ALK-tyrosine kinase inhibitor intrinsic resistance due to de novo MET-amplification in metastatic ALK-rearranged non-small cell lung cancer effectively treated by alectinib-crizotinib combination-case report

Background: Most patients with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) experience prolonged response to second-generation (2G) ALK-tyrosine kinase inhibitors (TKIs). Herein, we present a case of metastatic ALK+ NSCLC rapidly progressing on first-line treatment due to de novo amplification of the mesenchymal-epithelial transition factor (MET) gene, which is a still elusive and underrecognized mechanism of primary resistance to ALK-TKIs. Case Description: A 43-year-old, female diagnosed with T4N3M1c NSCLC harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variant 1 (EML4-ALK v.1) and TP53 co-mutation, displayed only mixed response after three months and highly symptomatic progression after 6 months of first-line brigatinib treatment. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis on re-biopsies from a new liver metastasis revealed overexpression of MET receptor (3+ in 80% of tumor cells) and heterogeneously increased MET gene copy number (CN) in tumor cells, including 20% with MET clusters (corresponds to ≥15 gene copies, thus exact CN uncountable by FISH) and the other 80% with median MET CN of 8.3, both changes indicating high-level MET-amplification. DNA and RNA next-generation sequencing (NGS) displayed preserved ALK fusion and TP53 co-mutation, but no additional genomic alterations, nor MET-amplification. Therefore, we retrospectively investigated the diagnostic biopsy from the primary tumor in the left lung with IHC and FISH revealing the presence of increased MET receptor expression (2+ in 100% of tumor cells) and MET-amplification (median MET CN of 6.1), which otherwise was not detected by NGS. Thus, given the well-documented efficacy of alectinib towards EML4-ALK v.1, combined second-line treatment with alectinib and the MET-TKI, crizotinib, was implemented resulting in very pronounced objective response, significantly improved quality of life, and no adverse events so far during the ongoing treatment (6 months). Conclusions: The combination of alectinib and crizotinib may be a feasible and effective treatment for ALK+ NSCLC with de novo MET-amplification. The latter may represent a mechanism of intrinsic ALK-TKI resistance and its recognition by FISH, in NGS-negative cases, may be considered before initiating first-line treatment. This recognition is clinically important as combined therapy with ALK-TKI and MET-inhibitor should be the preferred first-line treatment.