Dear readers,

The treatment paradigm for non-clear cell renal cell carcinoma (nccRCC) has evolved significantly, though it remains less clearly defined than that for clear cell RCC. Historically, management relied heavily on extrapolated data from clear cell trials, typically favoring tyrosine kinase inhibitors (TKIs). However, the growing body of evidence from prospective studies has established immune checkpoint inhibitors (ICIs), alone or in combination with TKIs, as important therapeutic options. The challenge now lies in choosing the most appropriate regimen from several active therapies. This decision should be tailored to each patient, accounting for factors such as histologic subtype, performance status, molecular markers, and the urgency of disease control.

Recent prospective data have helped clarify the role of ICI-ICI therapy. The phase II randomized SUNNIFORECAST trial, the largest to date in this population, evaluated ipilimumab plus nivolumab versus standard-of-care (monotherapy TKI) therapies in 309 treatment-naïve patients with advanced nccRCC. The combination achieved a significantly improved 12-month overall survival (OS) rate (78% vs. 68%, p=0.026) and a higher objective response rate (ORR: 32.8% vs. 19.3%) compared to SOC. While median OS (33.2 vs. 25.2 months) and progression-free survival (5.4 vs. 5.7 months) were not statistically different, patients with PD-L1 CPS >1 experienced a notable OS benefit (HR 0.56). Toxicities were consistent with known ICI profiles, with 17% discontinuing treatment due to adverse events. These data support ipi/nivo as a viable frontline option, particularly in patients with PD-L1–positive tumors or unclassified histologies.

Further support for ICI-TKI combinations comes from a phase II trial of cabozantinib plus nivolumab, which enrolled 40 patients with papillary, unclassified, or translocation-associated RCC. At a median follow-up of 34 months, the ORR was 48% (95% CI: 32–64%), with a median PFS of 13 months and median OS of 28 months. Responses were observed across all subtypes: 47% in papillary, 50% in unclassified, and 50% in translocation RCC. Notably, treatment-naïve patients experienced an even higher ORR of 54%. The median duration of response was 17 months, indicating sustained benefit. While grade 3–4 adverse events occurred in 55% of patients—most commonly fatigue, palmar-plantar erythrodysesthesia, and diarrhea—these were manageable, and dose reductions were common but reversible. These results reinforce cabozantinib/nivolumab as an effective and durable regimen for a broad nccRCC population.

Similarly, pembrolizumab plus lenvatinib has demonstrated excellent efficacy in the KEYNOTE-B61 trial, which enrolled 82 patients, predominantly with papillary RCC. The regimen produced an ORR of 47.6% (54.7% in papillary RCC), median PFS of 17.9 months, and 12-month OS rate near 88%. These represent some of the most impressive efficacy outcomes to date in this setting, with responses that are both rapid and durable. Toxicities were consistent with the known safety profiles of the agents involved, and most patients were able to maintain therapy with appropriate supportive care and dose modifications.

How do we translate this growing body of evidence into clinical practice? The answer lies in recognizing that each of these regimens has a role and should be selected based on the individual patient. For example, patients with aggressive or symptomatic disease may benefit from the rapid disease control of ICI-TKI combinations, while those with strong immunologic features (e.g., high PD-L1 expression, unclassified histology) may derive durable benefit from dual checkpoint

blockade. Patients with MET-driven papillary RCC may respond particularly well to cabozantinib-based regimens. Additional considerations include comorbidities, risk of immune-related toxicity, treatment goals, and patient preferences. Ultimately, the goal is to use clinical, pathologic, and molecular data to tailor therapy in a personalized, evidence-based way, optimizing outcomes while preserving quality of life.

To further explore how to navigate these complex treatment decisions, we invite you to tune in to the latest episode of the Oncology Decoded podcast. In this episode, we sit down with Dr. Stephanie Berg, a GU oncology expert, to discuss the frontline management of non-clear cell RCC, how to interpret emerging trial data, and what it means for real-world clinical decision-making. Whether you’re refining your therapeutic approach or staying current with the latest evidence, this discussion offers practical insights for managing a challenging disease space. Listen and subscribe to Oncology Decoded on Spotify or Apple Podcasts to stay informed on the latest in cancer science and care.

Sincerely,
Manojkumar Bupathi, MD
Oncology Decoded