A retrospective analysis suggests that patients with NSCLC who harbour specific HER2 mutations may benefit from certain anti-HER2 treatments

The largest study to date to explore the effect of anti-HER2 drugs among patients with these rare mutations who had already completed standard initial chemotherapy

New results from a retrospective study conducted in Europe suggest that anti-HER2 treatments have anti-cancer effects in a small subset of patients with advanced non-small cell lung cancer (NSCLC) harbouring specific HER2 protein mutations. Although genetic changes cause tumour cells to make too much of the HER2 protein in up to 20% of lung cancers, mutations in the HER2 gene occur in only 1-2% of cases. Such mutations in the HER2 gene lead to continuous activation of the protein, which keeps tumour cells alive and stimulates their growth. This is the largest study to date to explore the effect of anti-HER2 drugs among patients with these rare mutations who had already completed standard initial chemotherapy. The findings, published April 22 in the Journal of Clinical Oncology, suggest that HER2 testing to identify patients who might benefit from such treatments may be worthwhile.

According to lead study author, Dr Julien Mazières, professor of pulmonology at Larrey Hospital in Toulouse, France, while the observed benefit in this retrospective analysis still needs to be confirmed in a prospective clinical trial, the researchers hope that, based on their and other studies, HER2 status will be taken into account when making treatment decisions. In recent years, growing knowledge about the molecular basis of lung cancer has launched an era of personalised medicine, which offers the promise of better patient outcomes by tailoring treatments to key genetic mutations in each patient's tumour. These key mutations are known as "driver mutations," because they trigger and fuel tumour growth.

HER2 is a promising treatment target because a number of anti-HER2 drugs (e.g., trastuzumab, pertuzumab, lapatinib) are already approved to treat other types of cancer. Early studies in patients with lung tumours that make abnormal amounts of HER2, due to extra copies of the HER2 gene, showed minimal benefit from anti-HER2 treatment. But there has been little research on the benefit of such treatments in patients with the HER2 mutations what was a subject explored in this study.

In this study conducted in France, Switzerland, and Spain and which represents a consecutive series of all identified patients carrying a HER2 mutation in exon 20 in the participating centres, the researchers retrospectively identified HER2 mutation in 65 (1.7%) of 3,800 patients tested. It was almost an exclusive driver, except for one single case with a concomitant KRAS mutation. The researchers then collected and analysed clinico-pathologic characteristics, patients' outcomes, and treatments.

Their population presented with a median age of 60 years (range: 31-86), a high proportion of women (69%), and a high proportion of never-smokers (52.3%). All tumours were adenocarcinomas and 50% were stage IV at diagnosis. For these latter cases, 22 anti-HER2 treatments were administered after conventional chemotherapy in 16 patients. These 16 patients (all with stage IV and prior therapy which consisted of platinum-based doublet with or without bevacizumab) were treated with one or more anti-HER2 drugs – afatinib, trastuzumab, lapatinib, and masatinib. Trastuzumab was always used in combination with chemotherapy (carboplatin, paclitaxel, vinorelbin, or docetaxel), whereas the other three anti-HER2 agents were given as monotherapy.

Four of treated patients experienced progressive disease, seven experienced disease stabilizations, and 11 experienced partial responses (overall response rate: 50%; disease-control rate: 82%). Specifically, the researchers observed a disease-control rate of 93% for trastuzumab-based therapies and of 100% for afatinib, but no response recorded to other HER2-targeted drugs. Progression-free survival for patients with HER2 therapies was 5.1 months, about twice as much as typically seen in patients who undergo two or three rounds of conventional chemotherapy. Median survival was of 89.6 and 22.9 months for early-stage and stage IV patients, respectively.

Therapeutic perspective

Although HER2 mutations occur in only 2% of cases and confirmatory data are certainly needed, it appeared that HER2 mutations represent another 'druggable' target, and anti-HER2 drugs are already available and may be a reasonable treatment option for patients who harbour these mutations.

At recently held ESMO Signalling Pathways Symposium, first in the ESMO series of personalised medicine meetings entitled “Targeting the HER/EGFR family: Focus on breast, lung and colorectal cancers” (1-2 March 2013, Sitges, Spain), Dr Solange Peters of the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, who contributed to this article equally with Prof. Mazières, summarized a clinical perspective of testing and targeting HER2 in NSCLC.

Dr Peters said that HER2 mutated NSCLC represent a small distinct subgroup of oncogene addicted cancers with specific demographics and potentially outcomes. Prognostic features related to HER2 mutations remain to be studied in large cohorts of patients. NSCLC patients with mutated HER2 are mainly female, non-smokers, exclusively suffering from adenocarcinoma subtype. In the current study the researchers identified also some men and heavy smokers (up to 60 packs/year), a finding that suggest that HER2 testing should not be restricted to clinically defined subgroups.

Furthermore, Dr Peters stressed that trastuzumab is currently tested as a single agent in patients with HER2-immunohistochemistry positive, HER2-mutated or HER2-amplified NSCLC (NCT00004883 and NCT00758134), as well as in combination with carboplatin and paclitaxel. Pertuzumab is currently tested in a phase II trial in patients with advanced, pretreated NSCLC (NCT00063154). The relative efficacy of trastuzumab, as well as afatinib, clearly deserves prospective evaluation in larger prospective international clinical trials. Such a prospective phase II trial is currently under preparation within the European Thoracic Oncology Platform in collaboration with large European, national collaborative groups.

In this article, the authors published results of the largest series to date of patients with NSCLC and HER2 mutations. Despite the limitations of the retrospective analysis, it provides important insights into HER2-driven NSCLC. Furthermore, this largest dedicated study to HER2-mutated NSCLC reinforces the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.

Trastuzumab, lapatinib, and pertuzumab are approved for the treatment of HER2-overexpressed breast cancer. Trastuzumab is also approved in the treatment of metastatic, HER2-overexpressed gastric cancer. However, afatanib and masatinib are not approved for any indication yet. In January afatinib was granted priority review by FDA for treatment of patients with advanced NSCLC harbouring EGFR (HER1) mutations. Prof. Mazières projects that in about one or two years data from more patients will be available to validate the use of anti-HER2 drugs in this patient population.