Dr Merchán on the Future Treatment of Advanced RCC

Jaime R. Merchán, MD, associate professor, medicine, Department of Medicine, Division of Medical Oncology, co-leader, Translational and Clinical Oncology Research Program, director, Phase 1 Clinical Trials Program, Sylvester Comprehensive Cancer Center, the University of Miami Health System, discusses the future treatment of patients with advanced renal cell carcinoma (RCC).

In the realm of RCC research, the direction of future investigations is poised toward a biomarker-driven approach, particularly in the context of immuno-oncology (IO) and TKI combinations, Merchán begins. This vision entails the use of biomarker-driven clinical trials to stratify patients based on specific genomic or transcriptomic signatures that could predict efficacy in response to various treatment combinations, according to Merchán. Recent advancements in transcriptomic profiling have unveiled promising signatures that hold potential in guiding treatment selection, he explains.

The strategy involves identifying patients who harbor certain biomarkers that make them more likely to respond favorably to IO/TKI combinations. For instance, patients with distinct transcriptomic signatures indicative of responsiveness to IO/TKIs may be directed toward treatment with those agents, whereas patients exhibiting signatures indicating a stronger response to dual immunotherapies may be assigned accordingly, Merchán reports. This tailored approach aims to optimize treatment outcomes by matching patients with therapies that align with their molecular profiles, Merchán emphasizes.

RCC management will transition toward a biomarker-driven paradigm, as evidenced by the activation of several ongoing clinical trials designed to assess the efficacy and feasibility of these targeted combinations, he elucidates, adding that the results of these trials are eagerly anticipated. The incorporation of biomarker-driven strategies represents a progressive shift toward personalized medicine within RCC management, Merchán notes. The ongoing clinical trials exploring IO/TKI and IO/IO combinations are poised to provide critical insights into the efficacy and applicability of these tailored approaches, heralding a new era of precision medicine in the management of RCC, Merchán concludes.

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Jaime R. Merchán, MD, discusses the future treatment of patients with advanced renal cell carcinoma.

Dr Merchán on the Role of Immunotherapy and TKI Combinations in RCC

Jaime R. Merchán, MD, professor, co-leader, Translational and Clinical Oncology Research Program, director, Phase 1 Clinical Trials Program, Department of Medicine, Division of Medical Oncology, the University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, discusses the current roles for immunotherapy and TKI combination regimens in the management ofrenal cell carcinoma (RCC).

The use of TKIs and immunotherapy for patients with metastatic RCC has changed over the past several years, Merchán says. Ongoing research often generates potent, effective combination regimens for patients in this population, Merchán notes.

For patients with clear cell RCC (ccRCC), FDA-approved frontline immunotherapy and TKI combinations include: pembrolizumab (Keytruda) plus lenvatinib (Lenvima), nivolumab (Opdivo) plus cabozantinib (Cabometyx), and avelumab (Bavencio) plus axitinib (Inlyta), Merchán explains. Each of these combinations is associated with favorable efficacy compared with single-agent TKIs, Merchán emphasizes.

 for patients with previously untreated advanced RCC based on findings from the phase 3 CLEAR/KEYNOTE-581 trial (NCT02811861), in which the combination elicited a median progression-free survival (PFS) of 23.9 months (95% CI, 20.8-27.7) compared with 9.2 months (95% CI, 6.0-11.0) in patients who received sunitinib (HR, 0.39; 95% CI, 0.32-0.49; 

The combination of nivolumab and cabozantinib 

 for patients with advanced disease. This regulatory decision was supported by findings from the phase 3 CheckMate-9ER trial (NCT03141177), which demonstrated a median PFS of 16.6 months with nivolumab plus cabozantinib vs 8.3 months with sunitinib (Sutent; HR, 0.51; 95% CI, 0.41-0.64; 

 for patients with advanced ccRCC based on data from the phase 3 JAVELIN Renal 101 trial (NCT02684006), in which the combination induced a median PFS of 13.8 months (95% CI, 11.1-not evaluable) vs 8.4 months (95% CI, 6.9-11.1) with sunitinib (HR, 0.69; 95% CI, 0.563-0.840; 2-sided 

As immunotherapy and TKI combination regimens continue to drive progress in the management of ccRCC, they are also evolving for patients with non-ccRCC, Merchán notes. Non-ccRCC, which is rarer than ccRCC, is considered an orphan disease that has historically lacked standard treatments, Merchán concludes.

Jaime R. Merchán, MD, discusses the current roles for immunotherapy and TKIs in patients with renal cell carcinoma.

Dr Merchan on Key Data Supporting Pembrolizumab-Based Regimens in Advanced RCC

Jaime R. Merchán, MD, associate professor, medicine, Department of Medicine, Division of Medical Oncology, co-leader, Translational and Clinical Oncology Research Program, director, Phase 1 Clinical Trials Program, Sylvester Comprehensive Cancer Center, the University of Miami Health System, discusses key data supporting the role of pembrolizumab (Keytruda) plus axitinib (Inlyta) or lenvatinib (Lenvima) as a standard-of-care regimen for patients with previously untreated advanced renal cell carcinoma (RCC).

Immuno-oncology (IO) and targeted therapy combinations continue to show efficacy in both clear cell RCC (ccRCC) and non-ccRCC, Merchán begins. Two pivotal trials that support the use of pembrolizumab-based regimens in RCC are the phase 3 CLEAR (NCT02811861) and KEYNOTE-426 (NCT02853331) trials.

In the CLEAR trial, the combination of pembrolizumab and lenvatinib demonstrated high response rates in patients with advanced RCC, Merchán reports. Recent extended follow-up data 

 further highlighted the efficacy of lenvatinib plus pembrolizumab in this patient population. Notably, improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were observed across all patients, regardless of baseline tumor size. Patients with a high tumor burden experienced a median OS of 39.5 months(95% CI, 32.1-48.7), indicating substantial benefit from the combination therapy. Moreover, the data revealed that OS rates improved as tumor volume decreased, with 3-year OS rates ranging from 55.6% in the highest burden subgroup to 73.0% in the lowest burden subgroup. In the final prespecified analysis, the regimen also elicited an 18.3% complete response rate vs 4.8% with sunitinib, further highlighting its efficacy across different RCC subtypes.

Pembrolizumab plus axitinib was evaluated in the randomized KEYNOTE-426 trial, which compared this combination with sunitinib monotherapy in treatment-naive patients with stage IV ccRCC, Merchán continues. Data from the trial's first interim analysis showed significant improvements in PFS, OS, and ORR with pembrolizumab plus axitinib compared with sunitinib. The regimen generated an ORR of approximately 60%, further supporting its efficacy in patients with advanced RCC. In April 2019, 

gained FDA approval for patients with advanced RCC

Jaime R. Merchán, MD, discusses the role of pembrolizumab plus axitinib or lenvatinib in previously untreated advanced renal cell carcinoma.

Jaime R. Merchán, MD

Articles

Dr Merchán on the Future Treatment of Advanced RCC

Dr Merchán on the Role of Immunotherapy and TKI Combinations in RCC

Dr Merchan on Key Data Supporting Pembrolizumab-Based Regimens in Advanced RCC