Recent clinical studies have highlighted the growing importance of immunotherapy-based combination regimens in treating renal cell carcinoma (RCC), offering more personalized treatment options for patients. These advancements aim to improve long-term outcomes and address the diverse therapeutic needs of individuals with RCC.
Immunotherapy Combinations in First-Line Treatment
Combination regimens have become a cornerstone in the first-line treatment of advanced clear cell RCC. Updated data from key trials such as CheckMate 214 (NCT02231749) and CheckMate 9ER (NCT03141177), which investigated nivolumab (Opdivo) plus ipilimumab (Yervoy) and nivolumab plus cabozantinib (Cabometyx), respectively, alongside the phase 3 CLEAR study (NCT02811861) of lenvatinib (Lenvima) plus pembrolizumab (Keytruda), have solidified the benefit of these approaches.
Pedro Barata, MD, MSc, noted, "We’ve seen huge advancements in terms of landscape changes and how new therapies for the frontline setting are now considered. For the majority of patients, we often consider an immunotherapy-based combination regimen."
Long-Term Follow-Up Data
Long-term follow-up data from CheckMate 214, with a median follow-up of 99.1 months, demonstrated a median overall survival (OS) of 52.7 months (95% CI, 45.8-64.5) for patients treated with nivolumab plus ipilimumab, compared to 37.8 months (95% CI, 31.9-43.8) for those treated with sunitinib (HR, 0.72; 95% CI, 0.62-0.83). Martin H. Voss, MD, emphasized the striking duration of response (DOR) data, stating, "Fifty percent of patients who are still being tracked after achieving a response to ipilimumab/nivolumab remain in response. The median DOR for this regimen is greater than 80 months."
CheckMate 9ER also showed significant benefits with the combination of nivolumab and cabozantinib. At a median follow-up of 55.6 months, the median progression-free survival (PFS) was 16.4 months (95% CI, 12.5-19.3) for the combination arm versus 8.4 months (95% CI, 7.0-9.7) for sunitinib (HR, 0.58; 95% CI, 0.49-0.70). The median OS was 46.5 months (95% CI, 40.6-53.4) versus 36.0 months (95% CI, 29.2-42.8), respectively (HR, 0.77; 95% CI, 0.63-0.95).
Biomarker Analysis in the CLEAR Trial
The CLEAR trial's biomarker analysis revealed that the PFS benefit observed with pembrolizumab plus lenvatinib compared to sunitinib was consistent across various analysis sets, including PD-L1 expression (HR, 0.47; 95% CI, 0.37-0.60), gene expression (HR, 0.52; 95% CI, 0.41-0.68), and gene alterations (HR, 0.49; 95% CI, 0.38-0.63).
Evolving Treatment Landscape in Non-Clear Cell RCC
Research in non-clear cell RCC is also advancing, with a focus on incorporating immunoncology agents. The phase 2 PAPMET trial (NCT02761057) demonstrated that cabozantinib improved PFS compared to sunitinib in patients with papillary RCC (9.0 months vs. 5.6 months; HR, 0.60; 95% CI, 0.37-0.97; 1-sided P = .019).
Building on these findings, the phase 2 PAPMET2 study (NCT05411081) is underway, randomizing patients to cabozantinib alone or in combination with atezolizumab. Additionally, the KEYNOTE-B61 study (NCT04704219) is evaluating pembrolizumab plus lenvatinib as a first-line treatment for advanced or metastatic non-clear cell RCC. Updated findings showed an objective response rate (ORR) of 50.6% (95% CI, 42.6%-58.7%) and a median PFS of 17.9 months (95% CI, 15.1-22.1) with the combination.
Elizabeth Wulff-Burchfield, MD, noted the promising results in specific subtypes, stating, "Patients with translocation type disease did well with lenvatinib plus pembrolizumab and had the highest ORR... Patients with papillary disease also did very well, with an ORR of approximately 50% and a DCR of approximately 80%."
These studies collectively highlight the ongoing efforts to refine treatment strategies for RCC, with a focus on personalized approaches and the integration of immunotherapy to improve patient outcomes.
