Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised phase 3 trial

By R. Motzer, B. Rini, D. McDermott, O. Arén Frontera, H. Hammers, M. Carducci, P. Salman, B. Escudier, B. Beuselinck, A. Amin and 28 more. The Lancet Oncology, 2019

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Summary Background In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab (NIVO+IPI) demonstrated superior efficacy over sunitinib (SUN) in patients with previously untreated IMDC intermediate/poor-risk advanced renal cell carcinoma (aRCC) with a manageable safety profile. We assessed efficacy and safety after extended follow-up to inform the long-term clinical value of NIVO+IPI versus SUN in this setting. Methods In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced or metastatic renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by IMDC risk status into favourable, intermediate, and poor risk subgroups and randomly assigned (1:1) to open-label NIVO 3 mg/kg IV plus IPI 1 mg/kg IV every 3 weeks for four doses, followed by NIVO 3 mg/kg IV every 2 weeks; or SUN 50 mg orally once daily for 4 weeks (6-week cycle). Randomisation was done with a block size of four and stratified by risk status and region. Here, we report overall survival (OS), investigator-assessed PFS, the proportion of patients achieving an investigator-assessed objective response per RECIST v1.1, characterisation of response, and safety in all patients (ITT and across risk groups) with extended follow-up. The co-primary endpoints of the trial reported previously were OS, proportion of patients achieving an objective response per IRRC, and progression-free survival (PFS) per IRRC in intermediate/poor-risk patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but is now closed to recruitment. Findings Between October 16, 2014, and February 23, 2016, of 1390 patients screened, 1096 (79%) were randomised to NIVO+IPI versus SUN (550 vs 546 ITT; 425 vs 422 intermediate/poor risk, 125 vs 124 favourable risk). Efficacy outcomes were assessed in all randomised patients; safety outcomes were assessed in all treated patients. Median follow-up was 32·4 months (IQR 13·4–36·3). In intermediate/poor-risk patients, improved OS (HR 0·66; 95% CI 0·54–0·80; p<0·0001; median not reached [95% CI 35·6-not estimable] vs 26·6 [95% CI 22·1–33·4] months), PFS (HR 0·77; 95% CI 0·65–0·90; p<0·01; median 8·2 [95% CI 6·9–10·0] vs 8·3 [95% CI 7·0–8·8] months), and proportion of patients achieving objective response (178 [42%] of 425 vs 124 [29%] of 422; p<0·01, Δresponse = 12·8% [95% CI 6·5–19·2]) were maintained with NIVO+IPI versus SUN, respectively. Similarly in ITT patients, longer OS (HR 0·71; 95% CI 0·59–0·86; p<0.01; median not reached [95% CI not estimable] vs 37·9 [95% CI 32·2-not estimable] months), longer PFS (HR 0·85; 95% CI 0·73–0·98; p=0·03; median 9·7 [95% CI 8·1–11·1] vs 9·7 [95% CI 8·3–11·1] months), and a higher proportion of patients achieving objective response (227 [41%] of 550 vs 186 [34%] of 546; p=0·02, Δresponse = 7·6% [95% CI 2·0–13·2]) were observed with NIVO+IPI versus SUN, respectively.Of all treated patients (547 NIVO+IPI; 535, SUN), the most common grade 3–4 treatment-related AEs were increased lipase (57 [10%]), amylase (31 [6%], and alanine aminotransferase (28 [5%]) with NIVO+IPI vs hypertension (90 [17%]), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]) with SUN. Eight deaths in the NIVO+IPI arm (one each due to pneumonitis, pneumonia and aplastic anaemia, immune-mediated bronchitis, lower gastrointestinal haemorrhage, hemophagocytic syndrome, sudden death, liver toxic effects, and lung infection) and four deaths in the SUN arm (two cardiac arrests and one each of heart failure and multiple organ failure) were reported as treatment-related. Interpretation These results suggest that the superior benefit-risk profile of NIVO+IPI over SUN were maintained in intermediate/poor-risk and ITT patients with extended follow-up and demonstrate the long-term benefits of NIVO+IPI in patients with previously untreated aRCC across all risk categories.

Subfields: Oncology, Pulmonary and Respiratory Medicine

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