Camu camu联合nivolumab/ipilimumab(N/I)作为转移性肾细胞癌(mRCC)一线治疗：一项随机I期临床试验

Background: N/I is a standard first-line therapy for mRCC. Our group has shown that gut microbiome modulation may enhance immune checkpoint inhibitor (ICI) efficacy in mRCC (Dizman et al, 2022; Ebrahimi et al, 2024). In preclinical models, camu camu, a polyphenol-rich Amazonian berry, enriched Ruminococcus spp. in the gut microbiome and improved responses to ICI in mice (Messaoudene et al 2022). We prospectively evaluated the biological and clinical effects of adding camu camu to N/I for mRCC therapy. Methods: This single-center, randomized, phase I trial enrolled pts. ≥18 years with clear-cell mRCC, IMSC intermediate- or poor-risk disease, ECOG 0-1, measurable disease, and adequate organ function. Prior systemic therapy was not allowed, except adjuvant or neoadjuvant therapy completed ≥6 months without prior ICI exposure. Patients were randomized 2:1 to receive standard-dose N/I (3 mg/kg plus 1 mg/kg every 3 weeks for 4 doses, then N 480 mg every 4 weeks) with or without camu camu 1500 mg PO daily. The primary endpoint was the change in Ruminococcus spp. abundance in stool from baseline to week 13. Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), safety, changes in microbiome diversity, and plasma cytokine assessment. A 2-group t-test with a 1-sided type I error of 0.05 was used to assess the primary endpoint, increase in Ruminococcus spp. with camu camu. Results: We enrolled 31 patients (21 N/I plus camu camu; 10 N/I alone) with a median follow-up of 15.9 months. Median age was 64 years (range 45-84),10% had sarcomatoid features, 35% had a nephrectomy, and 29% presented poor-risk disease. Median PFS was 16.4 months (95% CI 5.5-not estimable [NE]) in the camu camu arm vs 5.4 months (95% CI 2.6-NE) with N/I alone (p=0.04). ORR was 33% in the experimental and 10% in the control arm (p=.2). Median OS was not reached in either arm. No significant differences in Ruminococcus spp. abundance present. Alpha diversity as measured by species richness in the placebo arm decreased from baseline to week 13 (p=0.02), whereas it remained stable in the camu camu arm (p=0.5). In the N/I arm, there was an increased differential abundance at week 13 compared to baseline in deleterious bacteria such as Collinsella aerofaciens , Veillonella rogosae , and Enterococcus gallinarum , while beneficial bacteria including Ruminococcus lactaris remained enriched at week 13 in the camu camu arm. The proportion of beneficial SIG2 TOPOscore (Derosa et al., Cell 2024) bacteria significantly increased at week 13 in responders (15% vs. 29%, p<0.001), not observed in the N/I group. The most frequent adverse events (AEs) in both arms were fatigue and anemia. Patients in the camu camu arm displayed a distinct pattern of immune-related AEs (irAEs), including cerebritis (n=2), immune thrombocytopenic purpura (n=1), and adrenal insufficiency (n=6). Cytokine assessment showed significant changes at week 13 compared with baseline in this group, with increased IL-10 and IL-17A, and reduced IL-8 levels. Conclusion: In this first randomized trial evaluating a natural prebiotic with ICI in first-line mRCC, the addition of camu camu prolonged PFS and beneficially shifted the gut microbiome. The irAEs observed with camu camu, together with associated cytokine alterations, emphasize the need for close monitoring in future studies.