Dr. Thomas Hutson on Conventional and Novel Combination Therapies for First-Line Advanced RCC

Thomas Hutson, DO, PharmD, FACP, Baylor University Medical Center, provides an overview of different combination therapies used and being investigated in the first-line advanced renal cell carcinoma setting.

Can you provide an overview of different combination therapies used and being investigated in the first-line advanced RCC setting?

Dr. Hutson: In the first-line advanced RCC setting, several combination therapies have become the standard of care for patients with clear cell RCC, the most common subtype of kidney cancer. These therapies should be administered to nearly all patients unless there are contraindications. The backbone of these treatments is immunotherapy, specifically a PD-1 inhibitor, which falls into two categories of combination therapies.

The first category is an IO/IO combination, which involves combining immune therapies with a PD-1 inhibitor. The approved combination used worldwide is nivolumab and ipilimumab, an anti-CTLA-4 agent. This dual approach to immune modulation has been approved for frontline use in patients with intermediate and poor-risk RCC.

The second category is a combination of a checkpoint inhibitor with an oral targeted multikinase inhibitor. There are three major inhibitors approved for this purpose: pembrolizumab, nivolumab, and cabozantinib. Pembrolizumab can be combined with either axitinib or lenvatinib, while nivolumab is combined with cabozantinib. These IO/TKI combinations are the primary therapies chosen by doctors worldwide for advanced and metastatic RCC in the frontline setting.

At the 2023 ASCO Annual Meeting, I presented the final update analysis on overall survival for the lenvatinib pembrolizumab combination with 4 years of follow-up. My colleague, Dr. Brian Rini, presented the 5-year overall survival and updated results of axitinib/pembrolizumab.

For patients who are not candidates for checkpoint inhibitors due to ongoing chronic immune diseases or organ transplants, single-agent oral TKIs are used. Approved drugs in this category include cabozantinib, sunitinib, pazopanib, and axitinib. However, the use of single agents is less common, and most patients are eligible for combination therapy.

Regarding experimental combinations, there are ongoing studies exploring the combination of the HIF-alpha inhibitor belzutifan with checkpoint inhibitors. Belzutifan has shown benefit in patients with VHL syndrome by inhibiting HIF, which is part of the VEGF pathway. Triplet therapy, combining 2 immune therapies with cabozantinib, has also been investigated, but it is not yet ready for widespread use due to concerns about added toxicity and financial implications.

Future combinations are expected to include immune modulating agents that enhance the effectiveness of checkpoint inhibitors and overcome resistance pathways to immunotherapy in cancer cells. Doublet and triplet combinations, as well as potentially quadruplet regimens, may emerge as unique molecules with different mechanisms of action are developed. However, the primary approach will likely continue to be the doublet combination of an immune therapy with an oral TKI, with additional molecules being added as they become more significant.

View Dr. Hutson’s further comments on Long-Term Durable Response After 4 Years Follow-Up in the CLEAR Study.