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Background Acquired resistance to immune checkpoint inhibitors (ICIs) remains an urgent unmet need in the management of advanced solid tumors. ICI retreatment has demonstrated minimal clinical benefit. Accumulating preclinical and translational data indicate that the gut microbiota plays a pivotal role in antitumor immunity and ICI efficacy. 1 We hypothesized that targeted modulation of the microbiome with dietary intervention could restore sensitivity to ICIs. It has been reported that intake of highly fermentable dietary fiber decreases gut microbial alpha-diversity while increasing the abundance of Bifidobacterium species.2 Here, we report interim results from a Phase II single-arm trial evaluating a novel microbiota-targeting therapeutic using high dose galactomannan-derived high-fermentable dietary fiber in patients with ICI-resistant solid tumors.Methods This was a multicohort, open-label Phase II study designed using Simon’s two-stage minimax method. Each cohort (non small cell lung, gastric, esophageal cancer) required 7 patients, with interim analysis after 4 enrollments. The null hypothesis assumed a 6-month progression-free survival (PFS) rate of 5%, with an expected rate of 35%. With a one-sided α of 0.1 and 70% power, efficacy was defined as ≥2 patients per cohort achieving 6-month PFS. Eligible patients had histologically confirmed those tumors with documented acquired resistance after prior clinical benefit on ICI therapy. Patients received oral high dose galactomannan-based high-fermentable dietary fiber in combination with their most recent ICI regimen until progression or unacceptable toxicity.Results At the time of data cutoff, 7 lung cancer patients, 5 gastric cancer patients, and 2 esophageal cancer patients were enrolled. In the lung cancer cohort, 3 of 7 patients achieved the primary endpoint of 6-month PFS, surpassing the predefined efficacy threshold. In the gastric cancer cohort, 2 of 5 patients achieved 6-month PFS, also meeting efficacy criteria. The esophageal cancer cohort is ongoing and has not yet reached interim evaluation ( table 1). The regimen was well tolerated, with no unexpected grade ≥3 adverse events. Exploratory analyses demonstrated favorable shifts in gut microbiota composition consistent with restored ICI responsiveness.Conclusions This Phase II trial provides the first clinical evidence that microbiota-targeting therapeutics using high dose galactomannan-derived high-fermentable dietary fiber can restore ICI sensitivity in patients with solid tumors who developed acquired resistance. The therapy achieved the predefined efficacy endpoint in both lung and gastric cancer cohorts, demonstrating clinically meaningful activity with a favorable safety profile. These findings highlight a revolutionary therapeutic concept—targeting the gut microbiota—to overcome immune resistance, and strongly support further development in randomized Phase III trials.Trial Registration Japan Registry of Clinical Trials (jRCT), identifier jRCTs031230606.References Hamada K, Isobe J, Hattori K, Hosonuma M, Baba Y, Murayama M, Narikawa Y, Toyoda H, Funayama E, Tajima K, Shida M, Hirasawa Y, Tsurui T, Ariizumi H, Ishiguro T, Suzuki R, Ohkuma R, Kubota Y, Sambe T, Tsuji M, Wada S, Kiuchi Y, Kobayashi S, Kuramasu A, Horiike A, Kim YG, Tsunoda T, Yoshimura K. Turicibacter and Acidaminococcus predict immune-related adverse events and efficacy of immune checkpoint inhibitor. Front Immunol. 2023;14:1164724.Rosli D, Shahar S, Manaf ZA, Lau HJ, Yusof NYM, Haron MR, Majid HA. Randomized controlled trial on the effect of partially hydrolyzed guar gum supplementation on diarrhea frequency and gut microbiome count among pelvic radiation patients. JPEN J Parenter Enteral Nutr. 2021;45:277-286.Ethics Approval This specified clinical trial was approved by the Clinical Research Review Board of Showa Medical University (SHOWA Medical University Clinical Research Review Board) and is registered in the Japan Registry of Clinical Trials under identifier jRCTs031230606. The study was conducted in accordance with the principles of the Declaration of Helsinki and the Japanese Clinical Trials Act. Written informed consent was obtained from all participants prior to enrollment.Abstract 1324 Table 1Patient Enrollment and Six-Month PFS Outcomes by Cohort. Summary of patient enrollment and clinical outcomes by tumor type. The primary endpoint (6-month PFS) was achieved in both lung and gastric cancer cohorts. Data cutoff: 8th Sep 2025