Frontline IO/TKI Regimens Continue to Evolve in ccRCC

Jaime R. Merchán, MD

As research demonstrating the benefit of immuno-oncology (IO) and targeted therapy combinations in both clear cell renal cell carcinoma (ccRCC) and non-ccRCC continues to expand, efforts to optimally harness these therapies in these difficult-to-treat disease types may require a greater emphasis on genomic profiling and biomarker identification, according to Jaime R. Merchán, MD.

“IO/TKI regimens are making significant progress and are shown to be very promising and effective in [both ccRCC and non-ccRCC],” Merchán said following his participation in an OncLive® State of the Science Summit on genitourinary cancers.

In an interview with OncLive®, Merchán discussed the evolution and current role of IO/TKI regimens in advanced RCC; highlighted data from the phase 3 CLEAR (NCT02811861) and KEYNOTE-426 (NCT02853331) trials supporting the use of pembrolizumab (Keytruda)-based regimens in untreated ccRCC; and speculated on how future biomarker-driven research could improve the benefit seen with these combinations in this disease.

Merchán is an associate professor of medicine in the Department of Medicine, Division of Medical Oncology, co-leader of the Translational and Clinical Oncology Research Program, and director of the Phase 1 Clinical Trials Program at Sylvester Comprehensive Cancer Center, part of the University of Miami Health System in Florida.

OncLive: How has the use of frontline IO/TKI-based regimens evolved in advanced and metastatic RCC?

Merchán: The use of IO and TKIs has significantly evolved in metastatic RCC in the past 4 or 5 years. Every time a study is done, [data on] more potent and effective combinations are reported. Currently, at least for ccRCC, 3 IO/TKI combinations [are available] in the first-line setting. Each [regimen] is associated with high response rates and excellent progression-free survival [PFS] compared with single-agent TKIs. IO/TKI combinations are evolving not only in ccRCC, but also in the non–clear cell subtype. Although it’s less common than ccRCC, non-ccRCC is considered an orphan disease, where standard treatments have not been available.

Could you highlight key data supporting the use of pembrolizumab plus axitinib (Inlyta) or lenvatinib (Lenvima) as the standard of care in patients with previously untreated ccRCC?

Two pivotal trials that support the use of pembrolizumab and axitinib or lenvatinib have been completed, published, and presented at different oncology meetings. The data [from these studies] are convincing. For example, in the phase 3 CLEAR trial, the combination of pembrolizumab and lenvatinib was associated with high response rates of approximately 70%. In the most recent update, [the regimen produced an approximate] 18% complete response [CR] rate in the non–clear cell population. [Pembrolizumab plus lenvatinib] is associated with a significant prolongation in PFS for patients both in the favorable-risk group as well as the intermediate- and poor-risk groups.

Pembrolizumab plus axitinib [was also evaluated] in the randomized phase 3 [KEYNOTE-426] trial. This combination was associated with an overall response rate of 60.6% and a CR rate of 11.6%. [The regimen also led to] a significant prolongation in median PFS compared with the control agent, which was sunitinib [Sutent].

What future developments still need to occur to maximize the clinical benefit of IO/TKI regimens?

Future research with IO/TKI combinations in RCC [may] include biomarker-driven clinical trials, where biomarkers for efficacy that are being evaluated right now, especially transcriptomic signatures, [findings with which] have been published recently, will be used to try to stratify and select patients for the best combinations. [These biomarkers could be utilized] not only for IO/TKI regimens, but also for IO/IO combinations. Some patients have a genomic or transcriptomic signature that may make them more likely to respond to IO/TKI combinations than patients who have a transcriptomic signature that may make them more likely to respond to doublet immunotherapies.

The future for contemporary treatments in RCC will be biomarker driven. Several trials have already been activated and are ongoing. We do not have the results yet, but we are enthusiastically awaiting them.