The CheckMate 214 trial's eight-year follow-up data highlight the durable benefits of nivolumab plus ipilimumab in advanced renal cell carcinoma (RCC), particularly in intermediate- and poor-risk patients. The data suggest a potential shift in treatment strategies, even for favorable-risk patients, challenging the conventional use of IO-TKI combinations in all risk groups.
Long-Term Outcomes of Nivolumab Plus Ipilimumab
The phase 3 CheckMate 214 trial (NCT02231749) evaluated nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with intermediate- or poor-risk RCC. According to Alan Tan, MD, Vanderbilt-Ingram Cancer Center, the Kaplan-Meier overall survival (OS) curves with this IO combination have now surpassed those of IO-TKI combinations in favorable-risk populations. For favorable-risk disease, the hazard ratio (HR) is now 0.82, which is superior to HRs historically reported in IO-TKI trials.
IO-IO vs. IO-TKI: Balancing Speed and Durability
The decision between an IO-IO vs IO-TKI regimen often hinges on clinical presentation. Patients with high disease burden or aggressive symptoms often benefit more from an IO-TKI combination because they need a rapid response to stabilize their condition. While IO-TKI combinations have demonstrated long-term survival benefits extending up to 5 years, maintaining disease control off treatment can be more challenging.
In contrast, the CheckMate 214 trial showed that 35.1% of patients treated with nivolumab and ipilimumab were alive at 90 months, with some still off therapy and potentially cured. This dataset represents the longest follow-up for an immunotherapy doublet regimen in RCC, setting the stage for future advances in combination therapies.
The Role of TKIs in the Evolving RCC Treatment Landscape
With the increasing range of immuno-oncology (IO)-based treatment regimens for patients with renal cell carcinoma (RCC), treatment decisions are typically informed by symptom manifestation and patient characteristics in the absence of predictive biomarkers. Four major doublet regimens are FDA approved for patients with RCC: ipilimumab plus nivolumab, pembrolizumab plus axitinib, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab.
While IO-TKI regimens show a significant progression-free survival benefit and higher overall response rate compared with the IO-IO regimen, it remains uncertain whether these regimens extend OS compared with sunitinib, which is becoming less common in RCC treatment. The key question is whether IO-TKI regimens help patients live longer without toxicity and with the durability seen from IO-IO treatment with ipilimumab plus nivolumab.
Future Directions and Novel Targets
Ongoing research focuses on overcoming resistance to immune checkpoint inhibition and identifying novel targets for RCC management. The phase 3 LITESPARK-12 study is investigating a triplet regimen that adds a HIF2α inhibitor, addressing the pathogenesis of clear cell kidney cancer. Additionally, trials are exploring LAG-3 inhibitors, which have shown efficacy in melanoma, as potential immunologic targets in RCC.
Clinical Considerations for Favorable-Risk Patients
For patients with favorable-risk disease, the decision to use nivolumab plus ipilimumab depends on tolerability and the absence of symptoms. Not every patient with favorable-risk disease needs systemic therapy; stereotactic radiation for a few lung lesions may provide long-term disease control or even cure. However, if systemic therapy is warranted, nivolumab plus ipilimumab is a viable option, provided the patient can tolerate the combination.
