Continued survival and quality of life benefit of cabozantinib-nivolumab over sunitinib as first-line treatment of advanced clear-cell renal cell carcinoma

Updated results from CheckMate 9ER provide additional clinical support for the use of cabozantinib plus nivolumab as first-line treatment for patients with advanced renal cell carcinoma (RCC), showing a confirmed superiority over sunitinib in terms of progression free and overall survival. In addition, the combination regimen also induced a higher response rate than sunitinib, with a markedly higher incidence of complete treatment responses. In a second CheckMate 9ER analysis, cabozantinib plus nivolumab also continued to show clinically meaningful benefits over sunitinib with respect to health-related quality of life (HRQoL).

Over the last years, combination therapies based on the use of immune checkpoint inhibitors (ICIs) and receptor tyrosine kinase inhibitors (TKIs) have dramatically changed the first line treatment landscape of patients with metastatic RCC. In the phase III CheckMate 9ER trial, the combination of nivolumab and cabozantinib already proved to be associated with a significantly longer progression-free (PFS) and overall survival (OS) compared to sunitinib in the first line treatment of patients with advanced or metastatic clear-cell RCC. During ASCO GU 2022 updated results of this trial were presented with a median follow-up for OS of 32.9 months, which is nearly twice as long as the follow-up in the primary analysis.¹ In addition, a second CheckMate 9ER related presentation provided updated results with respect to health-related quality of life (HRQoL).²

Study design

CheckMate 9ER is an open-label, randomized, phase III trial including 651 patients with previously untreated advanced or metastatic RCC and a clear-cell component. Patients in the trial were randomly assigned (1:1) to receive nivolumab (240 mg every 2 weeks) plus cabozantinib (40mg once daily) or sunitinib (50 mg once daily, 4 weeks on 2 weeks off). The primary endpoint of the study was PFS, with OS and objective response rate (ORR) as key secondary objectives.^1,2

Results

After a median follow-up of 32.9 months (minimum follow-up: 25.4 months), the combination of nivolumab and cabozantinib continued to show superiority over sunitinib in terms of OS with a hazard ratio of 0.70 (95%CI: 0.55-0.90). The median OS obtained with the cabozantinib-nivolumab combination reached 37.7 months as compared to 34.3 months with sunitinib. The updated results also confirmed the PFS benefit of cabozantinib-nivolumab over sunitinib with a median PFS of 16.6 and 8.3 months respectively (HR[95%CI]: 0.56[0.46-0.68]). In total, 55.7% of patients treated with the cabozantinib-nivolumab combination achieved an ORR while this was only the case for 28.4% of patients in the sunitinib arm. Importantly, also the rate of complete responses (CR) was markedly higher for patients treated with cabozantinib-nivolumab compared to sunitinib at 12.4% and 5.2%, respectively. Moreover, responses to cabozantinib-nivolumab occurred more rapidly compared to sunitinib and proved to be more durable (median time to response: 2.8 vs. 42 months; median duration of response: 23.1 vs. 15.1 months). In an exploratory analysis looking at the depth of response in target lesions by organ site, a higher percentage of patients experienced tumor shrinkage benefits with the cabozantinib-nivolumab combination than with sunitinib across all organ sites (kidney, liver, lung, lymph node and bone). No new safety signals emerged with the extended follow-up.¹

In a separate analysis with a median follow-up of 32.9 months, patients treated with cabozantinib-nivolumab in the CheckMate 9ER trial continued to report clinically meaningful HRQoL benefits compared to sunitinib-treated patients. These exploratory outcomes were measured using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) which assessed quality of life (QoL) associated specifically to kidney cancer as well as EQ-5D-3L instruments which assessed QoL more generally. HRQoL scores from these instruments were found to be improved or maintained over time amongst patients treated with the combination, while reductions in scores were observed with sunitinib. Moreover, patients treated with the combination regimen were also 48% less likely to be notably bothered by treatment side effects than patients in the sunitinib arm.²

Conclusions

Updated results from CheckMate 9ER provide additional clinical support for the use of cabozantinib plus nivolumab as an important first-line treatment option in patients with advanced RCC, with a confirmed superiority over sunitinib in terms of PFS, OS, ORR, and CR rate. Moreover, responses to the combination occurred more rapidly and were more durable than with sunitinib. With this extended follow-up no new safety signals were reported, while an updated analysis assessing QoL continued to show clinically meaningful benefits for the cabozantinib-nivolumab combination.

References

1. Powles T. et al. Final overall survival analysis and organ-specific target lesion assessments with 2-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. Presented at ASCO GU 2022; Abstract 350.
2. Cella D. et al. Health-related quality of life (HRQoL) in previously untreated patients with advanced renal cell carcinoma (aRCC): CheckMate 9ER updated results. Presented at ASCO GU 2022; Abstract 323.