Asim Amin, MD, PhD, director of immunotherapy, Levine Cancer Institute, discusses the pivotal CheckMate-214 trial in advanced renal cell carcinoma (RCC).

The CheckMate-214 trial took root in the RCC space, when the initial phase I data from the CheckMate-016 trial was published. Results showed clinical benefit and tolerability for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy). The checkpoint inhibitor combination had previously demonstrated significant clinical activity in patients with advanced melanoma and had received FDA approval in that setting, Amin says.

One of the standards of care for the frontline treatment of RCC was sunitinib (Sutent), a VEGF tyrosine kinase inhibitor (TKI). CheckMate-214 compared the effectiveness of the immunotherapy combination with single-agent sunitinib in previously untreated patients with advanced RCC. Patient stratification was based on the International Metastatic Renal Cell Carcinoma Database Consortium risk model and by geographic location, Amin adds.

The promising findings from CheckMate 214 have led to significant interest among in examining the use of checkpoint inhibitors in combination with VEGF TKIs.

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Asim Amin, MD, PhD, director of immunotherapy, Levine Cancer Institute, discusses the rationale for the pivotal CheckMate-214 trial in advanced renal cell carcinoma.

Dr. Amin on CheckMate-214 Trial in RCC

Asim Amin, MD, PhD, director of immunotherapy, Levine Cancer Institute, discusses methods of evaluating response to immunotherapy in renal cell carcinoma (RCC).

Traditionally, physicians have used RECIST criteria to evaluate response to therapy in RCC, explains Amin. Originally, RECIST criteria were based on response to chemotherapy, but have since developed to evaluate response to immunotherapy. Now that physicians are seeing combinations of VEGF TKIs and other targeted therapies with immunotherapy, Amin believes that criteria will have to be adapted to fit the changing landscape.

Discontinuation criteria, for example, do not take into account lingering responses following discontinuation. When investigators evaluate toxicity, they have to discern how many patients discontinued treatment as a result. However, as physicians know from using immunotherapy in melanoma and early-stage RCC, responses can continue even after a patient has discontinued treatment. However, if a targeted therapy is stopped on account of toxicity, the responses generally follow-suit, notes Amin.

Dr. Amin on Evaluating Response to Immunotherapy in RCC

Asim Amin, MD, PhD, director of immunotherapy, Levine Cancer Institute, discusses the management of toxicities associated with immunotherapy and tyrosine kinase inhibitor (TKI) combinations in patients with renal cell carcinoma (RCC).

Community oncologists will have to re-learn how to overcome autoimmune-related breakthrough toxicities as 2 treatment modalities—immunotherapy and TKIs&mdash;are increasingly used in combination for patients with RCC.

This task is going to become even more complex because the mechanisms of VEGF TKIs largely differ from the underlying mechanisms of toxicities associated with immunotherapy, Amin explains.

For example, a common adverse event associated with immunotherapy is diarrhea, a result of the activated T cells attacking the colon. Diarrhea can sometimes be a dose-limiting toxicity for VEGF inhibitors, and Amin notes that this is a chemical effect.

For diarrhea associated with cabozantinib (Cabometyx) or sunitinib (Sutent), treatment should focus on masking symptoms, while a completely different approach would be used for diarrhea induced by autoimmune colitis. In these cases, symptoms need to be recognized and treated with steroids. Since the underlying mechanisms of these toxicities largely differ, approaches to manage the 2 mechanisms will also be very different.

Asim Amin, MD, PhD, director of immunotherapy, Levine Cancer Institute, discusses how to manage toxicities associated with immunotherapy and tyrosine kinase inhibitor combinations in renal cell carcinoma.

Dr. Amin on Toxicities With Immunotherapy/TKI Combinations in RCC

Asim Amin, MD, PhD, director of immunotherapy, Levine Cancer Institute, discusses next steps with immunotherapy in the treatment of patients with advanced renal cell carcinoma (RCC).

In April 2018, the nivolumab (Opdivo) and ipilimumab (Yervoy) combination was FDA approved for the frontline treatment of patients with intermediate- or poor-risk advanced RCC. With the proof-of-concept for immunotherapy combinations in RCC, there has been significant interest in exploring other combinations, Amin says. In the CheckMate-214 study, response rates with combination immunotherapy were 40%, meaning that 60% of patients did not respond. This is still an area of unmet need, and Amin notes that work is ongoing to identify and overcome mechanisms of resistance to immunotherapy.

Understanding the tumor microenvironment is an important factor. Mechanistically, RCC is associated with increased VEGF, which is immunosuppressive. This can happen several different ways. Researchers know that VEGF can hinder dendritic cell function and increase regulatory T cells. Amin concludes that it may be logical to combine checkpoint inhibitors with VEGF tyrosine kinase inhibitors.

Asim Amin, MD, PhD, director of immunotherapy, Levine Cancer Institute, discusses next steps with immunotherapy in the treatment of patients with advanced renal cell carcinoma.

Asim Amin, MD, PhD

Articles

Dr. Amin on CheckMate-214 Trial in RCC

Dr. Amin on Evaluating Response to Immunotherapy in RCC

Dr. Amin on Toxicities With Immunotherapy/TKI Combinations in RCC

Dr. Amin on Next Steps With Immunotherapy in Advanced RCC