Novel clinical trials are currently assessing the combination of VEGF-targeted agents and immune checkpoint inhibitors as frontline therapies for patients with metastatic renal cell carcinoma (RCC).
Sumanta K. Pal, MD
Novel clinical trials are currently assessing the combination of VEGF-targeted agents and immune checkpoint inhibitors as frontline therapies for patients with metastatic renal cell carcinoma (RCC), which could result in a dramatic transformation in the treatment paradigm, according to Sumanta K. Pal, MD, in a talk at the 2016 GU Cancers Symposium.
For the past decade, VEGF-targeted therapies were considered the optimal frontline treatment for patients with metastatic clear cell RCC. 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).
“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, Kidney Cancer Program, City of Hope. However, when assessing the current treatment landscape, Pal said that he didn’t think nivolumab was appropriate as a monotherapy in the frontline setting.
The leading frontline VEGF 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.2In 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 terms of adverse events, pazopanib appeared to be more tolerable.
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.3A 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 CABO-SUN 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.
Several Combination Strategies Under Exploration
Early phase clinical trials exploring VEGF TKIs in combination with antiPD-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.4In this trial, the most common grade 3/4 adverse events were diarrhea (9.1%) and increased alanine transaminase (9.1%). In addition to a manageable toxicity profile, axitinib plus pembrolizumab demonstrated sustained and prolonged responses. Overall, the objective response rate was 45.5%.
“This bodes well for a clinical trial that is currently under way exploring axitinib and avelumab,” said Pal. “This particular trial has already inspired a phase III trial that will randomized patients to either sunitinib or axitinib and avelumab. We are very excited to see how that study turns out.”
Outside of TKIs, other opportunities for combination strategies exist as treatments for patients with advanced RCC. Historically, the VEGF-targeted antibody bevacizumab (Avastin) has paired well with other novel agents, according to Pal.
At this point, phase I trials have demonstrated sustained responses and tolerable safety for the combination of bevacizumab and the PD-L1 agent atezolizumab (MPDL3280A), leading to the initiation of a phase III study comparing the combination with sunitinib. The current endpoint for the study is PFS and the targeted enrollment is 830 patients (NCT02420821).
Building on success in other areas, the combination of nivolumab and the CTLA-4 inhibitor ipilimumab (Yervoy) is also being assessed for patients with RCC (NCT02231749). In a phase I study exploring the combination the objective response rate was between 43% and 48%, depending on the dose of each medication utilized.5Additionally, these responses were durable, according to Pal.
In patients receiving a higher 3 mg/kg dose of ipilimumab and a 1 mg/kg dose of nivolumab, the adverse events associated with the combination were unacceptably high, noted Pal. However, when nivolumab was given at 3 mg/kg and ipilimumab was administered at 1 mg/kg, the combination was far more tolerable, he said.
“This is the dose that has made its way into the phase III experience comparing nivolumab and ipilimumab with sunitinib therapy,” according to Pal.
A number of studies are currently exploring various combination strategies. Among these studies are those assessing cabozantinib with ipilimumab plus nivolumab or nivolumab alone. Also, a study is examining bevacizumab with nivolumab for patients with RCC.
RCC Biomarkers Being Explored
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, noted Pal.
“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.