S2433: Randomized phase III study of second-line chemotherapy with or without panitumumab for KRAS wild type, locally advanced, or metastatic pancreatic adenocarcinoma.

Abstract

TPS4264 Background: Pancreatic ductal adenocarcinoma (PDA) is characterized by driver mutations in KRAS , TP53 , CDKN2A , and SMAD4 . KRAS wild type (WT) tumors, present in 5-10% of PDA, often harbor alternative mitogen-activated protein kinase (MAPK) pathway drivers or other targetable molecular alterations (e.g., microsatellite instability [MSI-high], DNA damage repair mutations), enabling targeted therapy in approximately 30% of cases; however, most lack actionable drivers and require a tailored treatment approach. EGFR is overexpressed in 30%-70% of PDA. Prior studies of EGFR-targeted therapy demonstrated modest overall survival (OS) benefit in unselected populations, with retrospective analyses suggesting benefit confined to KRAS WT PDA. Recent data showed survival benefit from the anti-EGFR antibody nimotuzumab when added to 1 st line gemcitabine vs gemcitabine alone in KRAS WT PDA. These findings provide a strong rationale to evaluate anti-EGFR mAb in combination with multi-agent chemotherapy in KRAS WT PDA in the United States. Methods: This randomized (1:1) phase III study will enroll 94 pts to investigator choice 2 nd -line chemotherapy – 5 fluorouracil (5FU) plus irinotecan or nanoliposomal irinotecan following 1 st -line gemcitabine-based therapy, or gemcitabine plus nab-paclitaxel following 1 st -line 5FU-based therapy – with or without panitumumab. Eligibility requires KRAS WT and BRAF V600E WT status by tumor tissue-based next-generation sequencing and no known mutations in PTEN , NRAS , EGFR extracellular domain exons 1-16, no amplifications of HER2 and MET , and no gene fusions of RET , NTRK1 , and ALK . One prior line of chemotherapy for locally advanced or metastatic PDA is permitted. Pts with cancers harboring molecular alterations (e.g., MSI-high, ROS fusion) may have received prior targeted therapy, and past maintenance therapy with a PARP inhibitor does not count as a line of therapy. The primary endpoint is OS; secondary endpoints include safety, progression-free survival, overall response rate, disease control rate, and duration of response. Quality of life will be assessed using the Functional Assessment of Cancer Therapy – General (FACT-G), Functional Assessment of Chronic Illness Therapy (FACIT) Item GP5, and selected patient-reported outcome (PRO)-CTCAE items. Blood and tumor samples will be collected for correlative studies. Standard eligibility criteria apply. Assuming panitumumab improves median OS from 6.3 to 12.6 months, 84 eligible patients provide 90% power with a one-sided alpha of 0.05. Kaplan-Meier methods will estimate OS, with early stopping for efficacy or futility. This study is open to accrual (NCT06998940). Clinical trial information: NCT06998940 .