Addition of CBM588 to Cabozantinib/Nivolumab Shows Potential in Metastatic RCC

Although data thus far have been derived from smaller studies, the addition of the live bacterial product CBM588 to immune-oncology–based combinations could boost the efficacy of these standard-of-care regimens in patients with metastatic renal cell carcinoma (RCC), according to Hedyeh Ebrahimi, MD, MPH.

Data from a phase 1 trial (NCT05122546) presented at the 2025 Genitourinary Cancers Symposium demonstrated that progression-free survival (PFS) and overall response rate (ORR) were improved in patients treated with CBM588 plus cabozantinib (Cabometyx) and nivolumab (Opdivo; n = 20) compared with those given cabozantinib plus nivolumab alone (n = 10). In the CBM588 plus cabozantinib/nivolumab arm, the ORR was 84%, the stable disease rate was 5%, and the progressive disease rate was 11%. In the cabozantinib/nivolumab arm, these respective rates were 20%, 50%), and 30%. All responders in both arms had partial responses.

The median PFS was 19.7 months in the CBM588 arm vs 13.4 months in the control arm (HR, 0.74; 95% CI, 0.25-2.23; P = .59).

However, the study did miss its primary end point of change in Bifidobacterium spp. levels from baseline to week 13

“We hypothesized that the addition of CBM588 would result in an increase in Bifidobacterium spp. in the experimental arm,” said Hedyeh Ebrahimi, MD, MPH. “However, we saw that neither experimental nor control arm had any significant difference in the abundance of Bifidobacterium spp. at week 13 compared with baseline.”

In an interview with OncLive®, Ebrahimi highlighted CBM588’s unique mechanism of action, the rationale of the phase 1 study, efficacy and safety data, and potential clinical implications of adding CBM588 to cabozantinib and nivolumab.

Ebrahimi is a postdoctoral fellow at the City of Hope in Duarte, California.

OncLive: How is the live bacterial product CBM588 constructed and what is unique about its mechanism of action?

Ebrahimi: CBM588 is a live bacterial product. Patients ingest [it] in a spore form, and it is deposited in the lower gastrointestinal [GI] tract. Previous studies showed that proliferation in the lower GI tract is followed by the production of butyrate, and it will eventually result in an increase in beneficial species, including Bifidobacterium, in the lower GI tract, and we hypothesized that this would lead to an antitumor effect of CBM588.

What is the rationale for combining CBM588 with cabozantinib and nivolumab in RCC, and how could this addition enhance clinical benefit?

Our team, and especially my mentor, Sumanta Kumar Pal, MD, [of City of Hope], became interested in this compound after seeing results from a retrospective study conducted in Japan. In that study, 118 patients were included, and all patients had [advanced or recurrent] non–small cell lung cancer. Thirty-nine patients [received] CBM588, and that retrospective study showed that patients who received CBM588 had prolonged PFS and increased overall survival compared with the other group [of patients who did not receive CBM588]. That was the start of our interest in this compound.

[Dr Pal] designed the first investigator-initiated [phase 1] study [NCT03829111] using this same compound, CBM588, in patients with metastatic RCC who were receiving ipilimumab [Yervoy] plus nivolumab. In that first study, we saw that the addition of CBM588 to ipilimumab plus nivolumab in a prospective, randomized trial resulted in increased PFS and ORR. Those were the previous results we saw with CBM588 before starting the current trial.

What was the design, methodology, and patient population included in this phase 1 trial of CBM588 plus cabozantinib and nivolumab?

In the current study, we wanted to test whether adding CBM588 to the combination of VEGF-targeted treatment plus an immune checkpoint inhibitor in patients with metastatic RCC would also potentiate this regimen. We included patients with metastatic RCC who had measurable disease; 30 patients were randomly assigned in a 2:1 fashion. Ten patients were in the control arm to receive cabozantinib plus nivolumab alone, and 20 patients received CBM588 in addition to cabozantinib and nivolumab. Patients had to have ECOG performance status of 0 or 1. Our eligibility criteria were more permissive in the current study: we included patients with papillary RCC as well as clear cell RCC. We also included patients with favorable risk disease in addition to the intermediate- and poor-risk groups.

What efficacy findings from the study were presented at the 2025 Genitourinary Cancers Symposium?

We previously showed that our primary end point, which was an increase in Bifidobacterium spp., was not met in the current trial. Moving to the secondary end point of clinical outcomes, we saw that the median PFS in patients from the experimental arm who received CBM588 in addition to cabozantinib and nivolumab [was] 19.7 months. However, the median PFS [was 13.4 months] in the control arm—patients who only received cabozantinib plus nivolumab in a standard dosing [HR, 0.74; 95% CI, 0.25-2.23; P = .59].

In addition, we saw that the ORR was higher in the experimental arm and those who received CBM588; 84% of patients in the CBM588 arm had [partial] responses compared with only 20% of patients in the control arm.

How did the safety profiles in both arms compare, and were there any new safety signals identified?

We did not see any new signal of toxicity in our updated outcome assessment. There was no significant difference in the toxicity profile between the experimental and control arms. Forty percent of patients in the control arm had grade 3 [adverse effects] compared with 45% of patients in the experimental arm. We did not see any grade 4 toxicities in either arm of this study.

With these findings, what is the potential clinical impact of adding CBM588 to cabozantinib/nivolumab, and what are the next steps for further investigation?

In 2 small investigator-initiated studies, we saw that patients who received CBM588 had longer PFS and an increased ORR compared with the control arm. However, both of these trials were very small. Therefore, we believe that further studies of this compound should be prioritized in the future.

Right now, we see an influx of patients who are asking us whether they should start taking CBM588 on our own, but we need to tell our patients to be cautious about that. We do not want any of them to start any type of probiotic on their own. Both of these studies were very small, and we do not have the definitive answer right now. We are waiting for future cooperative group studies, which probably will be larger and will include more patients, to have a definitive answer. Before that, we cannot tell anyone to take it on their own.

Reference

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