Agenus

Introduction:Botensilimab (BOT) is a fragment crystallizable (Fc)-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody with differentiated mechanisms of action, designed to extend therapy to cold/poorly immunogenic solid tumors. Patients with hepatocellular carcinoma (HCC) who progress on or after first-line immunotherapy have limited treatment options. Here, we report findings from a phase 1b study of BOT plus balstilimab (BAL; anti-programmed cell death protein 1 [PD-1] antibody) in previously treated patients with HCC. Methods:This is an open-label, nonrandomized, phase 1b, multicenter study of BOT±BAL in patients with advanced solid tumors. The study began with dose escalation (3 + 3 design) then dose expansion with multiple disease-specific cohorts. An expanded cohort of 19 patients with HCC who progressed on or after prior immunotherapy (primarily atezolizumab/bevacizumab) are included in this analysis. Patients with HCC received BOT intravenously at 1 or 2 mg/kg once every 6 weeks for up to 2 years plus BAL intravenously 3 mg/kg once every 2 weeks, for up to 2 years. Endpoints included safety, objective response rate (ORR), disease control rate, duration of response, and progression-free survival (PFS). Overall survival (OS) was an exploratory endpoint. Results:Among 18 efficacy evaluable patients (with ≥1 post-baseline 6-week imaging scan), ORR was 17% (3/18; 95% CI: 4-41), and 18-week clinical benefit rate (a complete or partial response or stable disease) 50% (9/18; 95% CI: 26-74). Median PFS was 4.4 months (95% CI: 1.4-6.9), and median OS was 12.3 months (95% CI: 8.4-21.4). Thirteen patients (68%) experienced any-grade immune-mediated treatment-related adverse events (TRAEs), with 37% (7/19) grade 3. The most common immune-mediated TRAEs included diarrhea/colitis (37% [7/19]; 16% grade 3 [3/19]), hepatitis (21% [4/19]; 16% grade 3 [3/19]), and dermatologic events (21% [4/19]; 5% grade 3 [1/19]). There were no treatment-related deaths or new safety signals outside of the class. Conclusions:The BOT+BAL combination demonstrated durable responses and manageable safety in treatment-refractory patients with HCC previously treated with immunotherapy, supporting further investigation in randomized studies. Despite the small sample size and high percentage of patients with albumin-bilirubin grade 2 liver disease, these results provide early evidence of antitumor activity in a difficult-to-treat disease setting.

TPS278 Background: Colorectal liver metastases (CRLM) are the leading cause of death in metastatic colorectal cancer. Standard perioperative chemotherapy has not improved overall survival, underscoring the urgent need for novel therapeutic strategies. Implantable microdevices (IMDs) enable in vivo, patient-specific drug sensitivity testing using microdoses of multiple agents, providing rapid pharmacodynamic readouts without systemic toxicity. IMDs have been evaluated in other solid tumors but never in CRLM. This investigator–initiated clinical trial aims to establish the safety and feasibility of IMD implantation and retrieval during hepatectomy for CRLM, and to generate individualized drug sensitivity profiles. Methods: This single–institution, first–in–human pilot study (NCT registered but # pending) will enroll 10 adults with CRLM ≥2 cm in an accessible location undergoing curative-intent hepatectomy. Up to four IMDs, each containing 22 reservoirs, will be placed percutaneously 3 days prior to metastasectomy. Reservoirs will be loaded with cytotoxic and immunomodulatory agents formulated in polyethylene glycol (PEG), including 5-fluorouracil (5-FU), FOLFOXFIRI (5-FU, oxaliplatin, leucovorin, irinotecan), bevacizumab, Fc–enhanced multifunctional anti–CTLA–4 antibody (botensilimab, AGEN1181), anti–PD–1 antibody (balstilimab), and anti–CD137 antibody (AGEN2373). PEG–only reservoirs serve as controls. Doxorubicin autofluorescence will allow orientation and confirm local drug diffusion. All drugs are delivered at microdose levels (∼1/100,000th systemic dose) with diffusion limited to a radius from each reservoir of ∼600–800μm, minimizing systemic exposure. IMDs will be retrieved en bloc with the surgical specimen and analyzed for histopathology, immunofluorescence, spatial transcriptomics, and proteomics. The primary endpoint is safety of IMD placement and retrieval, assessed by CTCAE v5.0. Secondary endpoints include feasibility, defined as histopathologic analysis of ≥50% of reservoirs, and creation of individualized drug sensitivity profiles. Exploratory endpoints include immune-modulatory effects and transcriptomic and proteomic pathway profiling. This trial is currently open to enrollment but has not yet enrolled its first patient. Conclusions: This is the first–in–human study of IMDs in CRLM, establishing a novel in vivo platform for rapid, patient-specific therapeutic profiling. If successful, IMDs could redefine therapeutic development in CRLM by enabling real-time, patient-specific drug testing to guide precision treatment.

TPS3676 Background: Despite significant progress and newly approved agents, metastatic colorectal cancer (mCRC) has limited prognosis after progressing on standard cytotoxic chemotherapies. Many patients remain well enough for treatment at the time when their cancer is refractory to all available therapy, creating a significant unmet need. Once refractory, patient management with best supportive care (BSC) results in a median overall survival (OS) of 4–6 months. To date, immune checkpoint inhibitors (ICIs) have shown limited activity in mCRC that is not mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H). Prior data from the CCTG CO.26 randomized phase 2 trial demonstrated doublet ICI with durvalumab + tremelimumab improved OS in refractory mCRC; however, a phase 3 trial was not undertaken. Botensilimab (BOT) is an Fc-enhanced multifunctional anti–CTLA-4 antibody designed to increase efficacy in poorly immunogenic cancers. The combination of BOT with the anti–PD-1 antibody balstilimab (BAL) has shown impressive objective response rates (ORRs), durations of response (DOR), and survival in heavily treated non–MSI-H/dMMR mCRC across phase 1 and 2 studies. The CO.33/BATTMAN trial will evaluate BOT + BAL + BSC versus BSC alone in patients with refractory mCRC that is not MSI-H/dMMR. Methods: BATTMAN (NCT07152821) is an international multi-centre, open-label randomized phase 3 trial that will be conducted in Canada (CCTG), Australia/New Zealand (AGITG) and France (Unicancer). Eligible patients will be ≥18 years old, have received and progressed on or been intolerant of all available therapies, have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1, have RECIST 1.1 measurable/evaluable disease, have a life expectancy of ≥12 weeks, and have adequate end organ function without concurrent illness contraindicating ICI. Exclusion criteria include: prior organ transplant or primary immunodeficiency, ongoing use of non-physiologic corticosteroid dosing, autoimmune disorders requiring ongoing management, and prior ICI exposure. The trial’s statistical plan will ascertain efficacy of BOT and BAL in all comers, as well as key subgroups based on the presence or absence of liver metastases. A planned 834 patients will be randomized 1:1 to BOT (75 mg IV every 6 weeks up to 4 doses) + BAL (450 mg IV every 3 weeks until progression) + BSC or BSC alone, with stratification for region of recruitment, ECOG PS, and presence of liver metastases. The primary endpoint is OS, with secondary endpoints including progression-free survival, ORR, clinical benefit rate, quality of life, safety, and toxicity, with correlative studies and economic evaluations planned. Support for this study is provided by: The Canadian Cancer Society and Agenus Inc. Clinical trial information: NCT07152821 .

2535 Background: Predicting immunotherapy response is challenging in treatment-refractory/resistant (R/R) tumors where heterogeneity limits conventional biomarker utility. BOT (Fc-enhanced anti–CTLA-4) augments T-cell priming, depletes Tregs, and activates antigen-presenting cells. BOT+BAL (anti–PD-1) has shown activity across “cold” and R/R tumors including PD-L1–low and tumor mutational burden–low disease; thus, non-conventional predictive biomarkers are needed. A self-supervised AI foundation model applied to routine pretreatment H&E images was used to infer spatial transcriptomics and identify features associated with therapeutic benefit from BOT+BAL in microsatellite-stable colorectal cancer (MSS CRC), sarcoma, and ovarian cancer. Methods: A self-supervised AI foundation model was trained to infer spatial transcriptome expression from H&E images using purpose-built multimodal training data from thousands of human tumors profiled with multimodal assays. Pretreatment H&E images (not used for training) from 121 BOT+BAL–treated patients (pts) with R/R MSS metastatic CRC (included 20 pts with liver metastases), sarcoma, and ovarian cancer from the phase 1b C-800-01 trial (NCT03860272) were analyzed. Pt-specific embeddings were used to fit cross-validated classifiers predicting BOT+BAL clinical benefit (defined as complete or partial response [CR/PR] or stable disease [SD]). Results: Fitted logistic regression classifiers separated responders and non-responders in all tumor types, as measured by area under the receiver operating characteristic curve (AUROC; ranges from 0.5 [chance] to 1.0 [perfect separation]). Cross-validated AUROC was 0.61 in MSS CRC, 0.67 in sarcoma, and 0.77 in ovarian cancer (table; shows all findings). The model-recommended population is predicted to have a higher rate of clinical benefit, as measured by cross-validated precision. Beyond this binary analysis, the concordance index (C-index; measures accuracy and ranges from 0.5 [chance] to 1.0 [perfect]) for predicting overall survival (OS; via Cox proportional hazards model) was >0.5 in all tumor types, and highest in ovarian cancer. Conclusions: A self-supervised AI foundation model applied to routine pretreatment H&E images predicted BOT+BAL responses in MSS CRC, sarcoma, and ovarian cancer. These findings support AI-derived, H&E–based biomarker strategies for BOT+BAL and warrant prospective validation. Sample characteristics and model predictions. MSS CRC Sarcoma Ovarian Sampled population a No. of pt samples 67 30 24 Pts with CR/PR or SD 65% 57% 54% Modeled population AUROC 0.61 0.67 0.77 OS prediction, C-index 0.58 0.69 0.78 Model recommended population Population size 43% 50% 46% Estimated pts with CR/PR or SD 76% 67% 73% a Data cutoff: Mar 13, 2025; analyses ongoing.