'Momentous' Data for First-Line Combo in Liver Cancer

Alexander M. Castellino, PhD

May 14, 2020

New clinical data are set to change the treatment landscape for advanced liver cancer.

This space has been dominated for a more than a decade by sorafenib (Nexavar, Bayer), which was the first systemic therapy to confer "a meaningful survival benefit in the treatment of advanced hepatocellular carcinoma [HCC]," notes Robin K. Kelley, MD, from the University of California, San Francisco.

"Since then, no treatment had surpassed the effect of sorafenib in the first line until the regimen of atezolizumab and bevacizumab" that is now being reported, she notes.

Those new data come from the IMbrave150 study, published on May 14 in the New England Journal of Medicine.

"The combination of atezolizumab plus bevacizumab has become the new benchmark for first-line therapy in advanced hepatocellular carcinoma," Kelley writes in an accompanying editorial.

"These data are momentous, since they identify not only the first therapy to improve survival beyond sorafenib, but also the first successful combination regimen and the first positive randomized, phase 3 trial of immune checkpoint inhibition in this challenging cancer," she added.

The IMbrave 150 study was sponsored by Roche, manufacturer of both the checkpoint inhibitor atezolizumab (Tecentriq, Genentech/Roche) and the antiangiogenic agent bevacizumab (Avastin, Genentech/Roche); the company has submitted an FDA approval application for use of this combination for inoperable liver cancer.

"Results Represent a Breakthrough"

"These results represent a breakthrough in the management of advanced HCC," said Josep M. Llovet, MD, PhD, director of the Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York City, and professor of medicine in hepatic oncology at the University of Barcelona, Spain.

The combination has already been acknowledged as a milestone in the management of HCC, he said.

Llovet was approached for comment by Medscape Medical News. He was not involved with IMbrave150 but was the lead author on the SHARP study, which led to the first-line approval of sorafenib.

He explained that since the approval of sorafenib in 2008, lenvatinib (Lenvima, Eisai) has been the only other agent approved for the front-line treatment of HCC after hitting the noninferiority endpoint for survival in comparison with sorafenib. "Up to now there was no agent superior to sorafenib, the standard of care," he said.

Now the combination of atezolizumab-bevacizumab has shown superior efficacy compared with sorafenib, Llovet noted. It is not only the first combination to show efficacy but is also the first checkpoint inhibitor that has demonstrated efficacy in HCC. "Previous studies of checkpoint inhibitors used as single agents in the front-line or second-line setting of advanced liver cancer were negative," he said.

"Game-Changer" in Liver Cancer

"The atezolizumab-bevacizumab combination is a game-changer in liver cancer," the lead author of the IMbrave 150 trial, Richard S. Finn, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, told Medscape Medical News.

The atezolizumab-bevacizumab combination is a game-changer in liver cancer. Dr Richard Finn

"The combination has established a new standard of care that is predicated on the gold standard of overall survival [OS] and is underscored by prolonged progression-free survival [PFS] and high response rates that are durable," Finn said.

In the IMbrave150 trial, treatment-naive patients who had unresectable liver cancer received either atezolizumab-bevacizumab (n = 336) or sorafenib (n = 165).

After a median follow-up of 8.6 months, median survival was significantly longer for the patients who received atezolizumab-bevacizumab: 13.2 months. For the patients who did not receive the combination, median survival was not reached (hazard ratio [HR], 0.58; P < .001). Six-month OS was 84.8% with the combination vs 72.2% with sorafenib.

Median PFS was also significantly longer for patients who received combination therapy: 6.8 months with the combination vs 4.3 months with sorafenib (HR, 0.59; P < .001). Six-month PFS was 54.4% with the combination vs 37.3% with sorafenib.

The objective response rate was 27.3% (complete response, 5.5%) with the combination vs 11.9% (complete response, 0%) with sorafenib

Median time to deterioration of quality of life was also longer for patients who received combination therapy: 11.2 months with atezolizumab-bevacizumab and 3.6 months for sorafenib.

Incidence of grade 3 or 4 adverse events was similar in both arms of the study: 56.5% for the combination vs 55.1% with sorafenib. Adverse events leading to withdrawal from any study drug was not significantly different: 15.5% vs 10.3% for sorafenib.

The percentage of patients who experienced bleeding of any grade (attributed to bevacizumab) was 25.2% with the combination vs 17.3% with sorafenib. In addition, six incidents of fatal bleeding or perforated ulcer were recorded in the combination group, compared with one for the sorafenib group.

Appropriate for All Patients?

Llovet told Medscape Medical News that the combination of atezolizumab and bevacizumab, although still awaiting approval for use in liver cancer, will be adopted by guidelines in the management of HCC as first-line therapy.

It has been accepted as the new front-line standard of care in a soon-to-be-published consensus on trial design and endpoints in HCC that he has authored.

Llovet said that the intravenous (IV) dosing of the combination was not likely to be a problem (sorafenib is administered orally). For patients with untreated advanced HCC, median survival is 8 months; it is 11 to 13 months with sorafenib. With this combination, the median was not reached, but it is expected to be beyond 17 months. "In this scenario, IV vs oral dosing will only have implications if the treatments had similar efficacy but not significantly better performance," he said.

In her editorial, Kelley suggests caution when considering use of the combination in a patient population broader than that defined by the IMbrave150 study.

She points out that patients in IMbrave150 were required to have well-compensated liver disease (Child-Pugh class A liver function), and patients with untreated or incompletely treated esophageal or gastric varices with bleeding or or those who were at high risk of bleeding were excluded from the study.

"Safety has not been established for persons in the Childs-Pugh class B population; and alternative therapies should be considered for patients at high risk for bleeding," Kelley writes in her editorial.

Bleeding events, including fatal bleeding and perforated ulcers, "underscore important considerations for the application of the atezolizumab–bevacizumab regimen to a broader population beyond the clinical trial setting," Kelley noted.

She recommends that all patients at risk for varices undergo "appropriate endoscopic evaluation and management before treatment is initiated."

Llovet agreed and noted that upper endoscopy is not currently practiced in the management of advanced HCC. "One important issue in the clinical practice will be that all patients require an upper endoscopy to rule out esophageal varices, which are at risk of bleeding with bevacizumab," he said.

Trial investigator Finn explained that IMbrave 150 is not unique and that every phase 3 study has included patients with Child-Pugh class A liver function.

"Patients with Child-Pugh class B are a heterogeneous group of patients," Finn said. Physicians should use their judgment in providing this combination to patients with Child-Pugh scores of 7–9, he added. "All patients with advanced liver cancer need an endoscopy," Finn said.

Kelley and Llovet also observed that several ongoing trials, some of which have been completed, are evaluating combinations of immunotherapy and other antiangiogenic agents or combinations of immunotherapies. The results from these trials will inform how such combinations will be used in the future.

Kelley predicted that of some of these trials are positive, in the absence of a predictive biomarker, physicians will be guided by "the safety profiles of the combinations as well as the inference of synergy on the basis of depth and durability of responses."

"Results of these trials will be known within the next 12 to 18 months and might further improve the current standards for patients with inoperable HCC," Llovet said.

IMbrave150 was sponsored by F. Hoffmann–La Roche/Genentech. Finn has consulted for AtraZeneca, Bayer, Bristol-Myers Squibb, CStone, Eisai, Eli Lilly, Exelixis, Roche, Genentech, Merck & Co, Novartis, and Pfizer. Finn's coauthors also report relationships with pharmaceutical companies. Kelley reports institutional research support from many pharmaceutical companies and served on the independent data monitoring committee for the IMbrave150 trial. Llovet has received research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim, and Ipsen and consulting fees from Bayer HealthCare Pharmaceuticals, Merck, Eisai Inc, Bristol-Myers Squibb, Celsion Corporation, Eli Lilly, Roche, Genentech, Glycotest, Nucleix, Can-Fite Biopharma, AstraZeneca, and Exelixis.

New Engl J Med. Published May 14, 2020. Abstract, Editorial

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