METex14 ctDNA Dynamics & Resistance Mechanisms Detected in Liquid Biopsy (LBx) From Patients (pts) With METex14 Skipping NSCLC Treated With Tepotinib

Abstract

<h3>Purpose/Objective(s)</h3> In VISION Cohort A, tepotinib showed robust and durable clinical activity in pts with <i>MET</i>ex14 skipping NSCLC. Here, we present biomarker analyses on serial LBx samples. <h3>Materials/Methods</h3> LBx samples at baseline (BL), Week 6, 12, and end of treatment (EOT) were analyzed (73 genes). Investigator (INV)-assessed clinical outcome was evaluated per BL biomarker profiles and molecular response (MR; >75% depletion from BL in <i>MET</i>ex14 variant allele frequency [VAF] ctDNA confirmed in 2 consecutive samples) or molecular progression (MP; VAF increase >0 from BL). Per INV, acquired resistance was investigated in EOT samples. <h3>Results</h3> Of 99 LBx pts, median age was 72 yrs (range 49–88), 53% were male, 44% never smokers, and 85% had adenocarcinoma. INV ORR was 53% (95% CI: 42, 63); ORR in first line (1L; n=44) was 59% (43, 74) and 47% (33, 61) in ≥2L (n=55). 94 pts had BL biomarker profiles, similar in 1L to ≥2L except for <i>EGFR</i>amp (1/43 [2%] vs 8/51 [16%]). Location/type of <i>MET</i>ex14 alteration did not affect outcomes. 1 pt with concomitant <i>MET</i> M1250T had a 17.3-month PFS. A trend toward improved efficacy was seen with concomitant <i>MET</i>amp (6/8 responses). Tepotinib response occurred in pts with wt or mutant <i>TP53</i>, but there was a trend for longer mDOR and mPFS with wt<i>TP53</i>. Concomitant oncogenic mutations were rare: 3 pts with <i>KRAS, NRAS</i> alterations (no responses) and 5 with <i>PI3K/AKT</i> alterations (3 responses). 65 pts had 2 consecutive on-treatment samples (30 1L, 35 ≥2L): 46 (71%) had confirmed MR, 5 (8%) had confirmed MP, and 14 (22%) had no change in VAF/lacked confirmation. MR was associated with clinical response and MP with no response/short PFS (Table). 52 pts with progression had EOT LBx samples. Emerging <i>MET</i> resistance mutations (Y1230H/C & D1228H/N) occurred in 7 pts (13%): all responders and 5 had PFS >10 months. Non-MET-driven resistance mechanisms will be presented. <h3>Conclusion</h3> LBx biomarker analysis from the largest on-treatment data set for a MET inhibitor in <i>MET</i>ex14 skipping NSCLC showed that ctDNA depletion in <i>MET</i>ex14 VAF is associated with improved clinical response in pts treated with tepotinib. Serial LBx could help monitor responses, understand resistance and guide dose-adjustment strategies to improve outcomes and quality of life.