Published OnlineFirst April 2, 2018; DOI: 10.1158/2159-8290.CD-17-1004 RESEARCH BRIEF Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers Alexander Drilon1,2, Romel Somwar1, Biju P. Mangatt3, Henrik Edgren4, Patrice Desmeules1, Anja Ruusulehto4, Roger S. Smith1, Lukas Delasos1, Morana Vojnic1, Andrew J. Plodkowski1, Joshua Sabari1, Kenneth Ng1, Joseph Montecalvo1, Jason Chang1, Huichun Tai1, William W. Lockwood5, Victor Martinez5, Gregory J. Riely1,2, Charles M. Rudin1,2, Mark G. Kris1,2, Maria E. Arcila1, Christopher Matheny3, Ryma Benayed1, Natasha Rekhtman1, Marc Ladanyi1, and Gopinath Ganji3 ABSTRACT NRG1 rearrangements are oncogenic drivers that are enriched in invasive muci- nous 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 ther- apy (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, identifiedNRG1 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 identification ofNRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 1–10. ©2018 AACR. See related commentary by Wilson and Politi, p. 676. INTRODUCTION kinase inhibitors (TKI) are currently approved or being inves- Oncogenic gene fusions or rearrangements are identi- tigated for the treatment of these patients. Similarly, dramatic fied across a wide range of solid tumors (1). Many of these and durable responses have been reported in NTRK1/2/3– events, such as fusions involving ALK, ROS1, RET, NTRK1/2/3, rearranged solid tumors regardless of histology (2), and in FGFR1/2/3, and PDGFB, are clinically actionable. In lung ade- select cancers with FGFR1/2/3 or RET rearrangements (1). nocarcinomas, targeted therapy for patients with ALK- or Fusions involving the neuregulin-1 gene (NRG1) were iden- ROS1-rearranged tumors is highly effective, and several tyrosine tified by Fernandez-Cuesta and colleagues in non–small cell 1Memorial Sloan Kettering Cancer Center, New York, New York. 2Weill Corresponding Author: Alexander Drilon, Memorial Sloan Kettering Cornell Medical Center, New York, New York. 3GlaxoSmithKline, Collegeville, Cancer Center, 885 2nd Avenue, New York, NY 10017. Phone: 646-888- Pennsylvania. 4MediSapiens, Helsinki, Finland. 5University of British 4206; Fax: 646-888-4263; E-mail: [email protected] Columbia, Vancouver, British Columbia, Canada. doi: 10.1158/2159-8290.CD-17-1004 Note: Supplementary data for this article are available at Cancer Discovery ©2018 American Association for Cancer Research. Online (http://cancerdiscovery.aacrjournals.org/). OF1 | CANCER DISCOVERY JUNE 2018 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst April 2, 2018; DOI: 10.1158/2159-8290.CD-17-1004 ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers RESEARCH BRIEF lung cancers (NSCLC) with an initially approximated fre- tory volumetric analysis revealed a 90% reduction in tumor quency of 1.7% in lung adenocarcinomas (3). Transcriptome volume at the nadir. An on-treatment tumor biopsy was sequencing revealed fusion of CD74 to NRG1 exons encoding performed on day 14 of therapy, but little tumor tissue was the NRG1 III-β3 isoform. Other fusions, such as SLC3A2– present, likely due to the robust response observed; pharma- NRG1 and SDC4–NRG1, have also been identified (4, 5).NRG1 codynamic changes thus could not be assessed. The patient fusions are particularly enriched in invasive mucinous adeno- tolerated the drug with no major issues. The response was carcinomas (IMA) of the lung, where they are found in 27% durable and lasted 1 year and 7 months, exceeding the dura- to 31% of cases. These are often mutually exclusive with KRAS tion, in aggregate, of the prior systemic therapies he received. mutations, a driver known to be enriched in IMAs (4, 6–8). Although GSK2849330 bears antibody-dependent cytotox- Activating NRG1 rearrangements are drivers of cancer icity (ADCC) and complement-dependent cytotoxicity (CDC) growth. NRG1 encodes several isoforms that contain an EGF- enhancements (13), no other responses were noted in the same like domain that serves as the ligand of the receptor ERBB3 trial (NCT01966445, n = 29), which enrolled several patients (9). Chimeric transmembrane proteins encoded by NRG1 with similar and higher ERBB3 expression. None of these fusions are predicted to maintain this extracellular domain, other tumors were known to harbor an NRG1 fusion. These thus activating ERBB3 in a para/juxtacrine or autocrine data strongly suggest that ADCC, CDC, or ERBB3 expression fashion (10). NRG1 binding to ERBB3 results in heterodi- alone do not predict responses, and that our index NRG1- merization of the latter with ERBB2, activation of down- rearranged patient was an exceptional responder to therapy. stream signaling including the ERK, PI3K–AKT, and NF-κB In contrast to these outcomes, treatment with afatinib did pathways, and increased tumor cell proliferation and growth not achieve a response in 4 patients with NRG1-rearranged (9, 11). Therefore, rational targeting of ERBB3 or ERBB2 in lung cancers. After progression of disease, the same patient NRG1-rearranged tumors could be efficacious (3). with a CD74–NRG1-rearranged lung cancer described above In this article, we provide proof of principle that targeting was immediately transitioned to afatinib (40 mg daily). Repeat ERBB3 in NRG1-rearranged cancers represents a novel thera- imaging after 8 weeks of therapy revealed progressive disease, peutic paradigm. In contrast, we demonstrate that targeting with an increase in the right basilar mass and paratracheal ERBB2 is not as effective in patients in this series despite pre- lymph node, and new satellite nodules. In addition to this clinical data supporting its use and previously published clin- case, three other targeted therapy–naïve patients with NRG1- ical reports. Finally, we present large-scale genomic profiling rearranged lung cancers received afatinib at 40 mg daily, none data supporting a basket trial drug-development approach of whom responded to therapy. The clinicopathologic and for NRG1 rearrangements that extends beyond NSCLCs to molecular details of these three additional patients are sum- other cancers. marized in Supplementary Table S1. The first patient with a CD74–NRG1 fusion had a best response of stable disease at RESULTS 5 weeks (7% disease shrinkage), but frank disease progression at 13 weeks. The second patient with an SDC4–NRG1 fusion Outcomes with Targeted Therapy in Patients with had frank disease progression at 6 weeks, similar to the third NRG1-Rearranged Lung Cancers patient with a CD74–NRG1 fusion who had primary disease An 86-year-old man presented with recurrent, unresectable, progression at 8 weeks; both patients died of disease progres- advanced invasive mucinous adenocarcinoma 9 months after sion shortly after discontinuing afatinib. an initial resection and radiation for stage IIA (pT2bN0M0) disease. He was treated with carboplatin and pemetrexed, Targeted Inhibition of ERBB3/ERBB2 Results in followed by paclitaxel and bevacizumab (with a best objec- Decreased Growth of Cell Lines with Aberrant tive response of stable disease with both regimens), and NRG1 Expression finally nivolumab (with primary progressive disease). Broad, Published preclinical data on ERBB3/ERBB2 inhibition hybrid capture–based next-generation sequencing (NGS) in NRG1-altered cell lines is limited (4), and the activity using MSK-IMPACT (12) identified an in-frameCD74–NRG1 of ERBB2 inhibition with select clinically available TKIs translocation (Fig. 1A), resulting in the fusion of exons 1 to has largely been examined in cells with ectopic expression 6 of CD74 with exons 6 to 13 of NRG1; the only other altera- of CD74–NRG1 cDNA (3). We thus explored the effect of tion identified was anARID2 c.592A>T nonsense mutation. ERBB3/ERBB2 inhibition by genetic and pharmacologic The patient was enrolled in an NSCLC expansion cohort of a approaches in cell lines with endogenous NRG1 alterations. phase I trial (NCT01966445) of GSK2849330, an anti-ERBB3 We first examined the breast cancer cell line MDA-MB-175- mAb. GSK2849330 is a humanized mAb that binds with high VII, previously published to harbor a DOC4–NRG1 fusion (10, affinity to the ERBB3 domain III, where it blocks the binding 14), and confirmed the finding via RT-PCR (Fig.