A phase I clinical trial of trametinib in combination with TAS-102 in patients with chemotherapy-resistant RAS-mutated (PIK3CA/PTEN-wild type) metastatic colorectal cancer.

Abstract

e15579 Background: TAS-102 was approved in 2015 after the phase III RECOURSE clinical trial demonstrated a modest improvement in overall survival in refractory metastatic colorectal cancer (mCRC). Preclinical models have shown synergistic activity between MEK inhibitors and TAS-102 in RAS-mutant (MT) and PIK3CA/PTEN wild-type (WT) models . We conducted a phase I study of trametinib plus TAS-102 in this molecularly selected refractory metastatic colorectal cancer patient population to explore the safety and efficacy of this combination. Methods: A 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with mCRC who progressed on prior standard therapies but with no prior TAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days. The primary endpoint of this study was to evaluate the maximum tolerated dose (MTD). Secondary objectives included an assessment of safety and toxicity of the combination regimen by CTCAE version 4.0 and any evidence of clinical activity including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) with this combination per RECIST guideline 1.1. Results: Between March 21, 2018, to March 19, 2020, 25 eligible patients were enrolled in this study. MTD was determined to be TAS-102 35 mg/m2 orally twice daily on days 1-5 and days 8-12 every 28 days with continuous trametinib dosing at 2mg orally daily. No patients achieved a partial or complete response. 5 of 21 evaluable patients (23.81%) achieved a stable disease response. Median PFS was 2 months (95% confidence interval (CI) 1.70-4.82) while median OS was 7 months (95% CI 6.36-11.48). Treatments were well tolerated with most common grade ≥ 3 adverse events being anemia (20%), neutropenia (12%), leukopenia (8%), diarrhea (8%), rash (4%), and fatigue (4%). Conclusions: Trametinib in combination with TAS-102 demonstrated a manageable safety profile however did not achieve meaningful clinical benefit in patients with RAS-MT and PIK3CA / PTEN-WT refractory mCRC. Research sponsor: Novartis. Clinical trial information: NCT03317119.