Expert Discusses Potential Expansions to the Treatment Landscape in RCC

Treatment of renal cell carcinoma (RCC) is awaiting the potential integration of combinations of immuno-oncology agents like nivolumab (Opdivo) and ipilimumab (Yervoy), or combinations of targeted therapies with checkpoint inhibitors into the treatment paradigm. In an interview with&nbsp;<em>Targeted Oncology</em>, Robert A. Figlin, MD, discusses the expanding RCC armamentarium and balancing the benefits and risks of standard and emerging treatments to achieve optimal outcomes.

Robert A. Figlin, MD, FACP

Treatment of renal cell carcinoma (RCC) is awaiting the potential integration of combinations of immuno-oncology agents like nivolumab (Opdivo) and ipilimumab (Yervoy), or combinations of targeted therapies with checkpoint inhibitors into the treatment paradigm.

Some of these regimens are moving through the pipeline. For example, the FDA granted a priority review designation in December 2017 to a supplemental biologics license application for the combination of nivolumab and ipilimumab as a frontline treatment for intermediate- and poor-risk patients with advanced RCC.

Other combinations of targeted therapy plus immunotherapy were granted breakthrough designations by the FDA for the treatment of RCC, including pembrolizumab (Keytruda) plus lenvatinib (Lenvima) for advanced or metastatic disease in January 2018, and avelumab (Bavencio) with axitinib (Inlyta) for treatment-naïve patients in December 2017.

The key with these combinations, according to Robert A. Figlin, MD, is balancing the toxicity profile of the regimen with the predicted effacious outcomes management.

“Overall, immune-oncology approaches are safer, but the magnitude and the difficulty associated with the side effects can be quite severe,” said Figlin. “Oncologists need to be clinically aware and on top of the side effects before they cause problems.”

In an interview withTargeted Oncology, Figlin, director, Division of Hematology/Oncology, professor of biomedical sciences and medicine, Cedars-Sinai Medical Center, discussed the expanding RCC armamentarium and balancing the benefits and risks of standard and emerging treatments to achieve optimal outcomes.

TARGETED ONCOLOGY:What new agents have entered the treatment landscape in kidney cancer?

Figlin:Over the past decade and a half we have had tremendous progress in kidney cancer. Originally, there was the approval of high-dose interleukin-2 in 1992. Now, we have a whole series of agents targeting the VEGF-receptor pathway, such as sunitinib (Sutent), pazopanib (Votrient), cabozantinib (Cabometyx), and others. There are also commercially available agents targeting the mTOR pathway that are either replacing our [frontline] standard of care, such as cabozantinib, or are soon to replace our standard of care, such as the combination of ipilimumab and nivolumab. This…immuno-oncology approach to kidney cancer has resulted in improvements in progression-free survival (PFS), overall survival (OS), and the possibility of durable remissions.

TARGETED ONCOLOGY:What does the safety profile look like with some of these agents?

Figlin:The agents we use in kidney cancer have pretty standard toxicity profiles, especially when they're inhibiting the VEGF pathway. They produce hypertension, hand-foot syndrome, fatigue, and some changes in endocrine function, such as hyperthyroidism. Over the past decade, doctors have come to understand how to manage the side effects and how to modify the treatments to maintain the effectiveness of the drugs.

TARGETED ONCOLOGY:How is intermittent dosing of sunitinib better versus continuous dosing of other agents in RCC?

Figlin:Sunitinib was approved by the FDA in 2006 for continuous dosing for 4 weeks on and 2 weeks off (4/2). Since then, we have realized through retrospective analyses, prospective studies, and personal experience that the 2-weeks-on/1-week-off (2/1) schedule is equally effective. It produces less toxicity and has indications of improved efficacy, because we are able to maintain patients on full doses for a longer period of time. In my practice, I start people on the 4/2 schedule. If they require changes as a result of toxicity, I quickly switch to the 2/1 schedule rather than dose reductions.

What are the key elements to consider with treatment selection for relapsed/refractory patients? As genitourinary cancer experts, the key is to balance the benefits and the risks with the patient’s and family’s therapy goals. The longer the person can be maintained on close to full doses of therapy, the greater chance the person will have with improved PFS, OS, and potentially durable remissions. I'm looking for positive outcomes that balance their life with their treatment; this is with the understanding that the treatment is going to be chronic and continuous. Ultimately, we have to obtain the balance between the toxicity profile for that person and the benefits.

TARGETED ONCOLOGY:What does the future of kidney cancer look like?

Figlin:We have the antiangiogenic agents with targeted therapy and checkpoint inhibitors, such as CTLA-4 inhibition and nivolumab. There is clear evidence that combinations are the future, specifically the combination of checkpoint inhibitors with targeted agents. Whether this is avelumab and a targeted agent, atezolizumab (Tecentriq) plus a targeted agent, or pembrolizumab and a targeted agent has yet to be seen.

Data suggest that response rates are going up. We hope that some of them are durable. The big unanswered question in kidney cancer is how to combine immuno-oncology and targeted agents to deliver the best outcome. There are a variety of immuno-oncology drugs and targeted agents. We’ll have to wait and see how these combinations compare with combination immuno-oncology drugs, such as ipilimumab and nivolumab, which we hope will soon be FDA approved.

TARGETED ONCOLOGY:What advice would you like to offer community oncologists?

Figlin: