MET-Amplification Predicts Benefit from Targeted Therapy with Crizotinib in NSCLC

A sub-analysis of PROFILE 1001, the ongoing phase 2 study of crizotinib, confirmed that the ALK and ROS-1 inhibitor crizotinib is effective in non-small cell lung cancer (NSCLC) patients with MET amplification. However, no responses were observed among 5 patients with concurrent KRAS, BRAF, or EGFR mutations. (J Thorac Oncol. 2021 Jun;16(6):1017-1029).

“MET amplification has been reported as a rare, potentially actionable, primary oncogenic driver in a subset of patients with NSCLC, with frequency depending on the definition used. This is separate from its role as an acquired resistance pathway to tyrosine kinase inhibitors (TKIs) in NSCLC. In studies evaluating MET amplification in the absence of MET exon 14 alteration, higher levels of MET amplification reveal increased objective responses with MET TKIs,” wrote lead author D. Ross Camidge, MD, PhD, University of Colorado Cancer Center, Aurora, and colleagues.

To test their hypothesis, the researchers conducted retrospective next-generation sequencing profiling of archival tumor tissue from 38 patients with MET-amplified NSCLC treated with crizotinib in the phase 2 portion of the ongoing PROFILE 1001 trial. Patients were enrolled into high (4 MET-to-CEP7 ratio), medium (>2.2 to <4 MET-to-CEP7 ratio), or low (1.8 to  2.2 MET-to-CEP7 ratio) amplification categories, and researchers retrospectively analyzed the influence of MET amplification on the clinical activity of crizotinib (250 mg twice daily).

Of patients in the subgroup, 21, 14, and 3 had high, medium, and low MET amplification, respectively. Objective response rates of 8 of 21 (38.1%), 2 of 14 (14.3%), and 1 of 3 (33.3%), median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival values of 6.7, 1.9, and 1.8 months were observed for those with high, medium, and low MET amplification, respectively.

“To date, all oncogene-driven predictive biomarkers in NSCLC associated with targeted therapies have been discrete gene rearrangements or mutations. However, increases in MET GCN are quantified continuously. Thus, criteria for ‘positivity’ may vary, for example, differing cutoff values for MET-to-CEP7 ratio or mean GCN per cell, measured directly using FISH, or GCN measured through NGS bioinformatic platforms,” investigators concluded.