Sitravatinib/Nivolumab Shows Modest Activity in Progressive Metastatic Clear Cell RCC Before Trial Termination

Progressive ccRCC | Image Credit:
© Sebastian Kaulitzki
– stock.adobe.com

Sitravatinib plus nivolumab (Opdivo) demonstrated minimal antitumor activity with a manageable safety profile in patients with metastatic clear cell renal cell carcinoma (ccRCC) following progression on an immune checkpoint inhibitor (ICI), according to data from the phase 2 SNAPI trial (NCT04904302). However, the study was terminated early after the development of sitravatinib was discontinued.1

In the overall patient population (n = 14), the 24-week objective response rate (ORR) was 14.3%, and the 24-week disease control rate (DCR) was 35.7%. Of note, 2 partial responses were reported in patients who experienced disease progression on nivolumab/ipilimumab (Yervoy; cohort A) and pembrolizumab (Keytruda)/axitinib (Inlyta; cohort B), respectively. In cohorts A and B, the 24-week ORR and DCR were 25% and 62.5%, respectively. Conversely, the ORR and DCR at 24 weeks were 0% each in patients previously treated with cabozantinib (Cabometyx) or lenvatinib (Lenvima; cohort C).

“In this phase 2 trial with limited sample size due to early determination, sitravatinib plus nivolumab demonstrated a manageable safety profile and produced modest clinical benefit in patients with metastatic ccRCC whose cancer progressed on an immune checkpoint inhibitor [ICI] and did not previously receive cabozantinib or lenvatinib,” the study authors wrote.

SNAPI Design and Patient Characteristics

The investigator-initiated, single-arm, open-label, multicenter study included patients 18 years of age or older with histologically or cytologically confirmed metastatic or advanced ccRCC or RCC with a clear cell component. Patients received 1 or 2 prior lines of treatment in the advanced or metastatic setting, with the most recent treatment including a PD-1/PD-L1 checkpoint inhibitor, cabozantinib, or lenvatinib. Evidence of disease progression on or following treatment at any point after completing prior therapy with a PD-1/PD-L1–containing regimen as the last treatment received within 6 months of study enrollment; at least 1 measurable site of disease; and a Karnofsky performance status of 70 or higher was also required.2

Eligible patients were divided into 3 cohorts based on prior treatments, which included cohorts A (n = 2), B (n = 6), and C (n = 6).1 All patients on the study were treated with oral sitravatinib at a starting dose of 100 mg daily plus intravenous nivolumab at 480 mg every 4 weeks.

The study’s dual primary end points were ORR per RECIST 1.1 criteria and DCR at 24 weeks. Secondary end points included overall survival (OS), progression-free survival (PFS), duration of response, incidence of adverse effects (AEs), and health-related quality of life.2

In the overall patient population, the majority of patients were male (71.4%), with a median age of 50 years (range, 40-75) at enrollment.1 Additionally, patients had previously received either 1 (42.9%) or 2 (57.1%) systemic therapies. International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups included favorable (14.3%), intermediate (78.6%), and poor (7.1%). Notably, patients had an ECOG performance status of 0 (71.4%) and 1 (28.6%).

Additional Efficacy and Safety Data

In the overall patient population, the median PFS was 5.5 months (95% CI, 3.8-not reached [NR]), and the median OS was 13.3 months (95% CI, 8.77-NR).

Regarding safety, all patients experienced any grade AEs, with grade 3 and 4 AEs observed in 42.9% of patients, and 14.3% experienced an any-grade immune-mediated AE. Of note, 64.3% of patients had dose interruptions, with 50% requiring a dose reduction of sitravatinib. Serious AEs occurred in 50% of patients.

“Since our ORR was 25% in cohorts A and B, we suspect sitravatinib was also ineffective at restoring sensitivity to ICIs, and [that] the clinical activity observed was due to the antitumor properties of sitravatinib alone,” the study authors concluded. “There is limited enthusiasm for further development of sitravatinib given the availability of similar agents in the post-ICI setting and introduction of belzutifan [Welireg].”

References

1. Hahn AW, Adra N, Vaishampayan U, et al. A phase II trial of sitravatinib + nivolumab after progression on immune checkpoint inhibitor in patients with metastatic clear cell RCC. Oncologist. 2025;30(4):oyaf053. doi:10.1093/oncolo/oyaf05
2. Sitravatinib and nivolumab for the treatment of metastatic or advanced clear cell renal cell cancer. ClinicalTrials.gov. Updated December 6, 2024. Accessed May 14, 2025. https://clinicaltrials.gov/study/NCT04904302