Abstract LB056: Accurate detection of MET exon 14 skipping using a liquid biopsy assay in NSCLC patients in the GEOMETRY mono-1 study
Authors: Heist Rebecca S. , Garon Edward B. , Tan Daniel S. , Groen Harry J. , Seto Takashi , Smit Egbert F. , Zou Mike , Yang Yiqun , Li Ying , Agostinho Andrea Chassot , Wolf Juergen 
Published: July 2021

Abstract
IntroductionCapmatinib, a highly selective and potent MET inhibitor, was approved for patients with advanced METex14 NSCLC in the US and Japan in 2020, with the FoundationOne® CDx (F1CDx; a next-generation sequencing assay using DNA isolated from FFPE tumor tissue), based on results of the ongoing phase 2 GEOMETRY mono-1 study (NCT02414139). Previously, the F1CDx demonstrated 99% concordance with the METex14 RT-PCR clinical trial assay (CTA) used in the GEOMETRY mono-1 study. Here, we report findings of METex14 detection using the an NGS-based liquid biopsy assay (LDx), which detects MET single nucleotide variants and indels that lead to METex14 in circulating tumor (ct)DNA. MethodsDuring the GEOMETRY mono-1 study, patients were screened for METex14 status using a METex14 RT-PCR CTA on FFPE tissue. Clinical validation of the LDx was performed using plasma samples from patients enrolled in the GEOMETRY mono-1 study, which include METex14-positive samples from Cohort (C)4 (pretreated) and C5b (treatment-naïve), in addition to METex14-negative samples from C1b, C2, and C3, and samples from commercial sources. Concordance of the CTA and LDx were evaluated by positive percent agreement (PPA) and negative percent agreement (NPA). Clinical utility of the LDx in identifying METex14 positive patients for treatment with capmatinib was evaluated by comparing overall response rate (ORR) by BIRC in METex14 positive patients by the CTA and LDx. ResultsOf the 97 patients with METex14 NSCLC in C4 (n=69) and C5b (n=28), 88 patients had plasma volume ≥2.5 mL and cell free DNA ≥20 ng (minimum input). Of the 88 CTA METex14 positive patients, 57 were LDx positive, 26 were LDx negative; 5 had invalid sequencing results. Review of the 26 CTA discordant (METex14-negative) cases on LDx identified 3 with an alternate MET alteration, while the vast majority had evidence of low ctDNA levels. Of the 97 CTA METex14-negative patients who met minimum input requirements, 88 were LDx negative and 9 had invalid sequencing results; the LDx identified no CTA METex14-negative patient as positive. The PPA and NPA for these were 68.7% (95% CI: 57.6%, 78.4%) and 100% (95% CI: 95.9%, 100%), respectively. A post-hoc analysis comparing LDx with F1CDx in patients with METex14 showed similar results. For patients identified as METex14-positive by the LDx, the ORR (95% CI) by BIRC was determined as 48.8% (32.9–64.9%; n=20/41) for C4, and 81.3% (54.4–96.0%; n=13/16) for C5b; corresponding ORRs for patients identified as METex14-positive by the CTA were 40.6% (28.9-53.1%; n=28/69) for C4 and 67.9% (47.6-84.1%; n=19/28) for C5b.ConclusionsCurrent findings from the GEOMETRY mono-1 study support the feasibility and clinical utility of identifying advanced NSCLC patients with METex14 in ctDNA using LDx. For patients identified as METex14-negative by LDx, further testing should be performed on tissue samples, as a negative liquid biopsy result does not preclude a positive result by tissue biopsy.
Citation Format: Rebecca S. Heist, Edward B. Garon, Daniel S. Tan, Harry J. Groen, Takashi Seto, Egbert F. Smit, Mike Zou, Yiqun Yang, Ying Li, Andrea Chassot Agostinho, Juergen Wolf. Accurate detection of MET exon 14 skipping using a liquid biopsy assay in NSCLC patients in the GEOMETRY mono-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB056.