Abstract 1353: Tolerability and outcomes of trametinib treatment in KRAS mutated solid tumors

Abstract

Abstract Background: RAS mutations are found in nearly one third of patients with cancer. As part of the Ras-Raf-MEK-ERK pathway, RAS mutations lead to uninhibited cell growth, proliferation, and survival. KRAS mutations account for a large majority of RAS mutations, especially in lung, colon, and pancreatic cancers. Trametinib, a MEK inhibitor, is approved at 2mg daily for the treatment of melanoma, lung, and thyroid cancers with BRAF mutations when in combination with dabrafenib, a BRAF inhibitor. However, trametinib's safety and efficacy in patients with KRAS-mutated tumors is still under investigation. The purpose of this analysis was to determine the tolerability of trametinib in patients with KRAS alterations. Methods: A retrospective, single-center, IRB-approved, cohort analysis was performed on patients with solid tumors at a regional cancer center. Patients who received at least one dose of trametinib were queried to be included in original chart review, including patients who had received trametinib as part of an IRB-approved precision oncology trial. The primary endpoint was tolerability as defined by proportion of patients who required dose reductions or complete discontinuation of therapy due to drug intolerance and by mean percent of FDA-approved dosing. Additional data collected includes patient demographics, cancer diagnosis, and outcome; number of previous therapy lines; agents combined with trametinib; and the nature of adverse events, if applicable. Results: Thirty-three patients were included for final evaluation. The average age of the patients included was 59.8 (range 32-81) years and the most common diagnoses were colon cancer, non-small cell lung cancer, and gynecological cancer. On average, patients had 2.5 (range 0-9) previous lines of therapy. Only 2 patients received single agent trametinib, while the remainder were treated in combination with additional agents (range 1-4). Seventeen (52%) patients tolerated trametinib therapy without progression for 2 months, including six (18%) who received treatment for 6 months or longer. Of these 17, three (9%) were initiated at 2mg daily, ten (30%) were initiated at half the approved dose, and the remaining patients were initiated at less than half of the approved dose. Twelve (36%) of these patients required dose reductions due to intolerance, and twelve (36%) patients ultimately discontinued trametinib therapy due to intolerance. None of these patients tolerated the full FDA-approved dose and the mean percent of recommended dose, after dose reductions, was 38%. Conclusion: This study demonstrates that trametinib therapy at 2mg daily is intolerable for most patients, especially in combination with other neoplastic therapies. The impact on efficacy of the subsequent dose reductions is unknown. Further investigation is required in order to determine the most tolerable dose of trametinib that is still efficacious. Citation Format: Julie R. Spangler, Rachel J. Elsey, Casey B. Williams. Tolerability and outcomes of trametinib treatment in KRAS mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1353.