Abstract

409 Background: MEK (mitogen-activated protein kinase kinase) is activated through mutated KRAS in > 90% of PDAC. Focal adhesion kinase (FAK) integrates signals from integrins and growth factor receptors. MEK and FAK are frequently co-activated in PDAC providing a rationale for dual inhibition with GSK2256098, an oral FAK inhibitor, and trametinib, an oral allosteric MEK1/2 inhibitor. Methods: Patients with advanced PDAC patients who progressed after first line chemotherapy were treated with GSK2256098 250mg twice daily and trametinib 0.5mg once daily in 28 day cycles. The primary endpoint was antitumor activity measured by clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks) by RECIST 1.1. We planned to enrol 24 patients using a 2-stage minimax design (p0 = 0.15, p1 = 0.40; alpha = 0.05, power 0.86). The combination would be considered active if > 7/24 response-evaluable patients achieved CB; and inactive if 2/12 or fewer patients achieved CB at the end of stage 1. Response assessment was performed every 2 cycles. Results: Between June/16 and June/17, 16 patients were enrolled. Five were not evaluable for response. Of 11 evaluable patients, 10 had PD as best tumor response and one had SD for 4 months. One response unevaluable patient who had rapidly progressed on 1st line FOLFIRINOX chemotherapy with a basal-like tumor by RNA-sequencing and KRAS amplification achieved clinical stability for 5 months with a > 50% decline in serum CA19-9 after 3 months of treatment and symptomatic improvement. No treatment related Grade≥3 adverse events (AEs) were observed. The most common treatment related grade 2 AEs were acneiform rash (19%), diarrhea (13%), nausea (6%), fatigue (6%), proteinuria (6%), paronychia (6%), and retinal detachment (6%). The median progression free survival was 1.6 (95% CI 1.5-1.8) months and the median overall survival was 3.6 (95% CI 2.7-not reached) months. Conclusions: GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC. Correlative studies are ongoing to evaluate RNA-expression subtypes and dynamic markers of pathway inhibition from serial tumor biopsies and cell free DNA. Clinical trial information: NCT02428270.

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