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Dramatic Changes on Horizon in Renal Cell Carcinoma

Silas Inman @silasinman
Published: Tuesday, Jan 12, 2016

Dr. Sumanta Kumar Pal

Sumanta Kumar Pal, MD

The optimal frontline treatment strategy for patients with metastatic renal cell carcinoma (RCC) could look dramatically different in the next few years, as studies assess combination strategies and predictive biomarkers for immunotherapy and targeted therapies, according to Sumanta Kumar Pal, MD.

For the past decade, VEGF-targeted therapies were considered the optimal frontline treatment for patients with metastatic clear cell RCC, Pal said during a presentation at the 2016 GU Cancers Symposium. However, this paradigm could be disrupted by the recent wave of immuno-oncology agents, which are gaining approval across indications for patients with cancer.

“There's a lot of hope here for perhaps the best of both worlds, with higher response rates and longer progression-free survival with VEGF therapy combined with more durable responses with the PD-1 and PD-L1 directed agents,” said Pal, co-director of the Kidney Cancer Program at City of Hope in Duarte, California.

In November 2015, the first immune checkpoint inhibitor, nivolumab (Opdivo), was approved as a second-line therapy for advanced RCC. This decision was based on the CheckMate-025 study, which showed a median overall survival (OS) of 25.0 months with nivolumab compared with 19.6 months for everolimus (HR, 0.73; P = .002).1

“There is a subset of patients who seem to derive an exceptional response. I think we need to find out who these exceptional responders are. There has been an emerging body of evidence to characterize these individuals,” said Pal. “I don't think nivolumab in the frontline setting is appropriate at this point.”

Anecdotal findings suggest that neoantigens are associated with better responses to immunotherapy, providing a potential tool for tailoring therapy. A correlation between mutational load and responses has also been observed. However, both of these observations still need to be vetted in larger trials, explained Pal.

The need for an effective biomarker also exists for VEGF therapies. A number of studies have hinted at markers of response with various agents, although one indicator has not yet conclusively emerged. Currently, early data suggest KDM5C alterations could be associated with long and durable responses to VEGF-targeted therapy, although these findings still need to be validated.

Tyrosine Kinase Inhibition

The leading frontline VEGF tyrosine kinase inhibitors (TKIs) currently used for RCC are sunitinib (Sutent) and pazopanib (Votrient). These therapies were compared in the phase III 1110-patient COMPARZ trial, which demonstrated similarity between the two agents.2 In the study, pazopanib was shown to be noninferior to sunitinib for progression-free survival (PFS; HR, 1.05; 95% CI, 0.90-1.22) and OS (HR, 0.91; 95% CI, 0.76-1.08).

In addition to established therapies, new agents have recently entered the RCC arena. Although not yet approved, the multikinase inhibitor cabozantinib (Cometriq) demonstrated superiority to everolimus in the phase III METEOR study.3 A rolling submission of data from this trial was completed in December 2015, with a decision from the FDA expected within the next 6 to 8 months.

After a minimum of 11 months of follow-up in the METEOR study, median PFS with cabozantinib was 7.4 months compared with 3.8 months with everolimus (HR, 0.58; 95% CI, 0.45-0.75; P <.001). At the interim analysis, a trend toward improvement in OS was observed; however, this did not yet pass a high bar for statistical significance (HR, 0.67; 95% CI, 0.51-0.89; P = .005).

The ongoing phase II CABOSUN trial is comparing frontline cabozantinib with sunitinib for patients with clear cell RCC. The study enrolled 150 participants to assess the dual primary endpoints of OS and PFS. Early data from this study are anticipated later this year.

Combination Strategies Under Exploration

Early-phase clinical trials exploring VEGF TKIs in combination with anti–PD-1 agents have shown prohibitive hepatic and gastrointestinal toxicity, explained Pal. These studies looked at nivolumab with sunitinib or pazopanib or at the PD-1 inhibitor pembrolizumab (Keytruda) with pazopanib.

Despite these setbacks, promising data were seen for the combination of the VEGF TKI axitinib (Inlyta) and pembrolizumab in a small, 11 patient study.4 In this trial, the most common grade 3/4 adverse events were hypertension (27.3%), and diarrhea and increased alanine transaminase (9.1% each).

In addition to a manageable toxicity profile, axitinib plus pembrolizumab demonstrated sustained and prolonged responses. Overall,  6 patients had confirmed partial responses and 5 patients had stable disease with tumor shrinkage.

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