Combination nivolumab and ipilimumab with and without camu camu in first-line treatment of metastatic renal cell carcinoma (mRCC).
Authors: Barragan-Carrillo Regina , Chawla Neal Shiv , Salgia Nicholas , Meza Luis A , Zengin Zeynep Busra , Li Xiaochen , Dizman Nazli , Ebrahimi Hedyeh , Hsu Joann , Castro Daniela V. , Mercier Benjamin D. , Dorff Tanya B. , Tripathi Abhishek , Bergerot Cristiane Decat , Bergerot Paulo Gustavo , Chehrazi-Raffle Alex , Pal Sumanta Kumar 
Published: February 2024

TPS491

Background: Combination immune checkpoint inhibition (ICI) with ipilimumab and nivolumab (ipi/nivo) is an established first-line treatment for patients (pts) with intermediate and poor-risk mRCC. CheckMate214 demonstrated a survival advantage with ipi/nivo over sunitinib; unfortunately, 20% of cases developed primary progression to immunotherapy. Recent data suggest that the gut microbiome is key in modulating clinical responses and immune-related toxicities. Therefore, modulating the gut microbiome is a novel adjunct strategy to dual ICI in mRCC. Our group has previously proven that the addition of a live bacterial product (CBM588) enhances clinical responses in pts with mRCC treated with ICI, and the combination of ICI (Dizman et al., 2022) or with a tyrosine kinase inhibitor (Ebrahimi et al., 2023). Camu camu ( Myrciaria dubia) is a comestible berry characterized by a polyphenol-rich nutritional profile. In extract form, it is rich in castalagin, which appears to have probiotic properties. In mouse tumor models, camu camu increased the abundance of fecal Ruminococcus spp. when combined with ICI (Messaoudene et al., 2022). This shift in the gut microbiome composition was associated with stronger CD8+ T-cell and CD4+ Th1-dependent antitumor responses. Camu camu and ICI reestablished the efficacy of anti-PD1 therapy, reducing tumor size compared to ICI alone. This pilot study aims to identify the biological effect of camu camu with ipi/nivo in pts with mRCC. Methods: This is an investigator-initiated, randomized, open-label, single-center trial comparing camu camu with ipi/nivo versus ipi/nivo alone in pts with treatment-naïve mRCC. Eligibility criteria include pts ≥ 18 year old, PS 0-1, histological confirmation of clear-cell RCC with or without a sarcomatoid component, intermediate or poor risk per IMDC, no prior systemic treatment and measurable disease,. 30 pts will be enrolled and randomized in a 2:1 fashion, favoring the study arm. Pts will be treated with camu camu at 1500 mg PO daily, in with ipi/nivo at standard dosing. Pts will be followed monthly. Treatment will be continued until progression (RECIST v1.1) or toxicity. The primary endpoint is change in the abundance of Ruminococcus spp. in the stool from baseline to week 12 of therapy. We have 80% power to detect a 1 SD difference between the mean change detected in the two groups using a two-group T-test with a one-sided type I error of 0.05. Secondary endpoints include overall response rate, progression-free survival, safety, effect on gut microbiome diversity and function, comparison of the proportion of circulating cytokines and chemokines from baseline to week 12, and changes in the abundance of metabolic pathways and fungal microbiome profile. Response will be assessed by CT after the first 12 weeks of therapy and every 12 weeks, thereafter. The study is currently open to enrollment. Clinical trial information: NCT06049576 .