Updated Findings Bolster the Use of Checkpoint Inhibitors in Treatment of Liver Cancer

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Although optimal regimens are still being determined, checkpoint inhibition has clearly established itself in the treatment of hepatocellular carcinoma, as judged by the number of abstracts on the topic at the 2021 Gastrointestinal Cancers Symposium. The ASCO Post brings readers short summaries of some of the important studies in locally advanced or metastatic hepatocellular carcinoma presented at this meeting.

IMbrave150 Update

An update of the phase III IMbrave150 trial of atezolizumab plus bevacizumab showed impressive survival in the front-line setting, reported Richard S. Finn, MD, Professor of Clinical Medicine at the Geffen School of Medicine, University of California, Los Angeles.1 The study of 501 treatment-naive patients compared the combination with single-agent sorafenib. After a median follow-up of 15.6 months, median overall survival was 19.2 months with the combination vs 13.4 months with sorafenib (hazard ratio [HR] = 0.66; P = .0009).

Richard S. Finn, MD

Richard S. Finn, MD

“The median survival for atezolizumab plus bevacizumab is now more than 19 months. This is the longest survival seen in a phase III study of advanced liver cancer,” Dr. Finn noted.

Patients were randomly assigned to receive 1,200 mg of atezolizumab every 3 weeks plus 15 mg/kg of bevacizumab every 3 weeks (n = 336) or 400 mg of sorafenib twice daily (n = 165). At 18 months, the overall survival rate was 52% vs 40%, respectively, and the progression-free survival rate was 24% vs 12%. Median progression-free survival was 6.9 months vs 4.3 months, respectively (HR = 0.65; P = .0001). The rate of confirmed responses was 30% with atezolizumab/bevacizumab vs 11% with sorafenib, again indicating a significant benefit for immunotherapy and signaling a change to the current paradigm.

“We see with longer follow-up that we have more responses with atezolizumab/bevacizumab than initially reported,” said Dr. Finn. The median duration of response was 18.1 months with the combination vs 14.9 months with sorafenib. At data cutoff, ongoing responses were observed in 56% vs 28%, respectively.

In May 2020, based on the primary analysis of IMbrave150, which showed both primary endpoints were met, the U.S. Food and Drug Administration approved atezolizumab/bevacizumab for previously untreated unresectable or metastatic hepatocellular carcinoma.

In the current analysis, 40% of patients in the combination arm remained on study vs 26% in the sorafenib arm; 18% and 3% of patients remained on treatment, respectively. Safety remained consistent with the primary analysis, Dr. Finn said.

Neoadjuvant Nivolumab Plus Cabozantinib

Neoadjuvant therapy with nivolumab and cabozantinib was associated with a high rate of pathologic responses and the feasibility of R0 resections in a small study reported by Mark Yarchoan, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.2 “To our knowledge, this study is the first use of a targeted therapy in combination with an immune checkpoint inhibitor in the neoadjuvant treatment of hepatocellular carcinoma, and the first prospective use of modern systemic therapies to attempt to downstage hepatocellular carcinoma outside of traditional resection criteria,” he said.

Mark Yarchoan, MD

Mark Yarchoan, MD

No systemic therapy is approved for the neoadjuvant or adjuvant treatment of hepatocellular carcinoma. However, preoperative strategies that can reduce tumor volume and the burden of micrometastatic disease have the potential to improve resectability and therefore outcomes, he added.

Thus, Dr. Yarchoan and colleagues evaluated the feasibility of neoadjuvant cabozantinib plus nivolumab in 15 patients with hepatocellular carcinoma with borderline resectable or locally advanced hepatocellular carcinoma. Some patients had multinodular disease (40%), portal vein invasion (27%), infiltrative disease (60%), and a tumor diameter greater than 10 cm (40%). Patients received cabozantinib at 40 mg/d for 8 weeks along with nivolumab at 240 mg every 2 weeks, and then underwent surgical reevaluation.

“The trial met its primary endpoint of feasibility,” Dr. Yarchoan reported. “No patient experienced a treatment-related adverse event that precluded continuing on to surgery within 60 days.”

Of the 15 patients, surgery was attempted in 13; 12 achieved successful margin-negative resections, and 5 achieved a major or complete pathologic response. Despite the brief neoadjuvant treatment course, multiple patients had radiographic tumor changes resulting in the possibility of secondary resectability. Immunohistochemistry staining showed a “brisk immune infiltrate” in pathologic responders, which suggested an “organized B-cell contribution to antitumor immunity,” according to Dr. Yarchoan.

CheckMate 040: Long-Term Follow-up

In CheckMate 040, the investigators examined different dosing schedules for the combination of nivolumab plus ipilimumab in the second-line setting.3Anthony B. El-Khoueiry, MD, Associate Professor of Clinical Medicine at the University of Southern California, Los Angeles, reported long-term follow-up at 44 months.

Anthony B. El-Khoueiry, MD

Anthony B. El-Khoueiry, MD

The study randomly assigned 148 previously treated patients into 3 dosing cohorts: (1) nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks (4 doses), followed by nivolumab at 240 mg every 2 weeks; (2) nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks (4 doses), each followed by nivolumab at 240 mg every 2 weeks; or (3) nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks.

For these respective dosing cohorts, updated survival rates at 36 months were 42%, 26%, and 30%, respectively. Durable responses were achieved across treatment arms, with the duration of response approaching 4 years in some cases, Dr. El-Khoueiry reported.

KEYNOTE-224: Single-Agent Pembrolizumab Upfront

In treatment-naive hepatocellular carcinoma, single-agent pembrolizumab demonstrated durable antitumor activity in the single-arm phase II KEYNOTE-224 trial, presented by Jean-Luc Van Laethem, MD, PhD, of Hôpital Erasme–Université Libre de Bruxelles, Belgium.4 Of 51 patients, 22 experienced at least some reduction in tumor size.

Jean-Luc Van Laethem, MD, PhD

Jean-Luc Van Laethem, MD, PhD

Dr. Van Laethem reported data from Cohort 2, in which study participants received pembrolizumab every 3 weeks for up to 35 cycles, or approximately 2 years, followed by a potential retreatment phase of 1 year. The median time from the first dose of therapy to data cutoff was 21 months.

In this front-line cohort, the objective response rate was 16%, and the stable disease rate was 41%. The median duration of response was not reached (range, 3 to 20+ months), with 70% of patients estimated to have a response duration of 12 months or more. Median progression-free survival was 4 months, and 12-month progression-free survival was 24%. Median overall survival was 17 months, and 58% of patients were alive at 12 months, Dr. Van Laethem reported.

The benefits in the front-line setting may be more encouraging than those for pembrolizumab among previously treated patients and should be further explored. Results from Cohort 1 of this study showed enough antitumor activity for the single agent to receive accelerated approval in 2018. However, a confirmatory phase III trial of pembrolizumab vs best supportive care, KEYNOTE-240, missed its co-primary endpoints of overall and progression-free survival.5

KEYNOTE-240 Update: Numerical Improvement Not Significant

The update of KEYNOTE-240 presented at this meeting was based on data analyzed 18 months after the final analysis and after a median follow-up of approximately 40 months.6 The analysis of 413 patients showed that pembrolizumab maintained the numerical improvements in overall survival and progression-free survival initially reported, which missed statistical significance, according to Philippe Merle, MD, PhD, Professor of Hepato-Gastroenterology and Digestive Oncology at the Centre of Research in Cancerology at Lyon University and Croix-Rousse Hospital, France.

Philippe Merle, MD, PhD

Philippe Merle, MD, PhD

Updated median overall survival was 13.9 months with pembrolizumab vs 10.6 months with placebo (HR = 0.77; P = .0112). At 24 months, the overall survival rates were 28.8% and 20.4%, respectively, whereas at 36 months, they were 17.7% and 11.7%, respectively. Median progression-free survival was 3.3 months and 2.8 months, respectively (HR = 0.70; P = .0011). At 24 months, 11.8% and 4.8% of patients, respectively, were progression-free, as were 9.0% and 0% at 36 months, Dr. Merle reported. 

DISCLOSURE: Dr. Finn has served as a consultant or advisor to AstraZeneca, Bayer, Bristol Myers Squibb, C Stone Pharma, Eisai, Exelixis, Genentech/Roche, Lilly, Merck, Novartis, and Pfizer; has received institutional research funding from Bayer, Bristol Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer, and Roche/Genentech; and has provided expert testimony on behalf on Bayer. Dr. Yarchoan has served as a consultant or advisor to AstraZeneca, Eisai, Exelixis, and Geneos and has received institutional research funding from Bristol Myers Squibb, Exelixis, Incyte, and Merck & Co. Dr. El-Khoueiry has received honoraria from Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Eisai, EMD Serono, Exelixis, Gilead, Merck, Pieris Pharmaceuticals, and Roche/Genentech; has served as a consultant or advisor to Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Eisai, EMD Serono, Exelixis, Gilead, Merck, Pieris Pharmaceuticals, and Roche; and has received research funding from Astex Pharmaceuticals, AstraZeneca, and Merck. Dr. Van Laethem reported no conflicts of interest. Dr. Merle has received honoraria from AstraZeneca, Bayer Schering Pharma, Bristol Myers Squibb, Eisai, Ipsen, Lilly, Merck, and Roche and has served as a consultant or advisor to Bayer Schering Pharma.


1. Finn RS, Qin S, Ikeda M, et al: IMbrave150: Updated overall survival data from a global, randomized, open-label phase III study of atezolizumab + bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma. 2021 Gastrointestinal Cancers Symposium. Abstract 267.

2. Yarchoan M, Zhu Q, Durham JN, et al: Feasibility and efficacy of neoadjuvant cabozantinib and nivolumab in patients with borderline resectable or locally advanced hepatocellular carcinoma. 2021 Gastrointestinal Cancers Symposium. Abstract 335.

3. El-Khoueiry AB, Yau T, Kang YK, et al: Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma: Long-term results from CheckMate 040. 2021 Gastrointestinal Cancers Symposium. Abstract 269.

4. Van Laethem JL, Borbath I, Karwal M, et al: Pembrolizumab monotherapy for previously untreated advanced hepatocellular carcinoma: Phase II KEYNOTE-224 study. 2021 Gastrointestinal Cancers Symposium. Abstract 297.

5. Finn RS, Ryoo BY, Merle P, et al: Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: A randomized, double-blind, phase III trial. J Clin Oncol 38:193-202, 2020.

6. Merle P, Edeline J, Bouattour M, et al: Pembrolizumab vs placebo in patients with advanced hepatocellular carcinoma previously treated with sorafenib: Updated data from the randomized, phase III KEYNOTE-240 study. 2021 Gastrointestinal Cancers Symposium. Abstract 268.