Are Combinations the Answer in Metastatic RCC? - Episode 1

Historic Level of Progress in First-Line RCC Treatment

March 29, 2021
Targeted Oncology

An expert in genitourinary oncology, Robert J. Motzer, MD, reviews the recent historic advances in frontline combinations for the treatment of advanced clear-cell renal cell carcinoma.

Robert J. Motzer, MD: In a first-line therapy for kidney cancer, there’s been a historical level of progress in terms of the treatments we give and the benefit to patients. Historically, kidney cancer was considered to be 1 of the most difficult cancers to treat because of a high resistance to chemotherapy. There was some activity with early trials with cytokine therapy that set the path for immunotherapy to be studied in this disease. The first breakthrough came with the tyrosine kinase inhibitors [TKIs] and their high response rate and improvement of progression-free survival for sunitinib-pazopanib and a number of others. More recently, immunotherapy was shown to be effective for kidney cancer, and immunotherapy has since been studied in first-line treatment for kidney cancer, in a series of large phase 3 trials that have shown benefit compared with sunitinib, which was the standard of care. The regimens include nivolumab plus ipilimumab, axitinib plus pembrolizumab, cabozantinib plus nivolumab, avelumab plus axitinib, and more recently lenvatinib plus pembrolizumab. All have been studied and compared with sunitinib in large phase 3 trials, and they’ve shown a high level of clinical benefit. They have really changed the way we treat patients with this disease for the better.

There’s recently been considerable success with TKI–I/O [immuno-oncology] combinations. Tyrosine kinase inhibitors, like axitinib, lenvatinib, and cabozantinib, have their own high level of activity as single agents for clear-cell carcinoma based on their targeting profile of VEGF receptor. I/O therapies, including PD-1 inhibitors, pembrolizumab, and nivolumab, likewise, have activity as monotherapy. In addition to the single-agent activity that’s seen in combination, there’s strong evidence that there’s synergistic effect for the 2 given together. Part of this involves the effects that the VEGF tyrosine kinase inhibitors have on the environment around the tumor. It appears that they are able to increase the number of T-helper cells that help the immune response, and also decrease the number of myelocytes that seem to suppress response to these immunotherapies. In effect, they prepare the environment around the tumor for a better effect of these immunotherapies. I think the profound efficacy effects we’ve seen with TKI–I/O combinations are really a result of these 3 different factors.

Transcript edited for clarity.