<i>MET</i>ex14 ctDNA dynamics &amp; resistance mechanisms detected in liquid biopsy (LBx) from patients (pts) with <i>MET</i>ex14 skipping NSCLC treated with tepotinib.
Authors: Paul K. Paik, Remi Veillon, Enriqueta Felip, Alexis Cortot, Hiroshi Sakai, Julien Mazieres, Michael Thomas, Niels Reinmuth, Jo Raskin, Pier Franco Conte, Marina Chiara Garassino, Wade Thomas Iams, Frank Griesinger, Dariusz M. Kowalski, Christopher Stroh, Dilafruz Juraeva, Juergen Scheuenpflug, Andreas Johne, Xiuning Le
Journal: Journal of Clinical Oncology (2021)

9012 Background: In the VISION study, tepotinib in METex14 skipping NSCLC pts (Cohort A) had robust and durable clinical activity. Serial LBx samples were collected for biomarker analyses, presented herein. Methods: LBx samples taken at baseline (BL), Week 6, 12, &amp; end of treatment (EOT) were analyzed using Guardant360 ® CDx (73 genes). Investigator (INV)-assessed clinical outcome was evaluated per BL biomarker profiles and by molecular response (MR; defined as &gt; 75% depletion from BL in METex14 variant allele frequency [VAF] ctDNA confirmed in 2 consecutive samples) or molecular progression (MP; defined as VAF increase &gt; 0 from BL). Acquired resistance was investigated in EOT samples, following progression per INV. Results: LBx pts (n = 99) had a median age of 72 yrs (range 49–88), 53% were male, 44% never smokers, 85% had adenocarcinoma. INV ORR was 53% (95% CI 42, 63); ORR in 1L (n = 44) was 59% (43, 74) &amp; ≥2L (n = 55) was 47% (33, 61). 94 pts had BL biomarker profiles; these were similar in 1L and ≥2L pts, except EGFR amp: 1/43 1L [2%] vs 8/51 ≥2L [16%]. Outcomes were not impacted by location/type of METex14 alteration. 1 pt with concomitant MET M1250T mutation had a PFS of 17.3 months. A trend towards better efficacy was seen in pts with concomitant MET amp (6 responses in 8 pts). Response to tepotinib occurred both in pts with wt or mutant TP53; however, there was a trend for longer mDOR in pts with wt TP53 (18.3 [95% CI 9.7, ne] vs 7.1 [4.7, 10.9] months) and mPFS (9.5 [6.7, 19.7] vs 5.1 [2.8, 6.9] months). Concomitant oncogenic mutations were rare, with no responses in 3 pts with KRAS, NRAS alterations and 3 responses in 5 pts with PI3K/AKT alterations. 65 pts had 2 consecutive on-treatment samples: 46 (71%) had confirmed MR, 5 (8%) had confirmed MP, 14 (22%) had no change in VAF or lacked confirmation. MR was associated with clinical response and MP was associated with no response/short PFS (Table). 52 pts with progression had EOT LBx samples. Emerging MET resistance mutations (Y1230H/C &amp; D1228H/N) occurred in 7 (13%) pts, all responders and 5/7 had PFS &gt; 10 months. Analyses on non-MET-driven resistance mechanisms will be presented. Conclusions: LBx biomarker analysis from the largest on-treatment data set for a MET inhibitor in METex14 skipping NSCLC, showed that ctDNA depletion in METex14 VAF is associated with improved clinical response in pts treated with tepotinib. This suggests serial LBx could help us to monitor response/non-response, understand resistance, and guide trials that test escalation/de-escalation strategies to improve outcomes and maximize QOL. Clinical trial information: NCT02864992. [Table: see text]