Phase II Trial of Trametinib and Panitumumab in RAS/RAF Wild Type Metastatic Colorectal Cancer.

Abstract

INTRODUCTION:

MEK inhibition may overcome resistance to EGFR inhibition in patients with RAS wildtype (wt) metastatic colorectal cancer (mCRC). We evaluated antitumor activity of trametinib (MEK1/2 inhibitor) with panitumumab (EGFR monoclonal antibody) in a phase II trial.

METHODS:

Patients with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior anti-EGFR therapy were treated with trametinib 1.5 mg oral daily and panitumumab 4.8 mg/kg IV every 2 weeks. Primary endpoint was clinical benefit rate (CB; CR, PR, or SD ≥24 weeks) by RECIST v1.1. A 2-stage minimax design was used. Serial plasma circulating free DNA (cfDNA) was collected and profiled using Oncomine Lung cfDNA assay.

RESULTS:

Fourteen patients were enrolled from November 2015 to April 2019. CB rate was 38% (5/13) and median progression free survival (PFS) was 4.4 months (95% CI, 2.9-7.1). Confirmed overall response rate was 38% (5/13). Treatment-related AE (trAE) included acneiform rash (85%), diarrhea (62%), maculopapular rash (54%), mucositis (46%), and others. Dose modifications and interruptions of trametinib occurred in 69% and panitumumab in 54% of patients. The trial did not progress to stage II accrual due to tolerability and short duration of response. RAS or BRAF mutations cfDNA were detected in 3/13 patients (23%) before radiographic disease progression.

CONCLUSION:

The addition of trametinib to panitumumab led to a high rate of tumor shrinkage in RAS/RAF wt metastatic colorectal cancer, with poor tolerability due to a high incidence of skin toxicity. Median PFS was similar to panitumumab alone in historical control data.

• Authors: Kanan Alshammari, Kyaw L Aung, Tong Zhang, Albiruni R A Razak, Stefano Serra, Tracy Stockley, Lisa Wang, Jessica Nguyen, Anna Spreafico, Aaron R Hansen, Dave Zwir, Lillian L Siu, Philippe L Bedard
• Journal: Clinical colorectal cancer (Clin Colorectal Cancer) Vol. 20 Issue 4 Pg. 334-341 (12 2021) ISSN: 1938-0674 [Electronic] United States
• PMID: 34417144 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• Pyridones
• Pyrimidinones
• trametinib
• Panitumumab

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Colorectal Neoplasms (drug therapy, genetics)
• Humans
• Panitumumab (therapeutic use)
• Pyridones
• Pyrimidinones (adverse effects)