Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial

Abstract

Background: In the ongoing phase 3, CheckMate 214 trial, nivolumab plus ipilimumab improved overall survival compared with sunitinib in patients with intermediate or poor risk, previously untreated, advanced renal cell carcinoma. We aimed to assess whether health-related quality of life (HRQoL) could be used to further describe the benefit-risk profile of nivolumab plus ipilimumab versus sunitinib.

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 risk status into favourable, intermediate, and poor risk subgroups and randomly assigned (1:1) to open-label nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg/day for 4 weeks of each 6-week cycle. Randomisation was done with a block size of four and stratified by risk status and geographical region. Patient-reported outcomes (PROs) were assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy-General (FACT-G), and EuroQol five dimensional three level (EQ-5D-3L) instruments. The coprimary endpoints of the trial, reported previously, were overall survival, progression-free survival, and the proportion of patients who had an objective response in those categorised as at intermediate or poor risk. PROs in all randomised participants were assessed as an exploratory endpoint; here we report this exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but is now closed to recruitment.

Findings: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) were randomly assigned to treatment, of whom 847 (77%) were at intermediate or poor risk and randomly assigned to nivolumab plus ipilimumab (n=425) or sunitinib (n=422). Median follow-up was 25·2 months (IQR 23·0-27·4). PROs were more favourable with nivolumab plus ipilimumab than sunitinib throughout the first 103 weeks after baseline, with mean change from baseline at week 103 for FKSI-19 total score being 4·00 (95% CI 1·91 to 6·09) for nivolumab plus ipilimumab versus -3·14 (-6·03 to -0·25) for sunitinib (p<0·0001), and for FACT-G total score being 4·77 (1·73 to 7·82) for nivolumab plus ipilimumab versus -4·32 (-8·54 to -0·11) for sunitinib (p=0·0005). Significant differences were also seen for four of five FKSI-19 domains (disease-related symptoms, physical disease-related symptoms, treatment side-effects, and functional wellbeing) and FACT-G physical and functional wellbeing domains. However, there was no significant difference between the treatment groups at week 103 in EQ-5D-3L visual analogue rating scale (VAS) scores, with mean change from baseline to week 103 of 10·07 (95% CI 4·35 to 15·80) for nivolumab plus ipilimumab and 6·40 (-1·36 to 14·16) for sunitinib (p=0·45). Compared with sunitinib, nivolumab plus ipilimumab reduced risk of deterioration in FKSI-19 total score (hazard ratio [HR] 0·54; 95% CI 0·46-0·63), FACT-G total score (0·63, 0·52-0·75), and EQ-5D-3L VAS score (HR 0·75, 95% CI 0·63-0·89) and UK utility scores (0·67, 0·57-0·80).

Interpretation: Nivolumab plus ipilimumab leads to fewer symptoms and better HRQoL than sunitinib in patients at intermediate or poor risk with advanced renal cell carcinoma. These results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib comes with the additional benefit of improved HRQoL.

Funding: Bristol-Myers Squibb and ONO Pharmaceutical.

Figure 1:. Schedule of treatment and PRO assessments

Participants assigned to nivolumab plus ipilimumab were given nivolumab and ipilimumab once every 3 weeks for four doses over two cycles (induction phase), followed by nivolumab monotherapy for the remainder of treatment (maintenance phase). Participants assigned to sunitinib were given sunitinib once daily for 4 weeks on and 2 weeks off. Treatment was continued until disease progression or unacceptable toxicity. Follow-up visit one was 30 days (or within 7 days before or after this timepoint) from the last dose, or on the date of discontinuation (or within 7 days before or after this timepoint) if discontinuation was more than 37 days after the last dose. Follow-up visit two was 84 days (or within 7 days before or after this timepoint) after follow-up visit one. During follow-up, administration of EQ-5D-3L was additionally scheduled every 3 months for the first 12 months and every 6 months thereafter. PRO=patient-reported outcome. EQ-5D-3L=EuroQol five dimensional three level.

Figure 2:. Trial profile

PRO=patient-reported outcome.

Figure 3:. Mean change from baseline FKSI-19 total score (A), FACT-G total score (B), EQ-5D-3L VAS (C), and EQ-5D-3L UK utility index (D) in participants with intermediate or poor risk

Data points are least-squares mean change from baseline, and error bars are standard errors and are from mixed-model repeated measures analysis. Mean change from baseline figures for FKSI-19 and FACT-G individual domains are in the appendix (pp 10–11). The number of patients at each timepoint are those with a non-missing score with an evaluable questionnaire. EQ-5D-3L=EuroQoL five dimension three level. FKSI-19=functional assessment of cancer therapy-kidney symptom index-19. FACT-G=functional assessment of cancer therapy-general. VAS=visual analogue scale. *Significant difference between treatment groups (p<0.05). †Significant difference between treatment groups (p<0.001).

Figure 4:. Time to deterioration in total and domain scores for FKSI-19 (A) and FACT-G (B) instruments among participants with intermediate or poor risk in the CheckMate 214 trial

Data points are hazard ratios and error bars are 95% CIs. A clinically meaningful deterioration was defined as a decrease of at least one threshold unit compared with baseline; threshold values are in the appendix (p 7). FKSI-19=functional assessment of cancer therapy-kidney symptom index-19. DRS=disease-related symptoms. DRS-P=disease-related symptoms-physical. FWB=functional wellbeing. DRS-E=disease-related symptoms-emotional. NE=not estimable. TSE=treatment side-effects. FACT-G=functional assessment of cancer therapy-general. PWB=physical wellbeing. EWB=emotional wellbeing. NR=not reached. SWB=social and family wellbeing.

Figure 5:. Association between change in total and domain scores and overall and progression-free survival for FKSI-19 (A) and FACT-G (B) questionnaires among participants with intermediate or poor risk in the CheckMate 214 trial

Data are from Cox regression analysis. Hazard ratios correspond to a 1-point increment in FKSI-19 DRS-E, TSE, and FWB scores; a 3-point increment in the FKSI-19 total and DRS, and FACT-G PWB, FWB, EWB, and SWB scores; a 4-point increment in FKSI-19 DRS-E score; and a 7-point increment in FACT-G total score (appendix). FKSI-19=functional assessment of cancer therapy-kidney symptom index-19. DRS=disease-related symptoms. DRS-P=disease-related symptoms-physical. DRS-E=disease-related symptoms-emotional. TSE-treatment side-effects. FWB=functional wellbeing. FACT-G=functional assessment of cancer therapy-general. PWB=physical wellbeing. EWB=emotional wellbeing. SWB=social and family wellbeing.