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Multiple randomized adjuvant therapy trials have been conducted in renal cell cancer (RCC), but almost all have shown no benefit except for S-TRAC, using sunitinib, and KEYNOTE-564, using adjuvant pembrolizumab post-nephrectomy. There are matching trials for sunitinib (ASSURE/ECOG2805) and for immune checkpoint inhibitors using atezolizumab (IMmotion010), nivolumab (PROSPECT), and combined nivolumab and ipilimumab (CheckMate 914) that have shown no benefit. S-TRAC showed a disease-free survival (DFS) benefit, whereas KEYNOTE-564 provided a DFS and overall survival benefit. Both sunitinib and pembrolizumab have received FDA approval for use in adjuvant RCC treatment, based on the DFS benefit noted in the trials.

The reaction within the community for the use of these agents, however, has been the polar opposite. Sunitinib was not accepted and was utilized sparingly, whereas pembrolizumab has been rapidly adapted into practice. This is especially interesting as the sunitinib toxicities are largely reversible, unlike the pembrolizumab toxicities, which can persist even after discontinuing the medication. The stakes are higher in treating an asymptomatic adjuvant patient population and potentially committing to lifelong toxicities, as compared with therapy considerations in metastatic RCC.

The raises four thought-provoking points about study design for adjuvant therapy:

• Overall survival (OS) remains the gold standard endpoint around which adjuvant therapy trials should be designed. DFS may not be an adequate surrogate for OS.

• Unequal early censoring or dropout within the arms of the trial can impact the results. When each early dropout was considered an event, the time to treatment failure was then no different between the pembrolizumab and placebo arms.

• The OS results are dependent upon the therapy received or available for patients at relapse, especially in the control arm. If the adjuvant therapy has shown to improve OS in the metastatic setting this should be made available to the patients in the control arm at the time of relapse. Only 36% of the relapsed control-arm patients received immunotherapy in the metastatic setting within this global trial. Although none of the adjuvant trials were designed with this provision, in the predominantly U.S.-based trials such as PROSPECT all patients at relapse would likely receive an immune checkpoint inhibitor-based regimen. In the absence of a mandate to provide the drug for patients relapsing with metastatic disease on the control arm, the OS difference cannot be correctly interpreted.

• The lack of consistency between the results of these trials is concerning. The study designs are very similar and the therapies used are comparable.

In summary, the risk-benefit ratio of immune checkpoint therapy in the adjuvant setting for RCC should be carefully considered on an individual case basis. Currently adjuvant pembrolizumab should be considered for higher-risk patients (T3/T4 patients) with either sarcomatoid/rhabdoid features, resected metastases, or lymph nodes positive for involvement with cancer.

In future trials, improved biomarker-based strategies may be helpful to select the patient population most likely to benefit. An Oncotype DX strategy to evaluate RCC patients who will not benefit from adjuvant therapy is needed.

Present evidence suggests there is likely a small benefit in the high-risk RCC population post-nephrectomy, and patient eligibility for adjuvant immunotherapy should be judiciously considered.

Ulka Vaishampayan, MD, is the Beverly Mitchell MD Research Professor of Medicine, Ambulatory Clinical Chief (Hem/Onc), Director of the MET (Phase I ) team, and Co-Leader of the Translational Clinical Research Program at Rogel Cancer Center of the University of Michigan in Ann Arbor.

Read the paper by Tannock and colleagues here and an interview about it here.