Nivolumab/Ipilimumab Shows Superior QOL in Advanced RCC

David Cella, FASCO, PhD

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) led to superior quality of life (QOL) compared with sunitinib (Sutent) in the frontline setting of patients with advanced renal cell carcinoma (RCC), according to results of a 5-year analysis from the CheckMate 214 (NCT02231749) trial.¹

Furthermore, the benefit was observed across multiple definitions and subgroup population analyses, suggesting that the combination is linked with favorable long-term health-related QOL (HRQOL) outcomes. The data were presented during the 2022 Genitourinary Cancers Symposium.

When compared with sunitinib, nivolumab/ipilimumab was associated with least square (LS) mean longitudinal changes from baseline, a longer time to confirmed deterioration, and less bothersome adverse events (AEs). These findings were consistent across both the all-randomized and intermediate-/poor-risk populations.

“Nivolumab plus ipilimumab continued to demonstrate HRQOL benefits with extended follow-up vs sunitinib, with significant differences in scale scores between the treatment arms favoring nivolumab plus ipilimumab,” lead author David Cella, FASCO, PhD, of Robert H. Lurie Comprehensive Cancer Center, Northwestern University, and coinvestigators, wrote in a poster presentation of the findings.

The FDA approved nivolumab plus ipilimumab in April 2018 as a frontline treatment for intermediate- and poor-risk patients with RCC, based on earlier findings from the phase 3 CheckMate-214 trial.²

CheckMate-214 enrolled 1096 patients with previously untreated advanced clear cell RCC. Eligible participants needed a Karnofsky performance status of at least 70. Participants were randomized 1:1 to receive either 3 mg of nivolumab plus 1 mg of ipilimumab every 3 weeks for 4 cycles, followed by 3 mg of nivolumab every 2 weeks, or to receive oral sunitinib at 50 mg once daily for 6 cycles on a 4-weeks-on/2-weeks-off schedule.

Patients received treatment until progression or unacceptable toxicity. A 2017 amendment to the study design permitted patients receiving sunitinib to switch over to the nivolumab/ipilimumab cohort. The amendment also permitted discontinuation of any study treatment after 2 years.

At the 5-year follow-up, patients who received nivolumab/ipilimumab demonstrated favorable overall survival (OS) rates compared with those who received sunitinib in both the intermediate-/poor-risk subgroup (HR, 0.68; P <.0001) and in the intent-to-treat (ITT) group (HR, 0.72; P <.0001).

Also with the longer follow-up, the median duration of response was not reached (NR) among those receiving the combination compared with 19.7 months with sunitinib in the intermediate-/poor-risk subgroup (HR, 0.46; P < .0001) and NR and 24.8 months, respectively, in the ITT population (HR, 0.49; P < .0001).

To assess HRQOL, patients were administered 3 different patient-reported outcome (PRO) instruments: the Functional Assessment of Cancer Therapy–Kidney Symptom Index 19 (FACT-KSI19), the Functional Assessment of Cancer Therapy- General (FACT-G), and the 3-level version of the EuroQol-5 Dimension (EQ-5D-3L).

Assessment responses were collected at baseline, on day 1 of weeks 1 and 4 of the first 2 cycles, on day 1 of weeks 1 and 5 of the next 2 cycles, and on day 1 week 1 of all subsequent cycles.

Baseline characteristics were well-balanced between the 2 treatment arms. Across all populations, PRO completion rates were high at baseline (>90%) and remained as such throughout treatment (>75%).

FKSI-19 and FACT scores were initially comparable with the general US population at baseline, indicating that patients began treatment with relatively low symptom burden and good functioning scores. In comparison, although EQ-5D-3L indicated good health status, they were also lower than the general population they were compared against, which was the UK general population.

Longitudinal Changes in PRO scores

A mixed model for repeated measures (MMRM) was utilized to assess longitudinal changes in PRO scores spanning from baseline through week 235. Time was treated as a continuous variable.

In both the ITT and intermediate-/poor-risk populations, nivolumab/ipilimumab elicited superior overall changes from baseline to 59 months.

ITT Population

For FKSI-19 total scores, nivolumab/ipilimumab induced a 0.45 LS mean (LSMean) change compared with –2.53 with sunitinib (LSMean change difference, 2.98; 95% CI, 2.04-3.92) in the ITT population.

FKSI-19 Disease-Related Symptoms (DRS) scores showed a –0.17 and a –0.93 LSMean change with nivolumab/ipilimumab vs sunitinib, respectively (LSMean change difference, 0.76; 95% CI, 0.36-1.16). DRS-P LSMean changes were 0.13 vs –1.17 (LSMean change difference, 1.30; 95% CI, 0.73-1.87), and FWB changes were 0.01 vs –0.58 (LSMean change difference, 0.58; 95% CI, 0.29-0.88), respectively.

FACT total score changes were 0.76 with nivolumab/ipilimumab vs –2.29 with sunitinib (LSMean change difference, 3.05; 95% CI, 1.55-4.55). Psychological well-being (PWB) changes were –0.73 vs –2.28, respectively (LSMean change difference, 1.55; 95% CI, 1.11-1.99) and FWB changes were 0.04 and –0.93, respectively (LSMean change difference, 0.97; 95% CI, 0.38-1.57).

EQ-5D-3L VAS changes were 2.82 vs 0.39 with nivolumab/ipilimumab and sunitinib, respectively (LSMean change difference, 2.44; 95% CI, 0.42-4.46), and the UK Utility Index score changes were 0.01 vs –0.03 (LSMean change difference, 0.04; 95% CI, 0.03-0.06).

Intermediate-/Poor-Risk Population

In the intermediate-/poor-risk population, for FKSI-19 total scores, nivolumab/ipilimumab induced a 0.96 LSMean change compared with –2.43 with sunitinib (LSMean change difference, 3.39; 95% CI, 2.31-4.47). FKSI-19 DRS scores showed LSMean changes of –0.03 and–0.90 with nivolumab/ipilimumab and sunitinib, respectively (LSMean change difference, 0.87; 95% CI, 0.40-1.33). DRS-P LSMean changes were 0.40 vs –1.16, respectively (LSMean change difference, 1.56; 95% CI, 0.91-2.21), and FWB changes were 0.11 vs –0.58, respectively (LSMean change difference, 0.69; 95% CI, 0.35-1.03).

FACT total score changes were 1.12 with nivolumab/ipilimumab vs –2.07 with sunitinib (LSMean change difference, 3.19; 95% CI, 1.45-4.92). PWB changes were –0.69 vs –2.39, respectively (LSMean change difference, 1.71; 95% CI, 1.20-2.21) and FWB changes were 0.21 and –0.79, respectively (LSMean change difference, 1.00; 95% CI, 0.31-1.70).

EQ-5D-3L VAS changes were 2.92 vs –0.38, respectively (LSMean change difference, 3.29; 95% CI, 0.96-5.63), and the UK Utility Index score changes were 0.01 vs –0.04 (LSMean change difference, 0.05; 95% CI, 0.03-0.07).

Time to Event Analysis

The study defined confirmed deterioration as a first clinically meaningful deterioration in PRO score that was confirmed by additional deterioration at the subsequent visit or dropout, resulting in missing data. A prespecified threshold considered to be clinically meaningful in previous literature was used to define clinically meaningful deterioration. A stratified log-rank test and Cox regression model were used to analyze time to confirmed deterioration.

ITT Population

A longer time to deterioration was observed across all FKSI-19 scores across both populations, including the total score, where the median time was 16.2 months vs 5.13 months in the nivolumab/ipilimumab vs sunitinib arms, respectively (HR, 0.64; 95% CI, 0.54-0.76; P <.0001), in the ITT population.

Furthermore, time to confirmed deterioration in the DRS score was 17.74 months vs 7.95 months, in the nivolumab/ipilimumab vs sunitinib groups, respectively (HR, 0.74; 95% CI, 0.62-0.88; P = .0007). Median months for the DRS-P score were 23.36 months vs 7.33 months (HR, 0.64; 95% CI, 0.54-0.77; P <.0001), and functional well-being (FWB) was 15.70 months vs 8.61 months (HR, 0.77; 95% CI, 0.65-0.92; P = .0040).

Time to overall FACT-G confirmed deterioration in the ITT population was 23.10 months vs 10.02 months (HR, 0.74; 95% CI, 0.62-0.88; P = .0009). PWB deterioration was 15.80 months vs 3.98 months (HR, 0.57; 95% CI, 0.48-0.67; P <.0001). FWB length was 13.57 months vs 8.61 months (HR, 0.83; 95% CI, 0.69-0.98; P = .0307).

Time to confirmed EQ-5D-3L visual analogue scale (VAS) deterioration was 21.42 months vs 13.14 months (HR, 0.83; 95% CI, 0.70-0.98; P = .0266). EQ-5D-3L UK utility index time to deterioration was 23.85 months vs 10.51 months (HR, 0.73; 95% CI, 0.62-0.86; P = .0002).

Intermediate-/Poor-Risk Population

In the intermediate/poor risk population, the FKSI-19 total score time to deterioration was 17.87 months vs 5.26 in the nivolumab/ipilimumab group vs sunitinib group, respectively (HR, 0.62; 95% CI, 0.51-0.75; P <.0001). DRS score was 19.88 months vs 7.33 months in the nivolumab/ipilimumab and sunitinib groups, respectively (HR, 0.72; 95% CI, 0.59-0.88; P = .0010). The median DRS-P scores were 25.89 months vs 7.23 months (HR, 0.57; 95% CI, 0.46-0.70; P <.0001), and functional well-being (FWB) was 19.06 months vs 10.58 months (HR, 0.75; 95% CI, 0.61-0.93; P =.0071) for nivolumab/ipilimumab and sunitinib, respectively.

The time to overall FACT-G confirmed deterioration in the intermediate-/poor-risk group was 24.38 months with nivolumab/ipilimumab vs 10.58 months with sunitinib (HR, 0.72; 95% CI, 0.59-0.89; P =.0021). PWB deterioration was 15.80 months vs 4.11 months (HR, 0.54; 95% CI, 0.44-0.65; P <.0001). FWB length was 15.34 months vs 10.58 months (HR, 0.84; 95% CI, 0.69-1.02; P = .0827).

Time to confirmed EQ-5D-3L visual analogue scale (VAS) deterioration was 18.92 months vs 13.14 months with nivolumab/ipilimumab and sunitinib, respectively (HR, 0.85; 95% CI, 0.70-1.03; P =.0935). EQ-5D-3L UK utility index time to deterioration was 22.93 months vs 9.46 months (HR, 0.69; 95% CI, 0.57-0.83; P = .0001).

Bothersome AE Ratings

Treatment-related adverse events (AE) impact was also analyzed. Researchers used generalized estimating equations models to descriptively assess pain impact with the following ratings:

• Minimal bother (Not at all? Or a little bit?)
• Notable bother (Somewhat? Quite a bit? Very much?)

In all populations, the nivolumab/ipilimumab combination was associated with a decreased AE burden compared with sunitinib. Specifically, patients receiving the combo regimen in the ITT population were 76% less likely to experience a bothersome AE (odds ratio (OR), 0.24; 95% CI, 0.16-0.35) and those in the intermediate-/poor-risk population were 73% less likely (OR, 0.27; 95% CI, 0.18-0.40).

“Treatment with nivolumab plus ipilimumab was also associated with a decreased risk of being bothered by treatment side effects,” the study authors concluded. “These results suggest that the superior efficacy of nivolumab plus ipilimumab vs sunitinib with extended follow-up continues to come with the additional benefit of improved long-term HRQOL and reduced disease-related symptoms in patients with [advanced] RCC.”

References

1. Cella D, Choueiri TK, Hamilton M, et al. Health-related quality of life (HRQoL) in previously untreated patients with advanced renal cell carcinoma (aRCC) in CheckMate 214: five-year follow-up results. J. Clin. Oncol. 2022;40(suppl 6):307. doi:10.1200/JCO.2022.40.6_suppl.307
2. Albiges L, Tanniir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079