Nivolumab Alone, Plus Ipilimumab Being Tested in Early-Stage, High-Risk RCC

The safety and efficacy of nivolumab (Opdivo), both as a single agent and in combination with ipilimumab (Yervoy), is under investigation in patients with early-stage, high-risk renal cell carcinoma (RCC) following radical or partial nephrectomy in the phase 3 CheckMate-914 trial (NCT03138512).¹

The randomized, placebo-controlled study is enrolling patients who have undergone radical or partial nephrectomy and experienced negative surgical margins for more than 4 weeks and no longer than 12 weeks prior to randomization. Investigators are theorizing how nivolumab alone and in combination with ipilimumab could prevent or prolong time until disease recurrence in this patient population.

Key inclusion criteria for the study include patients with predominantly clear cell histology; pathologic Tumor, Nodes, and Metastases (TNM) staging of T2a (grade 3 or 4), T2b (any grade), T3 (any grade),T4 (any grade) N0M0, or any T (any grade) N1M0; and an ECOG performance status of 0 or 1. Additionally, patients cannot have any clinical or radiological evidence of macroscopic residual disease or distant metastases following nephrectomy. Tumor tissue must be acquired no longer than 3 months prior to enrollment.

Those who require corticosteroids or immunosuppressive systemic treatment, have autoimmune disease, received prior agents targeting T-cell co-stimulation or checkpoint pathways, or have had prior systemic treatment for RCC are excluded from the study.

The trial will be divided into 2 parts, with a targeted accrual of 1600 patients across both part A and part B. In part A, patients are randomized 1:1 to receive nivolumab plus ipilimumab or a placebo infusion. Additionally, patients in part B will be randomized 1:1:2 to receive either the combination of nivolumab/ipilimumab, placebo, or nivolumab/placebo. Patients will be randomized based on TNM staging and the type of nephrectomy procedure they underwent.

All patients are treated for 24 weeks or until experiencing disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary end point is disease-free survival (DFS) by blinded independent central review (part A, nivolumab/ipilimumab vs placebo; part B, nivolumab vs placebo and nivolumab/ipilimumab vs nivolumab). Key secondary end points include overall survival (OS; part A, nivolumab/ipilimumab vs placebo; part B, nivolumab vs placebo and nivolumab/ipilimumab vs nivolumab), DFS (part B, nivolumab/ipilimumab vs nivolumab), and safety.

While surgery continues to be standard of care for patients with nonmetastatic disease, those who have stage II/III RCC trend towards being at a high risk for relapse; 5-year disease-free survival rates range from approximately 51% to 56%. Thus, prevention of recurrence is an unmet need in this patient population.

Previous findings have suggested anti–PD-1/PD-L1 may elicit notable benefit in patients with advanced RCC. Investigators theorize that those in the early-stage, adjuvant setting may able to achieve similar benefit, thus forming the rationale for CheckMate-914.

First-line nivolumab plus ipilimumab is currently indicated in patients with advanced or metastatic RCC, as seen in the phase 3 CheckMate-214 study.² The combination was approved by the FDA in April 2018 based on these data, which indicated that the combination yielded a 32% reduction in risk of death vs sunitinib (Sutent; HR, 0.68; 99.8% CI, 0.49-0.95; P = .0003).³ The preliminary data showed that the median OS in the overall patient population was not reached in patients who received the combination vs 32.9 months in those who were treated with sunitinib.

Patients with intermediate- and poor-risk disease, who made up the majority (~75%) of the intent-to-treat population experienced a 37% risk reduction.

Nivolumab is also approved for use in combination with cabozantinib (Cabometyx), having recently been approved by the FDA in January 20214 and in Europe in April 2021.⁵ Both regulatory decisions were based on the results of the phase 3 CheckMate-9ER trial.

Here, the median progression-free survival was 16.6 months with the combination vs 8.3 months with sunitinib (HR 0.51; 95% CI, 0.41-0.64; P <.0001). Moreover, the experimental arm experienced improvements in OS, as well as a favorable safety profile.

References

1. Bex A, Russo P, Tomita Y, et al. A phase III, randomized, placebo-controlled trial of nivolumab or nivolumab plus ipilimumab in patients with localized renal cell carcinoma at high-risk of relapse after radical or partial nephrectomy (CheckMate 914). J Clin Oncol. 2020;38(suppl 15). doi:10.1200/JCO.2020.38.15_suppl.TPS5099
2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126
3. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. News release. FDA. April 16, 2018. Accessed March 29, 2021. https://bit.ly/2QEirhF
4. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. News release. FDA. January 22, 2021. Accessed March 29, 2021. http://bit.ly/2Mjrt1i.
5. Bristol Myers Squibb receives European Commission approval for Opdivo (nivolumab) in combination with Cabometyx (cabozantinib) as first-line treatment for patients with advanced renal cell carcinoma. News release. Bristol Myers Squibb. April 14, 2021. Accessed April 14, 2021. https://bit.ly/3siKqAS