Abstract
Purpose: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%–2% of non–small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. Patients and Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). Results: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion–positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion–positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.
Original language | English (US) |
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Pages (from-to) | 34-42 |
Number of pages | 9 |
Journal | Clinical Cancer Research |
Volume | 27 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1 2021 |
ASJC Scopus subject areas
- Oncology
- Cancer Research
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Overcoming MET-dependent resistance to selective RET inhibition in patients with RET fusion⇓positive lung cancer by combining selpercatinib with crizotinib. / Rosen, Ezra Y.; Johnson, Melissa L.; Clifford, Sarah E. et al.
In: Clinical Cancer Research, Vol. 27, No. 1, 01.01.2021, p. 34-42.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Overcoming MET-dependent resistance to selective RET inhibition in patients with RET fusion⇓positive lung cancer by combining selpercatinib with crizotinib
AU - Rosen, Ezra Y.
AU - Johnson, Melissa L.
AU - Clifford, Sarah E.
AU - Somwar, Romel
AU - Kherani, Jennifer F.
AU - Son, Jieun
AU - Bertram, Arrien A.
AU - Davare, Monika A.
AU - Gladstone, Eric
AU - Ivanova, Elena V.
AU - Henry, Dahlia N.
AU - Kelley, Elaine M.
AU - Lin, Mika
AU - Milan, Marina S.D.
AU - Nair, Binoj C.
AU - Olek, Elizabeth A.
AU - Scanlon, Jenna E.
AU - Vojnic, Morana
AU - Ebata, Kevin
AU - Hechtman, Jaclyn F.
AU - Li, Bob T.
AU - Sholl, Lynette M.
AU - Taylor, Barry S.
AU - Ladanyi, Marc
AU - Janne, Pasi A.
AU - Michael Rothenberg, S.
AU - Drilon, Alexander
AU - Oxnard, Geoffrey R.
N1 - Funding Information: and sponsored research) during the conduct of the study; grants and personal fees from AstraZeneca (consulting fees for drug development and sponsored research), Boehringer Ingelheim (consulting fees for drug development and sponsored research), Daiichi Sankyo (consulting fees for drug development and sponsored research), Takeda Oncology (consulting fees for drug development and sponsored research), and PUMA (consulting fees for drug development and sponsored research); and personal fees from Pfizer (consulting fees for drug development), Roche/ Genentech (consulting fees for drug development), Chugai (consulting fees for drug development), Ignyta (consulting fees for drug development), SFJ Pharmaceuticals (consulting fees for drug development), Araxes Pharmaceuticals (consulting fees for drug development), Voronoi (consulting fees for drug development), Biocartis (consulting fees for drug development), Novartis (consulting fees for drug development), Sanofi Oncology (consulting fees for drug development), Mirati Therapeutics (consulting fees for drug development), Transcenta (consulting fees for drug development), Silicon Therapeutics (consulting fees for drug development), Revolution Medicines (sponsored research), and Astellas Pharmaceuticals (sponsored research) outside the submitted work. In addition, P.A. J€anne has a patent for EGFR Mutations issued and licensed to Lab Corp (receives postmarketing royalties from DFCI owned patent licensed to Lab Corp). S.M. Rothenberg reports other from Loxo Oncology (employee, stock options) during the conduct of the study and other from Pfizer (employee, stock options) outside the submitted work. A. Drilon reports other from Loxo/Lilly (honoraria/advisory), Ignyta/Genentech/Roche (honoraria/advisory), and Blueprint Medicines (honoraria/advisory) during the conduct of the study; other from Bayer (honoraria/advisory), Takeda/Ariad/ Millenium (honoraria/advisory), TP Therapeutics (honoraria/advisory), AstraZeneca (honoraria/advisory), Pfizer (honoraria/advisory), Helsinn (honoraria/advisory), Beigene (honoraria/advisory), BergenBio (honoraria/advisory), Hengrui Therapeutics (honoraria/advisory), Exelixis (honoraria/advisory), Tyra Biosciences (honoraria/advisory), Verastem (honoraria/advisory), MORE Health (honoraria/ advisory), AbbVie (honoraria/advisory), 14ner/Elevation Oncology (honoraria/ advisory), Remedica Ltd. (honoraria/advisory), ArcherDX (honoraria/advisory), Monopteros (honoraria/advisory), Novartis (honoraria/advisory), EMD Serono (honoraria/advisory), Melendi (honoraria/advisory), Exelixis (associated research to institution), GlaxoSmithKlein (associated research to institution), Teva (associated research to institution), Taiho (associated research to institution), and PharmaMar (associated research to institution) outside the submitted work; royalties from Wolters Kluwer; other from Merck (food/beverage), Puma (food/beverage), Merus (food/beverage), and Boehringer Ingelheim; and CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Funding Information: This work was supported by the NCI grants R01CA222823 (to P.A. J€anne) and R35CA220497 (to P.A. J€anne), NIH 2T32 CA009512–29A1 (to E.Y. Rosen), NIH Cancer Center Grant P30CA008748 to Memorial Sloan Kettering Cancer Center, and The Expect Miracles Foundation (to E.V. Ivanova) and Robert and Renée Belfer Foundation (to E.V. Ivanova). Funding Information: E.Y. Rosen reports grants from Bayer (research funding) outside the submitted work. M.L. Johnson reports grants and other from Loxo/Lilly (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI and payment to institution for consulting services performed by M.L. Johnson) during the conduct of the study; grants and other from AbbVie (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), AstraZeneca (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Atreca (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Boehringer Ingelheim (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Calithera Biosciences (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Lilly (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), EMD Serono (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Genentech/Roche (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), GlaxoSmithKline (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Gritstone Oncology (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Guardant Health (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Incyte (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Janssen (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Loxo Oncology (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Merck (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Mirati Therapeutics (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Novartis (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Pfizer (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Sanofi (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), WindMIL (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Ribon Therapeutics (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI and payment to institution for consulting services performed by M.L. Johnson); grants from Acerta (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Adaptimmune (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Apexigen (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Array BioPharma (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), BeiGene (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), BerGenBio (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Checkpoint Therapeutics (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Corvus Pharmaceuticals (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), CytomX (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Daiichi Sankyo (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Dynavax (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Genmab (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Genocea Biosciences (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Hengrui Therapeutics (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Immunocore (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Jounce Therapeutics (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Kadmon Pharmaceuticals (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Lycera (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Neovia Oncology (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), OncoMed Pharmaceuticals (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Regeneron Pharmaceuticals (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Seven and Eight Biopharmaceuticals (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Shattuck Labs (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Stem CentRx (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Syndax Pharmaceuticals (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Takeda Pharmaceuticals (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Tarveda (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), University of Michigan (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), TCR2 Therapeutics (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Arcus Biosciences (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), Amgen (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI), TMUNITY Therapeutics (payment to institution for conduct of clinical trial on which M.L. Johnson served as PI); other from Achilles Therapeutics, Association of Community Cancer Centers (payment to institution for consulting services performed by M.L. Johnson); personal fees from Astellas (consulting/advisory role for an immediate family member) and Otsuka (consulting/advisory role for an immediate family member) outside the submitted work. S.E. Clifford reports other from Foundation Medicine outside the submitted work. R. Somwar reports grants and nonfinancial support from Loxo Oncology (Loxo Oncology provided research funds as well as selpercatinib to conduct in vitro experiments) during the conduct of the study; grants from Helsinn Health Care (research grant), Elevation Oncology (research grant), and Merus (research) outside the submitted work. J.F. Kherani reports other from Loxo Oncology (employee of Loxo Oncology at Lilly) during the conduct of the study and other from Loxo Oncology (employee of Loxo Oncology at Lilly) outside the submitted work. B.C. Nair reports other from Loxo Oncology, Inc., a subsidiary of Eli Lilly and Company (full-time employment) during the conduct of the study. E.A. Olek reports other from Eli Lilly and Company (employee and stock grant) during the conduct of the study. K. Ebata reports other from Loxo Oncology, Inc., a subsidiary of Eli Lilly and Company (employment, stock) during the conduct of the study and other from Loxo Oncology, Inc., a subsidiary of Eli Lilly and Company (employment, stock) outside the submitted work. J.F. Hechtman reports personal fees from Illumina and grants from Eli Lilly outside the submitted work. B.T. Li reports grants and personal fees from Roche Genentech (consulting/advisory board and clinical trial funding), Guardant Health (consulting/advisory board and clinical research funding), and Hengrui Therapeutics (consulting/advisory board and clinical trial funding); personal fees from Thermo Fisher Scientific (consulting/advisory board) and Mersana Therapeutics (consulting/ advisory board); grants from Lilly [clinical trial funding and advisory board (uncompensated)], AstraZeneca [clinical trial funding and advisory board (uncompensated)], Daiichi Sankyo (clinical trial funding), Amgen [clinical trial funding and advisory board (uncompensated)], Illumina (clinical trial funding), GRAIL (clinical trial funding), and BioMedValley Discoveries (clinical trial funding); grants and nonfinancial support from MORE Health (clinical research funding, academic travel support); nonfinancial support from Resolution Bioscience (academic travel support) and Jiangsu Hengrui Medicine (academic travel support); and other from Boehringer Ingelheim [advisory board (uncompensated)] outside the submitted work. In addition, B.T. Li has a patent for US62/685,057 issued (methods for detecting HER2 dimerization in patients with HER2-mutant lung cancers and predicting responsiveness to ado-trastuzumab emtansine) and a patent for US62/ 514,661 issued (predicting Cancer Treatment Outcome with T-DM1). L.M. Sholl reports personal fees from EMD Serono and grants from Roche/Genentech (to her institution) outside the submitted work. B.S. Taylor reports grants from Genentech, Inc and personal fees from Boehringer Ingelheim and Loxo Oncology at Lilly outside the submitted work. M. Ladanyi reports grants from LOXO Oncology and personal fees from Lilly Oncology outside the submitted work. P.A. J€anne reports personal fees from LOXO Oncology (consulting fees for drug development) and grants and personal fees from Eli Lilly and Company (consulting fees for drug development Publisher Copyright: © 2020 American Association for Cancer Research.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Purpose: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%–2% of non–small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. Patients and Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). Results: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion–positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion–positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.
AB - Purpose: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%–2% of non–small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. Patients and Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). Results: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion–positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion–positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.
UR - http://www.scopus.com/inward/record.url?scp=85098167326&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098167326&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-2278
DO - 10.1158/1078-0432.CCR-20-2278
M3 - Article
C2 - 33082208
AN - SCOPUS:85098167326
VL - 27
SP - 34
EP - 42
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 1
ER -