Inhibition of HER2 driver mutations can confer benefits

Amplification or overexpression of HER2 (ErbB2) has been identified in NSCLC, and somatic HER2 mutations occur in approximately 2 % to 4 % of patients [1, 2]. Response to chemotherapy is poor in the setting of HER2-mutant advanced NSCLC [3]. Similarly, single-agent pan-HER inhibitors appear to have only limited benefit, with rare and short-lived responses [4, 5].

Neratinib plus temsirolimus

Dual pathway inhibition represents a potential treatment approach here. The HER2/ EGFR-inhibiting TKI neratinib and the mTOR inhibitor temsirolimus have synergistic effects, according to preclinical data [4] and a phase I study [5]. Therefore, an international, randomised phase II trial tested neratinib 240 mg OD with and without temsirolimus 8 mg/week in 60 patients with advanced or metastatic HER2-mutated NSCLC [6]. Each arm was evaluated independently, as single-agent neratinib had not been specifically assessed in lung cancer before.

This inhibition of both the HER2 and the PI3K pathways induced some activity that was superior to HER2 pathway block alone. Neratinib plus temsirolimus treatment gave rise to median PFS of 4.0 months (vs. 2.9 months with single-agent neratinib) and median OS of 15.1 months (vs. 10.0 months). Fourteen percent of the patients achieved responses with the combination (vs. 0 %). Here, one patient obtained complete remission (2 %), and five showed partial remission (12 %). The most common toxicity was diarrhoea, but this was manageable with upfront loperamide prophylaxis.
According to the analysis of the distribution of somatic HER2 mutations and best response to therapy, mutation-specific responses did not occur; occasional responses were observed across multiple HER2 variants. As some patients had prolonged responses of > 1 year, the search for predictive biomarkers is ongoing.

Promising results with pyrotinib

The novel oral TKI pyrotinib targets the binding of ATP to HER2 and EGFR in an irreversible manner. Encouraging preliminary findings from an open-label, single-arm phase II trial were presented at the WCLC [7]. This study assessed pyrotinib 400 mg OD in 11 patients with advanced, HER2-positive NSCLC after at least one chemotherapy regimen.

Partial responses were achieved in six patients (54.5 %), and three patients (27.3 %) experienced disease stabilisation (Figure). The median PFS was 6.2 months, while OS had not been reached at the time of analysis, when five patients were still on treatment. Diarrhoea, fatigue and rash were the most common AEs, but all of these were grades 1 or 2. A multi-centre, large-scale phase II clinical trial will be conducted to validate these results.

Moreover, a single-arm, open-label, multi-centre phase II trial is currently testing the ErbB family blocker afatinib in patients with advanced HER2-mutation-positive NSCLC, as a single agent and in combination with paclitaxel after failure of platinum-based chemotherapy [8]. Afatinib has demonstrated preclinical activity in HER2-mutant lung cancer models and has also shown clinical activity in patients with HER2-mutant NSCLC [2, 9].

Figure: Responses to pyrotinib in 11 patients with advanced, HER2-positive NSCLC