Nivolumab/Ipilimumab Plus CBM588 Generates Superior Efficacy in Metastatic RCC

The addition of CBM588, a live probiotic comprised primarily of Clostridium butyricum, to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) produced superior response rates and a progression-free survival (PFS) benefit vs nivolumab plus ipilimumab alone in previously untreated patients with metastatic renal cell carcinoma (RCC), according to findings from a phase 1b trial (NCT03829111).¹

Data presented at the 2022 International Kidney Cancer Symposium showed that patients treated with CBM588 plus nivolumab/ipilimumab (n = 19) achieved an objective response rate (ORR) of 58% compared with 20% for those given nivolumab/ipilimumab alone (n = 10; P = .06). In the CBM588 arm, all responders achieved partial responses (PRs), 21% of patients had stable disease, and 21% of patients had progressive disease. In the nivolumab/ipilimumab arm, both responders experienced a PR, 20% of patients had stable disease, and 60% experienced disease progression. The disease control rate was 79% in the CBM588 arm compared with 20% in the nivolumab/ipilimumab arm (P = .004).

“Although limited by the sample size, the combination of nivolumab, ipilimumab, and CBM588 demonstrated superior clinical outcomes over nivolumab/ipilimumab. PFS and ORR with nivolumab, ipilimumab, and CBM588 also exceeded those observed with nivolumab/ipilimumab in historical datasets,” lead study author Nazli Dizman, MD, a hospital resident at the Yale School of Medicine, said in a presentation.

CBM588 is a live bacterial product that contains Clostridium butyricum, a butyrate-producing anaerobic spore-forming bacterium that is commonly used and studied in gastrointestinal conditions in Japan.

A retrospective analysis of 118 patients with non–small cell lung cancer showed that those who received CBM588 before and/or after immune checkpoint inhibitors experienced an ORR of 48%, including a complete response rate (CR) of 8% compared with an ORR of 25% and no CRs for patients given immune checkpoint inhibitors alone.²

The phase 1b trial evaluated the efficacy and safety of nivolumab/ipilimumab with or without CBM588 in patients with RCC who had measurable metastatic disease with clear cell and/or sarcomatoid histology. Patients were also required to have no prior systemic treatment for metastatic disease, intermediate- or poor-risk IMDC classification, and an ECOG performance status of 0 or 1.

Patients were randomly assigned 2:1 to receive CBM588 plus nivolumab/ipilimumab or nivolumab/ipilimumab alone. The primary end point of the trial was the change in Bifidobacterium in the stool from baseline to week 12.³ Secondary end points included ORR, PFS, change in serum cytokine levels, change in immune cell populations, change in stool metabolic pathways, and toxicity.

The median age of patients in the CBM588 arm was 66 years (range, 45-90) compared with 64 years (range, 45-79) in the nivolumab/ipilimumab arm. Most patients had clear cell histology (63% and 70% in the CBM588 and nivolumab/ipilimumab arms, respectively), and had intermediate IMDC prognostic risk (89% and 70%). The minority of patients did not undergo prior nephrectomy (47% and 40%). All patients in both arms had at least 2 metastatic sites. The most common metastatic sites included lung (68% and 60%), lymph node (42% and 70%), bone (37% and 40%), soft tissue (37% and 30%), liver (16% and 20%), and pancreas (16% and 10%).

Additional data showed that patients in the CBM588 arm achieved a median PFS of 36.4 months (95% CI, 9.4-63.5) compared with 2.5 months (95% CI, 2.0-2.9) for those in the nivolumab/ipilimumab arm (HR, 0.10; 95% CI, 0.03-0.33; P < .001). The median duration of response in the CBM588 arm was 30.7 months.

The median overall survival was not reached in either arm. In the CBM588 arm, 82.8% of patients were alive at the time of data cutoff.

Regarding safety, at least 1 any-grade adverse effect (AE) was reported in all patients in the CBM588 arm compared with 90% in the nivolumab/ipilimumab arm. Grade 2 or higher AEs occurred in 63% and 50% of patients in the CBM588 and nivolumab/ipilimumab arms, respectively.

Two instances (11%) of grade 3 nephritis were reported in the CBM588 arm, and grade 3 events of adrenal insufficiency, fatigue, maculo-papular rash, arthritis/arthralgia, diarrhea, acute kidney injury, abdominal pain, transaminitis, glucose intolerance, increase alkaline phosphatase pancreatitis, acidosis, and chest wall pain each occurred in 1 patient. One grade 4 instance of decreased neutrophil count was reported in 1 patient in the CBM588 arm. No grade 4 or higher AEs were observed in the nivolumab/ipilimumab arm.

A randomized, double-blind phase 3 study will compare the combination of nivolumab/ipilimumab plus CBM588 or placebo as a frontline treatment for patients with intermediate- or high-risk advanced clear cell RCC.

“Larger efforts investigating the impact of CBM588 on clinical outcomes are underway. We are devoting our efforts to better understand the mechanism of action of CBM588 by studying metabolic samples in patients and in mice,” Dizman concluded.

References

1. Dizman N. Clinical outcomes with nivolumab/ipilimumab (nivo/ipi) with or without CBM588 in metastatic renal cell carcinoma (mRCC): long-term follow-up of a randomized phase Ib clinical trial. Presented at: International Kidney Cancer Symposium; November 4-5, 2022. Austin, Texas. Abstract 9.
2. Tomita Y, Ikeda T, Sakata S, et al. Association of probiotic Clostridium butyricum therapy with survival and response to immune checkpoint blockade in patients with lung cancer. Cancer Immunol Res. 2020;8(10):1236-1242. doi:10.1158/2326-6066.CIR-20-0051
3. CBM588, nivolumab, and ipilimumab in treating patients with stage IV or advanced kidney cancer. ClinicalTrials.gov. Updated October 14, 2022. Accessed November 7, 2022. https://clinicaltrials.gov/ct2/show/NCT03829111