4222 Background: Pancreatic ductal adenocarcinoma (PDAC) is predominantly driven by KRAS mutations; however, approximately 10% of tumors are KRAS wild-type (KRAS-WT). Among these, NRG1 gene fusions have recently gained heightened clinical relevance following the FDA’s accelerated approval of zenocutuzumab for NRG1 fusion–positive PDAC after prior therapy. Contemporary real-world data characterizing actionable alteration yield and outcomes in KRAS-WT PDAC remain limited. Methods: We analyzed patients with PDAC (OncoTree: PAAD) from MSK-CHORD 2024. KRAS status was defined by the presence or absence of pathogenic KRAS somatic mutations. NRG1 fusions were identified through structural variant analysis. A predefined clinically actionable alteration set included NRG1 and NTRK1–3 fusions, MSI-H/dMMR, BRCA1/2 or PALB2 alterations, ERBB2 amplification, and BRAF V600E mutation. The primary endpoint was overall survival (OS) from the date of molecular profiling. Secondary endpoints included prevalence of actionable alterations within KRAS-WT PDAC and enrichment of NRG1 fusions by KRAS status. Results: Among 2,703 patients with PDAC, 2,424 (89.7%) had KRAS mutations and 279 (10.3%) were KRAS-WT. NRG1 fusions were identified exclusively within KRAS-WT tumors (4/279; 1.43%) and were absent among KRAS-mutant PDAC. As summarized in Table 1, 25 of 279 KRAS-WT PDAC patients (9.0%) had at least one clinically actionable genomic alteration. These included NRG1 and NTRK fusions, MSI-H/dMMR, homologous recombination repair gene alterations, ERBB2 amplification, and BRAF V600E mutation. Median OS differed substantially by KRAS status. Patients with KRAS-WT PDAC demonstrated longer survival compared with those with KRAS-mutant disease (26.3 vs 14.9 months). Patients with NRG1 fusion–positive PDAC had a median OS of 22.9 months, acknowledging limited sample size (n=4). Conclusions: KRAS-WT PDAC accounts for approximately one-tenth of cases and is associated with significantly longer overall survival compared with KRAS-mutant disease. Nearly 1 in 10 KRAS-WT tumors harbored clinically actionable genomic alterations, including NRG1 fusions, now linked to an FDA-approved targeted therapy. These findings support routine comprehensive molecular profiling, including fusion detection, in KRAS-WT PDAC and underscore the clinical relevance of precision oncology approaches in this distinct subgroup. Genomic characteristics and actionable alterations in KRAS–wild-type PDAC (MSK-CHORD 2024). Characteristic KRAS-Mutant PDAC (n=2,424) KRAS–Wild-Type PDAC (n=279) Median OS, months 14.9 26.3 Any actionable alteration* — 25 (9.0%) NRG1 fusion 0 (0%) 4 (1.43%) NTRK1–3 fusion — 3 (1.08%) MSI-H/dMMR — 2 (0.72%) BRCA1/2 mutation — 6 (2.15%) PALB2 mutation — 1 (0.36%) ERBB2 amplification — 5 (1.79%) BRAF V600E — 7 (2.51%)
Al-Omari et al. (Wed,) studied this question.