RCC Research Moving Toward Combinations to Improve Responses, Durability

Rana R. McKay, MD

Rana R. McKay, MD

The treatment landscape of metastatic renal carcinoma (RCC) has rapidly evolved over the last decade with the approval of several new agents. Now, investigators are looking toward combination therapies in the frontline setting to improve response rates and durability of response for patients, says Rana R. McKay, MD.

Combination immunotherapy is now at the forefront of clinical studies. In the phase III CheckMate-214 trial, for example, nivolumab (Opdivo) and ipilimumab (Yervoy) reduced the risk of death by 32% compared with sunitinib (Sutent).

Furthermore, the results showed that patients with intermediate- and poor-risk disease (75% of the intent-to-treat population) experienced a 37% reduction in the risk of death.¹Based on these findings, the FDA granted a priority review in December 2017 to a supplemental biologics license application for this anti—PD-1/CTLA-4 combination as a frontline treatment for intermediate- and poor-risk patients with advanced RCC.

In an interview withTargeted Oncology, McKay, a medical oncologist and assistant professor at the Moores Cancer Center at the University of California, San Diego, discussed the evolving management of patients with advanced RCC, specifically the future of combinations of with immunotherapy regimens.

TARGETED ONCOLOGY:How is the management of advanced RCC evolving?

McKay:The treatment landscape for metastatic RCC has been rapidly evolving over the past 12 years. There have been multiple new agents approved, starting in the VEGF tyrosine kinase inhibitor area, as well as some immunotherapies. The field has been rapidly evolving into looking at combinations of immunotherapy with VEGF- targeted therapy, immunotherapy combinations, and new targets.

TARGETED ONCOLOGY:Could you touch on one 1 or two 2 milestones of the past year?

McKay:One of the landmark studies of the past couple of years was CheckMate-025. This was a phase III study looking at second-line treatment for patients with metastatic clear- cell RCC. Patients were randomized to receive treatment with nivolumab and everolimus (Afinitor). It was the first time that a treatment in the second-line setting was shown to improve overall survival (OS) for patients with metastatic clear- cell RCC.

Another landmark study of the past several years was METEOR, which compared the VEGF c-MET inhibitor cabozantinib (Cabometyx) to everolimus. Cabozantinib is the only agent that has been shown to improve OS, progression-free survival, and objective response rates in the second-line setting for patients with metastatic disease.

Some of the more exciting data that has have recently come out over the past year presented at the 2017 ESMO Congress is the data from CheckMate-214, which is the combination of nivolumab plus ipilimumab versus sunitinib in the front-line space. What we saw from the initial presentations of this trial was that the combination resulted in improved survival and response rates for patients with intermediate- and poor-risk disease. However, those with favorable disease seem to fair better with sunitinib (Sutent). It is going to be exciting how this treatment combination falls into the landscape of RCC.

TARGETED ONCOLOGY:Can you discuss ongoing trials investigating immunotherapy?

McKay:With regards to immunotherapy, the combination of nivolumab and ipilimumab is an interesting study. Nivolumab is a PD-1 inhibitor and ipilimumab is a CTLA-4 inhibitor. The combination has shown efficacy in other solid tumor malignancies, specifically melanoma. In this study, we saw that the combination did improve survival and response rates for patients with intermediate- and poor-risk disease.

In addition, there are combinations of VEGF inhibitors and immunotherapies that are being explored, specifically the combination of axitinib (Inlyta) and avelumab (Bavencio), pembrolizumab (Keytruda) and lenvatinib (Lenvima), cabozantinib and nivolumab with our or without ipilimumab, and axitinib and pembrolizumab. These combinations are being looked at in phase III studies at the present now.

TARGETED ONCOLOGY:Looking ahead 5 or 10 years, how do you envision the treatment landscape advancing for RCC?

McKay:Over the past decade, it has been monotherapy with VEGF-targeted agents and immunotherapy. The combination of nivolumab and ipilimumab is our first look at combinations. Over the next 5 to 10 years, we are going to see combinations coming in the frontline setting to improve response rates and durability of response for patients, whether with immunotherapy combinations or immunotherapy and VEGF combinations. We will be seeing more of that in the coming years.

TARGETED ONCOLOGY:Are there any remaining unmet needs or challenges in the management of this setting that should be addressed?

McKay:One of the biggest unmet needs was the management of patients with non-clear cell RCC. Patients with non-clear cell RCC are historically excluded from clinical trials. They comprise a heterogeneous group of patients with multiple different kinds of histologies. They are rare, and I think specifically targeting that patient population to improve outcomes is going to be key.

There are several trials exploring immunotherapy alone and in various combinations in those patients, but we need more of that to help inform the practice of patients with non-clear cell RCC.

TARGETED ONCOLOGY:Is there ongoing research you would like to discuss?

McKay:We are looking at the combination of radium-223 and VEGF-targeted therapy in patients with RCC in bone metastases. We recently presented data at the 2017 ESMO Congress from a phase I pilot study of the combination of radium-223, which is a liquid radium pharmaceutical that has been shown to improve survival for patients with prostate cancer. We are using that agent for patients with bone metastases in RCC and combining it with a VEGF -targeted therapy. We are looking at advancing that concept.

TARGETED ONCOLOGY:What are the main points that physicians need to know about this rapidly changing field?

McKay:The big message is that the treatment landscape is rapidly changing. We now have different kinds of drugs. In the practice of RCC, chemotherapy was the main form of treatment. Now it is treated with targeted therapies and immunotherapies. Learning how to administer these different novel drugs will be important moving forward.

The biggest thing for community providers is learning how to manage the toxicities, specifically the immune-related adverse events associated with combination immunotherapy. Our field is evolving rapidly from cytotoxic chemotherapy to treat cancer. We are at a different place now.

Reference:

Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presented atIn: Proceedings from the 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017; Madrid, Spain. Abstract LBA5.