Anthony El-Khoueiry, MD, Member of the Section of Gastrointestinal Cancers, Director of the phase I program, and Associate Professor of Clinical Medicine at the Keck School of Medicine of the University of Southern California and USC Norris Comprehensive Cancer Center, said the findings of the phase III HIMALAYA trial1 are convincing: “The STRIDE regimen—with the combination of one priming dose of tremelimumab and regular-interval durvalumab—is a new first-line treatment option for advanced hepatocellular carcinoma, with a differentiated toxicity profile.”
Dr. El-Khoueiry first noted the “strong rationale” for this combination: complementary but distinct mechanisms of action of PD-L1 and CTLA-4 targeting; the activity observed for both drugs in hepatocellular carcinoma as single agents; and the phase I/II study showing a “promising” median overall survival of 18.7 months with the STRIDE regimen.2
Anthony El-Khoueiry, MD
“What we learned is the STRIDE regimen is superior to sorafenib, with a hazard ratio of 0.78, a response rate of 20%, durability of response (median, 22 months), and an impressive 31% overall survival rate at 36 months,” he said. “We also learned that durvalumab is noninferior to sorafenib, with a response rate of 17% and an overall survival rate of 25% at 36 months; overall, the activity of durvalumab is comparable to that of nivolumab in CheckMate 459.3 We also know these agents have a favorable safety profile as compared with tyrosine kinase inhibitors.”
The side-effect profile for T300+D was “as expected,” yet just 20% of patients received high-dose steroids for immune-mediated events. In contrast, in CheckMate 0404 (which evaluated high-dose ipilimumab at 3 mg/kg plus four doses of nivolumab followed by single-agent nivolumab), 57% of patients needed steroids. “This supports the theory that the single priming dose of tremelimumab results in a favorable risk:benefit ratio,” he said.
Clinical Implications and Selection of Treatment
Where do the findings for T300D+D fit in relation to the current standard of care, atezolizumab plus bevacizumab? “We now have two regimens that have beaten sorafenib in the first-line setting,” noted Dr. El-Khoueiry, but no direct comparisons of them. In IMbrave150,5 clinical outcomes for atezolizumab plus bevacizumab were as follows: median overall survival of 19.2 months, median progression-free survival of 6.9 months, and disease control rate of 74%. However, Dr. El-Khoueiry cautioned against cross-study comparisons.
With two effective regimens from which to select treatment, “the side-effect profile becomes important,” he emphasized. In this regard, the STRIDE regimen may have some advantages: HIMALAYA had a lower rate of bleeding than atezolizumab/bevacizumab (1.8% vs 25.0%) and grade 3 or 4 bleeding (0.5% vs 6.4%). Further, HIMALAYA did not require endoscopy to screen and treat esophageal varices, although it did exclude patients with main portal vein thrombosis, who are at the highest risk for bleeding.
Meanwhile, “putting regulatory issues aside,” Dr. El-Khoueiry described his approach to selecting first-line therapy in patients with advanced hepatocellular carcinoma eligible for systemic therapy:
- With contraindications for immunotherapy: sorafenib or lenvatinib
- With contraindications for bevacizumab, at high risk for bleeding, or unable to undergo endoscopy at 6 months: T300+D
- With contraindications for anti-VEGF regimens or not a candidate for combination therapy: durvalumab or anti–PD-1/L1 single agent
- With Child-Pugh B disease, sorafenib, lenvatinib, or a single-agent anti–PD-1/L1 agent (as options)
- None of the above contraindications: atezolizumab plus bevacizumab or T300+D.The atezolizumab-plus-bevacizumab combination may be preferred if a patient is symptomatic from cancer or has high tumor burden since it has a higher response rate and did show improvement in progession-free survival.
The choice of first-line regimen could become more complicated in the future, based on early results of the phase III COSMIC trial,6 in which cabozantinib plus atezolizumab reduced the risk of disease progression, vs sorafenib. Additional studies are evaluating other combinations: LEAP-002 is comparing lenvatinib plus pembrolizumab with single-agent lenvatinib, and CheckMate 9DW is comparing nivolumab plus ipilimumab with sorafenib or lenvatinib.
“It’s amazing that we have multiple first-line treatment options. Now it’s time to go beyond choosing treatments based on toxicity profiles. We need biomarker enhancement to personalize our approaches,” he said.
DISCLOSURE: Dr. El-Khoueiry has received honoraria from or served as an advisor to ABL Bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Eisai, EMD Serono, Exelixis, Gilead, Merck, Pieris Pharmaceuticals, QED Therapeutics, and Roche/Genentech; and has received research funding from AstraZeneca, Astex, and Fulgent.
REFERENCES
1. Abou-Alfa GK, Chan SL, Kudo M, et al: Phase 3 randomized, open-label, multicenter study of tremelimumab and durvalumab as first-line therapy in patients with unresectable hepatocellular carcinoma: HIMALAYA. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 379. Presented January 21, 2022.
2. Kelley RK, Sangro B, Harris W, et al: Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: Randomized expansion of a phase I/II study. J Clin Oncol 39:2991-3001, 2021.
3. Yau T, Park JW, Finn RS, et al: Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): A randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 23:77-90, 2022.
4. Yau T, Kang YK, Kim TY, et al: Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: The CheckMate 040 randomized clinical trial. JAMA Oncol 6:e204564, 2020.
5. Finn RS, Qin S, Ikeda M, et al: Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382:1894-1905, 2020.
6. Kelley RK, Oliver JW, Hazra S, et al: Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 phase III study design. Future Oncol 16:1525-1536, 2020.
