Deeper Tumor Reduction Is Tied to Longer RCC Survival on Nivolumab Combination

The deeper the tumor shrinkage, the longer the survival benefit for patients with advanced renal cell carcinoma (RCC) treated with the frontline combination of cabozantinib (Cabometyx) and nivolumab (Opdivo), according to long-term follow-up data from an exploratory analysis of the phase 3 CheckMate 9ER study (NCT03141177).¹ These data were presented at the 2026 American Society of Clinical Oncology 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 subgroups (PR1, PR2, PR3), 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.¹

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), respectively.

Furthermore, progression-free survival (PFS) and overall survival (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, respectively.

“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.¹ “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. She is the group leader of the Genitourinary, Central Nervous System Tumors, Sarcoma, and Cancer of Unknown Primary Site Group at Vall d’Hebron University Hospital in Barcelona, Spain.

Rationale for the Study

Primary results from CheckMate 9ER helped establish cabozantinib plus nivolumab as the standard of care 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).^1,2

In a prior exploratory post hoc analysis of CheckMate 9ER, a greater proportion of patients in the nivolumab and cabozantinib arm achieved deep responses than 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

Study Design

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 included patients in the cabozantinib plus nivolumab arm with available BOR data per blinded independent central review (BICR) and who were alive 6 months after being randomly assigned.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 79% (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)

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%).

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 (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), GSK (Inst), Novartis (Inst), Pfizer (Inst), Roche/Genentech (Inst), Sanofi Aventis GmbH (Inst).

REFERENCES

1. Suárez C, Motzer RJ, 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