Nivolumab/Cabozantinib Shows More Sustainable Health-Related QOL in Frontline RCC

Nivolumab (Opdivo) plus cabozantinib (Cabometyx) was associated with more sustainable health-related quality of life (HRQOL) compared with sunitinib (Sutent) in patients with advanced renal cell carcinoma, according to longer follow-up of the CheckMate 9ER trial (NCT03141177).¹

In the 32.9-month follow-up, PRO scores revealed that patients receiving nivolumab/cabozantinib had maintained or improved HRQOL compared with patients in the sunitinib arm. The longitudinal changes from baseline consequently showed statistical significance (P < .05) in favor of the experimental regimen for all scores except for FKSI-19 functional well-being (FWB).

The findings, which were presented during the 2022 Genitourinary Cancers Symposium, demonstrated that this benefit was derived across multiple definitions of deterioration.

In the 151 weeks following baseline, patients receiving nivolumab/cabozantinib experienced a –0.47 least square (LS) mean change from baseline FKSI-19 total score compared with a –2.84 decline with those in the sunitinib arm (overall difference in mean change, 2.37; P < .0001). For the FKSI-19 DRS score, patients receiving nivolumab/cabozantinib experienced an LS mean change from baseline of 0.71 compared with –0.46 in the sunitinib arm (1.17; P <.0001).

Similarly, patients receiving nivolumab/cabozantinib experienced an EQ-5D-3L health status score of 2.73 compared with –0.95 in the sunitinib group (3.68; P = .0001). The EQ-5D-3L UK utility index score demonstrated that patients receiving nivolumab/cabozantinib experienced an LS mean change from baseline of –0.01 compared with –0.06 in the sunitinib arm (0.05; P = .001)

At baseline, both arms demonstrated a high PRO completion rate of at least 90%. By week 151, the rates were over 75% and 73% in the nivolumab plus cabozantinib and sunitinib arms, respectively. At baseline, both arms demonstrated relatively low symptom burden.

“At nearly 3 years of follow-up, patients continued to report improved HRQOL with nivolumab/cabozantinib compared with sunitinib,” David Cella, FASCO, PhD, of Robert H. Lurie Comprehensive Cancer Center, Northwestern University, and coinvestigators, wrote in a poster presentation of the findings. “Treatment with [nivolumab/cabozantinib] was observed to reduce the risk of clinically meaningful deterioration in HRQOL scores in comparison with sunitinib, regardless of definition of deterioration.”

The CheckMate 9ER trial enrolled 651 patients with advanced RCC who were randomized 1:1 to receive either intravenous nivolumab at a dosage of 240-mg intravenously every 2 weeks plus oral cabozantinib at 40-mg daily or 50 mg of oral sunitinib in 4-weeks-on/2-weeks-off cycles. Treatment continued until either disease progression or unacceptable toxicity occurred.

Patients could not have received nivolumab beyond 2 years from cycle 1; however, they were able to receive cabozantinib and sunitinib beyond 2 years, provided no disease progression or unacceptable toxicity occurred. If the investigator determined there may be benefit, patients could continue treatment beyond progression as well.

At an initial follow-up of 18.1 months, nivolumab/cabozantinib was associated with improved progression-free survival (HR, 0.51; 95% CI, 0.41-0.64; P < .001) and overall survival (HR, 0.60; 95% CI, 0.40-0.89; P = .001) than sunitinib.²

In this long-term analysis, FKSI-19 instruments were used to evaluate disease-related symptoms (DRS) while the EQ-5D-3L visual analogue scale (VAS) was utilized to assess HRQOL.

FKSI-19 and EQ-5D-3L were administered at baseline, at the beginning of each treatment cycle (every 2 weeks for nivolumab/cabozantinib and every 6 weeks for sunitinib), and during the 2 subsequent follow-up visits (30 and 100 days from last dose). The EQ-5D-3L were also administered every 3 months during survival follow-up. Of note, although PRO instruments were more frequently administered to the nivolumab/cabozantinib arm, the current analysis only included assessment time points that were concurrent in both treatment arms.

Investigators noted longitudinal changes from baseline that were assessed these changes via a mixed-model repeated measures (MMRM), which adjusted for baseline scores and stratification factors, and measured common timepoints every 6 weeks for 151 weeks. Kaplan-Meier estimates and Cox proportional hazards models were used to conduct time to first deterioration (TTFD), confirmed deterioration (TTCD), and definitive deterioration (TTDD) analysis.

Time to Event Analysis

In this analysis, TTFD was defined as the duration from baseline to the date of the first clinically meaningful deterioration in PRO scores. TTCD was defined as the duration from the date of randomization to the date of first clinically meaningful observed deterioration in PRO scores, provided that the deterioration was also confirmed at the next scheduled visit common for both arms or followed by death or dropout.

TTDD was defined as the duration of time from the date of randomization to the date of first clinically meaningful observed deterioration in PRO scores, provided that this deterioration was observed at all following check-ins or if the patient subsequently dropped out or died.

Treatment with nivolumab/cabozantinib induced significantly reduced TTFD in FKSI-19 score (HR, 0.71; 95% CI, 0.57-0.87; P = .0011), DRS score (HR, 0.70; 95% CI, 0.56-0.87; P = .0017), DRS-P score (HR, 0.73; 95% CI, 0.59-0.91; P = .0050), and FWB score (HR, 0.69; 95% CI, 0.54-0.87; P = .0019).

This benefit was also observed TTCD in the same scores with FKSI-19 (HR, 0.66; 95% CI, 0.52-0.84; P = .0005), DRS (HR, 0.65; 95% CI, 0.50-0.86; P = .0020), DRS-P (HR, 0.56; 95% CI, 0.43-0.73; P <.0001), and FWB (HR, 0.67; 95% CI, 0.50-.088; P = .0045).

Similarly, nivolumab/cabozantinib significantly reduced the risk of TTDD compared with sunitinib in FKSI-19 total (HR, 0.68; 95% CI, 0.52-0.90; P = .0070), DRS (HR, 0.53; 95% CI, 0.37-0.75; P = .0003), and DRS-P scores (HR, 0.52; 95% CI, 0.38-0.72; P <.0001). The HR for the FWB was 0.79 (95% CI, 0.37-0.75; P = .0003).

Finally, nivolumab/cabozantinib was also linked to significantly reduced deterioration in EQ-5D-3L VAS compared with sunitinib across TTFD (HR, 0.74; 95% CI, 0.59-0.92; P = .0071), TTCD (HR, 0.74; 95% CI, 0.58-0.95; P = .0183), and TTDD (HR, 0.64; 95% CI, 0.48-0.86; P = .0026).

Bothersome AE Ratings

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

Treatment-related adverse events (AE) impact were 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?) or notable bother (Somewhat? Quite a bit? Very much?)

This questioning method is associated with clinician-rated AE measurement and is supported as a valid form of measuring treatment-related toxicity, the study authors noted. Furthermore, this system was recommended in the latest draft of the FDA oncology guidance.

Overall, patients receiving nivolumab/cabozantinib experienced less bothersome adverse effects (AEs) compared with those receiving sunitinib. Findings from a weighted generalized estimating equations revealed that patients in the experimental group were 48% less likely to report bothersome AEs compared with the control group (odds ratio, 0.52; 95% CI, 0.35-0.77).

“Patients treated with [nivolumab/cabozantinib] showed decreased odds of being notably bothered by treatment side effects in contrast to sunitinib,” the authors concluded. “Along with the previously reported superior efficacy of [nivolumab/cabozantinib] versus sunitinib, the results show that the additional benefit of improved HRQOL with [nivolumab/cabozantinib] over sunitinib is maintained with longer follow-up.”

_References

_{Cella D, Motzer RJ, Blum S, et al. Health-related quality of life (HRQoL) in previously untreated patients with advanced renal cell carcinoma (aRCC): CheckMate 9ER updated results. J Clin Oncol. 2022;40(suppl 6; abstr 323). doi:10.1200/JCO.2022.40.6_suppl.323}

_{Shah AY, Motzer RJ, Apolo AB, et al. Cabozantinib exposure-response analysis for the phase 3 CheckMate 9ER trial of nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell carcinoma. J Clin Oncol. 2021;39(suppl 15):4561. doi:10.1200/JCO.2021.39.15_suppl.4561}