Human epidermal growth factor receptor 2 (HER2) gene mutations have been detected in a range of cancers, including in approximately 2% of patients with lung adenocarcinoma. HER2 mutations are typically not associated with HER2 amplification and represent a distinct subgroup of HER2-activated lung cancer that may be missed by standard analyses of HER2 positivity based on immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). However, both HER2 mutations and amplification can be detected by next generation sequencing (NGS), a method that recently entered clinical practice. Although several studies have investigated HER2-targeted therapy in HER2-mutant patients, the results were disappointing and current standard of care is chemotherapy. Efficacy of immune checkpoint inhibitors remains to be defined for HER2-mutated lung cancer, but it seems responses are low as for other oncogene-driven tumors.
Ado-trastuzumab emtansine (T-DM1) is a HER2-targeting antibody drug conjugate (ADC) approved for the treatment of HER2-amplified or overexpressing advanced breast cancer. In a phase II basket trial, the safety and efficacy of T-DM1 (3.6 mg/kg every 3 weeks until progression) was evaluated in a cohort of 18 patients with advanced HER2-mutated lung cancer.
At a median follow-up of 10 months, the overall response rate (ORR) was 44%, all of which were partial responses. Furthermore, an additional 39% of patients achieved stable disease. The median progression-free survival (PFS) was 5 months in all patients and 6 months in responding patients. At time of data cut-off, one patient with stable disease remained in response, with a PFS of over 11 months. Four of 8 responding patients had received treatment with prior HER2-targeted therapy (neratinib or trastuzumab).
Responses were seen regardless of HER2 mutation subtype, including exon 20 insertions and point mutations in transmembrane and extracellular domains. Level of HER2 expression by IHC was not predictive of response, and mass spectrometry analysis showed that patients responded regardless of HER2 protein levels. Of note, HER2 mutant responders had low or undetectable levels of HER2 protein expression, indicating that T-DM1 is functioning through a mechanism of action independent of HER2 protein expression.
Adverse events (AEs) were generally mild and consistent with the known safety profile of T-DM1. The most common AEs of any grade included elevated liver enzymes (44%), thrombocytopenia (33%), fatigue (33%), nausea (33%), and infusion reactions (28%). No patient discontinued treatment or required dose reduction due to AEs.
The investigators concluded that these data support the activity of T-DM1 in HER2-mutated lung cancer, with a meaningful response rate and manageable toxicity profile in a cohort that included heavily pretreated patients. They emphasized a need for a comprehensive genotyping and further studies of this and other agents in HER2-mutant lung cancer.