Sunil Verma, MD, senior vice president and global head of oncology, medical at AstraZeneca, explains the design of the HIMALAYA study, including the dosing strategy used.
Sunil Verma, MD, senior vice president and global head of oncology, medical at AstraZeneca, explains the design and development of the HIMALAYA study, which evaluated durvalumab and tremelimumab as a first-line treatment regimen in patients with advanced hepatocellular carcinoma.
What is the purpose and design of the HIMALAYA study?
Patients with liver cancer continue to have a significant unmet medical need. We know that this is an underserved patient population, and it remains the third leading cause of death for patients globally. So HIMALAYA was really designed with the current standard of care sorafenib, evaluating whether immunotherapy approaches can improve the outcomes of patients, both from a side effect profile but also from median survival opportunity. This was initially designed as a 4-arm trial, as we have shared and will be sharing shortly. The results that we were sharing are from the 3 arms that move forward. One is the STRIDE [single tremelimumab regular interval durvalumab] regimen, which is the combination of tremelimumab—which is a CTLA-4— with durvalumab, verus the standard of care of sorafenib, versus durvalumab monontherapy alone. The primary endpoint is overall survival.
Can you discuss the development of the dosing strategy?
I think we all know—and we've seen this data from melanoma; we recently saw this data in non-small cell lung cancer as well—that there's so much synergy between CTLA-4 and checkpoint inhibitors, with PD-1 or PDL-1 inhibitors. Yet, while there is synergy—and this is well known—it's also with significant toxicity when given together for a very long period of time. We had done some preliminary work looking to see how best can we dose and how best can we enhance activity with CTLA-4 inhibitors and checkpoint inhibitors. This was evaluated in one of our phase 2 studies called Study 22, where we found that a priming dose with tremelimumab at the 300 mg dose was effective in recruiting T-cells and thereby priming the cancer to respond to immunotherapy. Hence, we evaluated that in the HIMALAYA trial, where there was an arm that was looking at continuous tremelimumab and durvalumab. But there was 1 arm, which we call the STRIDE program, where there was just a priming dose of tremelimumab with maintenance dose of durvalumab given every 4 weeks. The priming dose was at a higher dose at 300 mg. The phase 2 trial was very supportive and that led to the design and the conduct of this phase 3 study.