Abstract CT025: A phase I trial combining MEK-1/2 inhibition in combination with 5-fluorouracil and radiation for KRAS, BRAF, and NRAS mutant locally advanced rectal adenocarcinoma

Introduction: 5-fluorouracil (5-FU)-based chemoradiation (CRT) is a standard neoadjuvant treatment strategy for the treatment of locally-advanced rectal adenocarcinomas (LARC). MEK-1/2 inhibition has been shown to radiosensitize Ras mutant tumors in preclinical models, including colorectal cancer. In this phase 1 trial, we will test MEK-1/2 inhibition in combination with neoadjuvant CRT for LARC. Methods: This trial is a standard 3+3 design testing 3 dose levels of the MEK-1/2 inhibitor trametinib (GSK1120212) in combination with CRT: 0.5 mg, 1.0 mg, and 2.0 mg daily, followed by an expansion cohort. All patients first receive a one week lead-in dosing of trametinib monotherapy, and undergo a tumor biopsy at the end of that week to assess pharmacodynamic inhibition by immunohistochemistry (IHC). Then, patients receive standard CRT (5-FU 225 mg/m2 per day by continuous infusion during radiotherapy, and 50.4 Gy in 28 fractions, 5 days/ week) in combination with trametinib (5 days/week). Patients have total mesorectal excision (TME) 6-10 weeks after completion of CRT. Results: The trial opened in 2013, and 31 patients have been screened for KRAS/BRAF/NRAS activating mutations, of which 11 (35.4%) tested positive for a mutation. Of these, 9 patients (8 male, 1 female) have been enrolled so far, with 3 patients accrued in each dose level. Regarding mutation status, six patients have KRAS mutations (five G12V, one G13D), two patients have BRAF mutations (one V600E, one D594N), and one patient is unknown (in dose level 1). Age of patients ranges from 38-64 years old (median 55). All patients have successfully completed neoadjuvant therapy and TME (5 low anterior resection, 4 abdominal-perineal resection). No dose-limiting toxicities were observed on dose levels 1 and 2, and additional patients are currently being accrued onto dose level 3 (2.0 mg). One patient in dose level 3 had pathologic complete response (pCR) at the time of TME. Examination of pre-treatment tumor tissue by IHC reveals baseline hyperactivation of ERK-1/2 (p42/44 MAPK) in most tumors with some heterogeneity in levels of phospho-ERK staining, reflecting hyperactivation of the RAS/RAF-MAPK pathway. Qualitatively, ERK-1/2 activity is reduced from pre-treatment to post-trametinib lead-in tumor tissue, particularly in patients on dose level 3. The patient who experienced a pCR had the most significant reduction in ERK-1/2 activity in tumor tissue and tumor-associated stroma. We will also present qu