Abstract A167: Targeting HER2 (ERBB2) amplification identified by next-generation sequencing (NGS) in patients with advanced or metastatic solid tumors
Authors: Ileana Dumbrava Ecaterina , Balaji Kavitha , Raghav Kanwal , Javle Milind , Blum-Murphy Mariela , Sajan Blessy , Kopetz Scott , Broaddus Russell , Routbort Mark , Pant Shubham , Tsimberidou Apostolia , Subbiah Vivek , Hong David S. , Rodon Ahnert Jordi , Shaw Kenna , Piha-Paul Sarina , Meric-Bernstam Funda 
Published: August 2018

Introduction: Personalized cancer treatment is becoming more tumor agnostic by choosing a treatment based on the tumor genomics rather than the tumor type. HER2 is an effective therapeutic target with FDA-approved treatments in breast and gastric/gastroesophageal junction (GEJ) cancers; however, less is known about the efficacy of HER2-targeted treatment in other tumor types. Methods: Next-generation sequencing (NGS) was performed in 2221 patients (pts) with advanced solid tumors in CLIA-certified laboratories using multiple platforms for personalized cancer therapy. HER2 amplification (amp) was assessed by NGS platforms that report copy-number variations as per their respective algorithm. We assessed clinical characteristics and coalterations with HER2 amp. We evaluated the clinical benefit of HER2-targeted therapy, by measuring the progression-free survival (PFS) on HER2-matched targeted therapy (PFS2) compared to the PFS on prior therapy (PFS1). We also evaluated the response rate and overall survival (OS) of pts who received vs pts who did not receive HER2-targeted therapy. Results: A total of 122 pts (5.5%) were found to have HER2 amp. The most frequent tumor types were colorectal, biliary/gallbladder, gastric/gastroesophageal, esophageal, endometrial, head and neck squamous cell and salivary gland, non-small cell lung, and bladder cancers. Coalterations included mutations in TP53, APC, PIK3CA, LRP1B, NF1, KRAS, mutations and deletions in CDKN2A, and amp in MYC and CCNE1. Frequent amp in CDK12, RARA, and TOP2A amp (all within chromosome 17q) were also found in our pts. Concurrent mutations in HER2 were found in 16 pts (13%). Forty pts with HER2 amp on NGS also underwent HER2 IHC testing: 30 pts (75%) had overexpression (3+), 4 pts (10%) had equivocal expression (2+), 2 pts (5%) had low expression (1+), and 4 pts (10%) had no HER2 expression. FISH analysis was performed in 14 patients, out of which 12 patients were positive for amplification. Forty-four of 115 pts received at least 1 line of HER2-targeted therapy (range 1-4) with 42 pts receiving trastuzumab in combination with other drugs, including 11 (92%) of 12 pts with gastric, GEJ cancers with HER2 amp having received trastuzumab with chemotherapy (8 pts in the first line). Median OS of pts who received HER2-targeted therapy was 42 months vs 23 months for pts who did not receive HER2-targeted therapy (Hazard Ratio [HR] 0.6, 95% CI 0.38-0.97, p=0.0384). For 32 evaluable pts, PFS2/PFS1 ratio was ≥1.3 in 17 pts (53%) and ≥2 in 11 pts (34%) with median PFS2 of 23 weeks vs PFS1 of 11 weeks (p=0.0089). After exclusion of pts with gastric or GEJ cancers, pts receiving HER2-targeted therapy still had an improved OS (53 vs 23 months) (HR 0.56, 95% CI 0.33-0.93, p=0.0307) and the PFS2/PFS1 ratio was ≥1.3 in 15 (52%) of 29 pts with a median PFS2 of 23 weeks vs PFS1 of 12 weeks (p=0.0174). Conclusion: NGS reveals HER2 amp in a clinically relevant proportion of tumors and in a variety of tumor types. HER2-targeted therapy may confer clinical benefit in tumor types beyond those for which HER2 inhibitors are approved. The association of HER2 amp with genomic alterations in other oncogenic drivers provides rationale for novel therapeutic combinations.

Citation Format: Ecaterina Ileana Dumbrava, Kavitha Balaji, Kanwal Raghav, Milind Javle, Mariela Blum-Murphy, Blessy Sajan, Scott Kopetz, Russell Broaddus, Mark Routbort, Shubham Pant, Apostolia Tsimberidou, Vivek Subbiah, David S. Hong, Jordi Rodon Ahnert, Kenna Shaw, Sarina Piha-Paul, Funda Meric-Bernstam. Targeting HER2 (ERBB2) amplification identified by next-generation sequencing (NGS) in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A167.