0.96 [0.61–1.50], p=0.85 for ITT; OS HR 1.24 [0.63–2.43], p=0.54 for MET IHC+; OS HR 0.83 [0.44–1.56], p=0.56 for MET IHC−; RR 57.3% vs. 57.7% for ITT, 43.2% vs. 57.1% for MET IHC+, 66.1% vs. 60.8% for MET IHC−). More edema (65.7% vs. 12.9%) and venous thromboembolic events (30.3% vs. 16.1%) were seen with O vs. P, respectively. Grade ≥3 events were similar (86.9% vs. 84.9%) and events leading to discontinuation were increased (48.5% vs. 37.6%) with O vs. P. Conclusions: Adding onartuzumab to FOLFOX/bevacizumab did not prolong PFS in first-line unselected or MET IHC+ mCRC. A trend towards PFS benefit was seen in those with MET IHC− mCRC, contrary to prior reports in other tumor types. Clinical trial information: NCT01418222.

L’analyse principale de coBRIM a montré une amélioration significative de la PFS et du taux de réponse globale (ORR) chez des patients (pts) atteints d’un mélanome avancé avec mutation BRAFV600 traités par vem + cobi. Nous présentons une mise à jour de la PFS médiane et une analyse de corrélation entre la réponse clinique et les mutations oncogéniques initiales coexistant avec les mutations BRAFV600. La méthodologie de l’étude a déjà été présentée. La PFS et l’ORR ont été mis à jour (16 jan 2015), le suivi médian était d’environ 14 mois. La mutation BRAFV600et 528 mutations activatrices connues dans 17 protéines kinases oncogéniques ont été analysées à l’aide d’un séquençage de nouvelle génération (profondeur de lecture moyenne > 3000 ×). Une analyse par Reverse-Phase Protein Array (RPPA) a été utilisée pour évaluer la voie d’activation oncogénique des tumeurs. Les données de co-mutations ont été corrélées avec la PFS et l’ORR. La PFS médiane mise à jour était de 12,3 mois pour vem + cobi vs 7,2 mois pour vem + placebo (pbo). Le hazard ratio était de 0,58 [IC 95 % ; 0,46–0,72]. Les résultats d’ORR sont présentés. Sur 46 des 423 (11 %) échantillons tumoraux des patients, des mutations coexistantes initiales ont été observées pour H-, K-, N-Ras, non-V600 BRAF, ou pour les récepteurs de la tyrosine kinase (RAS/RAF/RTK), avec une fréquence médiane d’allèles de 8 %. Les co-mutations n’étaient pas corrélées à une réduction de la PFS ou une ORR plus faible chez les pts traités par vem + pbo ou vem + cobi, bien que les tumeurs aient présenté un taux plus élevé d’activation d’ERK et MEK que celles sans mutations coexistantes (détecté par RPPA). La co-existence de mutations BRAFV600 avec des mutations activatrices RAS/RAF/RTK à l’état initial ne semble pas impacter la progression de la maladie ou le taux de réponse d’un traitement par vem + cobi ou vem. Le suivi prolongé confirme le bénéfice clinique de vem + cobi chez des patients atteints d’un mélanome avancé avec mutation BRAFV600 positive.