Nivolumab/Cabozantinib Combo Improves Patient-Reported Outcomes Over Sunitinib in RCC

David Cella, MD

The combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) was associated with improved quality of life (QoL) compared with sunitinib (Sutent) in patients with previously untreated advanced renal cell carcinoma, according to patient-reported outcome (PRO) data from the phase 3 CheckMate-9ER trial (NCT03141177) published in Lancet Oncology.¹

Results indicated that nivolumab/cabozantinib stabilized or improved patient symptoms whereas those who received sunitinib experienced a deterioration in their health status. These QoL data follow findings published in 2021, which had demonstrated that the combination doubled survival rate in this population vs sunitinib, the current standard of care.^2,3

“Historically in cancer, most new treatments that extend survival come at a cost,” David Cella, MD, study investigator and chair of the Department of Medical Social Sciences at Northwestern University Feinberg School of Medicine, stated in a press release. “In this study, we found that the combination is actually easier on patients, so it has the double benefit.”

The open-label, randomized, international phase 3 trial enrolled patients with previously untreated advanced renal cell carcinoma and a clear-cell component. Eligible patients needed to be at least 18 years of age, have measurable disease per RECIST v1.1 criteria, a Karnofsky performance status score of 70% or more, and available tumor tissue. Patients could have any International Metastatic RCC Database Consortium (IMDC) risk score.

Those with active central nervous system metastases, active autoimmune disease, conditions requiring systemic treatment with corticosteroids or immunosuppressive medications within 14 days of randomization, malignancy within the prior 3 years, tumors invading the superior vena cava, or select predefined gastrointestinal and vascular disorders, were excluded.

A total of 651 study participants with advanced RCC were randomized 1:1 to receive either nivolumab/cabozantinib (n = 323) or sunitinib (n = 328). Those in the investigative arm received intravenous nivolumab at 240 mg every 2 weeks plus oral cabozantinib at 40 mg daily. Those in the control arm were given oral sunitinib at a daily dose of 50 mg on a 4-weeks-on/2-weeks-off schedule. Treatment was continued until disease progression or unacceptable toxicity.

The primary end point of the trial was progression-free survival (PFS) via blinded independent central review (BICR) in the intention-to-treat population. Key secondary end points comprised overall survival (OS) and objective response rate (ORR) per BICR in the ITT population, and safety in those who received at least 1 dose of treatment on the study. PROs served as an exploratory end point for the research.

Investigators analyzed PROs in the ITT population at baseline and every 6 weeks until week 115. Disease symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the 3-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. Change from baseline was evaluated using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events.

The proportion of patients who completed PRO assessments proved to be comparable across the treatment arms. Those who completed the FKSI-19 and EQ-5D-3L instruments at baseline was high, at 93%, for both groups. The completion rate for both instruments remained at 75% or higher at most time points for the investigative group until week 103; then, the completion rate dropped to less than 65%. In the control group, the completion rate was 75% or higher at most time points until week 79, and then was noted to decrease thereafter.

Patients in both treatment groups had relatively low symptom burden at baseline; the population was also noted to have a baseline health status that was slightly lower than population norms, but higher than previously reported patient scores.

Data from a mixed-model repeated measures (MMRM) analysis showed that following an initial decline in most scores across the groups, nivolumab/cabozantinib was linked with scores that were either stable (FKSI-19 total score, FSKI-19 functional wellbeing, and EQ-5D-3L UK utility index) or improved (FKSI-19 disease-related symptoms version 1, FKSI-19 disease-related symptoms physical scale, and EQ-5D-3L VAS) over time (Table). Those in the sunitinib arm were noted to experience a decline from baseline in scores across all instruments.

However, none of the changes from baseline were found to have exceeded the predefined clinically meaningful threshold in any group with the exception of deterioration of EQ-5D-3L UK utility index values in the control group; this was clinically meaningful at many time points following week 55.

For FKSI-19 total score, FKSI-19 disease-related symptoms version 1, and EQ-5D-3L UK utility index, the overall difference in mean score change from baseline until week 115 was found to be nominally significant in favor of the combination vs the monotherapy. Data from a pattern-mixture model sensitivity analysis favored the combination, generally aligning with what had been reported in the MMRM analysis.

Those in the combination group experienced a longer median time to first deterioration in FKSI-19 total score than those in the monotherapy group, at 6.24 months (95% CI, 4.34-8.34) vs 3.48 (95% CI, 2.86-4.21), respectively (HR, 0.70; 95% CI, 0.56-0.86; P = .0007). The median time to confirmed deterioration was 19.38 months (95% CI, 12.48–not estimable) vs 6.97 months (95% CI, 4.50-10.09), respectively (HR, 0.63; 95% CI, 0.50-0.80; P = .0001). The combination also resulted in a significant reduction in the risk of first and confirmed deterioration in all other FKSI-19 scores compared with sunitinib.

Previously, in January 2021, the FDA approved nivolumab plus cabozantinib for the frontline treatment of patients with advanced RCC based on data from CheckMate-9ER, which indicated that the doublet resulted in a 49% reduction in the risk of disease progression or death, significantly improved OS, and doubled the ORR compared with sunitinib in this population.⁵

At a median follow-up of 18.1 months, the median PFS was 16.6 months with nivolumab plus cabozantinib vs 8.3 months with sunitinib (HR, 0.51; 95% CI, 0.41-0.64; P <.0001).

CheckMate-9ER data presented during the 2020 ESMO Virtual Congress showed that the doublet induced activity across several subgroups evaluated, spanning age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.³

The median OS had not yet been reached in either treatment arm, translating to a 40% reduction in the risk of death with the investigational doublet (HR, 0.60; 95% CI, 0.40-0.89; P = .0010). The ORRs in the investigative and control arms were 55.7% and 27.1%, respectively (P < .0001).

The doublet also demonstrated a favorable safety profile. Any-grade and high-grade treatment-related adverse effects (TRAEs) were comparable between the arms. More than half of the participants who received the doublet required dose reductions of cabozantinib due to AEs.

Moreover, 15.3% of patients who were given cabozantinib/nivolumab reported TRAEs that resulted in treatment discontinuation vs 8.8% of those who were administered sunitinib. Specifically, 3.1% of patients discontinued both nivolumab and cabozantinib because of toxicities, 5.6% discontinued nivolumab only, and 6.6% discontinued cabozantinib only.

The rate of serious AEs was also similar between the arms, although liver toxicity was found to be more commonly experienced by those who received the combination. Nineteen percent of participants in the investigative arm required corticosteroids because of immune-associated toxicities; 4% of these patients needed to receive corticosteroids for at least 30 days.

“Immune therapy is revolutionizing the treatment of advanced kidney cancer,” Cella, who is the associate director for cancer prevention and control research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, added in the release. “For the first time in decades, we are seeing benefits to both survival and quality of life with these new treatments. People with kidney cancer have more effective treatment options than ever before. Not only are they living longer, [but] they are living better.”

References

1. Cella D, Motzer RJ, Suarez C, et al. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol. Published online January 12, 2022. doi:10.1016/S1470-2045(21)00693-8
2. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. News release. FDA; January 22, 2021. Accessed January 20, 2022. http://bit.ly/2Mjrt1i
3. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982
4. In cancer treatment, quality of life matters more and more: study found fewer side effects from new, more effective chemotherapy. News release. Northwestern University; January 13, 2022. Accessed January 25, 2022. https://bit.ly/3IJ9yt9
5. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. News release. FDA; January 22, 2021. Accessed January 25, 2022. http://bit.ly/2Mjrt1i