Phase I trial of trametinib with neoadjuvant chemoradiation in patients with locally advanced rectal cancer

Christina Wu, Terence M. Williams, Ryan Robb, Amy Webb, Lai Wei, Wei Chen, Sameh Mikhail, Kristen K. Ciombor, Dana B. Cardin, Cynthia Timmers, Somashekar G. Krishna, Mark Arnold, Alan Harzman, Sherif Abdel-Misih, Sameek Roychowdhury, Tanios Bekaii-Saab, Evan Wuthrick

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3þ3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples. Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.

Original languageEnglish (US)
Pages (from-to)3117-3125
Number of pages9
JournalClinical Cancer Research
Issue number13
StatePublished - Jul 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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