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Combination checkpoint and VEGF inhibitors now first-line treatment for advanced liver cancer

JAMA Oncology
Reuters Health - 28/10/2020 - Combination therapy with the checkpoint inhibitor (CPI) atezolizumab and the vascular endothelial growth factor inhibitor (VEGFi) bevacizumab emerged as the standard of care for advanced liver cancer in a systematic review and network meta-analysis.

"Our findings establish the most effective treatment sequence in advanced hepatocellular cancer (HCC) and should be integrated in practice," Dr. Tanios Bekaii-Saab of Mayo Clinic in Phoenix told Reuters Health by email.

That said, he added, "Although these findings facilitate current care for patients with advanced HCC, future trials need to focus on other potential combinations, sequencing, and optimizing sequencing strategies following CPI/VEGFi exposure."

As reported in JAMA Oncology, the team searched the literature from inception through March 2020 for phase 3 trials evaluating various VEGFis, CPIs, and their combinations in advanced HCC, either as first-line treatment or for refractory cases.

Fourteen trials - eight in the first-line setting and six in the second-line/refractory setting - at low risk of bias were included (one refractory trial was included only in the subgroup analysis). The first-line trials included 6,290 patients ranging in age from 18-89; the refractory trials included 2,653 patients with a similar age range.

In the first-line setting, the combination of atezolizumab and bevacizumab was superior compared with lenvatinib (HR, 0.63), sorafenib (HR, 0.58), and nivolumab (HR, 0.68).

In the refractory setting, all studied drugs had a progression-free survival benefit compared with placebo; however, only patients taking regorafenib (HR, 0.62) and cabozantinib (HR, 0.76) experienced an overall survival benefit.

In a subgroup network meta-analysis of patients with alpha-fetoprotein (AFP) levels of 400 ng/mL or greater, regorafenib, cabozantinib, and ramucirumab showed progression-free and overall survival benefits compared with placebo; no drug was superior to another in comparative studies.

Summing up, the authors state, "This systematic review and NMA of 14 trials found that atezolizumab and bevacizumab in combination is now considered the standard of care in the first-line setting in patients with advanced HCC. Regorafenib and cabozantinib are preferred options in refractory patients, with ramucirumab as an additional option in those with levels of AFP of 400 ng/mL or higher."

Dr. Bekaii-Saab said, "We are developing clinical trials that will help to identify a potential role for the combinations of CPI with various multi-kinase inhibitors or an IL-6 inhibitor in patients refractory to CPI/VEGF inhibition."

"There are also a number of studies that have been completed or are near completion in the first-line setting testing various combinations, although none of them is being compared to atezolizumab and bevacizumab, and as such, are unlikely to move the needle forward in a meaningful fashion," he concluded.

Dr. David Geller, Director, UPMC Liver Cancer Center, and the Richard L. Simmons Professor of Surgery at the University of Pittsburgh, commented by email to Reuters Health, "This finding is confirmatory of the recent landmark randomized clinical trial published in the New England Journal of Medicine in May showing superior overall survival and progression-free survival of atezolizumab plus bevacizumab versus sorafenib." (https://bit.ly/3ky2aF8)

"Use of atezolizumab plus bevacizumab as first-line therapy in advanced HCC is practice-changing," he said. "However, some patients may have contraindications to immunotherapy (such as transplant patients), and then sorafenib or lenvatinib are excellent first options."

"Clinicians should be aware that most of the trials analyzed in the current study were restricted to cirrhotic patients with good liver function (Childs A)," he added. "Future studies need to the address the safety and efficacy of HCC treatment in Childs B patients with more advanced cirrhosis."

By Marilynn Larkin

SOURCE: https://bit.ly/34DX6tw JAMA Oncology, online October 22, 2020.

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