PURPOSE:Effective immunotherapy for mismatch repair proficient colorectal cancer (CRC) is lacking. We examined the safety and efficacy of the novel next-generation immune activator/Fc-enhanced CTLA-4 inhibitor botensilimab (BOT) plus PD-1 inhibitor balstilimab (BAL) in the neoadjuvant setting for patients with resectable CRC. PATIENTS AND METHODS:Patients 18 years of age or older with non-metastatic CRC awaiting surgical resection were eligible. BOT/BAL was administered followed by surgical resection. In cohort A, patients received BOT 75 mg d1 and BAL 240 mg d1, 15; in cohorts B/C, patients received 2 additional BAL doses (d29, 43). The primary study objectives were safety, feasibility (based on surgery delay), and pathologic response. Exploratory analyses examined changes in the tumor microenvironment. RESULTS:Twenty-four eligible patients (26 tumors, n=22 pMMR; n=4 dMMR) were enrolled (two patients had synchronous primary tumors). Neoadjuvant BOT/BAL was safe and did not delay planned surgery in any patient. The major pathologic response rate was 41% (95% CI, 21%-64%) for pMMR, and 100% (95% CI, 40%-100%) for dMMR CRC. BOT/BAL was associated with significant anti-tumor effects in the tumor microenvironment, with an increase in the density and proportion of CD8+ T cells, a reduction in tumor infiltrating FOXP3+ Tregs, and evidence of increased immune cell-cell interaction in responding patients. CONCLUSIONS:These findings demonstrate safety, feasibility, and encouraging pathological responses for BOT/BAL in both non-metastatic pMMR and dMMR CRC. Tumor microenvironment remodeling suggests a robust anti-tumor immune response induced by immunotherapy. These data support the continued development of BOT/BAL in CRC.

Abstract Background: VCN-01 (zabilugene almadenorepvec) is an oncolytic adenovirus expressing hyaluronidase to degrade tumor stroma, facilitate chemotherapy penetration and stimulate tumor immunity, which is being developed for different cancer indications. The randomized, open-label, Phase 2b VIRAGE trial tested the efficacy and safety of 2 intravenous (IV) doses of VCN-01 combined with standard of care (SoC) gemcitabine/nab-paclitaxel (GA) in mPDAC. Methods: Chemonaïve mPDAC patients were randomized 1:1 to receive SoC doses of GA on days 1, 8 and 15 of repeated 28-day cycles (Arm I) or 2 separate IV doses of VCN-01 (1x1013 vp/dose) 1 week prior to cycles 1 and 4 of GA (Arm II). Primary endpoints were overall survival (OS) and safety. Secondary objectives included progression free survival (PFS), objective response rates (ORR), duration of response (DoR) and Ca19.9 changes. VCN-01 genomes in blood and serum levels of neutralizing anti-adenovirus antibodies (anti-Ad-NAb’s) were also analyzed. Results: 96 patients in the trial received at least 1 dose of GA or VCN-01+GA (48 patients in each arm). Median OS was 10.8 vs. 8.6 months for Arm II and Arm I, respectively (HR 0.57, 95% CI 0.34-0.96; P=0.055) and PFS was 7.0 vs. 4.6 months (HR 0.55, 95% CI 0.34-0.88; P=0.011). OS benefits with VCN-01+GA vs. GA alone were consistent across different subgroups, including patients aged over 70 years, presence of hepatic metastases, or patients with >2 metastatic sites. Compared to patients in Arm I who started cycle 4 of GA, patients in Arm II who received 2 VCN-01 doses and started cycle 4 of GA showed greater improvement in OS (14.8 vs 11.6 months; HR 0.44; 95% CI 0.21-0.92; P=0.046) and PFS (11.2 vs 7.4 months; HR 0.48; 95% CI 0.25-0.91; P=0.017). ORR was 39.6% vs. 31.3% (P=0.314), and more patients had target tumor shrinkage with VCN-01 + GA than GA (84.1% vs. 69.8%; P=0.13). DoR was longer for VCN-01+GA (11.2 vs 5.4 months; HR 0.22; 95% CI 0.08 - 0.62; P=0.004) and 8 of 19 patients in this group achieved late objective responses after the second VCN-01 dose (>4 months after randomization). Ca19.9 levels declined more markedly in Arm II, with a median reduction of -61.0% versus -64.9% in Arm I vs. Arm II by cycle 3, and a further decrease to -16.7% vs -86.3% by cycle 9, following the second VCN-01 dose. No correlation between baseline levels of anti-Ad-NAbs and OS or PFS were observed. The peak of viral genome levels in blood was similar between the first and the second dose of VCN-01. Conclusions: Compared to patients in Arm I (GA), mPDAC patients in Arm II (VCN-01+GA) showed improved OS and PFS and later and more durable responses. Patients that received a second VCN-01 dose+GA showed a further delayed disease progression and extended patient survival compared to patients that received equivalent cycles of GA. Citation Format: Rocio Garcia-Carbonero, Roberto Pazo, Teresa Macarulla, Berta Laquente, Alana Nguyen, Carmen Guillén-Ponce, Andres J. Muñoz, Edward J. Kim, Mireya Cazorla, Tara Seery, Miriam Lobo de Mena, Chris Nevala-Plagemann, Vivek R. Sharma, Eva Martinez de Castro, Charles Le, Ana Mato-Berciano, Luis A. Rojas, Carmen Blasco, Manel Cascallo, Manuel Hidalgo. Analysis of tumor and biomarker responses in the VIRAGE Trial, a randomized Phase IIb, open-label, study of nab-paclitaxel and gemcitabine with/without intravenous VCN-01 in patients with metastatic pancreatic cancer (mPDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT162.

4196 Background: PrP, a phase 2/3 Bayesian adaptive platform trial sponsored by the Pancreatic Cancer Action Network, was developed to test multiple experimental arms efficiently against common controls and explore biomarkers of response/resistance in mPDAC (Picozzi, ASCO TPS 4188, 2022). Methods: At screening, core tissue biopsies and matched blood collection were performed for first- and second-line patients (pts) with mPDAC. Week 8 (W8) core tissue biopsies and blood collection were performed for pts receiving study drug. Formalin-fixed paraffin embedded (FFPE) tissue slides were prepared at the central lab; tissue and matched blood samples were analyzed for genomic and transcriptomic analyses using Tempus xT (DNA) and xR (RNA) testing, respectively. The workflow prioritized DNA followed by RNA isolation. Results: Tissue biopsies were obtained at screening from 491 of 700 (70%) pts across 24 US sites; W8 tissue biopsies were obtained from 228 of 443 (51%) pts receiving study drug. Reasons for biopsies not being collected included: contraindicated; attempted, but no tissue obtained; pt screened out; pt stopped study drug before W8 (W8 only). 21% (103/491) screening and 32% (74/228) W8 biopsies submitted for biomarker testing contained insufficient tumor tissue for testing; 4% (20 pts) of screening and 4% (10 pts) of W8 biopsies were not processed into FFPE or testing was cancelled. Of the 368 pts with screening tissue sequenced, genomic data were generated for 83% (304 pts); 17% (64 pts) had Quantity Not Sufficient (QNS) for DNA. Transcriptomic data were generated for 49% (179 pts); in 42% (155 pts) insufficient tumor tissue remained for RNA testing and 9% (34 pts) had QNS for RNA. Of the 144 pts with W8 tissue sequenced, genomic data were generated for 71% (102 pts); 29% (42 pts) had QNS for DNA. Transcriptomic data were generated for 31% (44 pts); in 58% (84 pts) insufficient tumor tissue remained for RNA testing and 11% (16 pts) had QNS for RNA. Locations of tissue biopsies across both timepoints (719) were: 68% liver, 16% pancreas, 16% other metastatic sites. Success rates for biomarker testing across all tissue obtained was higher for liver metastases (65% DNA results; 37% RNA results) than for primary tumors in the pancreas (42% DNA results; 19% RNA results). Distribution of actionable biomarkers detected will be presented. Conclusions: These data demonstrate success rates of paired biopsy acquisition and subsequent genomic and transcriptomic analysis in a large phase 2/3 multi-center platform trial for mPDAC. Attrition was noted for biopsy collection and downstream biomarker testing at screening and more so at W8 on study drug. Biomarker testing success rates varied by tissue location. These findings along with planned data interrogation and future sample analyses will provide insights to guide future trial design and clinical decision making. Clinical trial information: NCT04229004 .

Studies reported that atopic individuals exhibit a 36% reduced risk of developing pancreatic ductal adenocarcinoma (PDAC); however, the underlying molecular mechanisms remain unclear. This study examines the specific role of type‐2 immune response in the atopy–PDAC inverse association. To endotype atopic conditions using type‐2 immune effectors (i.e., eosinophils and immunoglobulin‐E[IgE]) and investigate their protective effect against PDAC risk, IgE levels were measured in 688 PDAC cases and 558 controls from the PanGenEU case–control study. ‘IgE‐sensitization’ was defined as having >100 kU/L total IgE with lab‐tested sensitization to ≥1 food‐ or aeroallergens. Atopic conditions were determined using the European Community Respiratory Health Survey questionnaire. The UK Biobank cohort's 544 PDAC cases and 92,038 nested controls were categorized based on a threshold of 0.15 × 10 9 eosinophil cells/L plus self‐reported atopy. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Restricted cubic splines were applied to examine the nonlinear relationship between type‐2 immune effectors and PDAC risk. PDAC risk was not linearly associated with type‐2 immune effectors levels. Compared to low IgE‐sensitized non‐atopic individuals, the low IgE‐sensitized atopic population had significantly reduced PDAC risk (OR = 0.56, 95% CI: 0.35–0.84). Similar trends were observed among atopic individuals with low eosinophil counts (OR = 0.67, 95% CI: 0.47–0.95). Atopic conditions were inversely associated with PDAC risk, particularly among those with low levels of type‐2 immune effectors. This indicates the protective effect of atopy against PDAC risk is modulated by low type‐2 immune response.

TPS4231 Background: Traditional immune checkpoint inhibitors have shown limited benefit in pancreatic ductal adenocarcinoma (PDAC) owing to non-redundant immune resistance mechanisms dominating the tumor microenvironment (TME). Transforming growth factor (TGF)-β and cluster of differentiation (CD)73-adenosine represent two major immunoregulatory and pro-tumorigenic pathways responsible for therapeutic resistance and progressive disease in PDAC. AGEN1423 (also known as dalutrafusp alfa and GS-1423) is a bifunctional, humanized, aglycosylated immunoglobulin G1 kappa antibody that selectively inhibits CD73-adenosine production and neutralizes active TGF-β signaling. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody. We hypothesize that the combination of AGEN1423 with BOT can rescue T-cell functional activity leading to responses in advanced PDAC. Methods: An investigator-initiated open label Phase 2 study to evaluate the safety, tolerability, and initial efficacy of BOT + AGEN1423 +/- chemotherapy in patients with metastatic PDAC (NCT05632328). In cohort 1, 12 patients with metastatic PDAC with disease progression to at least one line of treatment will receive AGEN1423 30mg/kg IV Q2W for 4 doses + BOT 150mg IV Q6W ongoing for up to 2 years. If the combination is considered safe and tolerable, and objective response is achieved in at least 1 subject, the study will proceed to Cohort 2. In Cohort 2, 12 additional patients with disease progression on first-line fluorouracil-based chemotherapy will be enrolled to receive second-line gemcitabine and nab-paclitaxel in combination with AGEN1423 30mg/kg IV Q2W for 4 doses + BOT 150mg IV Q6W. Key eligibility criteria include histologically or cytologically confirmed metastatic pancreatic adenocarcinoma, age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤1, adequate organ function, and measurable disease by RECISTv1.1. A pre-treatment and on-treatment tumor biopsy will be obtained for translational studies. The primary endpoint is to estimate the objective response rate (ORR) according to RECISTv1.1 criteria. Secondary endpoints include safety and tolerability as defined by the incidence of AEs as assessed according to CTCAE v5, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Translational endpoints include the characterization of the transcriptional signatures in paired biopsies obtained before and on-treatment with BOT + AGEN1423, as well as the changes in cell composition of the TME following treatment using multiplexed immunofluorescence spatial technology. Enrolment has started and accrual is anticipated to complete in Q4 2025. Clinical trial information: NCT05632328 .

e16403 Background: Activating KRAS mutations in pancreatic ductal carcinomas (PDAC) occur in > 90% of patients (pts). Avutometinib (A) is a RAF/MEK clamp that potently inhibits MEK kinase while blocking compensatory reactivation of MEK. Defactinib (D) is a selective inhibitor of FAK, a target shown to mediate resistance. RAMP 205 (NCT05669482) is a Phase 1b/2 study assessing A/D + gemcitabine/nab-paclitaxel (GnP) in first-line metastatic PDAC. Preliminary data suggest synergistic activity with this combination. Updated data on additional dosing cohorts are presented here. Methods: Eligible pts had histologically confirmed newly diagnosed metastatic PDAC and measurable disease, ECOG PS ≤1, adequate organ function, and no prior treatment for metastatic disease. Pts were treated in 3+3 cohorts with escalating oral doses of A and D in combination with IV doses of GnP on a 4-week schedule (Table). Results: At data cutoff (03Jan2025), 54 pts were enrolled and included in the safety analysis: 46% men, median age 59 years (range, 36-79), and 42.5% (23/54) ECOG PS of 1. Pts were enrolled in the following dose levels: DL1 (n = 12), DL0 (n = 6), DL-1 (n = 12), DL1a (n = 12), and DL2a (n = 12). The MTD has not been reached. There was one DLT: grade 3 febrile neutropenia in DL1, that resolved within 3 days. The most common treatment-related adverse events (all grades, all dose groups) were fatigue (63%), nausea (46%), neutropenia (46%), alopecia (41%), diarrhea (39%), anemia (30%), maculo-papular rash (30%), peripheral edema (28%), hyperbilirubinemia (24%), vomiting (24%), dermatitis acneiform (22%), thrombocytopenia (22%), and blurred vision (22%). The most common grade ≥3 treatment-related adverse events were neutropenia (39%), anemia (20%), fatigue (7%), and increased ALT (7%). Thirty-nine efficacy evaluable pts were enrolled at least 6 months prior to data cutoff. Objective Response Rate (ORR) and Disease Control Rate (DCR) for ≥4 cycles are listed in the Table. Conclusions: A/D + GnP have been combined in 5 dose cohorts. The MTD has not been reached. Enrollment and evaluation of mature data are ongoing to identify the recommended phase 2 dose. Clinical trial information: NCT05669482 . RAMP 205 dose levels and efficacy for patients enrolled ≥6 months prior to data cutoff. Dose Level A(mg) BIW* D(mg) BID* Gemcitabine (mg/m 2 ) Nab-Paclitaxel (mg/m 2 ) Days Chemo Dosing ORR% (n/N) DCR≥4 cycles% (n/N) 1 2.4 200 800 125 1,8,15 83% (5/6) 83% (5/6) 0 3.2 200 800 100 1,8,15 100% (1/1) 100% (1/1) -1 ^ 2.4 200 800 100 1,8,15 27% (3/11) † 82% (9/11) 1a # 3.2 200 800 125 1,15 33% (3/9) ◊ 56% (5/9) 2a 3.2 200 1000 125 1,15 25% (3/12) 58% (7/12) *Dosing 3 / 4 weeks. ^ 1 pt excluded from efficacy analysis due to no post baseline scan. # 3 pts excluded from efficacy analysis: 1 due to no post baseline scan and 2 due to incorrect histology per eligibility criteria. † Includes 2 unconfirmed responses. ◊Includes 1 unconfirmed response.

673 Background: Pamrevlumab (Pam) is a fully human recombinant monoclonal antibody against connective tissue growth factor. Early clinical data with Pam plus chemotherapy showed a favorable safety profile and potential efficacy in PDAC. In PrP, Pam + GA was tested as first line (Line 1) and second line (Line 2) therapy for mPDAC vs GA. PrP is a phase 2/3, innovative Bayesian adaptive platform trial sponsored by the Pancreatic Cancer Action Network testing multiple experimental arms efficiently against common controls (1). Methods: Randomization is 70% (adaptive amongst experimental arms in stage 1) and 15%:15% amongst two control arms (GA, mFOLFIRINOX). Pam + GA graduates from stage 1 to 2 if the Bayesian predictive power (PP) of eventual success is ≥ 35% for one of the arm’s signatures [Line 1, Line 2 or Line 1 & 2 (All)]. All participants (pts) are followed for 12 months (mos) after last pt randomized and treated in Pam + GA. Stages 1 and 2 are combined for final analysis. Efficacy is defined by overall survival (OS) hazard ratio (HR, experimental vs control), by a Bayesian statistical model. Superiority (HR < 1) is claimed at final analysis if the Bayesian probability of superiority is ≥ 98%. Results: Pam + GA entered PrP in Jun 2021. Between 6/2021 - 1/2023, at 23 US sites, 317 pts were treated and are included in the mITT analysis. 213 pts were treated in the Pam + GA arm (102 Line 1; 111 Line 2), 45 in the GA arm (23 Line 1; 22 Line 2), 31 in the mFOLFIRINOX arm and 28 in other experimental arms. All treated pts before and during Pam + GA enrollment were in the Bayesian model, with outcomes adjusted via a time machine to increase the trial’s statistical power. Baseline characteristics were balanced across the arms. Pam + GA met criteria to graduate to stage 2 in Sep 2022 in the All signature (Line 1 & 2). At final analysis, Pam + GA did not meet the OS primary endpoint [model estimated HR: 1.18 (95% credible interval, 0.88, 1.56), posterior Pr(HR < 1) = 0.14, below specified ≥ 0.98]. No benefit was seen in PFS nor ORR (Table). No new safety signals were seen. Conclusions: PrP, the first Bayesian platform trial in mPDAC, performed as designed; Pam + GA did not improve OS versus GA in Line 1 and Line 2 mPDAC. The novel Bayesian design warrants further study in mPDAC to enhance efficiency of drug development. Future designs should explore different strategies to allocate patients to control arm(s) vs experimental arms and accommodate novel agents intended to benefit subsets of mPDAC. 1. Picozzi, ASCO TPS 4188, 2022. Clinical trial information: NCT04229004 . Line 1 Line 2 GA Pam + GA Hazard Ratio GA Pam + GA Hazard Ratio Model Estimated mOS (mos) 11.3 9.7 1.18(95% CI* 0.88, 1.56) 7.8 6.6 1.18(95% CI* 0.88, 1.56) mPFS (mos) 5.3 5.9 0.64(95% CI^ 0.36, 1.14) 7.0 3.9 1.35(95% CI^ 0.78, 2.33) ORR (%) 26.1 35.3 4.5 9.0 *Credible Interval. ^Confidence Interval.

23 Background: BOT is an Fc-enhanced, multifunctional anti-CTLA−4 antibody designed to improve Fc gamma receptor-mediated effector functions and extend the reach of I-O to tumor types such as MSS mCRC. Here we present preliminary data from a randomized, open-label, phase 2 study in patients (pts) with MSS mCRC NLM treated with BOT ± BAL (anti-PD−1; NCT05608044). The study aimed to inform dose and contribution of components based on the primary endpoint of objective response rate (ORR) by RECIST 1.1 per investigator, and safety, and was not powered for statistical comparisons between arms. Methods: A total of 234 pts (intent-to-treat [ITT]) were randomized to BOT (up to 4 doses) 75 or 150 mg every 6 wks (Q6W), BOT 75 or 150 mg Q6W plus BAL 240 mg Q2W (up to 2 years), or standard of care (SOC; regorafenib or trifluridine/tipiracil). Results: Median age was 58 yrs (range 23—90), 50% male, 39% rectal, 44% 3L+, 43% ECOG 1, 58% KRAS mutant, 4% NRAS mutant, 83% prior bev, all MSS and/or pMMR by local testing. Key characteristics were well balanced with some exceptions including median time from diagnosis of metastatic disease to study entry (30 mos across arms; 45 mos SOC) and presence of peritoneal metastases (34% across arms; 42% 75 mg BOT / 240 mg BAL; 27% SOC). As of July 29, 2024, median follow-up was 9.8 mos. Key efficacy and safety data are shown (Table). Image based endpoints by blinded independent review, as well as overall survival will be reported in the future. Grade ≥3 treatment-related adverse events (TRAEs) were highest with SOC followed by BOT + BAL combination, and then BOT monotherapy, with dose dependency. Treatment-related immune-mediated diarrhea/colitis (imDC) was manageable and highest with 150 mg BOT / 240 mg BAL. No new safety signals and no treatment-related deaths occurred. Conclusions: The study met the objectives of informing dose and contribution of components. Overall ORR was higher with BOT + BAL vs BOT monotherapy. ORR was highest with 75 mg BOT / 240 mg BAL with less toxicity as compared to 150 mg BOT / 240 mg BAL. Consistent with published data, there were no objective responses in SOC whereas most responses seen with BOT + BAL were ongoing, similar to the durable responses observed in the ph1 study. These responses are differentiated from previous I-O-only combinations and SOC, supporting further investigation of 75 mg BOT / 240 mg BAL vs SOC in a planned global ph3 trial. Clinical trial information: NCT05608044 . 75 mg BOT/240 mg BAL 150 mg BOT/240 mg BAL 75 mg BOT 150 mg BOT SOC ITT (Randomized) n=62 n=61 38 n=40 n=33 ORR, % (95% CI) 19%(10—31) 8%(3—18) 0%(0—10) 8%(2—20) 0%(0—11) Safety (Treated) n=62 n=60 n=37 n=39 n=21 Any Grade TRAEs, n (%) 54 (87) 59 (98) 28 (76) 31 (79) 19 (90) Grade ≥3 TRAEs, n (%) 22 (35) 25 (42) 8 (22) 9 (23) 12 (57) Any Grade Treatment-related IMDC, n (%) 19 (31) 28 (47) 13 (35) 12 (31) 0 (0)

207 Background: Checkpoint inhibitors (CPI) have been transformative for localized dMMR CRC (microsatellite instability-high [MSI-H]), but not for localized pMMR CRC (microsatellite stable [MSS]). The combination of BOT, a novel Fc-enhanced multifunctional CTLA-4 antibody, and BAL, an anti-PD-1 antibody, has demonstrated significant activity in metastatic CRC. We examined this novel dual CPI therapy in patients with MSI-H and MSS localized CRC. Methods: This is a single arm trial of neoadjuvant BOT 75 mg/m 2 (day 1) and BAL 240 mg/m 2 every 2 weeks x2 (NEST1) or x4 (NEST2) in patients with localized CRC who were candidates for surgery. The primary endpoint was major pathologic response (MPR), defined as ≥90% pathologic tumor regression. The 95% confidence interval (CI) was computed based on exact method for binomial distribution. Results: NEST1 (n=12: 9 MSS / 3 MSI-H) accrued from 3/21/23 to 9/25/23 and NEST2 (n=14: 13 MSS / 1 MSI-H; 2 MSS patients had synchronous CRC) accrued from 2/15/24 to 5/6/24; 2 patients in NEST1 were not evaluable (1 with rectal cancer not resected [ypT0N0 on local excision] and 1 patient with occult lung metastasis). In total, 7 MSS CRC tumors were evaluable from NEST1 and 15 from NEST2; and 3 MSI-H tumors were evaluable from NEST1 and 1 from NEST2, leaving a final evaluable study population of 24 patients (20 MSS / 4 MSI-H) and 26 tumors (22 MSS / 4 MSI-H). The Table provides pathologic response rates across NEST1, NEST2, and MSI-H. With a median follow-up of 13.1 months (NEST1) and 4.8 months (NEST2), no patients have recurred and ctDNA testing remains negative. No grade 4 toxicities were observed and the only treatment-related grade 3 toxicity was diarrhea/colitis in 15% and fever in 4%. Treatment-related grade 2 diarrhea/colitis occurred in 8%, grade 2 fever in 15%, and grade 2 fatigue in 4% of patients. Diarrhea/colitis resolved in all cases with steroids ± anti-TNFα therapy. All patients underwent laparoscopic resection, with 1 conversion to open. No surgeries were delayed due to treatment-related adverse events. Median length of stay was 2 days (range 1-14). Translational data including pathologic evaluation of tumor infiltrate and response will be presented. Conclusions: Neoadjuvant BOT/BAL is safe, with no delays to surgery, and effective. We observed high MPR rates in both MSS and MSI-H CRC with no recurrences to date. The MPR and pCR rate improved with extended time to surgery. Clinical trial information: NCT05571293 . Pathologic response to neoadjuvant BOT/BAL in localized CRC. Pathologic Response NEST 1n=7 MSS tumors NEST 2n=15 MSS tumors MSI-H (3 NEST1, 1 NEST2) 100% (CR%, 95%CI) 1 (14%, 0.4-58%) 6* (40%, 16-68%) 3** (75%, 19-99%) ≥ 90% (MPR%, 95%CI) 2 (29%, 4-71%) 7 (47%, 21-73%) 4^ (100%, 40-100%) ≥ 50% 4 (57%) 9 (60%) 4 (100%) Median days to Surgery (range) 29 (21-37) 57 (45-104) 46 (34-78) *2 with carcinoma in situ , no tumor bed. ^MPR was in NEST1. **1 was rectal.

696 Background: Advanced PDAC has limited therapeutic options. BPM31510-IV, a novel nano formulation of Ubidecarenone was evaluated in Phase 2 in patients with advanced PDAC. In addition to response and safety, the study included FDG-PET and omics as exploratory analyses. Multi-omics analyses from longitudinally collected patient samples including a subset of Adequately Treated Analysis Set (ATAS) (n=19) were performed to determine potential biomarkers associated with clinical outcomes. Methods: Metastatic PDAC patients (N=45) who had previously received between one and three lines of prior therapy were enrolled in this study. Omics analyses including proteomic, structural lipidomic, signaling lipidomic, and metabolomic measurements were performed on patient buffy coat and plasma samples. Biomolecules with significant association to patient outcome (PFS, OS & TTP) were identified by linear regression analysis. Additional analysis with mixed effect linear modeling approach was used to relate omic values during ten weeks of treatment and patient ATAS status and time on study. Previous analysis of proteomics from patients in a phase 1 solid tumor study was mapped onto a similar omics output for phase 2 to reveal predictive biomarkers for disease status. Results: Proteomics analysis on patient buffy coats revealed enrichment of dicarboxylic and tricarboxylic metabolic processes, mitochondrial membrane space proteins, pyruvate metabolism, and malate/aspartate shuttle pathway with a positive correlation with TTP in the model, demonstrating an integrated connectivity to Ubidecarenone’s functional effects on metabolism. Medium chain acyl carnitines and c-reactive protein (CRP) were identified as having the most significant differences in trajectories between patient ATC status by mixed effect linear modeling. Medium chain acyl carnitines differences could likely be the result of an integrated adaptation of liver homeostasis and physiological activity impacted by treatment. Analysis of RECIST1.1 evaluated in Phase 1 clinical trial and subsequently validated in Phase 2 trial identified 4 proteins with predictive utility at the start of treatment (t=0) (SERPINA5, Vitronectin, Lumican, Proteosome 20S subunit alpha 4), 5 lipid molecular species, and 1 metabolite (2-keto-isovalerate). These markers exhibited differential expression in both clinical trials related to clinical outcome, thus demonstrating a biological relevance to BPM31510 treatment. Conclusions: Our results point to biomarkers associated with (a) length on trial, (b) outcome and (c) involvement of mitochondrial biology in the mechanism of BPM31510-IV in the adequately treated PDAC population. The data herein supports further study of these biomarkers in late-stage trials to confirm the biological mechanism of BPM31510 in PDAC patients. Clinical trial information: NCT02650804 .

4140 Background: More than 90% of pancreatic ductal adenocarcinomas (PDAC) harbor an activating KRASmutation .Avutometinib (avuto) is an oral RAF/MEK clamp. Defactinib (defact) is an oral selective FAK inhibitor. Avuto/defact combined with gemcitabine/paclitaxel have shown synergistic antitumor activity in preclinical PDAC models. RAMP 205 (NCT05669482) is a Phase 1b/2 study assessing the safety and efficacy of avuto/defact + gemcitabine/nab-paclitaxel (GnP) in first-line metastatic PDAC. Methods: Eligible patients (pts) were enrolled and treated in 3+3 cohorts with escalating doses of avuto orally (PO) twice weekly (BIW) and defact PO twice daily (BID), both 3 out of 4 weeks, in combination with GnP dosed intravenously (IV) on a D1, D8, D15 or D1, D15 (modified) 4wk schedule (Table 1). Key eligibility criteria include histologically confirmed newly diagnosed metastatic PDAC with measurable disease, ECOG performance status (PS) ≤1, adequate organ function, and no prior treatment. Results: At the 24Jan2024 data cutoff, 18 pts were enrolled, 44% were male, 65 y median age, and 61% ECOG PS 1. Pts were enrolled to DL-1 (n=3), DL1 (n=6), DL1a (n=6), and DL2a (n=3). No dose-limiting toxicities (DLTs) were reported and the majority of treatment related adverse events (TRAEs) were mild to moderate. The most frequently reported TRAEs of any grade in the safety population (N=18) were nausea (50%), alopecia (44%), fatigue (39%), maculo-papular rash (33%), and peripheral edema (28%). The most common grade ≥3 TRAEs included alanine aminotransferase increase (17%), neutropenia (17%), peripheral edema (11%), anemia (11%), and sepsis (11%). Four patients experienced serious AEs (SAEs). Grade ≥3 treatment emergent SAEs included pulmonary embolism (n=2; unrelated), sepsis (n=2), febrile neutropenia (n=1; did not meet DLT criteria), and neutropenia (n=1). One patient discontinued treatment due to TRAE (febrile neutropenia and blood bilirubin increased). All efficacy evaluable pts (n=8) experienced a reduction in target lesions (100% disease control rate) and partial responses were observed in 6/8 (75%), 3 being confirmed at data cutoff. All efficacy evaluable pts with an elevated CA19-9 at baseline (n=7) had a ≥60% CA19-9 reduction from baseline. Conclusions: Avuto/defact and GnP are combinable and show notable preliminary efficacy in first-line metastatic PDAC based on RECIST v.1.1 criteria and CA19-9 levels. No DLTs were reported across the 4 dosing cohorts/schedules and safety signals were consistent with previous clinical data. Updated safety and efficacy will be reported. Clinical trial information: NCT05669482 . [Table: see text]

2596 Background: Tifcemalimab, a humanized IgG4 antibody against BTLA, showed a tolerable safety profile and preliminary single-agent anti-tumor activity in pretreated pts with advanced malignancies. Here we report the dose escalation and cohort expansion study of tifcemalimab in combination with toripalimab (anti-PD-1) in pts with pretreated advanced malignancies. Methods: Eligible pts with advanced malignancies refractory to standard therapies were enrolled in the dose escalation and the cohort expansion phases of this study (NCT04137900). During dose escalation, tifcemalimab was administered at escalating doses of 20, 70, 200 and 500 mg in combination with 240 mg toripalimab given intravenously once every three weeks (Q3W) until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated. Study objectives included safety and efficacy. During cohort expansion, the combination of tifcemalimab (200mg Q3W) and toripalimab (240 mg Q3W) were further evaluated in five indication-specific cohorts (melanoma, non-small cell lung cancer [NSCLC], renal cell carcinoma [RCC], urothelial carcinoma [UC] and lymphoma) for safety and efficacy. Results: By December 16, 2023, a total of 16 pts received study treatment during dose escalation and 69 pts were treated during cohort expansion from 18 participating sites from the US. Pts were heavily pretreated with a median of 4 prior lines of therapy. The median age was 65 (range 32-85) years, 69% of pts were male. As of December 16, 2023, the median follow-up was 11.4 weeks. No DLT was observed during dose escalation. Treatment-emergent adverse event (TEAEs) occurred in 92% pts, 44% experienced grade 3 or higher TEAEs, including 2 (2%) treatment-related Grade 5 events. The most common TEAEs included: fatigue (27%), diarrhea (17%), nausea (17%), anemia (15%), arthralgia (15%), decreased appetite (15%), and dyspnea (15%). TEAE led to discontinuation of study drug in 6% of pts. Nineteen percent of pts experienced immune-related AEs. No new safety signal was identified outside the known risk profiles of tifcemalimab and toripalimab. Among 14 evaluable pts in the dose escalation phase, 8 had stable disease. Among 57 evaluable pts in the cohort expansion phase, 1 complete response (lymphoma), 6 partial responses (2 melanoma, 2 RCC, 1 NSCLC, 1 UC) and 17 stable disease were observed. The ORRs were 5%, 11%, 17%, 18% and 33% in the NSCLC, melanoma, UC, RCC and lymphoma cohorts respectively. All responders were refractory to prior immunotherapy and all responses were still ongoing by the cutoff date. Conclusions: Tifcemalimab in combination with toripalimab showed preliminary efficacy in immunotherapy-refractory pts with a manageable safety profile. Phase II combination studies in various advanced solid tumors are ongoing. Clinical trial information: NCT04137900 .

117 Background: There is an unmet need to have an effective systemic immunotherapeutic option for patients with mismatch repair proficient/microsatellite stable (pMMR/MSS) colorectal cancer. The neoadjuvant platform presents an ideal setting as a window of opportunity to evaluate new drugs. The NEST-1 trial explored the safety and efficacy of neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti–CTLA–4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in patients with colon and rectal cancer who were candidates for surgery. Methods: NEST-1, was a single-arm trial testing the feasibility, safety, and efficacy of the BOT/BAL regimen in neoadjuvant settings for patients with colorectal cancer before resection. All patients received 1 fixed dose of 75 mg of BOT and 2 fixed doses of 240 mg of BAL 2 weeks apart. Patients could proceed to surgery 1 week after completion of the 2nd dose of BAL. Less than 25% of patients were allowed to be mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H). Other inclusion and exclusion criteria were in accordance with ongoing immunotherapy-based clinical trials. Results: The study met its primary endpoints. A total of 12 patients with colon and rectal cancers were safely treated with the BOT/BAL combination without delaying surgery or increasing the risk of any severe adverse events. Significant regression of tumors was noted (Table). Spatial biology analyses on pre-treatment biopsy and post-treatment surgical samples using RareCyte Inc. revealed novel mechanisms of action and patterns of response/regression; most of the viable tumor if present was superficially oriented near the luminal surface. ctDNA reductions correlated with pathological responses. Conclusions: BOT/BAL appears to be a safe and active regimen both in pMMR/MSS and dMMR/MSI-H colon as well as rectal cancers. The downstaging observed may spare surgery and/or adjuvant chemotherapy. Given the findings, the study has now expanded to two additional cohorts that are now enrolling to study further the dosing, and timing and/or need for surgery in these patients. Clinical trial information: NCT05571293 . [Table: see text]

Abstract Introduction: The pancreatic tumor microenvironment (TME) is a major driver of tumor progression, chemoresistance and immune suppression, and the IL-1 axis has been implicated in tumor-promoting signaling networks. The IL1RAP-IL1R1 receptor complex is required for both IL-1α and IL-1β signaling and is expressed on tumor and stromal/immune cells. Nadunolimab is a fully humanized, ADCC-enhanced IgG1 antibody that targets IL1RAP and disrupts both IL-1α/IL-1β signaling. In the phase 1/2a trial CANFOUR (NCT03267316) in which 73 PDAC patients with previously untreated, locally advanced or metastatic PDAC received nadunolimab with gemcitabine/nab-paclitaxel (GN), encouraging preliminary data show median iPFS of 7.2 mo, median OS of 12.9 mo and 1-year survival of 58%. The present analyses investigated the correlation between IL1RAP expression and disease severity as well as therapeutic efficacy of nadunolimab/GN. Methods: Evaluable screening biopsies from 46 CANFOUR PDAC patients were stained for IL1RAP by immunohistochemistry. mRNA data was obtained from the GTEx, TCGA and Pancreatic Cancer Action Network’s Know Your Tumor (KYT) databases and correlated to patient data (TCGA, KYT) and mutational data (KYT). Results: IL1RAP expression was detected on tumor cells, fibroblasts, and infiltrating immune cells in tumor biopsies. Notably, all tumor cells expressed IL1RAP and stratification of evaluable samples into high or low tumor cell expression of IL1RAP revealed significantly prolonged median OS on nadunolimab/GN in IL1RAP high compared to IL1RAP low patients (14.2 vs 10.6 mo, p=0.017). This was also reflected in longer iPFS (8.0 vs 5.8 mo), 1-year survival (69 vs 40%) and iORR (52 vs 32%). Although varying in intensity, IL1RAP expression on stromal cells did not correlate significantly with treatment efficacy. In interrogating bulk RNA seq data from the GTEx, TCGA and KYT databases, IL1RAP was overexpressed in pancreatic cancer compared to normal tissue, with higher expression in advanced stage disease. Moreover, as KRAS mutations promote tumor inflammation and KRASG12D has been implicated in activating the IL-1 axis, we observed that KRASG12D tumors had a higher expression of IL1RAP and IL-1α, but not IL-1β, compared to KRAS-wildtype tumors. In both early and late-stage PDAC, high levels of IL1RAP strongly correlated with poor survival (both p<0.0001). Patients responding to GN tended to have lower IL1RAP levels than patients with progressive or stable disease, in stark contrast to the results with nadunolimab/GN. To understand the effects of nadunolimab/GN in the TME, spatial transcriptomics in screening and on-treatment biopsies are being analyzed with Nanostring GeoMx. Conclusion: IL1RAP is upregulated in pancreatic cancer, its expression correlates with oncogenic KRAS driver mutations and is strongly associated with poor survival. The IL1RAP-targeting antibody nadunolimab has shown promising target-dependent efficacy in combination with 1st line chemotherapy, indicating that IL1RAP is a both highly relevant and targetable protein in PDAC. Citation Format: Eric Van Cutsem, Kawther Abdilleh, Jashodeep Datta, Manuel Hidalgo, Camilla Rydberg Millrud, Petter Skoog, Annika Sanfridson, Dominique Tersago, David Liberg. Interleukin-1 receptor accessory protein (IL1RAP) overexpression is associated with worse prognosis in PDAC and is targetable by nadunolimab [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C002.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) accounts for ~90% of pancreatic cancer. Surgery is the only curative treatment. Unfortunately, most patients are diagnosed with advanced disease and are not candidates for resection. Combination chemotherapy approaches have provided incremental improvements to PDAC outcomes. However, impact on survival for patients with inoperable disease remains modest, with a 2-year survival rate of less than 7%. Activating mutations in the KRAS oncogene are a key initiating event in ~80-90% of PDAC. Permanent activation of KRAS drives tumor cell proliferation and survival, tumor microenvironment modulation, and metabolic alterations in PDAC. Patients with KRAS mutant PDAC have worse outcomes compared to those with KRAS wild-type PDAC. In addition, hyperactivation of focal adhesion kinase (FAK) has been correlated with high stromal density, resulting in therapeutic resistance and poor survival. Avutometinib is a first-in-class oral RAF/MEK clamp that potently inhibits MEK kinase activity while also blocking the compensatory reactivation of MEK by upstream RAF. Defactinib is a selective inhibitor of focal adhesion kinase (FAK), which has been shown to mediate resistance to multiple anticancer agents. Preclinical data have shown that the combination of avutometinib + FAK inhibition (FAKi) + chemotherapy (gemcitabine + paclitaxel as a surrogate for nab-paclitaxel) induced tumor regression in a autochthonous KRAS/TP53 mutant PDAC mouse model. Prior clinical experience of defactinib + pembrolizumab + chemotherapy was safe, showed responses, decreased stromal density, and increased CD8+ T cell infiltration in patients with PDAC (NCT02546531). Methods: RAMP 205 is a multi-center, open-label, single arm Phase 1b/2a study of gemcitabine and nab-paclitaxel in combination with avutometinib and defactinib in patients with previously untreated metastatic PDAC (NCT05669482). The study is being conducted in 2 parts: Parts A (dose evaluation) and Part B (dose expansion). The starting dose is 2.4 mg avutometinib orally (PO) twice weekly + 200 mg defactinib PO twice per day, in combination with standard once weekly gemcitabine/nab-paclitaxel (QW IV). All study drugs are dosed 3 weeks on, 1 week off. Following determination of the Recommended Phase 2 Dose (RP2D) in Part A, Part B will evaluate efficacy of the RP2D via objective response rate (primary endpoint). Mandatory tumor biopsies and blood samples will be collected for correlative studies, including circulating tumor DNA, molecular profiling and pharmacodynamic markers. Eligible patients must have histologic or cytologic evidence of metastatic PDAC and measurable disease according to RECIST v1.1. Patients with prior or concomitant treatment for metastatic PDAC or prior treatment with RAS/MAPK or FAK inhibitors are not eligible. The study will enroll ~35 patients with 6-12 patients in Part A, and 23 patients in Part B. Citation Format: Kian-Haut Lim, Manuel Hidalgo, Mark H. O'Hara, Kristen R. Spencer, Ignacio Garrido-Laguna, David G. DeNardo, Vijeta Bhambhani, Gloria Patrick, Yaofeng Cheng, Silvia Coma, Jonathan A. Pachter, Louis J. Denis. RAMP 205: A phase 1b/2a study of gemcitabine, nab-paclitaxel, avutometinib, and defactinib in untreated metastatic pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C003.

Genomics Mimicry for Personalized Cancer Treatment.