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AUSTIN, Texas -- Progression-free survival (PFS) in advanced kidney cancer improved dramatically with the addition of a gut-bacteria derivative to immunotherapy, a small randomized trial showed.

Median PFS increased from 2.5 months with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) to 36.4 months with the same doublet plus CBM588. Median overall survival (OS) had yet to be reached in either arm of the 30-patient trial, but early separation in the survival curves favored treatment with CBM588, reported Nazil Dizman, MD, of the Yale School of Medicine in New Haven, Connecticut, at the International Kidney Cancer Symposium (IKCS).

"Although limited by the sample size, the combination of nivolumab/ipilimumab and CBM588 demonstrated superior clinical outcomes over nivolumab and ipilimumab," she said. "Progression-free survival and objective response rate with nivolumab/ipilimumab and CBM5887 also exceeded those observed with nivolumab and ipilimumab in historical data sets. No new safety signals were observed with long-term CBM588, and larger cohorts investigating the impact of CBM588 on clinical outcomes are underway."

Clinical outcomes were a secondary objective of the phase Ib trial, Dizman noted. The primary outcome related to the effect of CBM588 on the abundance of Bifidobacterium species. As , the trial did not meet the biological endpoint, but initial results suggested a favorable effect of CBM588 on clinical outcomes.

Containing a live bifidogenic bacterial product from Clostridium butyricum, CBM588 has been studied extensively and used clinically as a probiotic to manage gastrointestinal conditions in Japan, where it was originally isolated from soil samples in Nagano. Several research groups have independently shown associations between the gut microbiome and response to cancer immunotherapy.

A from Japan showed patients with advanced non-small cell lung cancer treated with immunotherapy had prolonged PFS and OS if they also received CBM588, including patients treated with antibiotics, which are known to blunt immunotherapy's anticancer activity. A identified multiple gut bacteria associated with improved PFS in patients with lung cancer and renal cell carcinoma (RCC) treated with immune checkpoint inhibitors.

Dizman reported clinical outcomes from a randomized trial involving patients with metastatic clear cell or sarcomatoid RCC. Eligible patients had received no systemic therapy for metastatic disease, and all had intermediate- or poor-risk disease by the International Metastatic RCC Disease Consortium classification system.

The patients were randomized 1:2 to nivolumab and ipilimumab or to the same immunotherapy doublet plus CBM588. Data analysis included all 10 patients assigned to immunotherapy and 19 of 20 allocated to the CBM588 arm.

The results showed a numerical advantage for CBM588 for objective response (58% vs 20%, P=0.06) and a significantly higher disease control rate (79% vs 40%, P=0.004). Median duration of response with CBM588 was 30.7 months. The addition of CBM588 was associated with a 90% reduction in the risk of disease progression or death (95% CI 0.03-0.33, P<0.001).

With a median follow-up of about 2 years, median OS had yet to be reached in either treatment group. However, the survival curves separated early and showed an OS of about 80% with CBM588 versus 60%-65% for the immunotherapy doublet without the probiotic agent. OS for the entire cohort was 82.8%.

The adverse event (AEs) rate for the entire cohort was 93% and did not differ significantly between the two groups. Grade 3 AEs occurred in 63% of the CBM588 arm versus 50% of the patients who received nivolumab/ipilimumab without the probiotic. No grade 4 AEs occurred with CBM588 versus one episode of grade 4 decrease in neutrophil count.

"Grade 3 adverse events with nivolumab/ipilimumab and CBM588 appear to be single events, and none stood out more frequently than others," said Dizman.

A randomized will evaluate nivolumab/ipilimumab with or without CBM588 in patients with intermediate- and high-risk clear cell RCC.

During a post-presentation discussion, an IKCS attendee pointed out that "there's a lot of evidence that microbiome diversity plays a big role in potential response, and also potential major differences by geographic regions. Ancestry may end up playing an interesting role that we need to learn about."

"I'm curious if you are going to start exploring microbiome diversity in patients who are in this more poor-risk, potentially more likely to be exposed to antibiotics group. Could this end up playing a role in the effectiveness, adding basically one microbiome modulator for patients that may have a lack of diversity due to previous exposure to antibiotics and other treatment?," the attendee said.

The phase III study, which will be conducted in Europe, will include sequential sampling of the gut microbiome, as well as blood samples that should provide more insight into the role of microbiome diversity in response to immunotherapy in RCC, Dizman said.

In response to another question, she said participants in the small randomized trial had restrictions on consumption of certain foods that might confound the findings (such as yogurt and kefir). Patients were required to maintain a dietary journal, which suggested that the patients complied with the restrictions. However, she acknowledged that adherence to dietary restrictions could be more challenging in a large clinical trial.

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