Altering gut microbiome may benefit patients with metastatic kidney cancer
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Key takeaways:
- Changing the gut microbiome improved objective response rate among patients with metastatic kidney cancer.
- The approach could benefit patients with other solid tumors.
Combining gut microbiome manipulation with immunotherapy and tyrosine kinase inhibitor therapy conveyed clinical benefit for patients with metastatic renal cell carcinoma, results of a randomized phase 1 trial showed.
Researchers reported a significantly higher overall response rate among participants who received CBM588, a live bacterial product.
“My expectations were exceeded,” Sumanta K. Pal, MD, FASCO, co-director of City of Hope’s kidney cancer program and a Healio | HemOnc Today Editorial Board member, said in an interview. “I was certainly surprised by the results. The signal that we’re seeing justifies us migrating toward a phase 3 clinical trial.”
Background
Immune checkpoint inhibitors have improved outcomes in metastatic renal cell carcinoma. Guidelines recommend PD-1 inhibitor treatment in combination with a CTLA-4 inhibitor or VEGF receptor TKI. However, only 10% to 17% of patients achieve complete response; most patients develop disease progression while on treatment, according to study background.
Some researchers have proposed triplet regimens — for example, combining PD-1 and CTLA-4 inhibition with a VEGF receptor TKI — but the only phase 3 trial to compare doublet with triplet therapy revealed “notable toxicity concerns,” according to researchers.
Pal and colleagues have researched the gut microbiome and its impact on immunotherapy and adverse events in this patient population for more than a decade. Their work has included a focus on probiotics and live bacterial products — natural products that manipulate the microbiome, Pal said.
Results of a pilot trial showed the addition of CBM588 — a bifidogenic live bacterial product, — to nivolumab (Opdivo, Bristol Myers Squibb) and ipilimumab (Yervoy, Bristol Myers Squibb) resulted in “drastic improvement in outcomes” such as PFS and objective response for patients with metastatic renal cell carcinoma, Pal said.
Methods
Pal and colleagues conducted a phase 1 trial to evaluate the addition of CBM588 — which is available over the counter in Japan — to front-line treatment with the VEGFR TKI cabozantinib (Cabometyx, Exelixis) and the PD-1 inhibitor nivolumab.
The cohort included 30 patients (median age, 65 years; 67% men; 87% white) with locally advanced or metastatic renal cell carcinoma with a clear cell, papillary or sarcomatoid component who had received no prior treatment for metastatic disease.
All patients received 40 mg cabozantinib daily and 480 mg nivolumab monthly. Researchers randomly assigned two-thirds of study participants to also receive CBM588 as a powder mixed with water twice daily.
Change in Bifidobacterium species, which researchers hypothesized could be linked to better response, served as the primary endpoint. Secondary endpoints included ORR, PFS and safety profile.
Results
The study failed to meet its primary endpoint, as results showed no significant difference in the relative abundance of Bifidobacterium species between baseline and week 13 in either treatment cohort.
However, researchers reported a significantly higher ORR (74% vs. 20%, P = .01) and a higher clinical benefit rate (80% vs. 60%) in the CBM588 group.
Median PFS and OS had not been reached in either group; however, results showed improved landmark PFS at 6 months in the CBM588 group (84% vs. 60%).
A higher percentage of patients assigned CBM588 achieved reduction in target lesion size (89% vs. 80%). Median decrease in target lesions was 42% with CBM588 and 20% in the control group.
Forty percent of patients in each group experienced grade 3 or grade 4 adverse events attributable to treatment. The most common grade 3 or higher toxicities overall included transaminitis (10%), hypertension (7%) and diarrhea (7%), with comparable rates between treatment groups.
“One of the challenges in oncology is that we have a plethora of different medications that can potentially augment clinical responses, but they do so at the price of toxicity,” Pal said. “[We] may take a triplet to a quadruplet, or a quadruplet to a quintuplet, [but there is] a price to pay when it comes to their toxicity profile. I think CBM588 — and, in general, the strategy of live bacterial product modulation — stands to potentially improve these outcomes without adding too much additional toxicity.”
Next steps
Pal and colleagues are still unsure about the mechanism behind the improved outcomes for patients treated with CBM588, but they do have a theory.
“About 96% of the bacteria that we host within our gut sits in the large intestine,” he said. “CBM588 is a spore. We think that it deposits in the large intestine and flourishes there. When it’s there, it secretes a compound called butyrate, which is a short-chain fatty acid. It gets released in the bloodstream, and we think that’s what drives the T cells toward tumors. At least it helps in that process.”
Researchers acknowledged study limitations, including the small size and heterogeneity of the study population.
The data so far support further investigation, Pal said.
“[These products] are doing their job and they’re creating tumor reductions,” he said. “The onus is on us to take these compounds one step further and test them clinically.
“I don’t think there’s any chance that one would argue that the work that we’ve done to date could potentially influence clinical practice,” Pal added. “We need these phase 3 clinical trials such that one day we may influence clinical practice and have this represent a standard of care.”
The approach “absolutely” may be useful for patients with other solid tumors, Pal said.
“I’m hoping that this is something that just isn't a kidney cancer-specific phenomenon,” he said.
For more information:
Sumanta K. Pal, MD, FASCO, can be reached at spal@coh.org.
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