Indian Journal of Urology
UROSCAN
Year
: 2022  |  Volume : 38  |  Issue : 4  |  Page : 317--318

Long-term follow-up results of nivolumab plus cabozantinib versus sunitinib for advanced renal cell cancer: Checkmate 9ER trial


Vivek Tarigopula 
 Department of Urology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India

Correspondence Address:
Vivek Tarigopula
Department of Urology, All India Institute of Medical Sciences, Bhubaneswar, Odisha
India




How to cite this article:
Tarigopula V. Long-term follow-up results of nivolumab plus cabozantinib versus sunitinib for advanced renal cell cancer: Checkmate 9ER trial.Indian J Urol 2022;38:317-318


How to cite this URL:
Tarigopula V. Long-term follow-up results of nivolumab plus cabozantinib versus sunitinib for advanced renal cell cancer: Checkmate 9ER trial. Indian J Urol [serial online] 2022 [cited 2023 Jan 30 ];38:317-318
Available from: https://www.indianjurol.com/text.asp?2022/38/4/317/357723


Full Text



 Summary



The CheckMate 9ER is an open-labeled, phase-3 randomized controlled trial conducted in 125 hospitals across 18 countries. They studied the efficacy, safety and tolerability of nivolumab plus cabozantinib vs sunitinib in advanced renal cell cancer (RCC).[1] The investigators randomly assigned 651 patients with advanced clear-cell RCC, i.e., both inoperable and metastatic disease to either receive nivolumab (240 mg intravenously every 2 weeks) plus cabozantinib (40 mg orally daily) combination therapy or sunitinib (50 mg orally daily for 4 weeks, followed by 2 weeks off) alone as the first-line therapy. Patients with active brain metastasis or systemic diseases requiring immunosuppressive medications were excluded from the study. Progression-free survival (PFS) was the primary endpoint, while overall survival (OS), objective response according to RECIST 1.1, safety, and tolerability were the secondary endpoints. Multiple exploratory endpoints including quality of life, planned subgroup analysis, and post-hoc analysis for various parameters was done.

This trial concluded that combination therapy with nivolumab and cabozantinib had better PFS (16.6 months vs. 8.3 months, HR 0.56) and OS (37.7 months vs. 34.3 months, HR 0.70). The combination therapy also had a better clinical response (complete response in 12% vs. 5%; partial response in 43% vs. 23%), a quicker median time to response (2.8 vs. 4.2 months) as well as a longer duration of response (23.1 vs. 15.2 months). However, treatment-related adverse events causing discontinuation of the therapy (27% vs. 10%) as well as the overall incidence of grade 3–4 adverse events (65% vs. 54%) were higher in the combination therapy arm. Diarrhea, deranged liver function, and pruritus occurred more commonly with the combination therapy, while thrombocytopenia and neutropenia occurred more frequently with sunitinib. Exploratory subgroup analysis showed better OS in patients with previous nephrectomy, sarcomatoid differentiation, liver, lung, or bone metastasis at the time of recruitment with combination therapy as opposed to sunitinib.

 Comments



The advent of immunotherapy has caused a change in the management of advanced RCC. The combination of various immunotherapy agents with tyrosine kinase inhibitors has shown better outcomes when compared to previously available options. Based on the preliminary results of better PFS, combination therapy with nivolumab and cabozantinib has been recommended as a first-line therapy option for metastatic RCC irrespective of the risk stratification.[2] Other available first-line options are nivolumab plus ipilimumab, pembrolizumab plus lenvatinib, and pembrolizumab plus axitinib. The current study provides long-term results and final OS data. Even though the PFS advantage of almost double duration has remained, the final OS analysis translated to additional advantage of 3.4 months. The study initially recruited 50 patients in the third arm of triplet therapy with nivolumab plus ipilimumab plus cabozantinib but amended the protocol to a two-arm design after favorable results of nivolumab plus ipilimumab from CheckMate 214 Trial.[3] Even though survival and response outcomes favor combination therapy, it comes at the expense of an overall trend of higher incidence of side effects. However, health-related quality of life assessment showed better quality of life with combination therapy and decreased risk of being bothered by adverse events.[4]

Lack of masking is a limitation in this study. However, this may be impossible as dosage schedules, route of administration, and management of treatment-related adverse events are different for the three drugs. The subgroup analysis based on the organ site involved might not be truly representative as most patients had multiple organ site involvement. The trial was funded by a pharmaceutical company.

Comparison of the benefit of one combination therapy with another is not possible with the available literature currently as there are differences in baseline characteristics of patients recruited in various trials. The role of nivolumab plus cabozantinib combination therapy in other histological variants of RCC and as a second-line therapy option is being investigated currently.[5]

The trial establishes nivolumab plus cabozantinib as a potent primary option for advanced RCC patients. However, availability, cost analysis, and applicability outside a clinical trial setting when compared to other combination therapy options need to be analyzed. Drug availability outside the setting of a clinical trial and affordability in the Indian scenario need to be explored further. The improved OS advantage of 3.4 months is weighed against the increased incidence of adverse events and costs.

Financial support and sponsorship: Nil.

Conflicts of interest: There are no conflicts of interest.

References

1Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): Long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol 2022;23:888-98.
2Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2021;384:829-41.
3Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277-90.
4Cella D, Motzer RJ, Suarez C, Blum SI, Ejzykowicz F, Hamilton M, 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 2022;23:292-303.
5Lee CH, Voss MH, Carlo MI, Chen YB, Zucker M, Knezevic A, et al. Phase II trial of cabozantinib plus nivolumab in patients with non-clear-cell renal cell carcinoma and genomic correlates. J Clin Oncol 2022;40:2333-41.