Nivolumab/Cabozantinib Combo Shows Lasting OS Benefit for RCC in Final Analysis

In a final overall survival (OS) analysis of CheckMate 9ER (NCT03141177), investigators saw a continued survival benefit with first-line nivolumab (Opdivo) plus cabozantinib (Cabometyx) compared with sunitinib (Sutent) in the intention-to-treat (ITT) patients with untreated clear cell metastatic or advanced renal cell carcinoma (RCC).¹

Thomas Powles, MD, PhD, professor of genitourinary oncology and director of Barts Cancer Centre at St. Bartholomew's Hospital, discussed the updated findings at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium.

Furthermore, the combination demonstrated sustained progression-free survival (PFS) and objective response rate (ORR) benefit at a minimum of 2 years of follow-up. More patients receiving nivolumab/cabozantinib had tumor shrinkage benefit than those receiving sunitinib across the 4 organ types accessed on the trial as well.

“With this extended median follow-up of 33 months, nivolumab/cabozantinib provided improved survival versus sunitinib in the final OS analysis,” Powles said in his presentation. “With nivolumab/cabozantinib versus sunitinib, median PFS, ORR, and complete response rates were approximately double.”

The original results of the open-label, randomized phase 3 CheckMate 9ER trial showed superiority with first-line nivolumab/cabozantinib versus sunitinib, with 10.6 months of minimum follow-up.² Patients with treatment-naïve clear cell RCC were assigned 1:1 to nivolumab/cabozantinib (n = 323) at 240 mg every 2 weeks and 40 mg once daily, respectively, versus sunitinib (n = 328) at 50 mg once daily for 4 weeks of each 6-week cycle.

The primary end point was PFS by blinded independent central review (BICR) in the ITT population, and secondary end points included OS, ORR, and safety. There was a preplanned final OS analysis planned when 254 event were observed. Post hoc exploratory analyses included maximal reduction of target lung, lymph node, kidney, and liver lesions evaluated per BICR.

After 32.9 months median follow-up (range, 25.4-45.4), the hazard ratio for nivolumab/cabozantinib versus sunitinib was 0.70 (95% CI, 0.55-0.90).¹ Nivolumab/cabozantinib showed a median OS of 37.7 months (95% CI, 35.5-not evaluable [NE]) compared with 34.3 months (95% CI, 29.0-NE) for sunitinib.

The median PFS for those receiving nivolumab/cabozantinib was also improved versus sunitinib, at 16.6 months (95% CI, 12.8-19.8) and 8.3 months (95% CI, 7.0-9.7), respectively (HR, 0.56; 95% CI, 0.46-0.68).

Additionally, patients given nivolumab/cabozantinib achieved a confirmed ORR of 55.7% (95% CI, 50.1%-61.2%) compared with 28.4% (95% CI, 23.5%-33.6%) for those given sunitinib. Complete response rates were almost doubled with nivolumab/cabozantinib versus sunitinib, at 12.4% and 5.2%, respectively. The median time to response was shorter (2.8 months vs 4.2 months) and median duration of response was longer (23.1 months vs 15.1 months) for 180 patients who responded on the nivolumab/cabozantinib arm than the 93 who responded on the sunitinib arm.

Even though there were similar median diameters of target lesions at baseline between nivolumab/cabozantinib and sunitinib, the exploratory post hoc analysis showed a higher proportion of patients who experienced reductions in target lesions with nivolumab/cabozantinib. In bone (55.6% vs 20.0%, respectively), lymph node (74.4% vs 47.8%), lung (75.9% vs 46.4%), liver (47.7% vs 33.3%), and kidney (45.2% vs 29.7%) target lesions, a reduction of 30% or more was observed.

Ninety-two patients (28.8%) receiving nivolumab/cabozantinib remained on therapy compared with 46 patients (14.4%) receiving sunitinib. The median duration of therapy was 21.8 months (range, 0.2-42.0) versus 8.9 months (range, 0.5-41.4), respectively.

No new safety signals were observed in with longer follow-up. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 65.0% of those on the nivolumab/cabozantinib arm and 54.1% on the sunitinib arm. The most common grade 3 TRAEs occurring in 20% or more of all treated patients included hypertension, palmar-plantar erythrodysethesia, and diarrhea. TRAEs led to discontinuation of nivolumab, cabozantinib, or both in 27.2% of patients, and discontinuation of sunitinib 10.3% of patients. Since the original data cutoff, only 1 additional death related to treatment was observed with sunitinib, and none with nivolumab/cabozantinib.

“These results continue to support the use of nivolumab/cabozantinib as a first-line treatment option for patients with advanced RCC,” Powles concluded.

_References:

_{1. Thomas P, Toni KC, Mauricio B, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: Nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl 6):350. doi:10.1200/JCO.2022.40.6_suppl.350}

_{2. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982}