Pralsetinib and Sequential MET Inhibitors to Overcome MET Amplification Resistance in a Patient With a RET Fusion Driven Lung Cancer – Case Report

Published:August 19, 2022DOI:

      Clinical Practice Points

      • What is already known about this subject?
      • Rearranged during transfection (RET) gene fusion are unfrequent (1%-2%) but validated as target mutations in non-small cell lung cancer (NSCLC).
      • Selpercatinib and, pralsetinib have been authorized by the US-FDA in second line or more in NSCLC RET+.
      • The predominant independent mechanism of resistance to RET tyrosine kinase inhibitors (TKI) is the MET amplification but data to overcome MET resistance concern only selpercatinib resistance.
      • What are the new findings and how might they impact on clinical practice in the foreseeable future?
      • We report here the first case of a patient who developed a MET amplification as an initial mechanism of acquired resistance to pralsetinib for an advanced KIF5B-RET driven lung adenocarcinoma, successfully treated with a combination of pralsetinib and crizotinib then capmatinib due to an isolated cerebral progression.
      • An isolated progression under crizotinib should raise suspicion of poor penetration through the blood-brain barrier and motivate the switch by an anti-MET with better cerebral penetration like capmatinib.
      • Early evaluation by 18FDG/CT might be a compelling method to justifying the pursuit or not of combination TKI without being predictive of the duration of response.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Lung Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Pall G
        • Gautschi O.
        Advances in the treatment of RET-fusion-positive lung cancer.
        Lung Cancer Amst Neth. 2021 Jun; 156: 136-139
        • Cascetta P
        • Sforza V
        • Manzo A
        • et al.
        RET inhibitors in non-small-cell lung cancer.
        Cancers. 2021 Sep 1; 13: 4415
        • Drilon A
        • Oxnard GR
        • Tan DSW
        • et al.
        Efficacy of selpercatinib in RET fusion–positive non–small-cell lung cancer.
        N Engl J Med. 2020 Aug 27; 383: 813-824
        • Gainor JF
        • Curigliano G
        • Kim DW
        • et al.
        Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study.
        Lancet Oncol. 2021 Jul; 22: 959-969
        • Goto K
        • Wolf J
        • Elamin Y
        • et al.
        FP14.05 LIBRETTO-431: selpercatinib in treatment-naïve patients with RET fusion-positive non-small cell lung cancer (NSCLC).
        J Thorac Oncol. 2021 Mar 1; 16: S228-S229
        • Besse B
        • Felip E
        • Kim ES
        • et al.
        PUL01.02 AcceleRET lung: a phase 3 study of first-line pralsetinib in patients with RET-Fusion+ Advanced/Metastatic NSCLC.
        J Thorac Oncol. 2021 Jan 1; 16: S44-S45
        • Lin JJ
        • Liu SV
        • McCoach CE
        • et al.
        Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer.
        Ann Oncol Off J Eur Soc Med Oncol. 2020 Dec; 31: 1725-1733
        • Gautschi O
        • Menon R
        • Bertrand M
        • Murer C
        • Diebold J.
        Capmatinib and osimertinib combination therapy for EGFR-mutant lung adenocarcinoma.
        J Thorac Oncol. 2020 Jan 1; 15: e13-e15
        • Rosen EY
        • Johnson ML
        • Clifford SE
        • et al.
        Overcoming MET-dependent resistance to selective RET inhibition in patients with RET fusion-positive lung cancer by combining selpercatinib with crizotinib.
        Clin Cancer Res Off J Am Assoc Cancer Res. 2021 Jan 1; 27: 34-42
        • Dagogo-Jack I
        • Moonsamy P
        • Gainor JF
        • et al.
        A Phase 2 study of capmatinib in patients with MET-altered lung cancer previously treated with a MET inhibitor.
        J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2021 May; 16: 850-859
        • Zhu VW
        • Zhang SS
        • Zhang J
        • Swensen J
        • Xiu J
        • Ou SHI.
        Acquired tertiary MET resistance (MET D1228N and a Novel LSM8-MET Fusion) to Selpercatinib and Capmatinib in a patient with KIF5B-RET–positive NSCLC with Secondary MET amplification as initial resistance to selpercatinib.
        J Thorac Oncol. 2021 Jul 1; 16: e51-e54
        • Zander T
        • Scheffler M
        • Nogova L
        • et al.
        Early prediction of nonprogression in advanced non-small-cell lung cancer treated with erlotinib by using [(18)F]fluorodeoxyglucose and [(18)F]fluorothymidine positron emission tomography.
        J Clin Oncol Off J Am Soc Clin Oncol. 2011 May 1; 29: 1701-1708
        • Fledelius J
        • Winther-Larsen A
        • Khalil AA
        • et al.
        18F-FDG PET/CT for very early response evaluation predicts CT response in erlotinib-treated non-small cell lung cancer patients: a comparison of assessment methods.
        J Nucl Med Off Publ Soc Nucl Med. 2017 Dec; 58: 1931-1937
        • Mehlman C
        • Chaabane N
        • Lacave R
        • et al.
        Ceritinib ALK T1151R resistance mutation in lung cancer with initial response to Brigatinib.
        J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2019 May; 14: e95-e96
        • Kwee SA
        • Ko JP
        • Jiang CS
        • Watters MR
        • Coel MN.
        Solitary brain lesions enhancing at MR imaging: evaluation with fluorine 18–Fluorocholine PET.
        Radiology. 2007 Aug; 244: 557-565
        • Calabria FF
        • Barbarisi M
        • Gangemi V
        • Grillea G
        • Cascini GL.
        Molecular imaging of brain tumors with radiolabeled choline PET.
        Neurosurg Rev. 2018 Jan 1; 41: 67-76