Live bacterial supplementation may improve TKI-based treatment efficacy in kidney cancer

Data from a phase 1 trial (NCT05122546) recently published in Nature Medicine suggest that live bacterial supplementation with CBM588 while receiving treatment with cabozantinib and nivolumab may improve health outcomes for patients with locally advanced or metastatic renal cell carcinoma.^1,2

The objective response rate was 74% among those receiving CBM588 vs 20% among those in the control arm.

“We at City of Hope are the first to demonstrate a live bacterial product’s ability to improve clinical outcomes for patients with kidney cancer treated with immunotherapy. CBM588 could be exciting in cancer treatment because of its potential to enhance the efficacy of immune checkpoint inhibitor-based treatment, improve patient outcomes, and modulate the gut microbiota in beneficial ways,” senior author Sumanta Pal, MD, professor and vice chair of academic affairs in the Department of Medical Oncology & Therapeutics Research at City of Hope, said in a news release on the findings.² “Ongoing and larger clinical trials are crucial to validate these benefits and address current challenges. If the positive results observed in this small trial and a previous trial with nivolumab and ipilimumab are confirmed, CBM588 could become a valuable supplement in the treatment of various cancers, particularly for patients treated with immune checkpoint inhibitors."

For the trial, patients were randomly assigned 2:1 to receive cabozantinib and nivolumab with or without CBM588. The primary end point for the trial was a change in the relative abundance of Bifidobacterium spp from baseline to week 13 of treatment. Secondary outcome measures included the objective response rate (ORR), progression-free survival (PFS), and the toxicity profile of CBM588.

At a median follow-up of 15.9 months, 18 patients remained on treatment (of 30 enrolled).

Overall, the trial did not meet the primary end point, showing that the addition of CBM588 to cabozantinib and nivolumab had no effect on the relative abundance of Bifidobacterium spp.

However, patients receiving CBM588 demonstrated a significantly higher ORR vs those in the control arm, with a rate of 74% (14/19) with CBM588 vs 20% (2/10) without (P = .01). A reduction in target lesion size was achieved in 89% (17/19) patients receiving CBM588 vs 80% (8/10) in the control arm. The median reduction in target lesion size was 42% (range, 17%-94%) in the treatment arm vs 20% (range, 11%-100%) in the control arm.

Clinical benefit, defined as complete response, partial response, or stable disease for at least 6 months, was achieved in 80% (16/20) of patients receiving CBM588 vs 60% (6/10) patients in the control arm.

Additionally, the 6-month PFS among those receiving CBM588 was 84% (16/19), compared with 60% (6/10) among those in the control arm. At the time of data cutoff, the median PFS and overall survival had not been reached in either cohort.

The addition of CBM588 did not result in a significant difference in the toxicity profile between the 2 arms.

In total, the open-label, phase 1 study enrolled 30 patients with histologically confirmed locally advanced or metastatic RCC with a clear cell, papillary, or sarcomatoid component. All patients included in the trial had not received prior systemic therapy for metastatic RCC and had a Karnofsky performance status of 70 or higher.

The median age of participants was 65 years. The median follow-up was 14.2 months in the treatment arm and 16.1 months in the control arm.

Based on these findings, investigators from the trial are now working on plans to design a phase 2/3 trial in collaboration with the global SWOG Cancer Research Network to further evaluate CBM588 and microbiome modulation in patients with advanced cancer.

The authors concluded, “Our results provide a preliminary signal of improved clinical activity with CBM588 in treatment-naive participants with mRCC receiving cabozantinib and nivolumab. Further investigation is needed to confirm these findings and better characterize the underlying mechanism driving this effect.”¹

References

1. Ebrahimi H, Dizman N, Meza L, et al. Cabozantinib and nivolumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nature Med. Doi:10.1038/s41591-024-03086-4

2. City of Hope study suggests changing the gut microbiome improves health outcomes for people newly diagnosed with metastatic kidney cancer. News release. City of Hope. June 28, 2024. Accessed June 29, 2024. https://www.cityofhope.org/city-of-hope-study-suggests-changing-the-gut-microbiome-improves-health-outcomes-for-people-newly