Abstract A045: Clinical benefit of MAPK inhibition in appendiceal adenocarcinoma

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Abstract Background: Appendiceal adenocarcinomas (AA) are exceptionally rare malignancies that exhibit high rates of fatal peritoneal metastases with few effective treatment options. AAs have frequent MAPK signaling variants targetable with tyrosine kinase inhibitors. However, the efficacy of EGFR, BRAF, and KRAS inhibitors in AA is unknown. Methods: We performed a retrospective analysis of 1,505 patients with AA treated at Memorial Sloan Kettering (MSK) between 7/1993 and 11/2025. We curated clinicogenomic characteristics and treatment-specific outcomes for every patient who received EGFR-inhibitors[i], BRAF-V600Ei, or KRASi for metastatic AA. From the initial dataset, we also defined two separate propensity-matched comparison cohorts of patients treated with conventional non-MAPKi treatments to compare outcomes (1) in the second line (FOLFOX, FOLFIRI) or (2) treatment-refractory setting (TAS-102, regorafenib). Cohorts were generated using the nearest-neighbor method to balance patient sex, tumor histology, grade, KRAS and BRAF status between the main MAPKi cohort and each comparative cohort. Patient progression-free-survival (PFS) and overall survival (OS) after treatment initiation were assessed with the Kaplan-Meier curves with significance defined using log-rank and/or Restricted Mean Survival Time (RMST) methods when appropriate. Results: Forty-seven patients with metastatic AA were treated at MSK with EGFRi (n = 42), BRAF-V600Ei (n = 3), and KRASi (n = 2) primarily in the third line (66%, n=31/47). The cohort encompassed mucinous (55%), goblet cell colonic-type (40%) and colonic-type adenocarcinomas (4%) with predominantly poor differentiation (68%). EGFRi demonstrated limited efficacy with median PFS of 2.9 months and best tumor outcomes of progression (67%, n=28/42), stability (29%, 12/42), and regression (5%, 2/42) irrespective of treatment line, chemotherapy partner, and KRAS-mutation(mut) status. Two out of three patients treated with BRAF-V600Ei responded (67%), although responses were not durable (median PFS 3.5 months). One of the two patients treated with KRAS inhibitors exhibited exceptional ongoing disease control of 14.0 months while the other patient progressed within 2 months. Patients treated with EGFRi or BRAFi in the second line exhibited significantly worse 12-month PFS (p=0.03) and OS (p=0.003) compared to patients with propensity-matched clinicogenomic features treated with second-line FOLFIRI or FOLFOX. In a separate analysis of later-line therapy given to chemo-refractory patients, outcomes did not differ between MAPKi and regorafenib, but TAS-102 demonstrated the overall superior PFS (p=0.04). Conclusions: EGFR inhibitors are largely ineffective in metastatic appendiceal adenocarcinoma, whereas BRAF-V600E and KRAS inhibitors demonstrate early signs of clinical activity in a small subset of patients. Findings underscore the value of genomic profiling and future prospective trials for BRAF and KRAS inhibitors in AA. Citation Format: Somer Abdelfattah, Nayva Vemula, Tina Gowda, Efsevia Vakiani, Jinru Shia, Anne K. Koehne de Gonzalez, Henry Walch, Georgios Karagkounis, Nikolaus Schultz, Michael Berger, Rona Yaeger, Miteshkumar Patel, Garrett Nash, Andrea Cercek, Luis A . Diaz Jr, Michael B. Foote. Clinical benefit of MAPK inhibition in appendiceal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A045.

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