First-Line Nivolumab–Cabozantinib Boosts Advanced RCC Outcomes

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The CheckMate 9ER trial findings support the use of first-line nivolumab plus cabozantinib instead of sunitinib for patients with advanced clear cell renal cell carcinoma (RCC). 

The investigators report “significant benefits” in progression-free survival (PFS), overall survival (OS) and objective response rate achieved with the combination regimen compared with monotherapy, albeit with “substantial toxic effects”. 

After a median 18.1 months of follow-up, median PFS was 16.6 months for the 323 patients who were randomly assigned to receive nivolumab 240 mg every 2 weeks plus cabozantinib 40 mg/day compared with 8.3 months for the 328 patients given sunitinib 50 mg/day for 4 weeks out of each 6-week cycle. 

This gave a significant hazard ratio (HR) for progression or death of 0.51 in favour of nivolumab plus cabozantinib, say Toni Choueiri, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-authors in The New England Journal of Medicine. 

The median OS duration was not reached in either group, but the 12-month probability of OS was 85.7% with nivolumab plus cabozantinib and 75.6% with sunitinib, giving a significant HR for death of 0.60, again in favour of the combination. 

In addition, 55.7% of patients in the combination arm achieved an objective response compared with just 27.1% of sunitinib-treated patients, a significant difference. Complete responses were also more common with nivolumab plus cabozantinib than sunitinib (8.0 vs 4.6%) and median duration of response was almost twice as long (20.2 vs 11.5 months). 

The investigators say that the benefits reported for nivolumab plus cabozantinib versus sunitinib were “generally consistent” across subgroups of patients based on age, sex, region, IMDC prognostic risk score, PD-L1 expression, performance status, the presence of bone metastases and receipt of prior nephrectomy.  

Patients took nivolumab plus cabozantinib for a median of 14.3 months versus 9.2 months with sunitinib. Nivolumab, cabozantinib and sunitinib dose delays were required by 71.9%, 68.1% and 51.9% of patients, respectively, with reductions in cabozantinib and sunitinib reported for 56.3% and 51.6% of patients, respectively. 

Discontinuation of nivolumab, cabozantinib or both agents occurred in 6.6%, 7.5% and 5.6% of patients, respectively, giving an overall discontinuation rate of 19.7% compared with 16.9% among patients using sunitinib.  

Grade 3 and more severe treatment-related adverse events occurred in 60.6% of the combination arm and 50.9% of the monotherapy arm. Nivolumab plus cabozantinib was associated with grade 3–4 alanine aminotransferase elevations in 9.8% of patients and aspartate aminotransferase elevations in 7.9%, whereas these events occurred in 3.5% and 2.6% of sunitinib-treated patients, respectively. These events resolved to grade 0–1 in 82.9% of the combination arm and 66.7% of the sunitinib arm. 

A fatal small intestine perforation was attributed to nivolumab plus cabozantinib therapy, as was one case each of pneumonia and respiratory distress to sunitinib. 

“[N]evertheless, quality of life was maintained at a high level” with cabozantinib plus nivolumab over the 91 weeks of follow-up using the Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI-19), report Toni Choueiri and co-authors, whereas “a consistent deterioration” was reported for the sunitinib-treated patients. 

And while disease-related symptoms, measured on the FKSI-19 subscale, improved with treatment in the combination arm, patients given sunitinib had a decline in this measure from week 7 onwards, they say. 

“With improved treatment options, more patients are surviving substantially longer, and many receive treatment for an extended period of time”, the investigators remark.

“Therefore, overall efficacy, safety, and quality-of-life benefits as well as individual patient characteristics are important considerations when selecting appropriate therapy.” 

Reference 

Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2021;384:829–841. DOI: 10.1056/NEJMoa2026982