MEK inhibitor-based therapy in metastatic pancreatic adenocarcinoma with <i>KRAS</i> G12R alteration.

725 Background: Pancreatic ductal adenocarcinoma (PDAC) is largely driven by oncogenic alterations in the KRAS , TP53 , CDKN2A/B , and SMAD4 genes. KRAS G12R accounts for nearly 20% of KRAS alterations in PDAC, is biologically unique, and offers the potential for improved response to MEK inhibitor (MEK-inh)-based therapy. As part of the MCW-Master-PREDICT (NCT05802069) observational study, we evaluated the efficacy of MEK-inh-based therapy matched to the unique molecular alterations in the tumor of each patient as recommended by the molecular tumor board. Methods: From March 2022 to December 2023, 8 patients with metastatic PDAC were treated with MEK-inh-based therapy. Molecular profiling was performed by Tempus (648 genes) in 7 patients, and FoundationOne (324 genes) in 1 patient. Description of molecular alterations, matched therapies, and efficacy of treatment are provided. Results: The median age of patients starting MEK inhibitor-based therapy was 69 years, with 62% of them being female. The molecular characteristics and matched therapies are summarized (Table). MEK-inh-based therapy was administered to 3 (37.5%) patients as a first or second-line treatment, and to 5 (62.5%) patients as a third to fifth-line treatment for metastatic PDAC. The overall survival and progression free survival (PFS) on MEK-inh-based therapy was 8.4 and 4.9 months, respectively. Four patients had PFS beyond 4 months (4.9, 5.5, 5.6 and 6.9 months). Conclusions: Individualized MEK-inh-based therapy demonstrated efficacy in late-line treatment of metastatic PDAC with KRAS G12R alterations. Using this approach earlier in the treatment course and in combination with RAS inhibitors or cytotoxic systemic therapies may further enhance outcomes. Tumor alterations and matched therapies. Gene altered Number of patients (%) Number of patients matched (%) Drug family matched KRAS G12R 8 (100) 8/8 (100) MEK inhibitor TP53 7 (87.5) 4/7 (57) VEGF/VEGR inhibitor* CDKN2A 4 (50) 4/4 (100) CDK4/6 inhibitor** SMAD4 2 (25) 2/2 (100) MEK inhibitor + (EGFR or Pan-HER inhibitor)*** *PMID: 27466356; **PMID: 33472910; ***PMID: 36127339, PMID: 24625091.