Pembrolizumab and Lenvatinib Show Long-Lasting Efficacy in Non-Clear Cell RCC

In a significant advancement for renal cancer treatment, the combination of pembrolizumab and lenvatinib has demonstrated durable antitumor activity in patients with advanced non-clear cell renal cell carcinoma (RCC), according to the latest findings from the KEYNOTE-B61 trial presented at the Kidney Cancer Research Summit on July 17-18, 2025, in Boston, Massachusetts. This phase 2 trial, which included 152 evaluable patients, reported an overall response rate (ORR) of 50.6% and a disease control rate (DCR) of 82.3%, highlighting the potential of this combination therapy in managing this challenging cancer type.

The study, led by Dr. Laurence Albiges, MD, PhD, Head of the Department of Oncology at Institut Gustave Roussy, showed that pembrolizumab, an immune checkpoint inhibitor, combined with lenvatinib, a tyrosine kinase inhibitor, produced not only substantial antitumor responses but also encouraging survival outcomes. The median progression-free survival (PFS) was reported at 17.9 months, with PFS rates of 39% at 24 months and 26% at 36 months. Additionally, the median overall survival (OS) reached 41.5 months, with OS rates of 67% and 54% at 24 and 36 months, respectively.

The findings are particularly noteworthy as they encompass various histological subtypes of non-clear cell RCC, including papillary and chromophobe variants. Specifically, the ORR for patients with papillary disease was 53.8%, while those with chromophobe histology exhibited a lower response rate of 31.0%. In contrast, patients with translocation-driven tumors showed a remarkable ORR of 66.7%.

Dr. Albiges stated, "After a minimum of 3 years of follow-up, pembrolizumab plus lenvatinib continued to show durable antitumor activity and promising survival outcomes in the first-line setting for patients with advanced non-clear cell RCC. We are excited that this has changed the paradigm for our patients."

The KEYNOTE-B61 trial included a diverse patient population, with a median age of 60 years. The dominant histology among participants was papillary (58.9%), followed by chromophobe (18.4%) and other subtypes. Notably, 12% of patients presented with sarcomatoid features, indicating a more aggressive disease profile. The study's design allowed for rigorous evaluation, with a primary endpoint focused on ORR and secondary endpoints assessing duration of response, PFS, OS, and safety.

Adverse effects were prevalent, affecting 99.4% of participants, with over three-quarters experiencing grade 3 to 5 toxicities. Common treatment-emergent adverse events included hypertension (57.6%), diarrhea (50.0%), and hypothyroidism (41.1%). Despite the high incidence of adverse effects, the potential benefits of this combination therapy appear to outweigh the risks for many patients.

The results from this trial are poised to influence clinical practice significantly, as pembrolizumab plus lenvatinib emerges as a standard of care for managing advanced non-clear cell RCC. The findings also underscore the importance of continued research in this area, as further studies are likely needed to optimize treatment protocols and address the specific needs of patients with different histological subtypes. With the ongoing evolution of cancer therapies, the integration of immunotherapy and targeted treatments as seen in this trial represents a promising direction in the fight against renal cancer.

In conclusion, the combination of pembrolizumab and lenvatinib offers a new beacon of hope for patients grappling with advanced non-clear cell RCC, heralding a potential shift in treatment paradigms that could pave the way for improved patient outcomes in the future.