(UroToday.com) Following presentations by Dr. David Bauer discussing phase I/II data for the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma and by Dr. Toni Choueiri looking at the combination of MK-6482 and cabozantinib in patients with previously treated clear cell renal cell carcinoma, Dr. Braun provided a discussion of these data in the Oral Abstract Session: Renal Cell Cancer session at the 2021 ASCO GU Cancers Symposium.
Dr. Braun first gave an overview of the landscape of systemic therapy for patients with advanced clear cell renal cell carcinoma (ccRCC), with dramatic changes with the introduction of IO/IO and IO/TKI combination therapies. However, TKI alone remains an option for a subset of patients. In the second-line setting, things are much less clear and strongly influenced by what treatment was used in the first-line setting.
He emphasized that immunotherapy and anti-angiogenics form core pillars of the treatment of ccRCC. However, a third pillar is missing to date, with mTOR inhibitors failing to gain utilization or demonstrate benefit at the level of the other approaches. Thus, there is a need for novel targets. One such target arises from an understanding of oxygen sensing in ccrCC, through HIF2-alpha mediated gene transcription in hypoxic environments. ccRCC is associated with a “pseudohypoxic” state, leading to the importance of HIF2-alpha pathways. Thus, targeting of HIF2-alpha. MK-6482 (belzutifan) blocks the binding of HIF2-alpha with ARNT and thus prevents the downstream gene transcription necessary for angiogenesis, cell proliferation, and cell survival.
Dr. Braun then discussed the two relevant trials presented at this year’s meeting. The first of these, presented by Dr. Bauer, assessed the safety and efficacy of MK-6482 (belzutifan) monotherapy in heavily pre-treated patients. Notably, 62% of enrolled patients had received at least 3 prior lines of therapy including both TKI and IO regimes. While all patients had any-grade adverse events, grade 3-5 events were noted in 71% with the most common on-target effect being anemia. Further, there were no grade 4-5 treatment-related adverse events and very low rates of discontinuation due to toxicity. Thus, Dr. Braun concluded that MK-6482 (belzutifan) was safe. Further, given the objective response rate of 25% and 80% having disease control in such a heavily pre-treated population, he concluded that this demonstrates the efficacy of this approach.
Compared to other agents, he emphasized that this approach has at least a signal of efficacy compared to other treatment approaches.
In summary, Dr. Braun concluded that this abstract demonstrated that MK-6482 (belzutifan) has both an acceptable safety profile and suggestion of efficacy.
Dr. Braun then moved to discuss the second abstract examining MK-6482 (belzutifan) from Dr. Choueiri, examining the combination of this agent with cabozantinib following treatment with IO-regimes as a second or third-line treatment. He noted that the objective response rate of 22% may be further bolstered by 12% unconfirmed partial responses. Further, 90% had disease control with most having shrinkage of the target lesion. Further, all confirmed responses were still ongoing but median follow-up was only 11 months.
In the post-IO setting, Dr. Braun concluded that this combination approach may be effective though definitive conclusions are not feasible given the short duration of follow-up.
Overall, he concluded that there is a potential efficacy signal for this combination approach. In summary, between the two studies, he emphasized that these do not change practice but suggest further study. A number of ongoing trials will address these questions, including longer-term outcomes, comparative effectiveness, resistance to these therapies, and novel combination approaches.
Presented by: David A. Braun, MD, PhD, Dana-Farber Cancer Institute
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021