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Background Neuregulin-1 gene (NRG1) fusions function as oncogenic drivers across various solid tumors, most notably in invasive mucinous adenocarcinoma (IMA) of the lung, and represent a rational potential target for treatment. NRG1 is a growth factor, which binds to ErbB3 or ErbB4 inducing the formation of ErbB3 or 4-containing homo- or heterodimers and activating downstream ErbB-family signaling pathways. Therefore, the ErbB-family blocker afatinib may be a potential treatment option for patients with solid tumors harboring NRG1 fusions. Methods We report a case series of all known patients with NRG1 fusion-positive solid tumors who were treated with afatinib; afatinib therapy is ongoing for some patients. Results To date, 18 patients with NRG1 fusion-positive solid tumors have been treated with afatinib (Table). These include 12 cases of non-small cell lung cancer (NSCLC; 7 of which were reported as IMA), 5 cases of gastrointestinal (GI) cancer (primarily pancreatic ductal adenocarcinoma [PDAC]) and 1 case of ovarian cancer. Various NRG1 fusion partners were identified, most commonly CD74 in patients with NSCLC (n = 7; 58%) and ATP1B1 in patients with gastrointestinal cancer (n = 3; 60%). Best response with afatinib among patients with NSCLC was partial response (PR) lasting 24 months (10 months among those specifically with IMA of the lung). Patients with PDAC experienced PR of 3 and 5.5 months' duration, and one patient has an ongoing PR after 7 months. One patient with cholangiocarcinoma had a PR lasting 8 months; another patient with ovarian cancer had stable disease (SD) of unknown duration. Conclusions Afatinib is a potential treatment option for some patients with solid tumors harboring NRG1 fusions. The efficacy and safety of afatinib will be evaluated in ongoing/planned prospective non-randomized clinical trials of targeted drugs in patients with advanced cancer with potentially actionable genomic variants (NCT02925234 and NCT02693535). Table: 63O Tumor type    NRG1 fusion partner  Best response, physician assessed  Duration of response, mos  Refs  NSCLC  IMA  CD74  PR  10  1      CD74  PR  6.5  2      CD74  PD*    3      CD74  SD  3  3      SDC4  PD    3      CD74  PD    3      CD74  PR  -  4    ADC  SLC3A2  PR  12  1      SDC4  PR  12  5      -  PR  24  6      CD74  PR  14+  4, 6      SDC4  SD  4  6  GI  PDAC  ATP1B1  PR  3  7      ATP1B1  PR  5.5  8      APP  PR  7+  6, 8    Cholangiocarcinoma  ATP1B1  PR  8  5    Colorectal (KRASm +ve)  POMK  SD  4  9  Ovarian    CLU  SD  -  10  Tumor type    NRG1 fusion partner  Best response, physician assessed  Duration of response, mos  Refs  NSCLC  IMA  CD74  PR  10  1      CD74  PR  6.5  2      CD74  PD*    3      CD74  SD  3  3      SDC4  PD    3      CD74  PD    3      CD74  PR  -  4    ADC  SLC3A2  PR  12  1      SDC4  PR  12  5      -  PR  24  6      CD74  PR  14+  4, 6      SDC4  SD  4  6  GI  PDAC  ATP1B1  PR  3  7      ATP1B1  PR  5.5  8      APP  PR  7+  6, 8    Cholangiocarcinoma  ATP1B1  PR  8  5    Colorectal (KRASm +ve)  POMK  SD  4  9  Ovarian    CLU  SD  -  10  * PD on an anti-ErbB3 mAb prior to afatinib. -, not reported; ADC, adenocarcinoma; PD, progressive disease.1Gay. JTO 2017, 2Cheema. JTO 2017, 3Drilon. Cancer Discov 2018, 4Duruisseaux. WCLC 2019, 5Jones. Ann Oncol 2017, 6Laskin. JSMO 2019, 7Heining. Cancer Discov 2018, 8Jones. Clin Cancer Res 2019, 9Weinberg. ESMO GI 2019, 10Murumagi. AACR 2019. Table: 63O Tumor type    NRG1 fusion partner  Best response, physician assessed  Duration of response, mos  Refs  NSCLC  IMA  CD74  PR  10  1      CD74  PR  6.5  2      CD74  PD*    3      CD74  SD  3  3      SDC4  PD    3      CD74  PD    3      CD74  PR  -  4    ADC  SLC3A2  PR  12  1      SDC4  PR  12  5      -  PR  24  6      CD74  PR  14+  4, 6      SDC4  SD  4  6  GI  PDAC  ATP1B1  PR  3  7      ATP1B1  PR  5.5  8      APP  PR  7+  6, 8    Cholangiocarcinoma  ATP1B1  PR  8  5    Colorectal (KRASm +ve)  POMK  SD  4  9  Ovarian    CLU  SD  -  10  Tumor type    NRG1 fusion partner  Best response, physician assessed  Duration of response, mos  Refs  NSCLC  IMA  CD74  PR  10  1      CD74  PR  6.5  2      CD74  PD*    3      CD74  SD  3  3      SDC4  PD    3      CD74  PD    3      CD74  PR  -  4    ADC  SLC3A2  PR  12  1      SDC4  PR  12  5      -  PR  24  6      CD74  PR  14+  4, 6      SDC4  SD  4  6  GI  PDAC  ATP1B1  PR  3  7      ATP1B1  PR  5.5  8      APP  PR  7+  6, 8    Cholangiocarcinoma  ATP1B1  PR  8  5    Colorectal (KRASm +ve)  POMK  SD  4  9  Ovarian    CLU  SD  -  10  * PD on an anti-ErbB3 mAb prior to afatinib. -, not reported; ADC, adenocarcinoma; PD, progressive disease.1Gay. JTO 2017, 2Cheema. JTO 2017, 3Drilon. Cancer Discov 2018, 4Duruisseaux. WCLC 2019, 5Jones. Ann Oncol 2017, 6Laskin. JSMO 2019, 7Heining. Cancer Discov 2018, 8Jones. Clin Cancer Res 2019, 9Weinberg. ESMO GI 2019, 10Murumagi. AACR 2019. Editorial acknowledgement Greg Plosker of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study The authors. Funding Boehringer Ingelheim. Disclosure Y. Goto: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Chugai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Taiho Pharmaceutical; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Shionogi Pharma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Glaxo Smith Kline; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Kyorin. J. Cadranel: Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: AZ; Advisory / Consultancy, Non-remunerated activity/ies: BI; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy, Non-remunerated activity/ies: Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis. B.A. Weinberg: Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ipsen; Travel / Accommodation / Expenses: Caris Life Sciences; Travel / Accommodation / Expenses: Boehringer Ingelheim. M. Duruisseaux: Honoraria (self): Roche; Honoraria (self): Takeda; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): AbbVie; Honoraria (self): Boerhinger ingelheim. S.V. Liu: Advisory / Consultancy: Apollomics; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Heron; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy: Inivata; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Regeneron; Advisory / Consultancy: Taiho (DSMB); Advisory / Consultancy: Takeda/Ariad; Advisory / Consultancy: Tempus; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): Esanex; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Molecular Partners; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Rain Therapeutics; Research grant / Funding (institution): Threshold. K. Tolba: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self): Foundation One. R.C. Doebele: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties, Licenses are licensing fees from patents or biological materials : Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Trovagene; Advisory / Consultancy, Licensing / Royalties, Licenses are licensing fees from patents or biological materials : Ariad; Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self), Licenses are licensing fees from patents or biological materials : Ignyta; Advisory / Consultancy, Research grant / Funding (self), Licenses are licensing fees from patents or biological materials: Loxo; Research grant / Funding (self): Mirati; Licensing / Royalties, Licensing fees from patents or biological materials : Abbott Molecular; Licensing / Royalties, Licensing fees from patents or biological materials : GVKbio; Licensing / Royalties, Licensing fees from patents or biological materials: Chugai; Licensing / Royalties, Licensing fees from patents or biological materials : Genentech; Licensing / Royalties, Licensing fees from patents or biological materials: Foundation Medicine; Licensing / Royalties, Licensing fees from patents or biological materials: Black Diamond. R.F. Schlenk: Research grant / Funding (self): Boehringer Ingelheim. J.J. Laskin: Honoraria (self), Research grant / Funding (self): Roche Canada; Honoraria (self): BI Canada; Honoraria (self): AstraZeneca Canada; Research grant / Funding (self): Pfizer Canada. P.K. Cheema: Honoraria (self), Advisory / Consultancy: Astrazeneca; Honoraria (self), Advisory / Consultancy: BI; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: genomic Health; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck. M.R. Jones: Full / Part-time employment: Qiagen. L.A. Muscarella: Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. F. Solca: Full / Part-time employment: Boehringer Ingelheim. D.J. Renouf: Honoraria (self): Celgene; Honoraria (self): Tahio; Honoraria (self): Bayer; Honoraria (self): Ipsen; Honoraria (self): Servier. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study., Patients and Methods: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety., Results: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs., Conclusions: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending., Competing Interests: Disclosure FG has consulted or provided expert opinion for Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda; has received fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda; and has received funding for scientific research from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda. GC has consulted and/or had advisory roles for AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Foundation Medicine, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche/Genentech, Samsung, and Seattle Genetics; served on speakers’ bureaus for Daiichi Sankyo, Foundation Medicine, Lilly, Novartis, Pfizer, Roche/Genentech, and Samsung; received travel, accommodations, and expenses from Pfizer, Roche/Genentech; received honoraria from Ellipses Pharma and research funding from Merck; and is supported by the OPTIMA [grant number 101034347]. MT has received honoraria for scientific meetings (self) from AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; advisory-board honoraria (self) from AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; travelling support (self) from AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; and has received research funding (institution) from AstraZeneca, BMS, Roche, and Takeda. VS reports research funding/grant support for clinical trials from AbbVie, Agensys, Alfa-sigma, Altum, Amgen, Bayer, Berg Health, Biotherapeutics, Blueprint Medicines Corporation, Boston Biomedical, Boston Pharmaceuticals, Celgene, D3, Dragonfly Therapeutics, Exelixis, Fujifilm, GSK, Idera Pharma, Incyte, Inhibrx, Loxo Oncology, MedImmune, MultiVir, Nanocarrier, National Comprehensive Cancer Network, NCI-CTEP, Novartis, Northwest Biotherapeutics, Pfizer, PharmaMar, Roche/Genentech, Takeda, Turning Point Therapeutics, UT MD Anderson Cancer Center, and Vegenics; travel support from ASCO, ESMO, Helsinn, Incyte, Novartis, and PharmaMar; consultancy/advisory board participation for Helsinn, Incyte, Loxo Oncology/Eli Lilly, MedImmune, Novartis, R-Pharma US, QED Pharma; and other relationship with Medscape. CSB has received consulting fees from AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Turning Point Therapeutics, Guardant, Regeneron, Silverback, and Takeda; and has received research funding to their institution from AbbVie, AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Genentech Inc., Janssen, Lilly, Loxo Oncology, Novartis, Pfizer, Rain Therapeutics, Spectrum Pharmaceuticals, and Turning Point Therapeutics. DSWT has consulted and/or had advisory roles for AstraZeneca, Bayer, Lilly, Loxo Oncology, Merrimack, Novartis, Pfizer, and Takeda; received honoraria from Boehringer Ingelheim, Merck, and Roche; and research funding to their institution from AstraZeneca, Bayer, GSK, and Novartis. DHL has received personal fees from AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Chong Keun Dang, CJ Healthcare, Genexine, Janssen, Lilly, Merck, Menarini, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, and Takeda; and non-financial support from Blueprint Medicines Corporation and Takeda. DM has consulted and/or had advisory roles at scientific meetings for AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Roche, Sanofi, and Takeda (institution, no personal honoraria). EG has consulted and/or had advisory roles for Alkermes, BMS, Boehringer Ingelheim, Ellipses Pharma, Janssen, NeoMed, Roche, Seattle Genetics, TFS, Thermo Fisher Scientific; served on speakers’ bureaus for MSD, Roche, and Thermo Fisher Scientific; received travel and accommodation expenses from BMS, Glycotope GmbH, Menarini, and MSD; research funding to their institution from Novartis, Roche, and Thermo Fisher Scientific; and is supported by a grant from the ‘la Caixa’ Foundation [grant number LCF/PR/CE07/50610001]. DWK has received travel and accommodation expenses from Amgen and Daiichi Sankyo; and research funding to their institution from Alpha Biopharma, Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Daiichi Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan. AJvdW reports research funding/grant support for clinical trials from AstraZeneca [grant number ESR-16-12212], Boehringer Ingelheim, Pfizer, Roche, and Takeda [grant number 2019N0853/2020N0366]; and consultancy/advisory board participation for AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Pfizer, Roche, and Takeda. JFG has an immediate family member who is an employee of Ironwood Pharmaceuticals; has consulted and/or had advisory roles for Agios, Amgen, Array BioPharma, Blueprint Medicines Corporation, BMS, Genentech, Gilead Sciences, Jounce Therapeutics, Lilly, Loxo Oncology, Merck, Mirati, Silverback Therapeutics, GlydeBio, Moderna Therapeutics, Oncorus, Regeneron, Takeda, and Theravance; has stock and ownership in Ironwood Pharmaceuticals; has received honoraria from ARIAD, Incyte, Merck, Novartis, Pfizer, and Takeda; and research funding from Adaptimmune, ALX Oncology, ARIAD, Array BioPharma, AstraZeneca, Blueprint Medicines Corporation, BMS, Genentech, Jounce Therapeutics, Merck, Novartis, and Tesaro. LPA has a leadership role in ALTUM Sequencing and Genomica; served on speakers’ bureaus for AstraZeneca, BMS, Lilly, MSD Oncology, Merck Serono, Pfizer, Roche/Genentech; received travel, accommodation, and expenses from AstraZeneca, BMS, MSD, Pfizer, Roche, and Takeda; honoraria from Amgen, AstraZeneca, Bayer, Blueprint Medicines Corporation, BMS, Celgene, Ipsen, Lilly, Merck Serono, Mirati Therapeutics, MSD, Novartis, Pfizer, PharmaMar, Roche/Genentech, Sanofi, Servier, and Takeda; research funding to their institution from AstraZeneca, BMS, Kura Oncology, MSD, and PharmaMar; other relationships with Roche; and an immediate family member has other relationships with Amgen, Ipsen, Merck Novartis, Pfizer, Sanofi, Servier, and Roche. SVL served as a consultant or advisory board member to Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines Corporation, BMS, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/MSD, Novartis, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics; received research funding (to institution) from Alkermes, Bayer, Blueprint Medicines Corporation, BMS, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT Therapeutics, Turning Point Therapeutics; and is supported by the National Cancer Institute [grant number UM1CA186691]. GPK received research grants from Blueprint Medicines Corporation, Merck, AbbVie, Takeda, Daiichi, and Cullinan. DWB served on an advisory board for Blueprint Medicines Corporation. ASM received research funding from DoD, Mark Foundation, NIH, Novartis, and Verily; honoraria to institution for participation in advisory boards: AbbVie, BeiGene, BMS, Genentech, Inc., Janssen; travel support from: Roche; is a non-remunerated member of the Mesothelioma Applied Research Foundation Board of Directors; and is supported by the Mark Foundation for Cancer Research ASPIRE Award, the National Cancer Institute [grant number R21 CA251923], and Department of Defense Concept Award [grant number W81XWH-22-1-0021]. JJL served as a compensated consultant or advisory board member for Genentech, C4 Therapeutics, Blueprint Medicines Corporation, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, and Turning Point Therapeutics; received honorarium and travel support from Pfizer; received institutional research funding from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; and received CME funding from OncLive, MedStar Health, and Northwell Health. VSm is an employee and/or equity holder of F. Hoffmann-La Roche, Ltd. AR is an employee and/or equity holder of F. Hoffmann-La Roche, Ltd and equity holder of Merck/MSD. SK is a former employee and/or equity holder of F. Hoffmann-La Roche, Ltd. AZ, MLG and ALB are employees and/or equity holders of Blueprint Medicines Corporation. JM has provided expertise for Amgen, AstraZeneca, Blueprint Medicines Corporation, BMS, Daiichi Sankyo, Hengrui, MSD, Novartis, Pierre Fabre, Roche, and Takeda; and received research funding from AstraZeneca, BMS, Pierre Fabre, and Roche. YH has declared no conflicts of interest. Data sharing The anonymized derived data from this study that underlie the results reported in this article will be made available, beginning 12 months and ending 5 years after this article’s publication, to any investigators who sign a data access agreement and provide a methodologically sound proposal to medinfo@blueprintmedicines.com. The trial protocol will also be made available, as will a data fields dictionary., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited., Patients and Methods: This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH., Results: We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6-10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation., Conclusions: RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients., Competing Interests: Disclosure JJL has served as a compensated consultant or received honorarium from Chugai Pharma, Boehringer-Ingelheim, Pfizer, C4 Therapeutics, Nuvalent, Turning Point Therapeutics, Blueprint Medicines, and Genentech; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Roche/Genentech, Pfizer, and Novartis; received CME funding from OncLive, MedStar Health, and Northwell Health; and received travel support from Pfizer. SVL served as a compensated consultant or on the advisory board for AstraZeneca, Blueprint, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, G1 Therapeutics, Genentech/Roche, Guardant Health, Inivata, Janssen, Jazz, Lilly, Merck/MSD, PharmaMar, Pfizer, Regeneron, and Takeda; and received institutional research funding from Alkermes, AstraZeneca, Blueprint, Bristol-Myers Squibb, Corvus, Genentech, Lilly, Merck, Pfizer, Rain Therapeutics, RAPT, Spectrum, and Turning Point Therapeutics. CEM received honorarium from Novartis and Guardant Health; served on the advisory board for Genentech; and received research funding from Novartis and Revolution Medicines. ACT has served as a compensated consultant or received honorarium from Thermo Fisher. ID-J has received honoraria from Foundation Medicine; consulting fees from Boehringer Ingelheim and AstraZeneca; research support from Array, Genentech, Novartis, Pfizer, and Guardant Health; and travel support from Array and Pfizer. LJW has received personal fees from Bayer, Blueprint Medicines, Cue Biopharma, Exelixis, Genentech, and Rakuten Medical; received personal fees and nonfinancial support from Eisai, Lilly, Loxo Oncology, and Merck; and received institutional research funding from Loxo Oncology. ANH has received research support from Amgen, Pfizer, Novartis, Blueprint Medicines, Eli Lilly, Roche/Genentech, and Relay Therapeutics. MM-K has served as a compensated consultant for H3 Biomedicine and AstraZeneca; received institutional research support from Novartis. S-HIO has received personal fees from Pfizer, Merck, Takeda, AstraZeneca, Roche/Genentech, Daiichi Sankyo, Blueprint Medicines, and Janssen JNJ; and has stock ownership in Turning Point Therapeutics. DS-WT has served as a compensated consultant or received honorarium from Amgen, Boehringer-Ingelheim, Pfizer, C4 Therapeutics, Takeda, Bristol-Myers Squibb, MSD, Bayer, and Novartis; received institutional research funds from AstraZeneca, Pfizer, and Amgen; and received travel support from Pfizer and MSD. JFG has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech, Ariad/Takeda, Loxo/Lilly, Blueprint, Oncorus, Regeneron, Gilead, AstraZeneca, Pfizer, Incyte, Novartis, Merck, Agios, Amgen, and Array; research support from Novartis, Genentech/Roche, and Ariad/Takeda; institutional research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; and has an immediate family member who is an employee of Ironwood Pharmaceuticals. All remaining authors have declared no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents ≈2%-10% of lung adenocarcinomas and has a reported incidence of ≈10%-30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions., Competing Interests: Disclosures JL reports receipt of honoraria for academic/accredited talks from Roche and AstraZeneca; membership of an advisory board and consultancy for AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, and Takeda; and receipt of research grants (funds to institution) from AstraZeneca, Roche, and Eli Lilly. SVL reports membership of an advisory board and consultancy for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, Celgene, G1 Therapeutics, Genentech/Roche, Guardant Health, Janssen, Eli Lilly, Loxo, MSD, Pfizer, PharmaMar, Regeneron, and Takeda; and receipt of research grants (funds to institution) from Alkermes, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Corvus, Genentech, Eli Lilly, Lycera, Merck, Merus, Molecular Partners, Pfizer, Rain, RAPT, Spectrum, and Turning Point Therapeutics. KT reports employment with Foundation Medicine; receipt of honoraria from BMS and Merck; and receipt of research grants from AstraZeneca. PC reports membership of an advisory board and consultancy for Roche, Pfizer, AstraZeneca, Novartis, Merck, Takeda, and Bristol-Myers Squibb; and receipt of honoraria from Boehringer Ingelheim, Roche, Pfizer, Novartis, Merck, Takeda, and AstraZeneca. JC reports consulting/advisory relationship with AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Novartis, MSD, Pfizer, Roche, and Takeda; and receipt of research funding from AstraZeneca, Boehringer Ingelheim, Pfizer, and Novartis. MRJ reports employment with QIAGEN Inc. AD reports receipt of honoraria from and membership of an advisory board for Ignyta/Genentech/Roche, Loxo/Bayer/Eli Lilly, Takeda, Ariad, Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, and AbbVie; associated research grants (funds to institution) from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, and PharmaMar; research grants from Foundation Medicine; royalties from Wolters Kluwer; CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, and Research to Practice; and other fees from Merck (food/beverage), Puma (food/beverage), Merus, and Boehringer Ingelheim. AC reports employment with Boehringer Ingelheim. SG reports employment with AstraZeneca as of 4 May 2020. FS reports employment with Boehringer Ingelheim RCV GmbH & Co KG. MD reports membership of an advisory council or committee for Roche, BMS, NanoString, MSD, AstraZeneca, Abbvie, Takeda, Boehringer Ingelheim, Blueprint, Merus, and Pfizer; consulting fees from Roche, BMS, MSD, AstraZeneca, Abbvie, Takeda, Boehringer Ingelheim, and Pfizer; and receipt of research grants from Novartis, NanoString, and Blueprint. The other authors have declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The addition of atezolizumab to carboplatin and etoposide (CP/ET) significantly improved progression-free and overall survival for patients with extensive-stage small-cell lung cancer (ES-SCLC) in the IMpower133 study (NCT02763579). We have evaluated adverse events (AEs) and patient-reported outcomes in IMpower133 to assess the benefit-risk profile of this regimen., Patients and Methods: Patients received four 21-day cycles of CP/ET plus intravenous atezolizumab 1200 mg or placebo (induction phase), followed by atezolizumab or placebo (maintenance phase) until progression or loss of benefit. AEs were assessed and patient-reported outcomes were evaluated every 3 weeks during treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (QLQ-C30) and QLQ-LC13., Results: Overall, 394 patients were assessable for safety in the induction phase and 318 in the maintenance phase. The frequency of AEs, grade 3-4 AEs, and serious AEs was similar between arms in both phases. Immune-related AEs were more frequent in the atezolizumab arm during both induction (28% versus 17%; leading to atezolizumab/placebo interruption 9% versus 5%, leading to withdrawal 4% versus 0%) and maintenance (26% versus 15%; leading to atezolizumab/placebo interruption, 3% versus 2%, leading to withdrawal 1% versus 1%), most commonly rash (induction 11% versus 9%, maintenance 14% versus 4%), and hypothyroidism (induction 4.0% versus 0%, maintenance 10% versus 1%). Changes in patient-reported treatment-related symptoms commonly associated with quality of life impairment were generally similar during induction and most of the maintenance phase. Patient-reported function and health-related quality of life (HRQoL) improved in both arms after initiating treatment, with more pronounced and persistent HRQoL improvements in the atezolizumab arm., Conclusions: In patients with ES-SCLC, atezolizumab plus CP/ET has a comparable safety profile to placebo plus CP/ET, and the addition of atezolizumab did not adversely impact patient-reported HRQoL. These data demonstrate the positive benefit-risk profile of first-line atezolizumab plus CP/ET in ES-SCLC and further support this regimen as a new standard of care in this setting., Clinical Trials Number: NCT02763579., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)