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Mechanism in ALK-Positive Lung Cancer

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Mechanism in ALK-Positive Lung Cancer Author Manuscript Published OnlineFirst on February 21, 2020; DOI: 10.1158/1078-0432.CCR-19-3906 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 MET Alterations are a Recurring and Actionable Resistance 2 Mechanism in ALK-Positive Lung Cancer 3 Ibiayi Dagogo-Jack1,2*, Satoshi Yoda1,2*, Jochen K. Lennerz3, Adam Langenbucher1, 4 Jessica J. Lin1,2, Marguerite Rooney1, Kylie Prutisto-Chang1, Audris Oh1, Nathaniel A. 5 Adams1, Beow Y. Yeap1, Emily Chin1, Andrew Do1, Hetal D. Marble3, Sara E. Stevens1, 6 Subba R. Digumarthy4, Ashish Saxena5, Rebecca J. Nagy6, Cyril H. Benes1,2, 7 Christopher G. Azzoli1,2, Michael Lawrence1, Justin F. Gainor1,2, Alice T. Shaw1,2‡**, and 8 Aaron N. Hata1,2‡** 9 1Massachusetts General Hospital Cancer Center and Department of Medicine, 10 Massachusetts General Hospital, 2Harvard Medical School, 3Department of Pathology, 11 Center for Integrated Diagnostics, Massachusetts General Hospital, 4Department of 12 Radiology, Massachusetts General Hospital, 5Department of Medicine, Weill Cornell 13 Medicine, 6Guardant Health, Inc 14 ‡ Corresponding authors 15 *These authors contributed equally 16 **These authors contributed equally 17 18 Running title: MET Alterations in ALK-Positive Lung Cancer 19 Keywords: ALK, Lung Cancer, Resistance, MET Amplification 20 Figures/Tables: 6/0 21 Word Count: ~ 4500 22 Abstract Word Count: 252 words 23 Statement of Translational Relevance: 152 words 24 References: 26 25 Supplement: 5 Figures, 3 Tables 26 27 Corresponding Authors: 28 Alice T. Shaw, M.D., Ph.D. 29 Massachusetts General Hospital 30 Department of Medicine 31 32 Fruit Street 32 Boston, MA, USA, 02114 33 email: [email protected] 34 35 Aaron N. Hata, M.D., Ph.D. 36 Massachusetts General Hospital 37 Department of Medicine 38 149 13th Street, Charlestown, MA, 02129. 39 email: [email protected] Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 21, 2020; DOI: 10.1158/1078-0432.CCR-19-3906 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 40 ABSTRACT (252/250) 41 Background: Most ALK-positive lung cancers will develop ALK-independent resistance 42 after treatment with next-generation ALK inhibitors. MET amplification has been 43 described in patients progressing on ALK inhibitors, but frequency of this event has not 44 been comprehensively assessed. 45 Methods: We performed fluorescence in-situ hybridization and/or next-generation 46 sequencing on 207 post-treatment tissue (n=101) or plasma (n=106) specimens from 47 patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated 48 ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity 49 of ALK/MET blockade in ALK-positive cell lines and two patients with MET-driven 50 resistance. 51 Results: MET amplification was detected in 15% of tumor biopsies from patients 52 relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from 53 patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients 54 treated with a second-generation ALK inhibitor in the first-line setting were more likely to 55 develop MET amplification than those who had received next-generation ALK inhibitors 56 after crizotinib (p=0.019). Two tumor specimens harbored an identical ST7-MET 57 rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in 58 the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was 59 reversed with dual ALK/MET inhibition. MET inhibition re-sensitized a patient-derived cell 60 line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with 61 ALK-positive lung cancer and acquired MET alterations achieved rapid responses to 62 ALK/MET combination therapy. 63 Conclusions: Treatment with next-generation ALK inhibitors, particularly in the first-line 64 setting, may select for MET-driven resistance. Patients with acquired MET alterations 65 may derive clinical benefit from therapies that target both ALK and MET. 66 2 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 21, 2020; DOI: 10.1158/1078-0432.CCR-19-3906 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 67 STATEMENT OF TRANSLATIONAL RELEVANCE 68 With the development of highly potent and selective next-generation ALK inhibitors, 69 resistance is increasingly mediated by ALK-independent mechanisms. Here through 70 molecular profiling of >200 resistant tissue and plasma specimens, including the largest 71 dataset of post-lorlatinib specimens to date, we identified MET amplification in 15% of 72 tumor biopsies from patients relapsing on next-generation ALK inhibitors and detected 73 rare, novel ST7-MET rearrangements in two cases. Upregulation of MET signaling 74 through MET amplification and/or fusion of MET with ST7 decreased sensitivity of ALK- 75 positive cells to ALK inhibitors. In cell lines, combined blockade of ALK and MET 76 overcame resistance driven by MET bypass signaling. Consistent with these findings, 77 two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid 78 clinical and radiographic responses to ALK/MET combination therapy. Our study 79 demonstrates that MET bypass signaling is a recurring and actionable mechanism of 80 resistance to ALK inhibitors, providing rationale for pursuing ALK/MET combination 81 therapy in the clinic. 82 83 3 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 21, 2020; DOI: 10.1158/1078-0432.CCR-19-3906 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 84 CONFLICTS OF INTEREST/DISCLOSURES: 85 86 IDJ has received honoraria from Foundation Medicine, consulting fees from Boehringer 87 Ingelheim, research support from Array, Genentech, Novartis, Pfizer, and Guardant 88 Health, and travel support from Array and Pfizer. JJL has received honoraria or served 89 as a compensated consultant for Chugai, Boehringer Ingelheim, and Pfizer; institutional 90 research support from Loxo Oncology and Novartis; and CME honorarium from OncLive. 91 RJN is an employee of Guardant Health. SRD provides independent image analysis 92 through the institution for clinical research trials sponsored by Merck, Pfizer, Bristol 93 Myers Squibb, Novartis, Roche, Polaris, Cascadian, Abbvie, Gradalis, Bayer, Zai 94 Laboratories; and has received honoraria from Siemens Medical Solutions. AS has 95 served on advisory boards for AstraZeneca and Takeda and as a consultant for 96 Genentech, AstraZeneca, and Medtronic. JFG has served as a compensated consultant 97 or received honoraria from Bristol-Myers Squibb, Genentech, Ariad/Takeda, Loxo, 98 Pfizer, Incyte, Novartis, Merck, Agios, Amgen, Jounce, Regeneron, Oncorus, Helsinn, 99 Jounce, Array, and Clovis Oncology, has an immediate family member who is an 100 employee of Ironwood Pharmaceuticals, has received research funding from Novartis, 101 Genentech/Roche, and Ariad/Takeda, and institutional research support from Tesaro, 102 Moderna, Blueprint, BMS, Jounce, Array, Adaptimmune, Novartis, Genentech/Roche, 103 Alexo and Merck. ATS has served as a compensated consultant or received honoraria 104 from Achilles, Archer, ARIAD, Bayer, Blueprint Medicines, Chugai, Daiichi Sankyo, EMD 105 Serono, Foundation Medicine, Genentech/Roche, Guardant, Ignyta, KSQ Therapeutics, 106 LOXO, Natera, Novartis, Pfizer, Servier, Syros, Taiho Pharmaceutical, Takeda, and TP 107 Therapeutics, has received research (institutional) funding from Daiichi Sankyo, Ignyta, 108 Novartis, Pfizer, Roche/Genentech, and TP Therapeutics; has received travel support 109 from Pfizer and Genentech/Roche; and is an employee of Novartis. ANH has received 110 research grants/funding from Pfizer, Novartis, Amgen, Eli Lilly, Relay Therapeutics, and 111 Roche/Genentech. The remaining authors have no disclosures to report. 112 113 4 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 21, 2020; DOI: 10.1158/1078-0432.CCR-19-3906 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 114 115 FUNDING: 116 This work was support by a Conquer Cancer/Amgen Young Investigator Award (I.D.J), 117 an institutional research grant from American Cancer Society (I.D.J.), a National Cancer 118 Institute Career Development Award (K12CA087723-16 to I.D.J.), a Lung Cancer 119 Research Foundation Annual Grant Program award (S.Y.), a Conquer 120 Cancer/AstraZeneca Young Investigator Award (J.J.L.), grants from the National Cancer 121 Institute (R01CA164273 to A.T.S. and R01CA225655 to J.K.L.), by Be a Piece of the 122 Solution, and by Targeting a Cure for Lung Cancer Research Fund at MGH. 123 124 5 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 21, 2020; DOI: 10.1158/1078-0432.CCR-19-3906 Author manuscripts have been peer reviewed and accepted for publication but have
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