HER2 MUTATION IN NSCLC

Lung Cancer That Harbors an HER2 Mutation: Epidemiologic Characteristics and Therapeutic Perspectives

Mazières J, Peters S, Lepage B, et al
J Clin Oncol. 2013;31:1997-2003

Background

There have been many significant advances in the treatment of lung cancer over the past 5-10 years, largely motivated by the recognition of several driver mutations such as EGFR mutations and ALK and ROS rearrangements, with several other potentially relevant markers and associated targeted therapies suggested with every passing year. It is becoming increasingly possible to send for genomic profiling of tumors, which has the promise -- or peril -- of identifying a wide range of new targets that may or may not translate to effective therapies. Accordingly, we need to interpret new findings cautiously, including the one that the presence of a HER2/neu (HER2) mutation in non-small cell lung cancer (NSCLC) may represent a new clinically relevant marker with implications for treatment.

Study Summary

The report by Mazières and colleagues described the effort of a consortium of investigators in France, Switzerland, and Spain who retrospectively reviewed tumor tissue from 3800 patients with NSCLC, ranging from stage I through stage IV (though the report does not note the proportion tested in each of these stages). Within this large group, 65 (1.7%) were found to have a HER2 in-frame insertion in exon 20. The study patients were disproportionately female (45:20, 69%) and never-smokers (34, 52%), and all had an adenocarcinoma subtype. In other words, these patients had the same profile of patients most likely to have one of the already identified driver mutations, though a HER2 mutation was mutually exclusive with other mutations in all but 1 patient with a concurrent KRAS mutation.

Among the 33 patients with advanced NSCLC, 16 received a HER2-directed therapy such as trastuzumab, lapatinib, or afatinib at some point in their therapy. Clearly, this trial was born of a trend at 1 or more centers of testing for a HER2 mutation and treating with HER2-directed therapy on an individualized basis. The study looked retrospectively at HER2 mutation prevalence in a broader multicenter experience.

Of the 16 patients treated with HER2-directed therapy with or without concurrent chemotherapy, some received multiple lines with anti-HER2 therapies, so a total of 22 lines of HER2-directed therapy were evaluated. There were 11 partial responses (response rate 50%), 7 (32%) instances of stable disease, and 4 (18%) instances of progressive disease. The median progression-free survival (PFS), limited in analysis only to first-line treatment with a HER2-directed therapy, was 5.1 months.