Lung Adenocarcinoma With HER2 Mutations

Results from the European EUHER2 cohort in patients treated with chemotherapy and HER2-targeted drugs

HER2 mutations have been identified as oncogenic drivers in lung cancers and are found in 1-2% of lung adenocarcinomas. However, there is no standard of care for these patients. A retrospective EUHER2 cohort series shows chemosensitivity of HER2-driven non-small cell lung cancer (NSCLC) and the potential interest for HER2-targeted agents, according to results published on 23 November 2015 in the Annals of Oncology.

In a study background, the authors explained that tyrosine-kinase inhibitors have been approved for the treatment of advanced NSCLC with EGFR mutations or ALK translocations. Other actionable genetic alterations are also known in NSCLC, including MET and FGFR1 amplification, PIK3CA, AKT, KRAS, NRAS, BRAF, and HER2 mutations, as well as RET and ROS1 rearrangements. Drugs that target these alterations are currently being investigated in clinical trials.

HER2 mutations are found in 1-2% of lung adenocarcinomas. Some case reports and very few clinical trials have been reported for this patient population and all suggest that anti-HER2 drugs such as afatinib, dacomitinib, neratinib and trastuzumab can be associated with tumour response.

Large biomarker screening programmes, such as the French National Programme or the US Lung Cancer Mutation Consortium propose systematic testing for HER2 mutations. Therefore, the EUHER2 authors aimed to launch the study to provide further insights into the management of these patients by analysing the largest cohort to date (101 treated patients), particularly for the response to conventional chemotherapy and to HER2-targeted drugs. They anticipated that their findings might help to orient future clinical trials in this population.

The study was conducted in 38 centers from France, Switzerland, Spain, Italy, Poland, Portugal, and the Netherlands. Eligible patients had advanced NSCLC with an exon 20 HER2 mutation/insertion, had undergone at least one line of systemic anticancer treatment, and had received an adequate follow-up that included documented evaluation of the tumour (CT-scan every 2 or 3 months).

Clinical and pathological data were collected from each patient by the treating physician. Data were de-identified at the local institution, and then collected and centralised by the study coordinator at the coordinating center in Toulouse, France.

Histology was assessed by experienced local pathologists using WHO criteria and the last International Association for the Study of Lung Cancer classification. Clinico-pathological stage was assigned locally according to the 7th Tumour-Node Metastasis classification.

Responses were defined as the best response from the start of treatment until disease progression according to RECIST version 1.1 criteria.

Median age was 61 years (range: 30–87), 62.4% patients were women, 60.4% were never smokers. All tumours were adenocarcinomas.

Concomitant EGFR mutations, ALK translocations, and ROS translocations were observed in 5, 1, and 1 patients, respectively.

Median number of treatment lines was three (range: 1–11).

Median overall survival was 24 months. Overall response rate and median progression-free survival (PFS) with conventional chemotherapy (excluding targeted therapies) were 43.5% and 6 months in first-line, and 10% and 4.3 months in second-line therapies.

Sixty-five patients received at least one HER2-targeted drug, of which 47 received one line, 14 patients two lines, and four patients more than two lines of anti-HER2 drugs. Overall, 88 targeted treatments against HER2 were given and evaluated, including trastuzumab (57), trastuzumab emtansine - T-DM1 (1), neratinib (14), afatinib (11), and lapatinib (5).

Response rate (RR), disease control rate (DCR), and PFS were 50%, 75%, and 5.1 months, respectively, for trastuzumab in combination with chemotherapy. Chemotherapy included vinorelbine (24), docetaxel (12), paclitaxel (12), cisplatin (7), whereas 2 patients had trastuzumab alone.

The RR, DCR, and PFS were 18.2%, 63.7%, and 3.9 months, respectively, for afatinib.

Patients receiving neratinib were included in a clinical trial (PUMA-NER). Preliminary results have been reported, and the final results are awaited.

Lapatinib was prescribed to 5 patients in third- or fourth-line, all 5 patients had progressive disease when the first response assessment was made.

One patient had a rapid response to T-DM1.

Putting together the results of trastuzumab-based treatment and T-DM1, the authors observed a RR of 50.9% and a PFS of 4.8 months.


J. Mazieres, F. Barlesi, T. Filleron, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: Results from the European EUHER2 cohort. Ann Oncol 2015; First published online November 23. doi: 10.1093/annonc/mdv573