Pelster, Meredith

566 Background: FGFR inhibitors (FGFRi) have an established role in treating FGFR2-altered (alt) cholangiocarcinoma (CCA). Tinengotinib, a novel FGFRi, has shown promising activity overcoming acquired resistance to prior FGFRi. We present biomarker analyses evaluating tinengotinib’s ability to overcome prior FGFRi resistance and to elucidate mechanism of resistance to tinengotinib. Methods: Eligible patients (pts) with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy were treated with tinengotinib 10 mg daily across 4 Cohorts: A1: FGFR2 fusion (fus) with primary progressive disease (PD) on prior FGFRi; A2: FGFR2 fus with PD after prior response to FGFRi; B: FGFR alt without FGFR2 fus; C: FGFR wild-type. Efficacy was assessed by RECIST v1.1. All pts underwent liquid biopsy for circulating tumor DNA (ctDNA) at baseline; additional timepoints include cycle 3 day 1 (C3D1), time of PD, and end of treatment (EOT). Samples were analyzed using FoundationOne Liquid panel. Results: 27 out of 55 enrolled pts had biomarker samples collected at baseline and C3D1. Among them, pts in A1 (n=10, 107 mutations (mut)), B (n=8, 90 mut) and C (n=5, 74 mut) showed a significant decrease in short variant allele frequencies (VAF) from baseline to C3D1 by a median relative VAF reduction of 100% (p<0.0001) for each of the three cohorts. Although a median relative VAF reduction of 33.3% was seen in A2 (n=4, 15 mut), this was not significant (p=0.6093) likely due to low baseline mutation burden. A ≥50% reduction in ctDNA was associated with improved progression free survival (p<0.0014). Additionally, 100% of median relative reductions in FGFR2 kinase domain (KD) mut were seen in A1 and B (p<0.0001, 95% CI 100-100% and p=0.0156, 95% CI 83.6-100%, respectively), with 92% and 57% clearance of initial FGFR2 KD mut by C3D1. In a subgroup of 10 pts with biomarker sampling at baseline and EOT, 3 pts in A1 with acquired resistance showed emergence of novel FGFR2 mut, loss of FGFR-sensitive mut and new mut in alternate pathways (e.g., AKT, EGFR, RAS/MAPK) while retaining the original FGFR2 fus. 1 pt from B developed resistance due to new FGFR2 rearrangements and FGFR2 mut. 4 FGFR wild-type pts from C developed resistance involving mut in TP53, KRAS, and other oncogenic drivers. Conclusions: These findings provide genomic evidence that tinengotinib may overcome resistance to prior FGFRi treatment in FGFR2 fus-positive CCA, as reflected by significantly reductions in ctDNA VAFs and frequent clearance of FGFR2 KD mutations. The emergence of resistance alterations including de novo FGFR2 mutations and bypass pathways activations indicates acquired resistance that may limit long-term benefit. These results support further investigation with expanded biomarker sampling to better characterize resistance evolution and guide therapy optimization in an ongoing Phase 3 trial. Clinical trial information: NCT04919642 .

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited treatment options and poor survival. This study explores how a medically supervised ketogenic diet (MSKD) impacts the gut microbiome and treatment response in patients with newly diagnosed metastatic PDAC receiving gemcitabine, nab-paclitaxel, and cisplatin chemotherapy. Methods: As part of a randomized Phase II trial, 32 evaluable patients (median age 65.9 years; 53% male), 16 were randomized to either MSKD or standard diet (SD) combined with chemotherapy. Stool samples were collected from 4 patients in the MSKD group (13 samples) and 8 patients in the SD group (23 samples). Deep shotgun metagenomic sequencing was conducted using NovaSeq (Illumina). Taxonomical and functional microbiome characterization was performed using MetaPhlAn 4.0 and HUMAnN 3.6 (The Huttenhower Lab, Harvard). Comprehensive bioinformatics analyses, using QIIME2, were performed to analyze microbiome composition and function over time. Results: Patients in the MSKD group showed better treatment responses overall. Microbiome profiles between the two groups remained distinct throughout therapy. Though not statistically significant due to sample size, MSKD patients showed lower alpha diversity (Shannon diversity; p-value=0.1339), likely reflecting reduced intake of fermentable fiber. Differential abundance analysis using the ANCOM-BC method revealed a significant enrichment of beneficial taxa in the MSKD group compared to the SD group (p&lt;0.05, log-fold change [lfc]≥2), including Akkermansia muciniphila (linked to improved response to immune checkpoint inhibitors; p=0.017931, q=1), Intestinimonas butyriciproducens (a short-chain fatty acid [SCFA] and butyrate producer; p=3.09E-05, q=0.017), and Streptococcus thermophilus (a supporter of gut mucosal health; p=1.15E-05, q=0.006). During the course of the study, only MSKD patients showed sustained increases in Roseburia hominis (SFCA/butyrate producer; p=3.94E-05, q=0.021) and Lacticaseibacillus rhamnosus (with anti-inflammatory and immune-modulating properties; p=7.28E-19, q=3.98E-16), along with a marked reduction in potentially pro-inflammatory Actinomyces spp.(p≤4.47E-05, q≤0.024). Functional profiling showed increased abundance of cancer-relevant microbial pathways in MSKD patients, including phosphatidate metabolism (PWY-7039; involved in lipid signaling and immune regulation; p=4.36E-04, q=0.20) and allantoin degradation (PWY-5705; linked to redox balance; p=9.16E-06, q=0.004). Conversely, L-ascorbate biosynthesis V (PWY-6415) was reduced (p=3.80E-04, q=0.17), likely due to decreased D-galacturonate substrate availability from fiber restriction. Conclusion: These findings suggest that an MSKD may beneficially modulate the gut microbiome in ways that support and enhance therapeutic response in patients with PDAC. Further validation in a larger cohort is warranted to confirm these results and improve analytical resolution. Citation Format: Keehoon Lee, Derek Cridebring, Gayle S. Jameson, Denis J. Roe, Erkut Borazanci, Diana L. Hanna, Caroline G.P. Roberts, Meredith S. Pelster, Richard C. Frank, Angela T. Alistar, Alan M. Miller, J. Erin Wiedmeier-Nutor, Sandra D. Algaze, Alison R. Zoller, Sarah J. Hallberg, Betsy C. Wertheim, Joshua D. Rabinowitz, Stephen Gately, Jennifer Keppler, Sunil Sharma, Drew W. Rasco, Daniel D. Von Hoff. Ketogenic Diet Modulates Gut Microbiome Composition and Enhances Treatment Response in Patients with Advanced Pancreatic Cancer: A Phase II Study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B094.

131 Background: KRAS G12C mutations occur in 3%–4% of CRC cases and are associated with poor prognosis. In the phase 1/2 KRYSTAL-1 study (NCT03785249), at a median follow-up of 11.9 months (mo), Ada (irreversible inhibitor of KRAS G12C ) in combination with Cetux (anti-EGFR antibody) demonstrated promising clinical activity (objective response rate [ORR] of 34% per blinded independent central review [BICR] and 43% per investigator [INV]) and was well tolerated in patients (pts) with previously treated KRAS G12C -mutated mCRC. Based on these findings, Ada + Cetux was granted accelerated approval in the United States for these pts. Here, we present longer-term follow-up analyses from this study. Methods: Adults with previously treated KRAS G12C -mutated mCRC and ECOG performance status of 0 or 1 were treated with Ada (600 mg BID) in combination with Cetux (400 mg/m 2 followed by 250 mg/m 2 QW or 500 mg/m 2 Q2W) until disease progression, unacceptable toxicity, withdrawal of consent, or death, in separate phase 1 and phase 2 cohorts. Primary endpoints were safety (phase 1) and ORR per BICR (phase 2). Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (phase 2). Results: A total of 94 pts received Ada + Cetux. The median number of prior lines of systemic therapy was 3 (range, 1–9); 23 pts (24%) had received ≥ 4 prior lines of systemic therapy. The most frequent sites of metastases at baseline were the lung (71%) and liver (64%). At a median follow-up of 20.4 mo, ORR per INV was 43% (95% CI 32–53) and all were partial responses; median DOR was 5.9 (95% CI 5.5–7.6) mo. Disease control rate per INV was 86% (95% CI 78–92). Median PFS per INV was 6.9 (95% CI 5.9–7.4) mo; 6- and 12-mo PFS rates were 61% and 19%, respectively. Median OS was 16.0 (95% CI 13.3–18.8) mo; 6- and 12-mo OS rates were 88% and 66%, respectively. Any-grade treatment-related adverse events (TRAEs) were reported in 100% of pts, 28% of which were grade 3/4. TRAEs led to discontinuation in 10% of pts. Efficacy analyses by BICR, subgroup analyses, and additional safety results will be presented. Conclusions: In heavily pretreated pts with KRAS G12C -mutated mCRC, Ada + Cetux continued to demonstrate clinically meaningful activity and tolerable safety with longer follow-up. These updated results are consistent with those from the primary analysis and constitute the longest duration of follow-up for dual KRAS G12C /EGFR blockade in this setting. Efficacy of second-line Ada + Cetux vs chemotherapy in KRAS G12C -mutated mCRC is being investigated in the phase 3 KRYSTAL-10 study (NCT04793958). Clinical trial information: NCT03785249 .

TPS3160 Background: Patients (pts) with recurrent or metastatic solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), gastric adenocarcinoma (GC), and pancreatic ductal adenocarcinoma (PDAC), have limited treatment options with short PFS and OS despite recent advances (1-3). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is highly expressed across multiple solid tumors, such as CRC, GC, PDAC, and NSCLC. Restricted normal tissue expression and efficient lysosomal trafficking of CEACAM5 highlight its potential as an anticancer target. SGN-CEACAM5C is a novel investigational antibody-drug conjugate (ADC) directed to CEACAM5 composed of the humanized immunoglobulin G (IgG1) anti-CEACAM5 monoclonal antibody tusamitamab chemically conjugated to 8 molecules of the topoisomerase 1 inhibitor 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT). SGN-CEACAM5C selectively binds to CEACAM5 present on the cell surface and is internalized via the endo-lysosomal pathway, with subsequent release of the payload through enzymatic cleavage. Release of the cytotoxic payload induces DNA damage, cell cycle arrest in S phase, and apoptosis in tumor cells. In vitro bystander activity was observed against tumor cells without CEACAM5 surface expression. SGN-CEACAM5C is highly active in multiple patient-derived xenograft models, including CRC, GC, and NSCLC, across various levels of CEACAM5 expression (4,5). These preclinical findings justify evaluation of SGN-CEACAM5C in a clinical trial setting. Methods: SGNCEA5C-001 (NCT06131840) is a phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of SGN-CEACAM5C in adults with select advanced solid tumors. This study consists of dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C). Eligible pts are adults ≥18 years of age with confirmed metastatic or unresectable solid tumor malignancy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an ECOG PS of 0-1, and 1 of the following tumor types: CRC, GC/gastroesophageal junction adenocarcinoma (GEJ), PDAC, NSCLC (squamous/non-squamous), or SCLC. Primary endpoints include incidence of AEs, laboratory abnormalities, dose modifications due to AEs, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of PK parameters, incidence of antidrug antibodies, objective response rate and best response per RECIST v1.1 by investigator, duration of response, PFS, and OS. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part A in North America. 1. Bordry 2021. 2. Chakrabarti 2022. 3. Merle 2022. 4. Baudat 2023. 5. Baudat 2024. Clinical trial information: NCT06131840 .

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 .

PURPOSE Adagrasib, a KRAS G12C inhibitor, has demonstrated clinical activity in patients with KRAS G12C -mutated non–small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRAS G12C mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRAS G12C mutation. METHODS In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249 ; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRAS G12C -mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety. RESULTS As of October 1, 2022, 64 patients with KRAS G12C -mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients. CONCLUSION Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRAS G12C -mutated solid tumors.

425082 Background: KRAS, a mediator of signalling pathways essential for cellular growth, proliferation, and survival, is the most frequently mutated oncogene in cancer. Notably, KRAS mutations occur in ~90% of pancreatic cancers, of which ~2% are KRASG12C mutations. Other gastrointestinal (GI) tumors also harbor KRASG12C mutations, such as biliary tract cancer (BTC; 1%) and appendiceal cancer (3–4%), and they are also seen in non-GI tumors, such as endometrial and ovarian cancer (1–2%). Adagrasib, a covalent KRASG12C inhibitor that irreversibly and selectively binds KRASG12C in its inactive state, was selected for favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system penetration. Methods: KRYSTAL-1 is a multicohort phase 1/2 study (NCT03785249) evaluating adagrasib in patients (pts) with advanced solid tumors harboring a KRASG12C mutation. Here we report data from a phase 2 cohort evaluating adagrasib monotherapy administered orally at 600 mg BID in pts with unresectable or metastatic KRASG12C-mutated solid tumors (excluding non-small cell lung cancer and colorectal cancer), including pancreatic ductal adenocarcinoma (PDAC), BTC, other GI, and non-GI tumors. Study objectives include evaluation of clinical activity (ORR, DCR, DOR, PFS, OS) and safety. Results: As of October 1, 2022, 64 pts with KRASG12C-mutated solid tumors were enrolled and 63 were treated with adagrasib (median follow-up, 16.8 months); of these, 21 pts had PDAC, 12 BTC, 16 other GI tumors (9 appendiceal, 4 gastro-esophageal junction/esophageal, 3 small bowel), and 14 non-GI tumors (5 ovarian, 4 unknown primary, 3 endometrial, 1 breast, 1 glioblastoma). Overall, median age was 65 years, 61% had ECOG PS 1, and median prior lines of systemic therapy was 2. Among 57 pts with measurable disease (blinded independent central review), ORR was 35.1% (20/57; all partial responses); DCR was 86.0% (49/57); median DOR was 5.3 months (n=20; 95% CI 2.8–7.3); median PFS was 7.4 months (95% CI 5.3–8.6); and median OS was 14.0 months (n=64; 95% CI 8.5–18.6). Among 21 pts with PDAC, ORR was 33.3% (7/21); DCR was 81.0% (17/21); median PFS was 5.4 months (95% CI 3.9–8.2); and median OS was 8.0 months (95% CI 5.2–11.8). Among 12 pts with BTC, ORR was 41.7% (5/12); DCR was 91.7% (11/12); median PFS was 8.6 months (95% CI 2.7–11.3); and median OS was 15.1 months (95% CI 8.6–not estimable). Overall (n=63), treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of pts (most commonly [≥20%] nausea [49.2%], diarrhea [47.6%], fatigue [41.3%], vomiting [39.7%]), grade 3 TRAEs in 25.4%, and grade 4 TRAEs in 1.6%. No grade 5 TRAE occurred. Conclusions: Adagrasib is well tolerated and demonstrates promising clinical activity in pretreated pts with PDAC, BTC, and other solid tumors harboring a KRASG12C mutation. Clinical trial information: NCT03785249 .