Phase I study of SOF10 plus atezolizumab in patients with advanced/recurrent solid tumours

BackgroundTransforming growth factor beta 1 (TGF-β1) is released by cancer cells, stromal fibroblasts and other cells resulting in an immunosuppressive tumour microenvironment (TME). Targeting TGF-β1 with SOF10, an antibody that inhibits the activation of latent TGF-β1, may therefore enhance the efficacy of cancer immunotherapies such as atezolizumab (anti-PD-L1).MethodsThis multicentre, open-label, dose-escalation study (jRCT2031200407) evaluated the safety, pharmacokinetics (PK) and anti-tumour activity of SOF10 (100–1800 mg) plus atezolizumab (1200 mg) IV q3w in patients (pts) with advanced/recurrent solid tumours and ECOG PS 0–1. Dose escalation (DE) was done using a 3 + 3 design. Pts in the DE part Cohorts 1–5 received SOF10 (Cycle 1) then SOF10 + atezolizumab from Cycle 2; Cohort 6 received SOF10 + atezolizumab from Cycle 1. A backfill part enrolled pts to Cohorts 2–5 per the DE regimens. Tolerability was evaluated during Cycles 1–2 in the DE part. Primary endpoints were safety and PK; secondary endpoints included anti-tumour activity (per RECIST 1.1).ResultsAt clinical cutoff (15 June 2023) 52 pts were enrolled (22 in DE, 30 in backfill). See table for safety data. Treatment-related adverse events (TRAEs) were seen in 30 pts (57.7%). The most common TRAE was rash (grade 1–2). One dose-limiting toxicity (liver disorder) was seen with SOF10 (600 mg) + atezolizumab. The maximum tolerated dose was not reached. SOF10 exposure levels increased with dose and the SOF10 PK profile at Cycle 1 was similar between Cohort 5 (SOF10) and Cohort 6 (SOF10 + atezolizumab). Anti-SOF10 antibodies were seen in three pts (5.8%). The confirmed objective response rate was 8.0% (n = 4 of 50; all partial responses in pts on treatment for >200 days at cutoff; Table).ConclusionsSOF10 + atezolizumab was well tolerated in pts with advanced solid tumours, with no notable safety concerns. SOF10 showed an increase in exposure with dose and addition of atezolizumab did not appear to affect SOF10 PK. The partial responses were durable. Table: 1016P DE DE + backfill DE Cohort 1 (n = 3) 2 (n = 14) 3 (n = 12) 4 (n = 10) 5 (n = 10) 6 (n = 3) SOF10 dose, mg 100 300 600 1200 1800 1800 Atezolizumab dose, mg 1200 1200 1200 1200 1200 1200 Safety, n (%) TRAE 3 (100) 9 (64) 6 (50) 4 (40) 7 (70) 1 (33) Grade 3 0 1 (7) 0 0 1 (10) 0 Grade 4 0 0 1 (8) 0 0 0 Grade 5 0 0 0 0 0 0 Confirmed best response, n (%) Responders 1 (33) 2 (14) 0 0 1 (13) a 0 Partial responseb 1 (33) 2 (14) 0 0 1 (13) a 0 Disease control rate 1 (33) 5 (36) 2 (17) 1 (10) 4 (50) a 0 DE, dose escalation; TRAE, treatment-related adverse event.aCohort 5 objective response rate-evaluable pts: n = 8.bIn pts with renal, gallbladder, ovarian and colorectal cancer, respectively. Clinical trial identificationjRCT2031200407.Editorial acknowledgementBrian Law, PhD, of Nucleus Global, an Inizio company.Legal entity responsible for the studyChugai Pharmaceuticals, Ltd.FundingChugai Pharmaceuticals, Ltd.DisclosureT. Doi: Financial Interests, Personal, Other, Advisory Role: Noil-Immune Biotech, Oncolys BioPharma, Boehringer Ingelheim, A2 Healthcare, Nano Carrier, PRA Health Sciences, Kaken Pharma, Chugai Pharma, Sumitomo Pharma, Shionogi, Otsuka Pharma, Takeda, Kyowa Kirin, Rakuten Medical, Giliad; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Taiho, MSD, AbbVie, Eisai, Pfizer, BMS, Janssen Pharma, Daiichi Sankyo, Chugai Pharma, Boehringer Ingelheim, PRA Health Sciences, Amgen, GSK, Shionogi, RIN Institute, Ono Pharma. Y. Kuboki: Financial Interests, Personal, Advisory Board: Takeda, Amgen, Abbie, Incyte, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Taiho, Lilly; Financial Interests, Institutional, Local PI: Taiho, Astelas, Lilly, Takeda, AstraZeneca, Boehringer Ingelheim, Chugai, Genmab, Incyte, Abbie, Merck, Novartis, Hengrui; Financial Interests, Institutional, Coordinating PI: Amgen; Non-Financial Interests, Member: JSMO, ASCO, JSCO, JCA. S. Koganemaru: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: Chugai Pharma. T. Koyama: Financial Interests, Personal, Invited Speaker: Sysmex, Chugai, AstraZeneca; Financial Interests, Institutional, Research Grant: PACT Pharma, Boehringer Ingelheim; Financial Interests, Institutional, Local PI: Novartis, Chugai, Lilly, Daiichi Sankyo, Takeda, AstraZeneca, Zymeworks. J. Sato: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: Chugai Pharma. Y. Katsuya: Non-Financial Interests, Personal, Funding, Research funding, Support for third-party writing assistance: Chugai Pharma. E. Ueda, K. Higashikawa, T. Ishida, M. Nakamura, S. Nakagawa: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: Chugai Pharma; Financial Interests, Personal, Full or part-time Employment: Chugai Pharma. N. Yamamoto: Financial Interests, Institutional, Principal Investigator: Astellas, Chugai Pharma, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, Ono, Janssen Pharma, MSD, Merck, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogu, Toray, Kaken, AstraZeneca, Cmic, Rakuten Medical; Financial Interests, Personal, Advisory Board: Eisai, Takeda, Boehringer Ingelheim, Cmic, Chugai Pharma, Merck, Healios; Non-Financial Interests, Personal, Funding, Research funding, Support for third-party writing assistance: Chugai Pharma; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharma, Daiichi Sankyo, Eisai.