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• W4226450812 abstract "Purpose/Objective(s) In VISION Cohort A, tepotinib showed robust and durable clinical activity in pts with METex14 skipping NSCLC. Here, we present biomarker analyses on serial LBx samples. Materials/Methods 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 METex14 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. Results 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 EGFRamp (1/43 [2%] vs 8/51 [16%]). Location/type of METex14 alteration did not affect outcomes. 1 pt with concomitant MET M1250T had a 17.3-month PFS. A trend toward improved efficacy was seen with concomitant METamp (6/8 responses). Tepotinib response occurred in pts with wt or mutant TP53, but there was a trend for longer mDOR and mPFS with wtTP53. Concomitant oncogenic mutations were rare: 3 pts with KRAS, NRAS alterations (no responses) and 5 with PI3K/AKT 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 MET 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. Conclusion 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. Serial LBx could help monitor responses, understand resistance and guide dose-adjustment strategies to improve outcomes and quality of life. In VISION Cohort A, tepotinib showed robust and durable clinical activity in pts with METex14 skipping NSCLC. Here, we present biomarker analyses on serial LBx samples. 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 METex14 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. 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 EGFRamp (1/43 [2%] vs 8/51 [16%]). Location/type of METex14 alteration did not affect outcomes. 1 pt with concomitant MET M1250T had a 17.3-month PFS. A trend toward improved efficacy was seen with concomitant METamp (6/8 responses). Tepotinib response occurred in pts with wt or mutant TP53, but there was a trend for longer mDOR and mPFS with wtTP53. Concomitant oncogenic mutations were rare: 3 pts with KRAS, NRAS alterations (no responses) and 5 with PI3K/AKT 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 MET 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. 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. Serial LBx could help monitor responses, understand resistance and guide dose-adjustment strategies to improve outcomes and quality of life." @default.
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• W4226450812 date "2022-02-01" @default.
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• W4226450812 title "METex14 ctDNA Dynamics & Resistance Mechanisms Detected in Liquid Biopsy (LBx) From Patients (pts) With METex14 Skipping NSCLC Treated With Tepotinib" @default.
• W4226450812 doi "https://doi.org/10.1016/j.ijrobp.2021.10.185" @default.
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