Nivolumab plus ipilimumab not effective in localised renal cell carcinoma at high risk of relapse after nephrectomy

The CheckMate 914 trial of nivolumab plus ipilimumab (NIVO+IPI) versus placebo in patients with localised renal cell carcinoma (RCC) at high risk of relapse after nephrectomy did not meet the primary endpoint of disease-free survival. Safety of NIVO+IPI was consistent with its known profile in advanced RCC, although the rate of discontinuation due to treatment-related adverse events was higher with adjuvant NIVO+IPI versus placebo in this trial.

Standard treatment for localised non-metastatic renal cell carcinoma (RCC) is radical or partial nephrectomy. However, patients with stage II or III tumours have a substantial risk of post-nephrectomy relapse. Approved adjuvant options include sunitinib (US only) and pembrolizumab. Identification of new effective adjuvant therapies for patients at risk of relapse remains an unmet need. Dual immune checkpoint inhibition with nivolumab and ipilimumab (NIVO+IPI) has demonstrated long-term improvements versus sunitinib in patients with untreated advanced RCC. The phase III CheckMate 914 trial was designed to study clinical outcomes with adjuvant NIVO+IPI (parts A and B) and NIVO monotherapy (part B) in the setting of surgically resected stage II/III clear cell RCC with a high risk of recurrence. At ESMO 2022, Dr. Motzer presented the results from part A of CheckMate 914, assessing the efficacy and safety of NIVO+IPI versus placebo.

Study design

In total, 816 patients were included in the trial and randomised to NIVO+IPI (N= 405) or placebo (N= 411). The CheckMate 914 key inclusion criteria were radical or partial nephrectomy with negative surgical margins > 4 and ≤ 12 weeks before randomisation; predominant clear cell histology; pathological TNM stage T2a (grade [G] 3 or 4) N0M0, T2b (any G) N0M0, T3 (any G) N0M0, T4 (any G) N0M0, or any T (any G) N1M0; and no clinical/radiological evidence of residual disease or distant metastases. Patients were required to have an ECOG performance status of  0 or 1. Patients were randomised 1:1 to NIVO 240 mg Q2W (× 12 doses) + IPI 1 mg/kg Q6W (× 4 doses) or equivalent placebo for 24 weeks or until disease recurrence/unacceptable toxicity. Stratification factors were TNM stage and type of nephrectomy. Primary endpoint was disease-free survival (DFS) per blinded independent central review. Secondary endpoints include overall survival and safety. A hierarchical testing procedure was used for the secondary endpoint of OS. If the DFS endpoint was not significant, no formal analysis of OS would be performed.

Results

Baseline patient characteristics were balanced between the two arms. More than 90% of patients had radical nephrectomy and most patients were pT3 (78%). Only 5% of patients had sarcomatoid features. After a median follow-up of 37.0 months, the primary efficacy endpoint of DFS was not met (HR[95%CI]: 0.92[0.71-1.19], p= 0.5347). The median DFS was not reached with NIVO+IPI and was 50.7 months with placebo. The DFS probabilities at 24 months were 76.4% and 74.0%, respectively. DFS per investigator likewise did not show a difference between treatment arms (HR[95%CI]: 0.92[0.71-1.20], p= 0.5390). Across most subgroups, there was no difference between both treatment arms, however, there was a trend in favour of NIVO+IPI in small pT2 and pT4 N-positive subgroups, as well as in those patients with sarcomatoid features.  Due to hierarchical testing, no formal analysis of OS was performed. Median treatment duration was 5.1 months in both arms with more than half of patients in either arm completing treatment. However, the proportion of patients completing treatment was lower with NIVO+IPI as compared to placebo (57% vs. 89%). Any-grade treatment-related adverse events (TRAEs) were reported in 88.9% vs. 56.8% of patients treated with NIVO+IPI vs. placebo. Grade ≥ 3 TRAEs were reported in 28.5% vs. 2.0%, respectively. TRAEs led to discontinuation of NIVO+IPI in 29.0% of patients and of placebo in 1.0% of patients. The most common TRAEs in patients receiving NIVO+IPI were pruritus (27%), fatigue (25%), diarrhoea (20%) and rash (19%). The most common any-grade immune-mediated AEs with NIVO+IPI were endocrine- and skin-related. Deaths of four patients (1%) treated with NIVO+IPI were considered to be related to drug toxicity.

Conclusion

Part A of the CheckMate 914 trial, comparing NIVO+IPI vs. placebo in patients with localised RCC at high risk of post-nephrectomy relapse, did not meet the primary endpoint of DFS. The safety of NIVO+IPI in this population was consistent with the known profile for this combination in advanced RCC. The rate of discontinuation due to TRAEs was considerable with NIVO+IPI in the adjuvant setting.

Reference

Motzer R, et al. Adjuvant nivolumab plus ipilimumab (NIVO+IPI) vs placebo (PBO) for localized renal cell carcinoma (RCC) at high risk of relapse after nephrectomy: Results from the randomized, phase III CheckMate 914 trial. Presented at ESMO 2022; Abstract LBA4.