CANOPY phase III program: Three studies evaluating canakinumab in patients with non-small cell lung cancer (NSCLC)

Abstract

Background: MET exon 14 skipping mutations (METex14) occur in 3–4% of patients (pts) with NSCLC. Accurate detection of the genomic variants that result in METex14 in MET-driven tumors could facilitate timely intervention with selective MET inhibitors (METi) and improve clinical outcomes. Different detection assays for METex14 using various platforms have yielded mixed results across studies. It is imperative to utilize reliable and validated molecular assays to identify pts to be treated with METi. RNA-based detection of METex14 is considered the gold standard, since this assay measures the direct result of deletion of exon 14 event regardless of underlying genomic events. DNA-based next-generation sequencing (NGS) must detect genomic alterations within MET exon 14 and adjacent intronic regions that alter a splicing site or delete the whole MET exon 14. Methods: The GEOMETRY mono-1 study evaluated the efficacy and safety of capmatinib in pts with EGFR-wt, ALK-neg, NSCLC harboring METex14. This retrospective analysis compared DNA-based NGS with RNA-based RT-PCR in detecting METex14 in the GEOMETRY mono-1 study. Eligible METex14-mutated pts confirmed by RT-PCR qualitative assay using RNA extracted from baseline formalin-fixed, paraffin-dipped (FFPE) tissue samples were assigned to cohorts 4 (C4; previously treated) or 5b (C5b; treatment-naïve), independent of MET amplification status. Retrospectively, METex14 positive and prescreen failed negative baseline FFPE tissue samples were tested using a hybrid capture DNA-based NGS assay (FoundationOne®). The METex14 positive pts by DNA NGS were defined as having MET alterations that are predicted to lead to MET exon 14 skipping. Results: Of the 97 enrolled pts from the METex14-mutated cohorts C4 (n=69) and C5b (n=28) of the GEOMETRY mono-1 study, 73 pts had baseline tumor biopsy samples (C4, n=53; C5b, n=20) that met the requirements for the FoundationOne® NGS assay (minimum requirements: tissue volume ≥0.1 mm3, DNA yield ≥ 22 ng, percent tumor nuclei ≥10). The FoundationOne® NGS assay identified METex14 in 72 of 73 positive pts, with a concordance of 99% to the qualitative RT-PCR test used previously for testing. The variants detected included 41 unique canonical alterations that are predicted to lead to METex14. 1 pt with only a noncanonical METex14 rearrangement was not included in the concordance analysis and reported stable disease. None of the RT-PCR negative patients were reported as positive by NGS. Conclusions: Detection of MET exon 14 skipping events can be achieved by sequencing DNA or RT-PCR. A very high concordance was observed between DNA-based hybrid-capture NGS and RNA-based RT-PCR in the detection of METex14 in FFPE tumor tissue from advanced NSCLC pts. NGS enables parallel detection of actionable alterations without sequential testing by single gene. Furthermore, this technique provides a comprehensive genomic profile to inform treatment plan and any potential mechanisms of resistance.