Biotherapeutic Shows Efficacy With Immunotherapy in Renal Cell Carcinoma

A live biotherapeutic showed improved progression-free survival (PFS) in patients with metastatic renal cell carcinoma (RCC) when used in addition to immunotherapy agents, according to a press release from City of Hope and Osel Inc.¹

In a phase 1 study (NCT03829111) of the biotherapeutic CBM588 plus nivolumab (Opdivo) and ipilimumab (Yervoy), investigators found a PFS of 12.7 months versus 2.5 months with nivolumab/ipilimumab alone (HR, 0.15; 95% CI, 0.05-0.47, P = .001).² They concluded that CBM588 could enhance the efficacy of immune checkpoint inhibitors (ICI) in treating cancer, though it did not meet a primary end point related to improved gut microbiome activity. The results of the study were published in Nature.

“To our knowledge, this is the first randomized clinical trial to demonstrate that a live bacterial product can modulate the gastrointestinal microbiome and enhance immunotherapy response in [patients with] cancer,” Sumanta K. Pal, MD, a professor in the Department of Medical Oncology & Therapeutics Research at City of Hope and primary author of the study, stated in the press release.¹ “These results can help improve treatment options for patients with kidney cancer and is an important foundational step to bring about more effective targeted therapies for cancer treatment.”

CBM588, a probiotic strain of Clostridium butyricum bacteria, produces short-chain fatty acids including butyric acid and plays other beneficial roles in the gastrointestinal (GI) microbiome by inhibiting pathogenic organisms and restoring the GI lining. The study investigated whether its immunomodulatory qualities in the GI microbiome could play a role in the response to ICIs.

Patients in both arms of the study received 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for up to 4 cycles until disease progression or unacceptable toxicity occured.² In the fifth cycle, patients received 480 mg nivolumab every 4 weeks, continuing until disease progression or unacceptable toxicity. In the experimental arm, patients received the same schedule of immunotherapy but also received 80 mg of oral CBM588 twice daily. A total of 30 patients were randomized 2:1 to receive CBM588 with ICIs or ICIs alone.

“Over the last several years, the immunotherapy field has been closely studying how the GI microbiome can enhance immune checkpoint efficacy for the treatment of cancer,” Thomas Parks, PhD, director of product development at Osel, stated in the press release.¹ “Compared to microbiome modulation using fecal transplants, CBM588 given orally is potentially a more effective, reproducible, scalable, and safer method to treat patients.”

The primary end point was the level of Bifidobacterium species bacteria in patient’s stool from baseline up to week 12. Secondary end points were changes in the Shannon index of microbiome diversity, best overall response, and PFS for up to 2 years.

Investigators did not find a significant difference in Bifidobacterium overall between the 2 arms; however, they did observe that patients who had responses to the CBM588 and immunotherapy did have significant increases in Bifidobacterium.² Patients who received CBM588 had a response rate of 58% versus 20% with doublet ICI alone, but this was not statistically significant (P = .06) and there were no complete responses.

In terms of toxicity, there was no difference in treatment-related adverse events between the groups.

“City of Hope is currently conducting another phase 1 clinical trial [NCT05122546] of CBM588 in combination with nivolumab and tyrosine kinase inhibitor cabozantinib [Cabometyx] for the treatment of advanced or metastatic kidney cancer,” said Pal.¹ “We are working to open a large, randomized phase 3 trial of CBM588 in the future.”

City of Hope has granted Osel a worldwide license for using CBM588 to enhance the efficacy of immune checkpoint inhibitors in treating cancer.

“The field of microbiome research is exploding as evidenced by the clinical importance of this study, which points to the continued growth of clinical research and scientific understanding of the microbiome’s connection to disease and recovery,” said Jeffery Trent, PhD, a contributor to the study and president and research director of the Translational Genomics Research Institute.

_References:

_{1. City of Hope and Osel announce live biotherapeutic product CBM588 may enhance efficacy of immunotherapy for patients with metastatic kidney cancer. City of Hope. Published February 28, 2022. Accessed February 28, 2022. https://bwnews.pr/35yuSDe}

_{2. Dizman N, Meza L, Bergerot P, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med (2022). doi:10.1038/s41591-022-01694-6}