4097 - Targeting NRG1-fusions in multiple tumour types: Afatinib as a novel potential treatment option

Background

Neuregulin 1 (NRG1) is a growth factor that binds HER3/4 and activates ErbB signalling pathways. NRG1 fusions function as oncogenic drivers and represent a potential therapeutic target across tumour types. Afatinib, an ErbB-family blocker, may be a treatment option for some patients (pts) with NRG1 fusion-positive (NRG1+) tumours, as supported by preclinical evidence and published case reports (Table).Table: 1969P

ADC, adenocarcinoma; IMA, invasive mucinous lung adenocarcinoma; PD, progressive disease; PR, partial response; SD, stable disease

Methods

We report clinico-pathological and molecular characteristics of seven previously unreported cases of afatinib-treated NRG1+ tumours.

Results

Pt 1, 70 yo female, never-smoker with pan-wildtype, non-mucinous lung adenocarcinoma (ADC) received 15^th-line afatinib for 24 mos (PR). An NRG1 fusion was subsequently identified. The pt was re-challenged with afatinib (PR, 3 mos) before switching to atezolizumab (PD). Pt 2, 66 yo female, never-smoker with metastatic (m) non-mucinous lung ADC. CD74-NRG1 fusion was identified, and 5^th-line afatinib initiated. PR is ongoing after 14 mos. Pt 3, 68 yo male, >20 pack-yr smoking history with non-mucinous lung ADC. SDC4-NRG1 fusion was identified and 2^nd-line afatinib initiated. Best response: SD, 4 mos. Pt 4, 43 yo female, non-smoker with advanced invasive mucinous lung ADC. CD74-NRG1 fusion was identified and 3^rd-line afatinib initiated; PR is ongoing. Pt 5, 69 yo male, with KRAS-mutated m-colorectal cancer. Following a right hemicolectomy and liver/lung metastasectomies, a novel POMK-NRG1 fusion was detected and afatinib initiated (SD, 4 mos; treatment ongoing). Pts 6 and 7, male (54 & 59 yo) with KRAS WT, m-pancreatic cancers. Following PD on chemotherapy, APP-NRG1 and ATP1B1-NRG1 fusions, respectively, were detected and afatinib initiated. Pt 6 had a PR for 5 mos; treatment ongoing. Pt 7 had a PR for 5.5 mos.

Conclusions

These findings add to a growing body of evidence suggesting that afatinib is a potential treatment option for pts with NRG1+ tumours. Prospective study is ongoing in the Drug Rediscovery Protocol trial (DRUP; NCT02925234).

Clinical trial identification

N/A

Editorial acknowledgement

Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Christina Jennings, of GeoMed, an Ashfield company, part of UDG Healthcare plc.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

S.V. Liu: Advisory / Consultancy: Apollomics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Heron; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Janssen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Regeneron; Advisory / Consultancy: Takeda/Ariad; Advisory / Consultancy: Tempus; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Taiho. M. Duruisseaux: Honoraria (self): Roche; Honoraria (self): Takeda; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp and Dohme; Honoraria (self): AbbVie; Honoraria (self): Boerhinger Ingelheim. K. Tolba: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Boerhinger Ingelheim; Honoraria (self): Merck; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Foundation One. 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 Pharmaceuticals; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boerhinger Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceuticals; 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: Merck Sharp and Dohme; Speaker Bureau / Expert testimony: Shionogi Pharmaceuticals; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Advisory / Consultancy: GSK; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Dai-ichi Sankyo; Advisory / Consultancy: Kyorin. B.A. Weinberg: Travel / Accommodation / Expenses: Boehringer Ingelheim. D.J. Renouf: Honoraria (self): Celgene; Honoraria (self): Servier; Honoraria (self): Taiho; Honoraria (self): Ipsen; Honoraria (self): Bayer. R.C. Doebele: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties: Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Trovagene; Advisory / Consultancy, Licensing / Royalties: Ariad; Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self), Licensing / Royalties: Ignyta; Advisory / Consultancy, Research grant / Funding (self), Licensing / Royalties: Loxo; Research grant / Funding (self): Mirati; Licensing / Royalties: Abbott Molecular; Licensing / Royalties: GVKbio; Licensing / Royalties: Chugai; Licensing / Royalties: Genentech; Licensing / Royalties: Foundation Medicine; Licensing / Royalties: Black Diamond. R.F. Schlenk: Research grant / Funding (self): Boehringer Ingelheim. P.K. Cheema: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; 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. J. Cadranel: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck Sharp and Dohme; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Takeda. M.R. Jones: Full / Part-time employment: Qiagen Inc. A.E. Drilon: Honoraria (self): Medscape; Honoraria (self): OncLive; Honoraria (self): PeerVoice; Honoraria (self): Physicians Education Resources; Honoraria (self): Tyra Biosciences; Honoraria (self): Targeted Oncology; Honoraria (self): MORE Health; Honoraria (self): Research to Practice; Honoraria (self): Foundation Medicine; Honoraria (self): Peerview; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Genentech/Roche; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Ignyta; Honoraria (self): Loxo; Advisory / Consultancy: TP Therapeutics; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: Takeda; Advisory / Consultancy: Helsinn Therapeutics; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Hengrui Therapeutics; Advisory / Consultancy: Exelixis; Travel / Accommodation / Expenses, Other: Wolters Kluwer. L.A. Muscarella: Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim; Shareholder / Stockholder / Stock options, Husband: Mylan. F. Solca: Full / Part-time employment: Boehringer Ingelheim RCV GmbH & Co KG. J.J. Laskin: Honoraria (self), Research grant / Funding (self): Roche Canada; Honoraria (self): Boehringer Ingelheim Canada; Honoraria (self): AstraZeneca Canada; Research grant / Funding (self): Pfizer Canada. All other authors have declared no conflicts of interest.