1455 Phase 1 study of XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, in combination with atezolizumab in patients with advanced solid tumors
Year: 2024
Type: conference-abstract
Abstract: Background XTX101 is an investigational tumor-activated, Fc-enhanced, high affinity binding anti-CTLA-4 designed to block CTLA-4 and deplete regulatory T cells upon activation in the tumor microenvironment by proteases. XTX101 also contains mutations designed to enhance Fcγ receptor binding and improve effector function. Fc enhancement augments FcγR co-engagement on antigen presenting cells and has been linked with efficacy of anti-CTLA-4 combinations in patients with ‘cold tumors,’ including MSS colorectal cancer (CRC).1 Methods Parts 1A and 1B of the XTX101 study (NCT04896697) evaluated XTX101 monotherapy in patients with advanced solid tumors. XTX101 was generally well tolerated in line with observed limited peripheral activation (~13%), this was in contrast to higher tumor activation (73–96%, n=2 on-treatment biopsies). A durable partial response (PR) and resolution of hepatic metastases was observed in a patient with PD-L1 negative NSCLC at the monotherapy RP2D of 150 mg once every six weeks (Q6W).2 Data from part 1C evaluating XTX101 in combination with atezolizumab in patients with advanced solid tumors are presented here. Results As of July 15, 2024, 15 patients were enrolled in Part 1C: MSS CRC (n=12), esophageal cancer, NSCLC, and ampullary carcinoma (n=1 each). Median age 69 and 3 prior lines of therapy (range 1–12). Across all XTX101 dose levels (75 mg to 150 mg), treatment-related adverse events (TRAEs) of any grade with >10% incidence included infusion reactions (n=4), fatigue and diarrhea (n=2 each), and no G4 or G5 TRAEs were reported. In Part 1C, only 2 patients experienced a dose limiting toxicity: 1 patient had G3 colitis/diarrhea, and 1 patient had G3 hepatic enzyme elevation (both were at the XTX101 150 mg dose level and resolved with immunosuppression). Combination RP2D was established as XTX101 100 mg Q6W and atezolizumab 1200 mg Q3W. Unconfirmed PRs (n=2) were reported in a patient with MSS CRC (including resolution of a liver target lesion) and a patient with ampullary carcinoma (accompanied by a significant Ca 19-9 decrease). In addition, a decrease in intra-tumoral Tregs were observed in paired tumor biopsies from a patient. Conclusions In Part 1C dose escalation, the combination of XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4, and atezolizumab was generally well tolerated in patients with advanced solid tumors and demonstrated initial evidence of anti-tumor activity in cold tumors. These data support the initiation of an ongoing Phase 2 study evaluating the combination in patients with MSS CRC with and without liver metastases. Trial Registration NCT04896697. References Bullock A, Fakih M, Gordon M, et al. ESMO GI 2023. Davar D, Knecht J, Vandross A, et al. ESMO IO 2023. Ethics Approval This study obtained ethics approval though a central IRB (Advara IRB: Pro00057609) Participants gave informed consent before taking part in the study.
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4404066734