Adjuvant Nivolumab in combination with Ipilimumab falls short in improving DFS in localized RCC patients

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 431,000 new cases and 179,000 deaths worldwide each year. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. The five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 13%.

CheckMate-914 Phase III trial (NCT03138512) was evaluating OPDIVO in combination with YERVOY compared to placebo (Part A), and OPDIVO alone compared to placebo (Part B), in patients with localized renal cell carcinoma (RCC) who have undergone surgery to remove part or all of a kidney and who are at moderate to high risk of relapse. Both parts of the study had a primary endpoint of disease-free survival (DFS) as assessed by Blinded Independent Central Review (BICR).

According to the findings of the primary analysis for part A of this trial, the primary efficacy objective of DFS was not met after 37.0 months of median follow-up. The median DFS with nivolumab with ipilimumab was not attained at 50.7 months with placebo; DFS probabilities at 24 months were 76.4% and 74.0%, respectively. Any-grade treatment-related adverse events (AEs) were reported in 88.9% vs. 56.8% of patients treated with NIVO+IPI vs. PBO; grade ≥ 3 treatment-related AEs were reported in 28.5% vs. 2.0%, respectively. Treatment-related AEs led to discontinuation of NIVO+IPI in 29.0% of patients and of PBO in 1.0% of patients. The safety of NIVO+IPI was consistent with its known profile in advanced RCC, although the rate of discontinuation due to treatment-related AEs was higher with adjuvant NIVO+IPI vs PBO in this trial.

According to BMS, the findings showed that nivolumab in combination with ipilimumab was no better than placebo in terms of improving DFS. Part B of the trial, on the other hand, will continue to read out where Opdivo alone vs. placebo in this setting is being explored, even though it now looks to be unsatisfactory in combination with ipilimumab.

Obtaining adjuvant or neo-adjuvant approvals is an important goal for many checkpoint inhibitor developers since it allows them to present their therapies as the first cancer immunotherapy option in the treatment pathway. This failure is unquestionably a hiccup in the BMS's growth strategy in earlier RCC settings. Even though the combination failed in the RCC adjuvant setting, nivolumab and nivolumab in combination with ipilimumab have demonstrated clinical benefits across several RCC patient populations. 

In April 2018, the FDA granted approvals to nivolumab and ipilimumab in combination for the treatment of intermediate or poor risk, previously untreated advanced renal cell carcinoma. Additionally, in January 2021, the FDA approved the combination of nivolumab and cabozantinib as first-line treatment for patients with advanced renal cell carcinoma.

The failure of this trial has enhanced Merck & Co's KEYTRUDA's position as an adjuvant setting for RCC. The drug was approved in the United States in November 2021, based on the DFS benefit reported in the Keynote-564 study for the adjuvant treatment of patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Aside from BMS and Merck & Co., other pharmaceutical companies are developing checkpoint inhibitors for adjuvant RCC, such as Roche, which is testing its TECENTRIQ in the Phase III IMmotion010 study, and AstraZeneca, which is testing its IMFINZI ± tremelimumab (CTLA4 drug) in the RAMPART trial.

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