The management of advanced clear cell renal cell carcinoma (RCC) has been transformed by the introduction of immunotherapies and now combination therapies (Figure 1). As we have entered this combination therapy era, it is important to understand the historical context in which these advances have come about, to examine the durability of combination immunotherapy strategies in the first-line metastatic setting, and to critically evaluate the potential role of immunotherapy-based combination strategies after progression on prior immune checkpoint inhibition (ICI; particularly blockade of the PD-1 pathway).

Figure 1. The evolving landscape of systemic therapies for advanced cell renal cell carcinoma. ICI indicates immune checkpoint inhibition; TKI, tyrosine kinase inhibitor. Adapted from Kashima S and Braun DA, Urol Clin North Am. 2023;50(2):335-349.

Historically, early cytokine-based immunotherapies (interferon alfa and particularly high-dose interleukin-2) provided benefit for a small number of patients with RCC, but the median overall survival was still only around 1 year. In the mid-2000s, molecularly targeted therapies, particularly tyrosine kinase inhibitors (TKIs) that inhibit angiogenesis by targeting the vascular endothelial growth factor receptor, substantially improved the lives of patients with advanced RCC, increasing median overall survival to approximately 2 years. However, TKI therapies did not generally lead to long-term survival or cure in any patients. In 2015, ICI targeting the PD-1 pathway was shown to prolong overall survival in the TKI-refractory setting, and then beginning in 2018, a series of combination strategies emerged in the first-line setting, all based on a backbone of blocking the PD-1 pathway, and all demonstrating benefit over the TKI sunitinib. Long-term follow-up from the CheckMate-214 study of the combination of 2 ICIs (nivolumab plus ipilimumab) showed durable responses in a subset of patients a median overall survival of approximately 4 years. The combination of PD-1 blockade with a TKI showed promising early results in a series of trials (KEYNOTE 426, JAVELIN Renal 101, CheckMate-9ER, CLEAR), with high response rates and low primary progressive disease rates. With longer-term follow-up, we are now in a position to assess the durability of these responses.

In long-term follow-up of 2 of these ICI+TKI trials, KEYNOTE 426 (pembrolizumab plus axitinib) presented by Dr Brian Rini and CLEAR (pembrolizumab plus lenvatinib) presented by Dr Thomas Hutson, these regimens continued to show very high objective response rates and maintained their significant progression-free and overall survival benefits over sunitinib. However, while the magnitude of benefit appeared stable over time for the “pure” immunotherapy approach of nivolumab plus ipilimumab, qualitatively there appeared to potentially be less benefit of the ICI+TKI approach over time, at least raising the question of the durability of these approaches. This is particularly highlighted by duration of response data—for the pure immunotherapy combination of nivolumab plus ipilimumab, the majority of patients (56%) who have an initial response still maintain that response 5 years later. By contrast, for the ICI+TKI regimens, the median duration of response was about 2 years—framed another way, more than half of patients who achieve an initial response with an ICI+TKI regimen will no longer have a response approximately 2 years later.

How do these presentations impact our practice (Figure 2)? For most clear cell RCC patients with IMDC (International Metastatic RCC Database Consortium) intermediate- or poor-risk disease, we first ask whether there are widespread metastases, or oligometastatic disease potentially amenable to locally directed therapies. For widespread metastatic disease, we also specifically look for sarcomatoid histology, as nivolumab plus ipilimumab has very high response rates (and even complete responses) in patients with RCC with sarcomatoid features. For patients with clear cell RCC without sarcomatoid histology, we ask the fundamental question—does this patient require a rapid response? For those patients with rapidly progressive disease and potential impending visceral crisis, they may never live to receive a second-line of therapy, and so we utilize ICI+TKI regimens, given their very high objective response rates and low primary progressive disease rates. However, for most clear cell RCC patients, where we have time to consider not just what the response will be in 3 or 6 months but also in 3 years, we typically choose a pure immunotherapy approach with nivolumab plus ipilimumab because of the potential durability of response and consider the role of cytoreductive nephrectomy. The impact of cytoreduction is likely dependent on a variety of factors including drug regimen. The role of nephrectomy and selection criteria remain unclear and are expected to continue to evolve with changing drug landscape.

Figure 2. Treatment considerations for advanced clear cell renal cell carcinoma (IMDC [International Metastatic RCC Database Consortium] intermediate-/poor-risk disease). These represent our own views, and there are numerous reasonable approaches to therapy. This approach assumes clear cell renal cell carcinoma, patient who requires treatment (not active surveillance), no contraindication to immune checkpoint inhibition (ICI), and IMDC intermediate-/poor-risk disease. Actual treatment decisions made collaboratively with the patient. SBRT indicates stereotactic body radiation therapy; TKI, tyrosine kinase inhibitor. Adapted from Braun DA et al, Abstract presented at: American Society of Clinical Oncology Annual Meeting; July 5, 2023; Chicago, Illinois.

For the IMDC favorable-risk population, while there are clear objective response and progression-free survival benefits for the ICI+TKI combinations, the updated results presented at ASCO (American Society of Clinical Oncology) 2023 demonstrated no overall survival benefit for the combination strategy over sunitinib alone. This raises more questions than it answers and highlights the need for additional trials to clarify the best strategy for patients with favorable risk disease.

What is the optimal therapy for patients whose RCC tumors have progressed on anti-PD-1-based therapies? While the use of single-agent TKI (such as cabozantinib, axitinib, or in a later line tivozanib) or the combination of lenvatinib plus everolimus are standard approaches, there is a growing practice of rechallenging with an ICI+TKI. This approach was supported both by retrospective and phase 2 prospective data, demonstrating response rates up to 60% with this ICI+TKI rechallenge approach. To systematically evaluate this strategy, Dr Toni Choueiri and colleagues conducted the CONTACT-03 study, randomizing patients with disease progression on prior PD-1 blockade to either cabozantinib alone (TKI; control arm) or cabozantinib plus the anti-PD-L1 drug atezolizumab (experimental arm). The results, presented by Dr Choueiri, showed no clinical benefit with the addition of atezolizumab—no improvement in response rate, duration of response, primary progressive disease rate, progression-free or overall survival. Toxicity, however, was notably higher in the combination arm, with higher grade 3-4 adverse events and more than double the rate of serious treatment-related adverse events. There are some notable limitations of this study—primarily the use of the anti-PD-L1 agent atezolizumab, which, while it has known clinical activity in RCC, is not an approved drug for this disease. This issue will be addressed by the ongoing TiNivo-2 study, a similar trial that uses the more standard anti-PD-1 agent nivolumab in combination with the TKI tivozanib. Further, there are always individual exceptions where certain clinical scenarios indicate a patient might benefit from such an ICI rechallenge. Nevertheless, with this well-conducted, randomized, phase 3 study, it should no longer be routine practice to treat with combination ICI+TKI after progression on prior anti-PD-1 therapy.

These seminal studies presented at ASCO 2023 show the RCC community how far we have come with systemic therapies, but also how far we still have to go. We need to continue trials that further optimize existing therapies, which will hopefully improve the length and quality of life for patients with advanced RCC. However, we also need to listen to our patients—as demonstrated by a recent KCCure (Kidney Cancer Research Alliance) survey of RCC patients (presented by D Battle, ASCO 2023), their top goal remains cure. We should not be shy about trying to achieve it. We are in the proof-of-concept phase, where a limited subset of RCC patients treated with dual ICI therapy can achieve long-term clinical benefit or potentially even cure. To move to an era of cure for more or even most patients with advanced RCC, we need improved immunotherapy approaches. We need to better understand the fundamental immunobiology of RCC, and we need to utilize all of the tools in our therapeutic toolkits—releasing the immune brakes with ICIs, pressing on the immune gas pedal with cytokines and other immune agonists, and adding a steering wheel with antigen-directed therapies.