PMID- 38361741
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240217
IS  - 2666-3643 (Electronic)
IS  - 2666-3643 (Linking)
VI  - 5
IP  - 2
DP  - 2024 Feb
TI  - The Efficacy and Safety of Treating Acquired MET Resistance Through Combinations 
      of Parent and MET Tyrosine Kinase Inhibitors in Patients With Metastatic 
      Oncogene-Driven NSCLC.
PG  - 100637
LID - 10.1016/j.jtocrr.2024.100637 [doi]
LID - 100637
AB  - INTRODUCTION: Acquired MET gene amplification, MET exon 14 skip mutations, or MET 
      fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) 
      in patients with lung cancer. The efficacy and safety of combining MET TKIs (such 
      as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET 
      resistance are not well characterized. METHODS: Multi-institutional retrospective 
      chart review identified 83 patients with metastatic oncogene-driven NSCLC that 
      were separated into the following two pairwise matched cohorts: (1) MET cohort 
      (n = 41)-patients with acquired MET resistance continuing their parent TKI with a 
      MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable 
      resistance continuing their parent TKI with a platinum-pemetrexed added. 
      Clinicopathologic features, radiographic response (by means of Response 
      Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse 
      events (AEs) (by means of Common Terminology Criteria for Adverse Events version 
      5.0), and genomic data were collected. Survival outcomes were assessed using 
      Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain 
      metastases, TP53 mutations, and oligometastatic disease. RESULTS: Within the MET 
      cohort, median age was 56 years (range: 36-83 y). Most patients were never 
      smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). 
      The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK 
      (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 
      of 41, 78%) were frequent. Acquired MET alterations included MET gene 
      amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET 
      gene fusions (two of 41, 5%). After multivariate adjustment, the objective 
      response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort 
      (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number 
      (>/=10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 
      0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 
      0.021, p = 0.978). There was no difference in progression-free survival (5 versus 
      6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or 
      overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 
      0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, 
      dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but 
      less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant 
      between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate 
      of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). 
      Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most 
      common next-generation sequencing findings were loss of MET gene amplification 
      (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK 
      alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%). 
      CONCLUSIONS: The efficacy and safety of combining MET TKIs (crizotinib, 
      capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are 
      efficacious. Radiographic response and AEs did not differ significantly on the 
      basis of the underlying MET TKI used. Loss of MET gene amplification, development 
      of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification 
      were molecular patterns found on progression with dual parent and MET TKI 
      combinations.
CI  - (c) 2024 The Authors.
FAU - Patil, Tejas
AU  - Patil T
AD  - Division of Medical Oncology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Staley, Alyse
AU  - Staley A
AD  - University of Colorado Cancer Center Biostatistics Core, University of Colorado 
      School of Medicine, Aurora, Colorado.
FAU - Nie, Yunan
AU  - Nie Y
AD  - Department of Medical Oncology, Yale School of Medicine, Yale University, New 
      Haven, Connecticut.
FAU - Sakamoto, Mandy
AU  - Sakamoto M
AD  - Division of Medical Oncology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Stalker, Margaret
AU  - Stalker M
AD  - Division of Hematology-Oncology, Department of Medicine, Perelman School of 
      Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
FAU - Jurica, James M
AU  - Jurica JM
AD  - Division of Medical Oncology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Koehler, Kenna
AU  - Koehler K
AD  - Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt 
      University, Nashville, Tennessee.
FAU - Cass, Amanda
AU  - Cass A
AD  - Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt 
      University, Nashville, Tennessee.
FAU - Kuykendall, Halle
AU  - Kuykendall H
AD  - Division of Medical Oncology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Schmitt, Emily
AU  - Schmitt E
AD  - Division of Medical Oncology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Filar, Emma
AU  - Filar E
AD  - Division of Medical Oncology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Reventaite, Evelina
AU  - Reventaite E
AD  - Division of Medical Oncology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Davies, Kurt D
AU  - Davies KD
AD  - Department of Pathology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Nijmeh, Hala
AU  - Nijmeh H
AD  - Department of Pathology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Haag, Mary
AU  - Haag M
AD  - Department of Pathology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Yoder, Benjamin A
AU  - Yoder BA
AD  - Division of Medical Oncology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Bunn, Paul A
AU  - Bunn PA
AD  - Division of Medical Oncology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Schenk, Erin L
AU  - Schenk EL
AD  - Division of Medical Oncology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Aisner, Dara L
AU  - Aisner DL
AD  - Department of Pathology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Iams, Wade T
AU  - Iams WT
AD  - Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt 
      University, Nashville, Tennessee.
FAU - Marmarelis, Melina E
AU  - Marmarelis ME
AD  - Division of Hematology-Oncology, Department of Medicine, Perelman School of 
      Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
FAU - Camidge, D Ross
AU  - Camidge DR
AD  - Division of Medical Oncology, University of Colorado Cancer Center, University of 
      Colorado School of Medicine, Aurora, Colorado.
LA  - eng
PT  - Journal Article
DEP - 20240118
PL  - United States
TA  - JTO Clin Res Rep
JT  - JTO clinical and research reports
JID - 101769967
PMC - PMC10867444
OTO - NOTNLM
OT  - Acquired resistance
OT  - MET amplification
OT  - MET exon 14 skipping
OT  - NSCLC
OT  - Tyrosine kinase inhibitor
COIS- Dr. Patil reports personal fees from Astrazeneca, personal fees from Bicara, 
      personal fees from Bristol-Myers-Squibb, grants and personal fees from EMD 
      Soreno, grants and personal fees from Janssen, personal fees from Mirati 
      Therapeutics, personal fees from Pfizer, personal fees from Sanofi, personal fees 
      from Regeneron, personal fees from Roche/ Genentech, personal fees from Takeda, 
      grants and personal fees from Gilead, other from Elevation Oncology, outside the 
      submitted work; Dr. Camidge reports personal fees from Abbvie, personal fees from 
      Anheart, personal fees from Appolomics, personal fees from AstraZeneca, personal 
      fees from Beigene, personal fees from Dizal, personal fees from Elevation 
      Oncology, personal fees from Eli Lily, personal fees from EMD Soreno, personal 
      fees from Hengrui, personal fees from Hummingbird, personal fees from Imagene, 
      personal fees from Immunocore, personal fees from Janssen, personal fees from 
      Medtronic, personal fees from Mersana, personal fees from Mirati, personal fees 
      from Nalo Therapeutics, personal fees from Onkure, personal fees from Prelude, 
      personal fees from Regeneron, personal fees from Roche, personal fees from 
      Sanofi, personal fees from Seattle Genetics, personal fees from Takeda, personal 
      fees from Theseus, personal fees from Valence , personal fees from Xcovery, 
      outside the submitted work; Dr. Schenk reports personal fees from Actinium 
      Pharmaceuticals, personal fees from AstraZeneca, personal fees from BioAtla, 
      personal fees from BeiGeneius, personal fees from Bionest Partners, personal fees 
      from ClearView Healthcare Partners, personal fees from G1 Therapeutics, personal 
      fees from Harpoon, personal fees from Janssen, personal fees from MECC Global 
      Meetings, personal fees from Regeneron, personal fees from Takeda, personal fees 
      and other from Thetis, outside the submitted work; Dr. Bunn reports personal fees 
      from Ascentage, personal fees from Amgen, personal fees from Astrazeneca, 
      personal fees from Bristol Myers Squibb, personal fees from CStone, personal fees 
      from Daiichi, personal fees from Genentech, personal fees from Merck , personal 
      fees from Verastem, outside the submitted work; Dr. Iams reports personal fees 
      from Astrazeneca, personal fees from Amgen, personal fees from Bristol Myers 
      Squibb, personal fees from Clinical Care Options, personal fees from Chardan, 
      personal fees from Cello Health, personal fees from Curio Science, personal fees 
      from Genentech, personal fees from GI Therapeutics, personal fees from Janssen, 
      personal fees from Jazz Pharmaceuticals, personal fees from Mirati Therapeutics, 
      personal fees from NovoCure, personal fees from Outcome Heights, personal fees 
      from Sanofi, personal fees from Takeda, outside the submitted work; Dr. 
      Marmarelis reports grants and personal fees from Astrazeneca, personal fees from 
      Bayer, personal fees from Bristol Myers Squibb, personal fees from Eli Lily, 
      personal fees from Genentech, personal fees from Ikena, personal fees from 
      Janssen, personal fees from Takeda, outside the submitted work; Dr. Aisner 
      reports personal fees from AbbVie, personal fees from Bristol Myers Squibb, 
      personal fees from Inivata, outside the submitted work; the other authors have 
      nothing to disclose.
EDAT- 2024/02/16 06:42
MHDA- 2024/02/16 06:43
PMCR- 2024/01/18
CRDT- 2024/02/16 03:47
PHST- 2023/09/11 00:00 [received]
PHST- 2024/01/11 00:00 [revised]
PHST- 2024/01/14 00:00 [accepted]
PHST- 2024/02/16 06:43 [medline]
PHST- 2024/02/16 06:42 [pubmed]
PHST- 2024/02/16 03:47 [entrez]
PHST- 2024/01/18 00:00 [pmc-release]
AID - S2666-3643(24)00007-9 [pii]
AID - 100637 [pii]
AID - 10.1016/j.jtocrr.2024.100637 [doi]
PST - epublish
SO  - JTO Clin Res Rep. 2024 Jan 18;5(2):100637. doi: 10.1016/j.jtocrr.2024.100637. 
      eCollection 2024 Feb.