Depth of Response With Cabozantinib/Nivolumab Linked to Prolonged Survival Benefit in Advanced, Untreated RCC

Greater depth of response was associated with prolonged progression-free survival (PFS) and overall survival (OS) with cabozantinib (Cabometyx) plus nivolumab (Opdivo) in patients with advanced renal cell carcinoma (RCC), with complete or partial responders who achieved a tumor reduction of at least 60% experiencing the most durable responses and survival benefits, according to results from an exploratory analysis of the CheckMate 9ER study (NCT03141177).¹ These data were presented at the 2026 Genitourinary Cancers Symposium.

At a median follow-up of 67.6 months (range, 60.2-80.2), the median duration of response (DOR) was not reached (NR; 95% CI, 30.5-not evaluable [NE]) among patients who achieved a complete response (CR; n = 45), and was 6.6 months (95% CI, 4.3-8.5) for those who achieved stable disease (SD; n = 98). In the 3 partial response (PR1; PR2; PR3) subgroups, the median DOR was 22.1 months (95% CI, 15.1-26.0), 21.7 months (95% CI, 14.1-30.4), and 10.8 months (95% CI, 7.0-17.3), respectively. Across all depth of response subgroups, the median time to response (TTR) ranged from 2.8 to 2.9 months.

Following the discontinuation of cabozantinib plus nivolumab, patients with a best overall response (BOR) of CR or PR2 maintained durable responses. The median DOR for those who discontinued treatment in the CR (n = 23/45), PR1 (n = 8/27), PR2 (n = 10/38) and PR3 (n = 16/70) subgroups was NR (95% CI, 24.2 months-NE), 18.4 months (95% CI, 0.2-NE), NR (95% CI, 0.3-NE), and 2.3 months (95% CI, 2.1-3.5).

Furthermore, PFS and OS rates indicated the durability of clinical benefit in responders. The 4-year PFS rates were 54.4%, 23.8%, 12.0%, 3.7%, and 3.0% in the CR, PR1, PR2, PR3, and SD subgroups. OS rates at 4 years in these respective groups were 84.3%, 67.4%, 55.6%, 41.6%, 29.2%, and 20.0%.

“In patients with [advanced] RCC, early, deep, and durable responses continue to be seen with cabozantinib plus nivolumab in long-term follow-up of the CheckMate 9ER trial,” Cristina Suárez, MD, PhD, and colleagues wrote in a poster presentation of the data. “Patients with a [CR] exhibited durable responses…and a subset of patients continued to exhibit durable responses following discontinuation…”

Suárez is a medical oncologist and clinical investigator with a special focus on kidney and bladder cancer within the Genitourinary, Central Nervous System tumours, Sarcoma and Cancer of Unknown Primary Site Group, at Vall d’Hebron University Hospital, in Barcelona, Spain.

What prior data provided the rationale for evaluating the relationship between depth of response and outcomes with cabozantinib/nivolumab?

Primary results from CheckMate 9ER helped establish cabozantinib plus nivolumab as the standard of care (SOC) for first-line advanced RCC. In the final analysis, at a median follow-up of 67.6 months (range, 60.2-80.2), the updated PFS in the intention-to-treat population was 16.4 months (95% CI, 12.5-19.3) with the combination and 8.3 months (95% CI, 7.0-9.7) with sunitinib (HR, 0.58; 95% CI, 0.49-0.70).² The median OS was 46.5 months (95% CI, 40.6-53.8) in the cabozantinib arm and 35.5 months (95% CI, 29.2-42.8) in the sunitinib arm (HR, 0.79; 95% CI, 0.65-0.96).

In a prior exploratory post hoc analysis of CheckMate 9ER, a greater proportion of patients in the nivolumab and cabozantinib arm achieved deep responses vs those in the sunitinib arm, at a median follow-up of 32.9 months.³ However, CR or PR1 responses generally correlated with improved PFS and OS regardless of treatment arm, suggesting that depth of response could serve as an indicator for durable efficacy and improved prognosis.

Based on these data, investigators conducted an updated analysis of the relationship between depth of response and efficacy outcomes with cabozantinib plus nivolumab in this trial.¹

What was the design of this exploratory analysis, and what should be known about the patient population included?

The open-label, randomized, phase 3 trial compared outcomes with cabozantinib plus nivolumab vs sunitinib in 651 patients with previously untreated advanced RCC who had a clear cell component and were in any International Metastatic RCC Database Consortium (IMDC) risk group.^1,2

The current analysis comprised patients in the cabozantinib plus nivolumab arm who had available data for BOR per blinded independent central review (BICR) and were alive 6 months after randomization.¹ Partial responders were also required to have data on the sum of diameters of target lesions.

Of the 323 patients who received the experimental regimen, 293 were alive and 234 were alive and progression free at 6 months. These patients were categorized into the following depth of response subgroups according to BOR per BICR:

• CR (n = 45 complete responders alive at 6 months; n = 45 alive and progression free at 6 months).
• PR1: Defined as best percentage reduction in sum of diameters of target lesions by at least 80% (n = 27; n = 25)
• PR2: Defined a best percentage reduction in sum of diameters of target lesions by at least 60% but no more than 80% (n = 38; n = 36)
• PR3: Defined as best percentage reduction in sum of diameters of target lesions by less than 60% (n = 70; n = 63)
• SD (n = 98; n = 65)
• Progressive disease (PD; n = 15; not applicable)

End points for each subgroup included PFS and OS in patients alive or alive and progression free at 6 months post randomization, TTR, DOR, DOR after treatment discontinuation, and safety.The data cutoff was May 17, 2024.

Regarding baseline characteristics, responders included those with poor prognostic characteristics, including low IMDC risk score (range, 7%-17%), sarcomatoid features (range, 6%-15%), 2 or more metastatic sites (range, 60%-78%), and liver metastases (range, 16%-29%).

How did treatment duration correlate with safety outcomes?

“Despite longer treatment duration, responders did not experience substantially higher rates of treatment-related adverse effects [TRAEs] than nonresponders,” Suárez and colleagues wrote.

The median duration of cabozantinib plus nivolumab treatment in the CR, PR1, PR2, PR3, SD, and PD subgroups was 30.4 months, 29.9 months, 35.6 months, 23.0 months, 15.3 months, and 9.0 months, respectively.

The incidence of any-grade TRAEs in responders vs nonresponders was 99% vs 100%; respective rates of grade 3/4 TRAEs were 72% vs 67%. Among responders (n = 180), the most common grade 3/4 TRAEs were hypertension (13%), diarrhea (9%), hyponatremia (8%), and palmar-plantar erythrodysesthesia syndrome (8%).

Disclosures: Suarez disclosed serving in a consulting or advisory role for Astellas Pharma; Bristol-Myers Squibb; Eisai; EUSA Pharma; Ipsen; Merck Sharp & Dohme; Pfizer; Roche/Genentech (Inst); serving on the speakers' bureau for Bristol-Myers Squibb; Eisai; Ipsen; Merck Sharp & Dohme; Pfizer; Roche/Genentech; and receiving research funding from AB Science (Inst); Aragon Pharmaceuticals (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Bayer (Inst); Blueprint Medicines (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Clovis Oncology (Inst); Exelixis (Inst); GlaxoSmithKline (Inst); Novartis (Inst); Pfizer (Inst); Roche/Genentech (Inst); Sanofi Aventis GmbH (Inst).

References

1. Suárez C, Motzer R, Powles T, et al. Characterization of depth and durability of response in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) who received cabozantinib plus nivolumab (C+N): long-term follow-up and exploratory analysis of CheckMate 9ER. J Clin Oncol. 2026;44(suppl 7):508. doi:10.1200/JCO.2026.44.7_suppl.508
2. Motzer RJ, Escudier B, Burotto M, et al. Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2026;37(1):33-43. doi:10.1016/j.annonc.2025.09.006
3. Suárez C, Choueiri TK, Burotto M, et al. Association between depth of response (DepOR) and clinical outcomes: exploratory analysis in patients with previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 9ER. J Clin Oncol. 2022;40(suppl 16): 4501. doi:10.1200/JCO.2022.40.16_suppl.4501