Vandross, Andrae Lavon

3553 Background: Vilastobart (XTX101) is tumor-activated, high affinity, Fc-enhanced aCTLA-4 designed to focus activity toward the tumor and minimize systemic adverse events. Fc-enhancement augments FcγR co-engagement on antigen presenting cells and has been linked with efficacy of aCTLA-4 combinations in patients (pts) with microsatellite stable (MSS) colorectal cancer (CRC) and other tumors [Fakih ASCO GI 2025]. Vilastobart was generally well-tolerated and demonstrated evidence of anti-tumor activity in pts with immunologically “cold” advanced solid tumors, both as a monotherapy and in combination with atezolizumab [Davar SITC 2024]. Methods: Phase 2 of the NCT04896697 study evaluated the initial recommended Phase 2 dose of vilastobart 100 mg Q6W in combination with atezolizumab 1200 mg Q3W in pts with MSS CRC who had at least 1 prior chemotherapy regimen in the metastatic setting, excluding pts with prior immune checkpoint inhibitors. Pts with (LM) and without liver metastasis (NLM) were eligible. Tumor biopsies were obtained before and during treatment for translational analyses. Results: As of January 13, 2025, 40 pts were dosed in Phase 2. Median age was 55 (25-82) and 70% of pts had 3 or more prior lines of therapy. Of the 24 enrolled NLM pts, 11 were response-evaluable with an available on-treatment scan as of the data cut. In these 11 pts, two confirmed and one unconfirmed partial response (PR) were reported, all accompanied by significant decreases in ctDNA and serum tumor marker CEA and with each pt ongoing on therapy, for a preliminary ORR of 27%. One additional pt (with peritoneal metastasis) had a 24% reduction in target lesions (first scan) and was ongoing on therapy. Of the 16 enrolled LM pts, 7 were response evaluable, with one stable disease and another pt reporting a mixed response with significant serum tumor marker reductions, both ongoing on therapy. Of note, one LM pt in Phase 1C dose escalation treated with vilastobart (150 mg Q6W) combination had a confirmed PR with LM resolution. Six pts (15%) reported G3+ treatment-related adverse events (TRAEs), with two G4 laboratory TRAEs and no G5 TRAEs. Only three pts discontinued therapy for TRAEs. TRAEs occurring in ≥10% (all grade) or ≥5% (G3) of pts are summarized in the Table. Conclusions: The combination of vilastobart, a novel tumor-activated, Fc-enhanced a-CTLA-4, and atezolizumab demonstrated initial evidence of anti-tumor activity in late line, metastatic MSS CRC where immune checkpoint blockade has historically been relatively ineffective. Vilastobart was observed to have a differentiated safety profile distinct from systemically active a-CTLA-4, consistent with tumor-selective activation. Clinical trial information: NCT04896697 . AE term All Graden (%) Grade 3n (%) Fatigue 12 (30%) 0 Diarrhea 8 (20%) 0 Infusion related reactions 5 (13%) 0 Pyrexia 4 (10%) 0 ALT increased 4 (10%) 0 AST increased 4 (10%) 1 (3%) Colitis 2 (5%) 2 (5%)

206 Background: XTX101 is an investigational tumor-activated, Fc-enhanced, high affinity binding aCTLA-4 designed to block CTLA-4 and deplete regulatory T cells upon activation in the tumor by proteases. XTX101 also contains mutations designed to enhance Fcγ receptor binding. Fc enhancement augments FcγR co-engagement on antigen presenting cells and has been linked with efficacy of aCTLA-4 combinations in patients (pts) with “cold tumors”, including microsatellite stable (MSS) colorectal cancer (CRC). Parts 1A/1B of the study evaluated XTX101 monotherapy in pts with advanced solid tumors. XTX101 was generally well tolerated with limited peripheral XTX101 activation (~13%) compared to evidence of XTX101 activation in the tumor microenvironment (73-96%, in n=2 on-treatment tumor biopsies). A durable partial response (PR) and resolution of hepatic metastases was observed in a pt with PD-L1 negative NSCLC at the monotherapy recommended phase 2 dose (RP2D) of 150 mg once every six weeks (Q6W) [1]. Methods: Part 1C evaluated the safety and feasibility of XTX101 in combination with atezolizumab in pts with advanced solid tumors using 3+3 dose escalation to establish the RP2D. Phase 2 is enrolling pts with MSS CRC with at least 1 prior regimen for metastatic CRC. Initial safety and anti-tumor activity data from Phase 2 in ~20 pts will be presented. Results: As of July 15, 2024, 15 pts 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 (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), no G4 or G5 TRAEs were reported. In Part 1C, 2 pts experienced a dose limiting toxicity: 1 pt had G3 colitis, and 1 pt had G3 liver enzyme elevation (both were at the XTX101 150 mg dose level and resolved with immunosuppression). Two unconfirmed PRs were reported: in a pt with MSS CRC, including resolution of a liver target lesion, and in a pt with ampullary carcinoma (accompanied by a Ca 19-9 decrease from 700 to 41). In addition, a decrease in intra-tumoral Tregs was observed in paired tumor biopsies from a pt. The combination RP2D was established as XTX101 100 mg Q6W and atezolizumab 1200 mg once every three weeks (Q3W), and enrollment in the Phase 2 part of the study for pts with MSS CRC is ongoing at the RP2D. Conclusions: In Part 1C dose escalation, the combination of XTX101, a tumor-activated, Fc-enhanced aCTLA-4, and atezolizumab was generally well tolerated in pts 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 pts with MSS CRC with and without liver metastases. 1. Davar ESMO IO 2023. Clinical trial information: NCT04896697 .

3083 Background: Cancer-Specific Plectin (CSP) is a novel pro-tumorigenic target that is selectively expressed on the surface of tumors, while absent from benign tissue. CSP is highly expressed in many solid cancers, particularly pancreatic (PC), cholangiocarcinoma (CCA), and ovarian (OC). ZB131 (Zielbio), is a humanized anti-CSP IgG1 monoclonal antibody that binds specifically to CSP on the surface of tumor cells, rapidly internalizes and modulates key proliferative and cytoskeletal remodeling signaling pathways to decrease cancer cell growth and increase the recruitment of anti-tumor immune infiltrates. Methods: The dose escalation (3+3 design) and expansion are enrolling adult patients (pts) with advanced treatment-refractory solid tumors. ZB131 was administered IV over 60 minutes (without premedication) weekly. The starting dose of ZB131 is 0.3 mg/kg followed by 1,3, 9, 15 and 30 mg/kg. Primary objectives are safety, tolerability, and maximum tolerated dose/determination of Phase 2 dose. Secondary objectives are preliminary efficacy (RECIST v1.1), Pharmacokinetic (PK) and pharmacodynamic parameters in blood and paired tumor biopsies. Results: As of 31 Jan 2023, 24 pts had enrolled (9 PC, 6 CCA, 4 OC, 5 other). The median age was 59.5 yr (range, 35 – 84) with a median of 4 prior lines of therapy. The median ZB131 treatment duration is 5.3 weeks (range, 1 – 33). No dose-limiting toxicities were observed up to the dose of 30 mg/kg which is currently enrolling. Treatment-related adverse events (TRAEs) were grade 1/ 2: nausea (n=6), fatigue (n=5), anemia (n=3), diarrhea (n=2), flulike symptoms (n=2), and vomiting (n=2). Mild flu-like symptoms and nausea/vomiting were observed during or following infusion at doses of 9 mg/kg and above. Except for one episode of Gr 3 neutropenia at the 30 mg/kg dose, no other drug-related grade 3/4 TRAE’s were reported. Five pts had stable disease range, 12 – 33 weeks (2 PC, 1 CCA, 2 OC), with a 43% decrease in CA-125 observed in one OC pt. The PKs are linear and dose-proportional for all dose levels evaluated (estimated T ½ of 6-9 days). No antidrug antibodies have been detected. Conclusions: Interim data from dose-escalation of this first-in-class, anti CSP antibody, demonstrates good tolerability with encouraging signs of activity and target engagement in heavily pretreated pts. Results support further clinical evaluation of ZB131 in dose-expansion cohorts including OC and including combination therapy with gemcitabine. Clinical trial information: NCT 05074472 .