Nivolumab/Cabozantinib Combination Displays Activity in Non-Clear Cell RCC


Treatment with nivolumab plus cabozantinib yielded responses in patients with non-clear cell renal cell carcinoma.

Kelly N. Fitzgerald, MD

Kelly N. Fitzgerald, MD

Treatment with the PD-1 inhibitor nivolumab (Opdivo) plus the TKI cabozantinib (Cometriq) demonstrated efficacy and the potential for sustained responses among patients with non-clear cell renal cell carcinoma (RCC), according to findings from a phase 2 study (NCT03635892) published in European Urology.

At a median follow-up of 34 months (range, 20-51), updated efficacy findings from the study revealed that patients with non-clear cell RCC who received cabozantinib plus nivolumab (n = 40) achieved an overall response rate (ORR) of 48% (95% CI, 32%-64%). Additionally, the median progression-free survival (PFS) was 13 months (95% CI, 7-16) and the median overall survival (OS) was 28 months (95% CI, 23-43).

“This extended follow-up analysis demonstrates promising efficacy, and highlights the potential for sustained responses with cabozantinib plus nivolumab in patients with metastatic non-clear cell RCC,” Kelly N. Fitzgerald, MD, a genitourinary oncologist at UCSF Health in San Francisco, California, and coauthors wrote.

The single-center, investigator-initiated study enrolled patients with unresectable advanced or metastatic papillary, unclassified, or translocation-associated RCC. Patients could have received 1 prior line of systemic therapy and prior cabozantinib exposure was not allowed.

Patients received oral cabozantinib 40 mg daily and intravenous nivolumab 240 mg every 2 weeks, with dose reduction and reescalation permitted. Study treatment continued until disease progression, intolerable toxicity, or patient withdrawal. The primary end point was ORR by RECIST 1.1 criteria and secondary end points included OS, PFS, and safety.

The median age of the study population was 57 years (IQR, 51-66). Most patients were male (70%), underwent a prior nephrectomy (67%), and had papillary histology (80%), a Karnofsky performance status of 90 (73%), and intermediate International Metastatic Renal Cell Carcinoma Database Consortium risk disease (67%). Thirty-five percent of patients received prior systemic therapy including a VEGF inhibitor (25%), mTOR inhibitor (20%), and/or chemotherapy (5.0%). Further, patients had lymph node (78%), lung (45%), bone (30%), retroperitoneum/peritoneum (25%), and/or liver metastases (20%).

Additional findings from the study showed that the median duration of response (DOR) was 17 months (95% CI, 10-20); the 12- and 24-month DOR rates were 63% (95% CI, 38%-80%) and 32% (95% CI, 13%-52%), respectively. The estimated 18- and 36-month OS rates were 70% (95% CI, 53%-82%) and 44% (95% CI, 28%-60%), respectively, and the estimated 12- and 24-month PFS rates were 51% (95% CI, 34%-65%) and 23% (95% CI, 11%-37%), respectively.

Results from a subgroup analysis revealed that patients who were being treated in the first (n = 26) and second lines (n = 14) achieved ORRs of 54% (95% CI, 33%-73%) and 36% (95% CI, 13%-65%), respectively; one patient in the frontline subgroup achieved a complete response. The ORR was 47% (95% CI, 30%-64%) among patients with papillary disease (n = 32), 50% (95% CI, 12%-88%) among those with unclassified disease without papillary features (n = 6), and 50% (95% CI, 1%-99%) in patients with translocation-associated RCC (n = 2).

In terms of safety, 61% of patients discontinued study treatment due to disease progression, 40% discontinued cabozantinib due to toxicity, and 40% discontinued nivolumab due to toxicity. Any-grade adverse effects (AEs) were reported in 88% of patients and grade 3 or 4 AEs occurred in 55% of patients. Common any-grade AEs included fatigue (70%), palmar-plantar erythrodysesthesia syndrome (68%), diarrhea (63%), and dry mouth (48%). Grade 3 to 4 AEs that occurred were hypertension (13%), diarrhea (7.5%), palmar-plantar erythrodysesthesia syndrome (5.0%), and nausea (2.5%).

“Study limitations include the nonrandomized, single-arm design, and the heterogeneity of patient population with regard to prior treatment status and histology. Long-term follow-up is not reported for the prespecified cohort 2, which included patients with chromophobe RCC; cohort 2 was closed early because of inefficacy, with no responses seen in 8 patients,” study authors noted. 


Fitzgerald KN, Lee CH, Voss MH, et al. Cabozantinib plus nivolumab in patients with non-clear cell renal cell carcinoma: updated results from a phase 2 trial. Eur Urol. Published online May 22, 2024. doi:10.1016/j.eururo.2024.04.025

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