Zanzalintinib/Nivolumab Combo Shows Promise in Advanced RCC

Renal cell carcinoma: © peterschreiber.media - stock.adobe.com

The combination of zanzalintinib and nivolumab (Opdivo) has demonstrated encouraging effectiveness and acceptable tolerability in individuals with previously untreated stage 4 renal cell carcinoma (RCC). Initial findings from an expansion cohort of the STELLAR-002 study (NCT05176483) indicate a 63% response rate and a median progression-free survival (PFS) of 18.5 months.¹

“Zanzalintinib with nivolumab demonstrated promising clinical activity and tolerability in patient with first-line stage 4 RCC. Zanzalintinib in combination with immune checkpoint inhibitors, whether it's doublet or triplet, was shown to be safe and tolerable in patients with renal cell carcinoma. These encouraging preliminary clinical activity and acceptable tolerability support the ongoing studies of zanzalintinib plus immune checkpoint inhibitors in solid tumors, including RCC,” said presenting author Jad Chahoud, MD, MPH, of Moffitt Cancer Center in Tampa, Florida, at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

In his presentation, Chahoud explained that in previously reported data from the phase 1 STELLAR-001 study, single-agent zanzalintinib was associated with tolerability and promising antitumor activity in patients with heavily pretreated advanced clear cell renal cell carcinoma.² In addition, “Zanzalintinib activity could potentially be augmented when combined with the PD-1 inhibitor nivolumab and the LAG-3 inhibitor relatilmab, which together restore T-cell activation and result in increased antitumor activity,” the investigators wrote.³

For the study presented at ASCO 2025, patients had to be at least 18 years of age with unresectable advanced or metastatic RCC with a clear cell component, all IMDC risk groups, with no prior systemic anticancer therapy for RCC (prior non-VEGF[R]-targeted adjuvant or neoadjuvant therapy was allowed if disease recurrence had taken place 6 months following the last dose). Patients were sequentially assigned to receive zanzalintinib 100 mg orally once daily plus nivolumab 480 mg intravenously (IV) once every 4 weeks or zanzalintinib 100 mg orally once daily plus nivolumab/relatlimab 480/480 mg (IV) once every 4 weeks (fixed-dose combination). The primary end points were incidence and severity of adverse events (AEs) and objective response rate (ORR) per RECIST v1.1. The secondary end point was PFS per RECIST v1.1.

“Forty patients were enrolled in each arm in this non-randomized controlled trial. Therefore, you would expect some differences in each arm. Nevertheless, both arms were reflective of patients that we see in daily practice with RCC, with around 25% of the patient population falling under the favorable IMDC risk group, and 75% falling under the intermediate- to poor-risk group,” Chahoud said.

Median follow-up was 20.1 months (range, 17.7-26.7 months) in the zanzalintinib plus nivolumab arm and 15.9 months (range, 11.3-17.3 months) in the zanzalintinib plus nivolumab/relatlimab arm. Fifteen (38%) patients in the zanzalintinib plus nivolumab arm were continuing any study treatment at data cut-off vs 16 (40%) patients in the zanzalintinib plus nivolumab/relatlimab arm.

The most common reason for treatment discontinuation was radiographic progression, reported in 13 (33%) patients in the zanzalintinib plus nivolumab arm and 9 (23%) patients in the zanzalintinib plus nivolumab/relatlimab arm. This was followed by any treatment-emergent AE, occurring in 10 (25%) patients in the zanzalintinib plus nivolumab arm and 14 (35%) patients in the zanzalintinib plus nivolumab/relatlimab arm.

In addition, discontinuation due to an AE related to study treatment occurred in 3 (8%) patients in the zanzalintinib plus nivolumab arm and 8 (20%) patients in the zanzalintinib plus nivolumab/relatlimab arm. Discontinuation due to withdrawal of consent other than an AE occurred in 1 (3%) patient in the zanzalintinib plus nivolumab arm and 1 (3%) patient in the zanzalintinib plus nivolumab/relatlimab arm. Discontinuation due to physician decision occurred in 1 (3%) patient in the zanzalintinib plus nivolumab arm and 0 patients in the zanzalintinib plus nivolumab/relatlimab arm.

ORR in the zanzalintinib plus nivolumab arm was 63% (95% CI: 46-77) vs 40% (95% CI: 25-57) in the zanzalintinib plus nivolumab/relatlimab arm. Three (8%) patients in the zanzalintinib plus nivolumab arm had a confirmed complete response compared with 1 (3%) patient in the zanzalintinib plus nivolumab/relatlimab arm. Twenty-two (55) patients in the zanzalintinib plus nivolumab arm had a confirmed partial response compared with 15 (38%) patients in the zanzalintinib plus nivolumab/relatlimab arm. Disease control rate was 90% (95% CI: 76-97) in both arms.

Median duration of response (DOR) was not estimable in both arms, whereas 12-month DOR was 73.4% (50.0-87.1) in the zanzalintinib plus nivolumab arm compared with 74.1% in the zanzalintinib plus nivolumab/relatlimab arm. Median time to objective response was 2.1 months (range, 1.7-11.0 months) in the zanzalintinib plus nivolumab arm compared with 3.6 months (range, 1.7–12.8).

Median PFS was 18.5 months (95% CI: 9.5-not estimable) in the zanzalintinib plus nivolumab arm and 13.0 months (95% CI: 7.4-not estimable) in the zanzalintinib plus nivolumab/relatlimab arm. Six-month PFS was 83.4% (95% CI: 66.8-92.2) in the zanzalintinib plus nivolumab arm compared with 80.4% (95% CI: 63.1-90.2) in the zanzalintinib plus nivolumab/relatlimab arm. Twelve-month PFS was 64.4% (95% CI: 45.7-78.1) in the zanzalintinib plus nivolumab arm compared with 58.4% (95% CI: 39.9-73.0) in the zanzalintinib plus nivolumab/relatlimab arm.

Regarding safety, median exposure time for zanzalintinib plus nivolumab was 16.1 months (range, 0.5-24.8 months) compared with 10.9 months (range, 0.5-17.1 months) in the zanzalintinib plus nivolumab/relatlimab arm. Treatment-emergent AEs of any grade or grade 3-4 were observed in 40 and 33 patients in the zanzalintinib plus nivolumab arm and in 40 and 32 patients in the zanzalintinib plus nivolumab/relatlimab arm.

“I want to bring to your attention that we only had 2 patients in each arm that had grade 4 treatment-related adverse events,” Chahoud said.

“In conclusion, zanzalintinib plus nivolumab showed promising clinical activity and tolerability, with an overall response rate of 63%, a disease control rate of 90%, and a median PFS of 18.5 months. In this nonrandomized clinical trial, the addition of relatlimab did not appear to improve objective response rate, nor median PFS. Zanzalintinib in combination with immune checkpoint inhibitor, either in doublet or triplet, was safe and tolerable. This encouraging clinical activity and tolerability supports the ongoing investigation of zanzalintinib in combination with immune checkpoint inhibitors,” Chahoud said.

REFERENCES:

1. Chahoud J, McGregor B, Reig O, et al. Zanzalintinib (zanza) + nivolumab (nivo) ± relatlimab (rela) in patients (pts) with previously untreated clear cell renal cell carcinoma (ccRCC): Results from an expansion cohort of the phase 1b STELLAR-002 study. J Clin Oncol. 2025;43(suppl 17):4515. doi:10.1200/JCO.2025.43.16_suppl.4515

2. Pal S. Zanzalintinib (XL092) in Clear Cell Renal Cell Carcinoma (ccRCC): Results from STELLAR-001. Presented at: 2023 International Kidney Cancer Symposium. November 9-11, 2023; Nashville, TN.

3. Hofmann M, Thimme R, Schamel WW. PD-1 and LAG-3: synergistic fostering of T cell exhaustion. Signal Transduct Target Ther. 2024;9(1):291. doi:10.1038/s41392-024-02000-1