Cabozantinib Plus Nivolumab Demonstrates Disease Control in Refractory MSS mCRC

Treatment with the combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) led to disease control in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), according to data from phase 2 trial (NCT04963283).

Data presented at the 2025 Gastrointestinal Cancers Symposium demonstrated that evaluable patients treated with the combination (n = 47) achieved a 16-week overall response rate (ORR) of 9% (95% CI, 2.4%-20.4%) and 16-week disease control rate (DCR) of 40% (95% CI, 26.4%-55.7%). No patients experienced a complete response; best responses at week 16 included partial response (9%), stable disease (32%), and progressive disease (53%).

“This trial met its primary end point with 40% of evaluable patients achieving disease control at 16 weeks or longer,” lead study author Alexis D. Leal, MD, and colleagues wrote in a poster presentation of the data. Leal is an assistant professor of medicine at the University of Colorado Anschutz Medical Campus in Aurora.

Trial Rationale and Design

Study authors noted that although patients with MSS mCRC have historically experienced limited benefit with the use of immune checkpoint inhibitors, preclinical data informed a hypothesis that combining a TKI with one of these agents could augment the immune response, leading to increased immunogenicity.

“Preclinical studies from our group showing promising efficacy from the combination of cabozantinib and nivolumab in a humanized mouse model led to the development of this clinical trial in patients with MSS mCRC,” study authors wrote.

The investigator-initiated, single-arm, open-label study enrolled patients at least 18 years of age with metastatic or unresectable MSS CRC that was refractory to chemotherapy in the third-line setting or beyond. An ECOG performance status of 0 or 1 was required.

Prior treatment with an immune checkpoint inhibitor prevented patients from enrolling. Patients were allowed to received prior treatment with trifluridine/tipiracil (TAS-102; Lonsurf), but previous receipt of a small molecule inhibitor such as regorafenib (Stivarga) was not permitted.

Enrolled patients received cabozantinib at 40 mg once per day plus nivolumab at 480 mg once every 4 weeks. In the trial’s 2-stage design, 14 patients were initially enrolled for the first stage. If 5 or more patients from this group achieved 16-week progression-free survival (PFS), study investigators were allowed to enroll additional patients in the second stage. If 4 or fewer patients enrolled in stage 1 experienced a 16-week PFS, the study would be terminated. At the end of stage 2, if 17 or more patients out of 46 total achieved a 16-week PFS, further study of the combination would be warranted.

Along with the primary end point of 16-week DCR, secondary end points included ORR, PFS, overall survival (OS), and safety/tolerability.

All enrolled patients (n = 49) had a median age of 55 years (IQR, 50-64), and the majority were male (63%) and non-Hispanic Caucasian (69%). Patients received a median of 4 prior lines of therapy (IQR, 3-5), and 16% received prior treatment with TAS-102. Seventy-four percent of patients had liver metastases at baseline, and 45% had lung metastases. Notably, 1 patient (2%) had only lung metastases.

Additional Efficacy and Safety Data

Findings also showed that evaluable patients experienced a median PFS of 3.4 months (95% CI, 1.8-5.0) and a median OS of 10.9 months (95% CI, 4.7-13.8).

Among patients with liver metastases at baseline, the 16-week DCR was 40% (95% CI, 23.9%-57.9%) compared with 42% (95% CI, 15.2%-72.3%) for those without liver metastases. Disease was controlled in the 1 patient with lung-only metastases.

At the time of abstract submission, 3 patients remained on study; at the time of the poster presentation, 1 patient was still on treatment.

Regarding safety (n = 49), serious adverse effects (AEs) occurred in 39% of patients at grade 1 (4%), grade 2 (37%), grade 3 (35%), and grade 4 (4%). No grade 5 serious AEs were reported.

The most common any-grade AEs included diarrhea (53%), fatigue (43%), hypothyroidism (31%), weight loss (29%), nausea (29%), hypertension (27%), abdominal pain (24%), hypokalemia (24%), proteinuria (22%), anorexia (20%), cough (20%), increased aspartate aminotransferase levels (18%), hypomagnesemia (18%), constipation (16%), and vomiting (16%).

“The combination of cabozantinib and nivolumab was well tolerated and demonstrated an AE profile similar to other TKI/immune checkpoint inhibitor combinations,” study authors wrote.

Study investigators collected baseline and on-treatment biopsies and peripheral blood samples from 20 patients, and correlative data for biomarker analysis from this group will be presented in the future.

Reference

Leal A, Blatchford P, Kim S, et al. Phase II study of cabozantinib and nivolumab in refractory metastatic microsatellite stable (MSS) colorectal cancer (CRC). J Clin Oncol. 2025;43(suppl 4):229. doi:10.1200/JCO.2025.43.4_suppl.229