CBM588 Plus Cabozantinib/Nivolumab Shows Early Activity in Metastatic Renal Cell Carcinoma

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CBM588 plus cabozantinib (Cabometyx) and nivolumab (Opdivo) improved progression-free survival (PFS) and objective response rate (ORR) but did not lead to a significant increase in Bifidobacterium spp. in patients with metastatic renal cell carcinoma (mRCC), according to updated data from a phase 1 study (NCT05122546) shared during the 2025 Genitourinary Cancers Symposium.¹

Regarding relative abundance of Bifidobacterium spp., no statistically significant difference was observed between baseline and week 13 in the experimental arm of CBM588 plus cabozantinib and nivolumab (P = .3894) or the control arm of cabozantinib plus nivolumab alone (P = .9453) per Wilcoxon matched-pairs test. Moreover, no significant difference was seen in alpha diversity between baseline and week 13 in the investigative (P = .65) and control (P = .17) arms per a Kruskal-Wallis test.

The addition of CBM588 to cabozantinib and nivolumab (n = 20) led to a median PFS of 19.7 months vs 13.4 months with cabozantinib plus nivolumab (n = 10; HR, 0.74; 95% CI, 0.25-2.23; P = .59). With CBM588 plus cabozantinib and nivolumab, the partial response (PR) rate was 84%; the stable disease (SD) rate was 5% and the progressive disease (PD) rate was 11%. With cabozantinib plus nivolumab, the PR rate was 20%; SD and PD rates were 50% and 30%, respectively.

“The addition of CBM588 to cabozantinib/nivolumab continues to show promising efficacy in mRCC, with an improved PFS and ORR,” Hedyeh Ebrahimi, MD, MPH, of City of Hope Comprehensive Cancer Center in Duarte, California, and colleagues, wrote in the abstract. “The safety profile remains consistent with previous findings, supporting further exploration in larger trials. Further translational efforts are underway to characterize the mechanism through which CBM588 augments clinical activity.”

The single-center, randomized, open-label, investigator-initiated, phase 1 study enrolled patients with mRCC who have measurable metastatic disease and clear cell, papillary, and/or sarcomatoid components.^1,2 All patients had an ECOG performance status of 0 or 1. They had not previously received systemic treatment for metastatic disease, and did not have active autoimmune disease. They also were not receiving high-dose steroids.

Participants were randomly assigned in a 2:1 fashion to receive 40 mg of cabozantinib daily plus 480 mg of nivolumab every 4 weeks with or without 80 mg of CBM588 twice daily. The primary end point of the study was change in Bifidobacterium spp. from baseline to week 13, and key secondary end points were PFS, ORR, and safety.

The statistical analysis called for 80% power to detect a 1-standard deviation change in Bifidobacterium spp. between study arms with 30 patients, utilizing a 2-group t-test with a 1-sided type 1 error of 0.05.

Previous data published in Nature revealed that the primary end point of the study was not met and the addition of CBM588 to cabozantinib/nivolumab did not lead to a difference in the relative abundance of Bifidobacterium spp. or alpha diversity.² However, at that time point, which had a median follow-up of 15.9 months (interquartile range, 9.6-18.0), the ORR was higher with the addition of CBM588 at 74% vs 20% with cabozantinib plus nivolumab alone (P = .01). The 6-month PFS rates were 84% and 60%, respectively.

For the updated analysis, the median patient ages in the CBM588 and non-CBM588 arms were 68 years (range, 36-84) and 60 years (range, 48-67).¹ In the CBM588 arm, most patients were male (75%), White (95%), non-Hispanic or non-Latinx (55%), and had clear cell histology (90%). In this group, 45% had favorable prognostic risk, 35% had intermediate risk, and 20% had poor risk per International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Seventy percent of patients had prior nephrectomy. In the non-CBM588 arm, half of patients were male, most patients were White (70%), were Hispanic or Latinx (60%), and had clear cell histology (80%). Moreover, 30%, 50%, and 20% of patients had favorable-, intermediate-, or poor-risk disease, respectively, per IMDC criteria. Sixty percent had prior nephrectomy.

In terms of safety, in the CBM588 arm, grade 2 adverse effects (AEs) occurred in 25% of patients, and grade 3 AEs occurred in 45% of patients. The most common AEs were hypertension (grade 2, 35%; grade 3, 5%), transaminitis (10%; 5%), Palmar-plantar erythrodysesthesia syndrome (PPE; 10%; 5%), diarrhea (5%; 10%), hypoalbuminemia (5%; 0%), and anemia (5%; 0%), hypocalcemia (5%; 0%), and oral mucositis (0%; 5%). In the non-CBM588 arm, the most common AEs were hypertension (grade 2, 60%; grade 3, 10%), hypocalcemia (10%; 10%), PPE (10%; 0%), increased lipase (10%; 0%), hypoalbuminemia (10%; 0%), and transaminitis (0%; 20%).

References

1. Ebrahimi H, Meza LA, Dizman N, et al. Cabozantinib and nivolumab with or without CBM588 in patients with metastatic renal cell carcinoma: Updated clinical outcomes of a phase I study. J Clin Oncol. 2025;43(suppl 5):543. doi:10.1200/JCO.2025.43.5_suppl.543
2. Ebrahimi H, Dizman N, Meza L, et al. Cabozantinib and nivolumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2024;30(9):2576-2585. doi:10.1038/s41591-024-03086-4