Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers Journal Article
| Authors: | Drilon, A.; Somwar, R.; Mangatt, B. P.; Edgren, H.; Desmeules, P.; Ruusulehto, A.; Smith, R. S.; Delasos, L.; Vojnic, M.; Plodkowski, A. J.; Sabari, J.; Ng, K.; Montecalvo, J.; Chang, J.; Tai, H.; Lockwood, W. W.; Martinez, V.; Riely, G. J.; Rudin, C. M.; Kris, M. G.; Arcila, M. E.; Matheny, C.; Benayed, R.; Rekhtman, N.; Ladanyi, M.; Ganji, G. |
| Article Title: | Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers |
| Abstract: | NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3–ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1 -rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1 -rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1 -rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identifi ed NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers. SIGnIFICAnCE: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1 -rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identifi cation of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. © 2018 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 8 |
| Issue: | 6 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2018-06-01 |
| Start Page: | 686 |
| End Page: | 695 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-17-1004 |
| PROVIDER: | scopus |
| PMCID: | PMC5984717 |
| PUBMED: | 29610121 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 July 2018 -- Source: Scopus |
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