Expert Point of View: Ian Chau, MD

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Invited discussant Ian Chau, MD, Consultant Medical Oncologist at The Royal Marsden Hospital in London and Surrey in the United Kingdom, said the findings from COSMIC-3121 are not mature enough to establish cabozantinib/atezolizumab as a new front-line option for advanced hepatocellular carcinoma (HCC). For one thing, atezolizumab plus bevacizumab recently became an established standard of care, based on positive results of IMbrave150.2 

In IMbrave150, atezolizumab/bevacizumab not only led to a progression-free survival benefit (hazard ratio [HR] = 0.59; P < .001) but also an overall survival benefit (HR = 0.66; P = .0009) vs sorafenib. As a result, said Dr. Chau, in the first-line setting atezolizumab/bevacizumab has been incorporated into many international guidelines.

The rationale for pairing atezolizumab and cabozantinib, however, is “strong,” he said, describing cabozantinib’s effect on the immune environment, multiple oncogenic pathways, and proliferation. But he noted that cabozantinib does not increase PD-L1 expression in human HCC cell lines and mouse models, nor has it been shown to reduce tumor burden or improve survival in mice when combined with anti–PD-1 antibodies.

COSMIC-312 vs IMbrave150

Dr. Chau put the COSMIC-312 findings into context with those of IMbrave150. He first noted that at the primary analysis, improvement in progression-free survival was similar between the studies; both combinations achieved median progression-free survivals of 6.8 months, with hazard ratios of 0.63 (P = .0012) in COSMIC-312 and 0.59 (P < .001) in IMbrave150.

Ian Chau, MD

Ian Chau, MD

For overall survival, however, no difference has yet emerged in COSMIC-312, despite 76% of events having occurred, whereas at a similar time point, a significant difference had been detected in ­IMbrave150 (HR = 0.58; P < .001). (Median follow-up for the trials was 13 and 15 months, respectively.) He acknowledged that the sorafenib control in COSMIC-312 achieved the longest median overall survival (15.5 months) seen yet for this drug.

Dr. Chau also maintained that the lack of overall survival difference in COSMIC-312 could not be attributed to the receipt of subsequent therapy in control subjects, since crossover to immunotherapy was much more common in IMbrave150 (27%) than COSMIC-312 (17%). One factor, however, could be the dominance of hepatitis B virus as the disease etiology in IMbrave150 (48%) vs COSMIC-312 (29%), as this subset derives an especially strong benefit from an immunotherapy combination. Similarly, patients with hepatitis C virus (HCV) etiology do not appear to benefit from cabozantinib/atezolizumab, as shown also in the CELESTIAL trial3; HCV etiology accounted for 31% of the ­COSMIC-312 population but just 21% of the IMbrave150 population, he said.

Dr. Chau further noted that response rate and duration of response with atezolizumab/bevacizumab were much greater than with cabozantinib/atezolizumab. And although one combination is not associated with greater toxicity (just different ones), IMbrave150 alone has shown improved quality of life with its regimen so far. COSMIC-312 collected quality-of-life data, but these data have not been reported yet; “therefore, I cannot say COSMIC-312 found no improvement in quality of life,” he said.

At this point, the ESMO-Magnitude of Clinical Benefit Scale would rate atezolizumab/bevacizumab a 3, Dr. Chau said, “so it’s not going to be a highly significant intervention yet…. We are awaiting final overall survival results.”

More Data to Come

As for the single agents, Dr. Chau added, it must be recognized that the tyrosine kinase inhibitor levatinib was associated with a median progression-free survival of 7.4 months vs 3.7 months with sorafenib and a response rate of 40.6% in the REFLECT study,4 whereas the response rate was 6.4% with cabozantinib in COSMIC-312.

More data to further complicate the treatment landscape will come from first-line phase III trials currently in progress, according to Dr. Chau: HIMALAYA, evaluating dual checkpoint inhibition with tremelimumab and durvalumab vs sorafenib ( identifier NCT03298451); LEAP 002, evaluating lenvatinib with and without pembrolizumab (NCT03713593); and CheckMate 9DW, evaluating dual checkpoint inhibition with nivolumab and ipilimumab vs sorafenib or lenvatinib (NCT04039607).

DISCLOSURE: Dr. Chau has served on the advisory board or received honoraria from Eli Lilly, Bristol Myers Squibb, MSD, Bayer, Roche, Merck Serono, Five Prime Therapeutics, AstraZeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astellas, GlaxoSmithKline, Sotio, Eisai, Daiichi Sankyo, and Servier.


1. Kelley RK, Yau T, Cheng AL, et al: Cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma: Results from the randomized phase III COSMIC-312 trial. 2021 ESMO Virtual Plenary. Abstract VP10-2021. Presented November 20, 2021.

2. Finn RS, Qin S, Ikeda M, et al: Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382:1894-1905, 2020.

3. Abou-Alfa GK, Meyer T, Cheng AL, et al: Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 379:54-63, 2018.

4. Kudo M, Finn RS, Qin S, et al: Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet 391:1163-1173, 2018.

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