Dual Immunotherapy Makes Strides against HCC

For patients with inoperable hepatocellular carcinoma (HCC), a priming dose of AstraZeneca's investigational CTLA4 inhibitor tremelimumab followed by its PD-L1 inhibitor durvalumab (Imfinzi) yielded significantly longer overall survival (OS) than sorafenib (Nexavar; Bayer) as a first-line treatment. That's the conclusion of the phase III HIMALAYA trial, which was reported at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, held January 20–22.

Previously, first-line therapy for patients with inoperable HCC was limited to sorafenib or another multikinase inhibitor, lenvatinib (Lenvima; Eisai). These agents are associated with a median OS of about 1 year but have side effects that negatively affect patients’ quality of life.

Based on results of the IMbrave150 trial, reported at the virtual American Association for Cancer Research Annual Meeting 2021, the current standard of care for inoperable HCC is a combination of the PD-L1 inhibitor atezolizumab (Tecentriq; Genentech) and the antiangiogenic agent bevacizumab. In that study, after a median follow-up of 15.6 months, the median OS was 19.2 months for patients randomly assigned to an atezolizumab–bevacizumab regimen compared with 13.4 months for patients assigned to sorafenib.

HIMALAYA was designed to test whether the combination of two immune checkpoint inhibitors could further improve survival with acceptable safety and tolerability.

For HIMALAYA, researchers randomly assigned 393 patients to receive a single 300 mg priming dose of tremelimumab followed by 1,500 mg of durvalumab every 4 weeks, a regimen called T300+D, and 389 patients to receive 400 mg of sorafenib twice a day, explained Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who presented the data.

After a median of 32 months, the median OS was 16.4 months for those in the T300+D group compared with 13.8 months for the sorafenib group. OS rates at 18, 24, and 36 months of follow-up were 48.7%, 40.5%, and 30.7%, respectively, compared with 41.5%, 32.6%, and 20.2%.

In a separate comparison, the trial showed that durvalumab monotherapy was not inferior to sorafenib, with a median OS of 16.6 months compared with 13.8 months, respectively, and 36-month OS rates of 24.7% and 20.2%, respectively.

“The T300+D regimen and durvalumab monotherapy may represent new treatment options for patients with unresectable HCC,” said Abou-Alfa.

“There is strong rationale for this combination, given the complementary but distinct mechanisms of action of PD-L1 and CTLA4 targeting,” as well as the single-agent activity of each drug, commented invited discussant Anthony El-Khoueiry, MD, of the USC Norris Comprehensive Cancer Center in Los Angeles, CA.

He noted that the T-300+D regimen—also called STRIDE, short for Single Tremelimumab Regular Interval Durvalumab—was previously shown in a phase II trial comparing three different dosing schedules of the combination with tremelimumab monotherapy to be well tolerated and have encouraging efficacy, with a median OS of 18.7 months.

El-Khoueiry said that the safety profile of T300+D was as expected in HIMALAYA, but the incidence of immune-mediated adverse events leading to discontinuation occurred in just 2.6% of patients compared with 6% for the combination of Bristol Myers Squibb's anti-CTLA4 ipilimumab (Yervoy) and PD-1 inhibitor nivolumab (Opdivo) in the second-line CheckMate 040 trial.

“This supports the theory that the single priming dose of tremelimumab results in a favorable risk–benefit ratio,” he said.

He also pointed out, however, that the trial results were limited by the exclusion of patients with main portal vein thrombosis, one of the strongest negative prognostic factors, and that the trial was not powered to detect significant differences in efficacy between the T300+D and durvalumab monotherapy arms. –Neil Osterweil