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.

Abstract Background: Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and peritoneal metastasis are currently treated with standard systemic therapy. However, peritoneal-only metastasis represents a “regional” subtype of stage IV PDAC, and in select patients there may be an opportunity for a more aggressive locoregional approach. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) delivers low-dose intraperitoneal chemotherapy with enhanced pharmacokinetics, achieving high local tissue penetration while minimizing systemic toxicity, and uses aerosolization to promote homogeneous distribution throughout the peritoneal cavity. This trial will evaluate the feasibility, safety, and preliminary therapeutic activity of PIPAC in patients with PDAC and peritoneal-only metastasis. Methods: This is a prospective, single-center, non-randomized phase I trial evaluating the safety and tolerability of PIPAC with nab-paclitaxel administered in conjunction with standard-of-care systemic therapy (NCT07253662). Up to 10 patients with histologically confirmed PDAC and peritoneal-only metastases will be enrolled. Eligible patients are ≥18 years old, have ECOG performance status of 0-2, and are candidates for diagnostic laparoscopy. Key exclusion criteria include patients with bowel obstruction, life expectancy <4 months, >5 L abdominal ascites, or immunocompromised status; prior systemic chemotherapy is permitted. Patients will undergo up to 3 separate PIPAC treatments at 6-week intervals. Each procedure includes diagnostic laparoscopy to assess metastasis and obtain tissue biopsies for pathologic assessment and research correlatives, followed by PIPAC administration of nab-paclitaxel (112.5mg/m2) for 30 minutes.The primary objective is safety, including dose limiting toxicities, and tolerability of treatment in conjunction with standard-of-care systemic therapy. Secondary objectives include preliminary efficacy (disease control rate, peritoneal regression grading score, peritoneal carcinomatosis index, biochemical tumor response), treatment compliance (rate of completion of three treatments, delay or dose reduction of systemic therapy), and additional safety outcomes (adverse events, post-operative surgical complications, hospital readmissions, extended length of stay). Exploratory objectives include genomic and transcriptomic characterization of PDAC peritoneal metastasis with single cell RNA-sequencing to evaluate drivers that may lead to increased risk of peritoneal metastasis. In vitro tumor model chemotherapy response will be assessed in parallel and compared with patients via patient derived organoid cultures. Finally, circulating tumor DNA will be collected longitudinally to evaluate its utility as a biomarker of treatment response during standard-of-care systemic therapy with PIPAC. This trial opened for enrollment in December 2025, and as of January 2026, two patients have been enrolled. Citation Format: Julien T. Hohenleitner, Oliver J. Standring, Amber N. Habowski, Murtuza Hassan, Hai Huang, Matthew J. Weiss, Craig E. Devoe, Sepideh Gholami, Arvind Rishi, Daniel A. King, David A. Tuveson, Richard Whelan, Danielle K. Deperalta. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) in patients with peritoneal-only metastasis from pancreatic ductal adenocarcinoma [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 CT283.

TPS798 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) remains a deadly disease with 5-year survival rates below 5%, highlighting the need for improved therapeutic approaches. Intratumoral heterogeneity in transcriptional subtypes contributes to variable chemotherapy sensitivity. Alternating chemotherapy can accelerate exposure to diverse mechanisms of action while mitigating cumulative toxicity and resistance. The SEQUENCE trial demonstrated improved survival (OS & PFS) and overall response rate using alternating mFOLFOX/GnP vs. GnP alone. NALIRIFOX, which demonstrated superior OS compared to GnP in the NAPOLI-3 trial, is now a Category 1 NCCN recommendation for first-line mPDAC. Alternating NALIRIFOX with GnP may improve outcomes and tolerability. Methods: AltCAP is a single-arm, open-label phase II trial for treatment-naïve mPDAC patients with ECOG PS 0–1. Patients receive three 56-day macrocycles (6 months total), each comprising a 28-day NALIRIFOX sub-cycle A followed by a 28-day GnP sub-cycle B. NALIRIFOX (sub-cycle A): liposomal irinotecan (50 mg/m²), leucovorin (400 mg/m 2 ), oxaliplatin (60 mg/m²), 5-FU (2400 mg/m² over 46 hrs) on Days 1 & 15. GnP (sub-cycle B): Gemcitabine (1000 mg/m²) + nab-paclitaxel (125 mg/m²) on Days 1, 8* (optional per tolerability), & 15. The study uses a Simon’s two-stage design targeting 41 patients. The trial activated in June 2025, with anticipated enrollment completion in Q4 2026. The primary endpoint is 6-month PFS. Secondary endpoints include ORR, OS, time to treatment failure, and treatment-related adverse events (per CTCAE v5.0). Exploratory endpoints include serial circulating tumor DNA (ctDNA) testing at baseline, each subcycle, and progression to monitor response and early relapse, plus retrospective correlation of transcriptional subtypes with clinical outcomes.

Cellular immunity, mediated by tumor antigen-specific CD4 + and CD8 + T cells, has a critical role in the success of cancer immunotherapy by targeting intracellular driver and passenger tumor mutations. We present the final results of the phase 1 AMPLIFY-201 trial, in which patients who completed standard locoregional treatment, with minimal residual mKRAS disease ( n = 25, 20 pancreatic cancer and 5 colorectal cancer), received monotherapy vaccination with lymph node-targeting ELI-002 2P, including mutant KRAS (mKRAS) amphiphile-peptide antigens (G12D, G12R) and amphiphile-adjuvant CpG-7909. At a median follow-up of 19.7 months, efficacy correlated with mKRAS-specific T cell responses above or below a threshold 9.17-fold increase over baseline, with median radiographic relapse-free survival not reached, versus 3.02 months (hazard ratio (HR) = 0.12, P = 0.0002) and median overall survival not reached versus 15.98 months (HR = 0.23, P = 0.0099). Seventy-one percent of evaluable patients induced both CD4 + and CD8 + subsets, with sustained immunogenicity. Following ELI-002 2P treatment, antigen spreading was observed in 67% of patients, with increased T cells reactive to personalized, tumor antigens absent from the ELI-002 2P vaccine. Therefore, lymph node-targeting amphiphile vaccination induces persistent T cell responses targeting oncogenic driver KRAS mutations, alongside personalized, tumor antigen-specific T cells, which may correlate to clinical outcomes in pancreatic and colorectal cancer. ClinicalTrials.gov registration: NCT04853017 .

PURPOSE:To assess modified folinic acid/leucovorin, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX [mFFX]) versus gemcitabine/nab-paclitaxel (GnP) in de novo metastatic pancreatic ductal adenocarcinoma (PDAC) and explore predictive biomarkers. PATIENTS AND METHODS:Patients were randomly assigned 1:1 to mFFX or GnP with exclusion of germline pathogenic variants in BRCA1/2 or PALB2. The primary end point was progression-free survival (PFS) between arms with 0.3 significance. The per-protocol (PP) population included patients who received one dose of chemotherapy. Pretreatment biopsies underwent whole-genome/transcriptome sequencing and patient-derived organoid (PDO) development, providing correlate recommendations at a molecular tumor board and outcomes assessed according to RNA signatures (basal-like v classical). RESULTS:Of 160 patients randomly assigned (80 mFFX, 80 GnP), 140 patients were in the PP population (71 mFFX, 69 GnP), with median follow-up of 8.3 months. The median PFS was 4.0 months for mFFX versus 5.3 months for GnP (hazard ratio [HR], 1.37 [95% CI, 0.97 to 1.92]; P = .069) in intention-to-treat. Median overall survival (OS) was 8.5 months with mFFX and 9.7 months with GnP (HR, 1.57 [95% CI, 1.08 to 2.28]; P = .017). Genomic data were generated in 94%, transcriptomes in 74%, and PDOs in 50%. The median PFS for those with basal-like was 3.0 (mFFX) and 5.5 (GnP) months (P = .17), and classical PDAC was 6.3 (mFFX) versus 5.4 (GnP) months (P = .36). The median OS in basal-like was 7.5 (mFFX) and 8.9 (GnP) months (P = .75) versus in classical OS was 9.7 (mFFX) and 13.9 (GnP) months (P = .047). Overall, 75 (54%) of patients received second-line treatment, 33/75 (44%) correlate-guided. The median time on second-line treatment was only 2.1 months with a median OS of 5.4 months for a correlate-guided choice versus 4.4 months on a standard chemotherapy approach (P = .45). CONCLUSION:In the phase II Pancreatic Adenocarcinoma Signature Stratification for Treatment-01 (PASS-01) trial population, PFS was similar between GnP and mFFX; however, OS and safety trends favored GnP. The second-line setting appears inadequate to offer precision choices, given the short survival observed.

The peritoneum is the second most common site of metastasis in patients with pancreatic ductal adenocarcinoma (PDAC). Up to half of all patients that undergo curative-intent resection eventually develop peritoneal metastasis (PM), which accounts for significant morbidity and drives mortality. Despite recent advances in management, PM is associated with very poor prognosis, which is often measured in weeks to months. Clinical manifestations including bowel obstruction, ascites, and urinary obstruction have profound impact on quality of life. Even with relatively advanced disease, PM often remains occult on imaging and thus tend to be underdiagnosed and understudied. Many patients with peritoneal-only PM are excluded from clinical trials because response cannot be measured by standard radiographic criteria. Furthermore, as patients with PM are not eligible for surgical resection and low-volume peritoneal disease is often not amenable to percutaneous biopsy, tissue samples for peritoneal-specific translational studies are limited. Intraperitoneal therapeutics have been proposed as an attractive option for PM, as better penetration of tumor tissue can be achieved with less systemic toxicity compared with intravenous chemotherapy. Heated intraperitoneal chemotherapy (HIPEC), typically combined with cytoreductive surgery (CRS), is an option for select patients with PM from gynecologic or gastrointestinal primary, and for patients with primary peritoneal mesothelioma. However, the incorporation of locoregional therapy for PM in patients with PDAC has been poorly studied given the aggressive nature of pancreatic cancer and overall poor prognosis. With recent advances in existing treatment options, there may be a subset of patients who may derive benefits from locoregional control with cytoreduction and/or intraperitoneal chemotherapy. Critically, additional work is needed to determine PM-favorable clinical and tumoral predictive biomarkers to identify patients who may benefit from a more aggressive approach. We describe the current state of management of patients with peritoneal metastasis from PDAC and review the available data exploring peritoneal-directed therapy with cytoreductive surgery and/or intraperitoneal chemotherapy.

LBA4004 Background: Over 60% of patients with pancreatic ductal adenocarcinoma (PDAC) present with metastatic disease. Both modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel (GnP) are first-line options in advanced PDAC, however have not been compared prospectively in North American patients. Moreover, biomarkers to guide selection are lacking. Basal-like and Classical subtypes are prognostic, but their predictive impact is unknown. Patient-derived organoids (PDOs) are now feasible to study for drug pharmacotyping. Expedient molecular profiling with additional PDO drug sensitivities could enable better precision choices in PDAC. Methods: PASS-01 is a multi-center randomized phase II trial evaluating the benefit of 1st line mFFX vs GnP in de novo metastatic PDAC patients with ECOG PS 0-1, (germline BRCA1/2, PALB2 excluded) who have baseline tumor biopsies (bx) for whole genome/transcriptional sequencing (WGTS) and PDO generation/pharmacotyping with standard and novel drugs. The primary endpoint is the PFS of mFFX vs GnP (received at least 1 dose of assigned chemo, per protocol (PP)), 136 patients needed to reach 80% power to detect a difference in median PFS of 7 vs 5 months between mFFX and GnP at significance level of 0.3 in a 2-sided test. Secondary endpoints include: ORR, SAEs, OS, impact of RNA signatures and GATA6 expression on outcomes. Each patient is discussed at a molecular tumor board immediately following their 1st 8-week CT with the goal of recommending precision 2nd-line treatment options on progression. Results: This trial accrued 160 pts between 09/20 and 01/24, 45% in Canada, 55% in US with 140 eligible for 1st line PFS, data lock Mar 1/24 (see table). Median PFS (PP) was 5.1 mo for GnP and 4.0 mo for mFFX (p=0.14). Best response PR/SD for GnP: 29/45% and 24/35% for mFFX. SAEs attributed to the study were 3% GnP, 13% mFFX and 0.7% bx. Median OS (ITT) was 9.7 mo with GnP and 8.4 mo with mFFX, p=0.04. Of 113 patients in the PP analysis with progression, 64 (57%) received 2nd-line treatment (GnP, n= 30, mFFX n=34) Of these, a correlate-guided approach was delivered in 32 (50%), including 21 (66%) receiving chemo and 11 (34%) receiving a targeted or immunotherapy regimen. Correlative studies are underway. Preliminary analysis shows >80% successful whole genomes and >72% RNA signatures. PP patients include 9 % KRAS wild-type and 21% Basal-like PDAC. PDO-drug models have been established in 50%. Conclusions: Upfront multi-omic profiling of PDAC can be successfully incorporated into a multicenter randomized trial. While we have observed PP improved PFS and ITT longer OS favouring GnP in this cohort without gBRCA 1/2 or PALB2m, the benefit of chemo for advanced PDAC patients remains poor, with 43% unable to receive 2nd line, arguing strongly for the development of 1st-line biomarker selected strategies. Clinical trial information: NCT04469556 . [Table: see text]

Abstract Background: Mutations in RAS occur in > 25% of solid tumors and > 90% of patients (pts) with PDAC and > 40% of pts with CRC. ELI-002 2P is a vaccine comprised of lymph-node targeted Amphiphile (Amph)-modified G12D and G12R mutant KRAS peptides together with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Interim phase 1 AMPLIFY-201 data (O’Reilly et al; ASCO, 2023, #2528) showed that adjuvant administration of ELI-002 was well-tolerated, with T cell responses in 87%, and tumor biomarker responses in 77% (a subset of 32% had ctDNA clearance). Here we report relapse free survival data and correlations between ELI-002 2P- induced T cell levels and outcomes in pts with PDAC and colorectal cancer (CRC) at high risk for relapse following locoregional treatment. Methods: Resected PDAC (n=20) and CRC (n=5) pts with tumors harboring KRAS G12D or G12R who had minimal residual disease positivity (MRD+) defined as elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker (CA19-9/CEA), received up to 6 priming doses and 4 booster doses separated by a 3-month rest period of subcutaneous ELI-002 2P vaccine monotherapy comprised of Amph-peptides (700 mcg each G12D/G12R), admixed with Amph-CpG-7909 at 0.1, 0.5, 2.5, 5.0 and 10.0 mg per cohort dose level. Primary endpoints included safety and recommended phase 2 dose (RP2D) of Amph-CPG-7909; secondary endpoints: biomarker reduction/clearance; exploratory endpoints: included relapse free survival (RFS) using immune Response Evaluation Criteria in Solid Tumors (iRECIST) and immunogenicity assessed by direct ex vivo Fluorospot and intracellular cytokine staining of peripheral blood mononuclear cells. Results: Direct ex vivo polyfunctional mKRAS-specific T cell responses to ELI-002 2P were observed in 20/23 (87%; 50% induced both CD4+ and CD8+ T cells, median 13-fold and mean 56-fold increase from baseline), with response in 9/9 (100%) pts treated at highest two dose levels including the 10 mg RP2D. Clinical efficacy correlated with T cell response in evaluable pts (n=22): median tumor biomarker reduction/clearance was -86.9% vs -4.5% in above vs below median T cell responders, respectively (p < 0.0124). At 25 weeks median follow-up, the median RFS was not reached compared to 17.1 weeks in above versus below median T cell responders (HR 0.11; 95% CI 0.027-0.446; p = 0.0108). The association of RFS with T cell response was not confounded by other baseline prognostic variables (including tumor stage, recovery from prior cytotoxic therapy as assessed by absolute neutrophil count, or immune system subsets such as %CD4+ or %CD8+of CD3+ lymphocytes). Conclusions: The association of ELI-002 2P vaccine T cell responses with clinical outcomes in a novel MRD+ trial design underscores the potential to reduce recurrence in the setting of microsatellite stable PDAC and CRC. A new phase 1/2 trial, AMPLIFY-7P (NCT05726864), is evaluating a new seven peptide (G12D, G12R, G12V, G12C, G12A, G12S, G13D) ELI-002 7P formulation. Citation Format: Zev A. Wainberg, Shubham Pant, Colin D. Weekes, Muhammad Furqan, Pashtoon M. Kasi, Craig E. Devoe, Alexis D. Leal, Vincent Chung, James R. Perry, Lochana Seenappa, Lisa K. McNeil, Esther Welkowsky, Peter C. DeMuth, Christopher M. Haqq, Eileen M. O'Reilly. T cell responses and clinical outcomes in pancreatic and colorectal cancer patients with minimal residual disease in AMPLIFY-201, a phase 1 trial of a first-in-class amphiphile lymph node targeted mutant KRAS vaccine [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 C092.

2636 Background: Diverse KRAS mutations occur in 25% of solid tumors with G12D, V and R most frequent. ELI-002 7P is an expanded spectrum vaccine comprised of lymph-node targeted Amphiphile (Amph)-modified G12D, V, R, C, S, A, and G13D mutant KRAS peptides with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Earlier ELI-002 2P showed high rates of T cell and tumor biomarker response (both 21/25, 84%), with median relapse-free survival not reached versus 4.01 months (HR 0.14; p=0.0167) comparing patients (pts) above versus below T cell median (12.75X). Methods: This multicenter phase IA trial assessed safety, immunogenicity and preliminary antitumor activity of ELI-002 7P in pancreatic (PDAC) and colorectal pts with minimal residual disease (MRD) following standard locoregional treatment. Pts with elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker (CA19-9/CEA), and KRAS mutation were enrolled and treated with subcutaneous fixed dose Amph-CpG-7909 and 1.4 mg or 4.9 mg of Amph-Peptides 7P (Table). Safety, T cell change, and preliminary antitumor activity including biomarker reduction/clearance are reported. Results: No dose-limiting toxicities, no treatment related SAEs or cytokine release syndrome were observed, no maximum tolerated dose was identified, and the recommended phase 2 dose (RP2D) was 10.0 mg Amph-CpG-7909 with 4.9 mg Amph-Peptides 7P. Safety: all grade 1, fatigue (29%), malaise (21%), and injection site reaction (7.1%). At data cutoff Dec 18, 2023, polyfunctional mKRAS-specific T cells were observed in 100% (n=11/11). Both CD8+ and CD4+ responses were induced in 63.6% of pts (7/11), with higher median fold-change from baseline at RP2D and durable responses post-booster immunization in 100% of pts (7/7). Biomarker reductions were observed in 2/5 (40%) at the 1.4 mg Amph-Peptides 7P dose level and in 5/7 (71%) at the RP2D 4.9 mg dose level in pts with all the common G12X (D, V, R) and G13 (D) KRAS mutations; MRD clearance was observed in 1 G12V PDAC pt at 4.9mg. Conclusions: ELI-002 7P was safe with median RP2D T cell responses exceeding the prior formulation (7P median 109.2; 2P 12.75), and early indications of antitumor activity. The randomized phase II is now open in patients with pancreas cancer. Clinical trial information: NCT05726864 . [Table: see text]

TPS720 Background: KRAS mutations occur in 25% of human tumors, frequently in pancreatic where over 85% relapse after locoregional treatment. ELI-002 7P is a lymph node targeted immunotherapy comprised of Amphiphile (Amph)-modified G12D, G12R, G12V, G12C, G12A, G12S and G13D mutant KRAS peptides together with an Amph-modified CpG oligonucleotide adjuvant. In the first in human AMPLIFY-201 study, a two peptide G12D/G12R formulation increased KRAS-specific T cells in 87% of patients, and T cell responses 13-fold or higher over baseline correlated with outcomes including reduction in risk of relapse or death. The AMPLIFY-7P study hypothesizes that adjuvant administration of ELI-002 7P will be safe and will delay relapse compared to observation in patients with KRAS mutated pancreatic cancers who have completed curative intent locoregional treatment. Methods: This open-label, phase 1 and randomized phase 2 study is evaluating ELI-002 7P in patients with KRAS mutated pancreatic adenocarcinoma following standard of care chemotherapy and surgery. In phase 2, patients are randomized 2:1 to ELI-002 7P versus observation with crossover of the observation arm permitted at the time of confirmed radiographic relapse via iRECIST. Eligible patients must be within 6 months of completion of locoregional treatment for up-front resectable pathologically confirmed pancreatic cancer (Stage I-III) with radiographic NED (no evidence of disease). Phase 2 patients are included regardless of biomarker evidence of recurrent disease, however, those who have not recovered absolute lymphocytes to the normal range following cytotoxic therapy are excluded. The primary phase 2 objective is to compare the efficacy of ELI-002 7P versus observation, with primary endpoint disease-free survival per investigator. Secondary objectives compare biomarker response (reduction or clearance of ctDNA or if ctDNA was not detectable, serum tumor antigen CA19-9) in the subset with positive baseline values, OS, safety, and iRECIST response rate in the crossover subset. Exploratory endpoints include immunogenicity, the association of immunogenicity with high resolution HLA typing, and evaluation of tumor-infiltrating T cells and the tumor microenvironment in the event biopsy tissue is available. An Independent Data Monitoring Committee reviewed phase 1 data and recommended opening phase 2. Subsequent patients will receive up to 10 doses of Amph-peptides 7P 700 mcg each (4.9 mg total), together with Amph-CpG-7909 (10.0 mg) administered over a five-month treatment period. In Phase 2, approximately 135 patients will be enrolled in the United States. An interim analysis is planned using group sequential design for control of overall alpha 0.10. Clinical trial information: NCT05726864 .

Pancreatic and colorectal cancers are often KRAS mutated and are incurable when tumor DNA or protein persists or recurs after curative intent therapy. Cancer vaccine ELI-002 2P enhances lymph node delivery and immune response using amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909). We treated 25 patients (20 pancreatic and five colorectal) who were positive for minimal residual mKRAS disease (ctDNA and/or serum tumor antigen) after locoregional treatment in a phase 1 study of fixed-dose Amph-Peptides-2P and ascending-dose Amph-CpG-7909; study enrollment is complete with patient follow-up ongoing. Primary endpoints included safety and recommended phase 2 dose (RP2D). The secondary endpoint was tumor biomarker response (longitudinal ctDNA or tumor antigen), with exploratory endpoints including immunogenicity and relapse-free survival (RFS). No dose-limiting toxicities were observed, and the RP2D was 10.0 mg of Amph-CpG-7909. Direct ex vivo mKRAS-specific T cell responses were observed in 21 of 25 patients (84%; 59% both CD4+ and CD8+); tumor biomarker responses were observed in 21 of 25 patients (84%); biomarker clearance was observed in six of 25 patients (24%; three pancreatic and three colorectal); and the median RFS was 16.33 months. Efficacy correlated with T cell responses above or below the median fold increase over baseline (12.75-fold): median tumor biomarker reduction was -76.0% versus -10.2% (P < 0.0014), and the median RFS was not reached versus 4.01 months (hazard ratio = 0.14; P = 0.0167). ELI-002 2P was safe and induced considerable T cell responses in patients with immunotherapy-recalcitrant KRAS-mutated tumors. ClinicalTrials.gov identifier: NCT04853017 .

104 Background: CRC is characterized by hyperactivation of the Wnt pathway where DKK1 plays a critical regulatory role. DKN-01 is an IgG4 monoclonal antibody that potently neutralizes DKK1. DKN-01 has immunomodulatory activity and stimulates a pro-inflammatory tumor microenvironment. Elevated DKK1 expression has been shown to correlate with fluorouracil (5FU) resistance in CRC tumors. 5FU-based combination therapies have demonstrated promising clinical activity in combination with DKN-01 in gastric cancer. In pre-clinical models of 5FU-resistant CRC, DKN-01 showed potent anti-tumor effects. Methods: DeFianCe (NCT05480306) is a Phase 2 randomized, open-label, two-part, multicenter study to evaluate efficacy and safety of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab versus standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab] as 2L treatment of advanced MSS CRC patients (pts). The primary endpoint of the single arm Part A (DKN-01 + SOC) was safety and tolerability with secondary endpoints including overall response rate (ORR), progression-free survival (PFS) and overall survival. Retrospective analysis of tumoral DKK1 mRNA expression was measured centrally by in situ hybridization. Results: Thirty-three pts enrolled in Part A between Sept 2022-April 2023. As of 21 Aug 2023, median age 56 years (35, 84); 20 males. 29 pts had tumors with evaluable baseline DKK1 expression; 55% were DKK1-expressing (≥1% tumor cells). All patients had received prior 5FU-based therapies, 30 pts (91%) with oxaliplatin in combination and 17 pts (52%) had prior bevacizumab. 24 pts (73%) had RAS mutations (22 KRAS, 2 NRAS) and 23 pts (70%) had liver metastasis. 30 pts (91%) received DKN-01 + bevacizumab + FOLFIRI. 17 pts (52%) had ≥grade 3 treatment related adverse events (TRAE) with neutrophil count decreased, anemia and fatigue representing the most common. No pt discontinued DKN-01 due to a TRAE. Of the 27 response evaluable pts the ORR was 30% and the DCR was 93%: 8 PR, 17 SD and 2 PD. The median PFS has not been reached. Conclusions: DKN-01 in combination with SOC was well tolerated with promising preliminary activity (ORR 30% and DCR 93%) in the single arm Part A. PFS has not been reached and survival follow up is ongoing. Part B randomized expansion phase has begun and is enrolling an additional 130 pts. Tumoral DKK1 expression and correlation with clinical outcomes will be evaluated as an exploratory efficacy endpoint. Clinical trial information: NCT05480306 .

Abstract Overall survival for patients with advanced PDAC remains less than 1 year. Biomarkers are needed to select chemotherapy regimens, either alone or in combination with novel agents. PASS-01 compared mFOLFIRINOX and Gemcitabine/nab-Paclitaxel in a phase II randomised control trial while prospectively exploring tissue, liquid and organoid biospecimens to interrogate putative biomarkers of chemotherapy response and resistance. Methods PASS-01 was conducted across 6 sites in North America. Patients with de novo metastatic disease and a lesion amenable to core biopsy were included. Cases with germline pathogenic variants in BRCA1/2 or PALB2 were excluded. Up to 6 core biopsies were obtained with priorities for clinical diagnosis, patient derived organoids (PDOs), and whole genome and transcriptome sequencing (WGTS). WGTS were performed at a single site following laser capture microdissection. WGS reports were clinically (CAP) accredited and annotated mutations, copy number alterations, mutational signatures, TMB and structural variant patterns. KRAS allelic states were documented with major imbalances in mutant KRAS (KRASmaj) defined as mutant: WT copy number >3. Transcriptomic subtypes (classical vs. basal-like) were classified as previously described (Moffitt et al., 2015). WGTS results were discussed at a molecular tumor board with PDO pharmacotyping to determine best second line options. Results: 160 patients were included in the intention to treat population, of these WGS was available in 127 (79%) and additional NGS reports in 20 (13%). RNA-seq was successful in 119 (74%) and the basal-like subtype accounted for 29% and was associated with inferior outcomes. KRASm were evident in 91% and KRASG12D represented 45%. Tumor suppressors TP53, CDKN2A and SMAD4 were lost in 81%, 76% and 39% respectively. MTAP deletion was present in 40%, largely synonymous with CDKN2A deletions. Commonly co-altered genes in the dataset included epigenetic regulators (ARID1A, KMT2C, KDM6A) and TGFBR2. KRASmaj was present in 30% of cases and polyploid tumors in 50%. 50% of basal-like PDAC harboured KRASmaj compared to 22% of classical PDAC, p<0.01. Dominant signatures (SBS) included age related SBS1, 5 and 8. Additionally, we saw a prevalence of SBS17 and APOBEC SBS2/13, signatures which occurred more frequently compared to a similarly characterised resected cohort. Unstable genotypes were present in 24% with somatic-HRD evident in 3%. Of KRASWT PDAC, 58% harboured class I-II BRAF variants. KRAS WT PDAC had fewer co-mutations and in one case where an NGS report did not find a driver, a novel fusion in SLC4A4-RASGRF2 was identified. 28 molecular tumor boards took place throughout the trial influencing 50% obtaining a 2nd-line treatment. Conclusion: The PASS-01 cohort exhibits a heterogeneous group of genotypes and molecular subgroups. Certain mutational processes are more evident in advanced compared to resected PDAC. The impact of subgroups on survival and chemotherapy response is ongoing with a planned data lock on July 15th. Results will be presented at the meeting. Citation Format: Grainne M O'Kane, Gunho Jang, Trevor J Pugh, Julie Wilson, Stephanie Ramotar, Daniel A King, Dan Laheru, Ken H Yu, Kimberly J Perez, Amber Habowski, Erica S Tsang, Robert C Grant, Andrew J Aguirre, Raymond W-J Jang, Craig E Devoe, Eileen M O'Reilly, Anna Dodd, Brian M Wolpin, Xiang Y Ye, Elizabeth M Jaffee, David Tuveson, Steven Gallinger, Jennifer J Knox, Faiyaz Notta. Genomic and transcriptomic characterization of pancreatic cancer patients on the PASS-01 trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-17.

Background: Gastrointestinal Stromal Tumors (GISTs) are the most common mesenchymal tumors of the GI tract. SEER is an extensive cancer database which proves useful in analyzing population trends. This analysis investigated GIST outcomes between geriatric & non-geriatric patients. Methods: SEER*STAT 8.4.0.1 was used to extract relevant GIST data from 2000 to 2019. Geriatric age was defined as >= 70 years. Variables included age, sex, surgery, cancer-specific death, and overall survival. Statistical tests included univariate analysis using KM survival estimate (95% confidence interval) to calculate 5-year survival (5YS). Log-Rank tests determined statistical significance. Multivariable Cox's PH regression estimated the geriatric hazard death ratio adjusted for sex, stage, and surgery. Results: The number of patients included was 13,579, yielding overall 5YS of 68.6% (95% CI 67.7-69.5). Cancer-specific death was 39.11% in 2000 & 3.33% in 2019. Non-geriatric & geriatric patient data yielded 5YS of 77.4% (76.4%-78.3%) and 53.3% (51.7%-54.8%) respectively (p < 0.0001). For no surgery/surgery, younger patient data yielded 5YS of 48.7% (45.8%-51.4%) and 83.7% (82.7%-84.7%) respectively (p < 0.0001); geriatric data yielded 5YS of 29.3% (26.5%-32.1%) and 62.8% (60.8%-64.6%) respectively (p < 0.0001). Multivariable analysis yielded a geriatric hazard death of 2.56 (2.42-2.70) (p < 0.0001). Conclusions: Cancer-specific death decreased since 2000, indicating an improvement in survival & treatment methods. Observed lower survival rates overall in the geriatric group. Surgery appeared to enhance survival rates in both groups, suggesting that surgery is an important factor in GIST survival regardless of age. Large prospective studies will help define clinical management for geriatric patients.

ABSTRACT:Uveal melanoma (UM), arising from intraocular melanocytes, poses a complex clinical challenge with a substantial risk of distant metastasis, often to the liver. Molecular profiling, encompassing genetic, cytogenetic, gene expression, and immunological subsets, plays a pivotal role in determining prognoses. The evolving landscape includes promising systemic treatments, such as tebentafusp, a novel immune-modulating bispecific fusion protein, and targeted therapies. Combined regional and systemic approaches, including immune checkpoint inhibitors and innovative liver-directed therapy, are also under investigation. Although recent progress has improved outcomes, ongoing research aims to address the unique challenges of UM and develop effective therapies, particularly for HLA-A*02:01-negative patients who represent a significant unmet medical need. This review comprehensively discusses the molecular characteristics of UM, risk stratification methods, and the current and future spectrum of regional and systemic therapeutic modalities.

Introduction Retrospective studies have suggested that patients with poor performance status treated with immune checkpoint inhibitors have shorter overall survival and poorer response rates. This study was undertaken to investigate the possible relationships between inpatient immune checkpoint inhibitor use and clinical outcomes. Methods This was a retrospective chart review of cancer patients who received an immune checkpoint inhibitor while hospitalized from 1 January 2016 to 30 December 2020. The primary outcome was 90-day mortality or admission to hospice rate. Secondary outcomes included overall survival, time to death or discharge to hospice, and descriptive summarization of patient characteristics. Results A total of 52 patients were analyzed. At 90 days, 68.2% of subjects were expired or admitted to hospice (95% CI: 54.7–81%). 90-day overall survival was 47.1%; median survival time was 81 days (95% CI: 28–242 days). The median time to death or hospice was 35 days (95% CI: 24–72 days). The time to death or hospice was shorter for immune checkpoint inhibitor-naive patients compared to those who received immune checkpoint inhibitors prior to admission (29 days, 95% CI: 12–43 days vs. 242 days, 95% CI: 36–1288 days, respectively; HR: 2.74, 95% CI: 1.2–6.25; p = 0.0121). No differences were found when comparing other baseline characteristics. Conclusion A majority of patients who received an immune checkpoint inhibitor while hospitalized were either discharged to hospice or expired by 90 days. An increased rate of death or discharge to hospice was observed for patients who were immune checkpoint inhibitor-naive prior to their admission.