Amit Mahipal, MBBS, MPH, Consultant, Associate Professor of Oncology, Mayo College of Medicine, Rochester, put the findings for tremelimumab/durvalumab into context regarding other studies evaluating checkpoint inhibitors in advanced hepatocellular carcinoma. In the current study by Kelly et al, he noted, the 75-patient cohort receiving the 300 mg dose of tremelimumab plus durvalumab had the best outcomes, with a median overall survival of 18.7 months and a response rate of 24%, compared with 10% or less with the other dosing regimens. He noted that approximately 30% of the patients were sorafenib-naive.
The combination was also “reasonably well tolerated,” with grade ≥ 3 treatment-related adverse events reported in 36%, he pointed out.
Single vs Dual Checkpoint Inhibition
“Single-agent checkpoint inhibitors have demonstrated response rates between 10% and 20% in patients with previously treated hepatocellular carcinoma1,2; however, this has not translated into a median overall survival benefit in key phase III trials.3 There was the suggestion that PD-1/PD-L1 inhibitors may benefit a small proportion of patients, and the responses can be durable,” Dr. Mahipal said.
Dual checkpoint inhibitors with blockade of PD-1/PD-L1 and CTLA-4 have demonstrated higher response rates. In CheckMate 040, various combinations of nivolumab plus ipilimumab yielded responses in 31% of patients,4 leading to the combination’s approval by the U.S. Food and Drug Administration (FDA) in patients with hepatocellular carcinoma previously treated with sorafenib.
“Although dual checkpoint activity has demonstrated intriguing results, these findings have to be confirmed in larger trials. In addition, all the previously mentioned trials were conducted in immunotherapy-naive patients,” commented Dr. Mahipal.
Changing Standard of Care
Recently, the combination of atezolizumab plus bevacizumab was approved by the FDA as a first-line treatment of hepatocellular carcinoma based on the IMbrave150 trial.5 The regimen proved superior to sorafenib in terms of response rate (27.3% vs 11.9%), median progression-free survival (6.8 vs 4.3 months), and 12-month overall survival (67.2% vs 54.6%). In addition, it was relatively well tolerated, with hypertension being the most common grade 3 or 4 adverse event, Dr. Mahipal continued.
“For patients who are eligible to receive immunotherapy, atezolizumab plus bevacizumab has become the new standard of care. Thus, it remains unclear where in the treatment algorithm of hepatocellular carcinoma dual checkpoint inhibitors would fit,” Dr. Mahipal maintained. However, he suggested this approach might be useful in patients who are eligible for immunotherapy but at high risk of bleeding with bevacizumab.
“With the changing standard of care, dual checkpoint inhibitors need to be evaluated in patients whose disease has progressed on prior anti–PD-1/PD-L1 therapies,” noted Dr. Mahipal. “With the approval of a number of therapies, there is a great unmet need for developing biomarkers for appropriate treatment selection in hepatocellular carcinoma.”
DISCLOSURE: Dr. Mahipal has received honoraria from Eisai and Ipsen; has received research funding from Taiho Pharmaceutical; and has received institutional research funding from Astellas Scientific & Medical Affairs, Karyopharm Therapeutics, and Novartis.
REFERENCES
1. El-Khoueiry AB, Sangro B, Yau T, et al: Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase I/II dose escalation and expansion trial. Lancet 389:2492-2502, 2017.
2. Zhu AX, Finn RS, Edeline J, et al: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase II trial. Lancet Oncol 19:940-952, 2018.
3. Finn RS, Ryoo BY, Merle P, et al: Results of KEYNOTE-240: Phase III study of pembrolizumab vs best supportive care for second line therapy in advanced hepatocellular carcinoma. 2019 ASCO Annual Meeting. Abstract 4004.
4. Yau T, Kang YK, Kim TY, et al: Nivolumab + ipilimumab combination therapy in patients with advanced hepatocellular carcinoma: Results from CheckMate 040. 2019 ASCO Annual Meeting. Abstract 4012.
5. Finn RS, Qin S, Ikeda M, et al: Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382:1894-1905, 2020.
