Dr. Albiges first discussed the inhibitor of the hypoxia-inducible factors (HIFs). These are a target of treatment based on their accumulation related to loss of the Von Hippel Lindau gene on chromosome 3 and their multifaceted control of cell survival. A second-generation HIF-2alpha inhibitor, MK-6482 or belzutifan, has been tested in heavily pre-treated aRCC and resulted in an ORR of 25%, disease control rate of 80%, and a median PFS of 14.5 months. This PFS is quite long for pre-treated aRCC and is being further explored in a phase 3 study of belzutifan versus everolimus. Belzutifan is also being tested in combination with other therapies in clear cell aRCC as well as against tumors related to the hereditary von-Hippel-Lindau disease due to germline alterations in VHL. Tumors such as hemangioblastomas and pancreatic neuroendocrine tumors respond to this agent as well. The safety profile of this agent is different from VEGF TKIs in that it mostly causes anemia and hypoxia as on-target effects of the molecule.
Dr. Albiges then discussed metabolic targeting in aRCC. Preclinical evidence suggested that aRCC is dependent on glutamine metabolism to generate glutamate for entry into the Krebs cycle, leading to the randomized phase 2 CANTATA study. At this conference, the PFS results were presented, showing no difference in PFS with the addition of the glutaminase inhibitor telaglenastat to cabozantinib. It is possible that additional metabolic targeting agents will be tested in the future.
She then focused on therapeutic strategies to augment the immune response against aRCC. Dr. Albiges highlighted many immunomodulatory molecules that could potentially be targeted therapeutically.
She specifically mentioned an ongoing trial of NKTR-214 (bempegaldesleukin) in combination with nivolumab in previously untreated aRCC versus sunitinib. Additionally, Dr. Albiges mentioned two immune checkpoints of interest to her. These are HHLA2, which is over-expressed in aRCC, and TIGIT which has shown promising responses in lung cancer. Allogeneic chimeric antigen receptor T-cells are being developed against CD-70 in aRCC. Finally, there is some thought that epigenetic modulatory drugs may augment immune responses, but data from this is still early.
Beyond novel therapeutic targets, Dr. Albiges discussed different therapeutic approaches including triplet therapy in COSMIC-313 (nivolumab and ipilimumab +/- cabozantinib) and NCT04736706 (pembrolizumab and Lenvatinib +/- belzutifan +/- the anti-CTLA4 antibody quavonlimab). The opposite approach to escalating with triplet therapy is de-escalation trials, including TITAN RCC and PDIGREE.
Dr. Albiges stressed that biomarker-driven trials will be essential moving forward for how to choose between IO-only treatment, combination IO/TKI, and other emerging treatment strategies.
Presented by: Laurence Albiges, MD, PhD, Medical Oncologist at the Gustave Roussey Intitute in France.
Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021