Targeting HER2 Alterations in Non–Small-Cell Lung Cancer

A Comprehensive Review

Jing Zhao, MD; Yang Xia, MD, PhD


JCO Precis Oncol. 2020;4:411-425. 

In This Article


Although abnormalities in ERBB2 have been recognized as drivers in the development of NSCLC,[11] their explicit roles are still unclear. First, the associations among the three types of alterations (HER2 amplification and mutation and HER2 overexpression) are ambiguous, which highlights that HER2 alternations in lung cancer are far more complicated than in breast cancer. This may explain why trials targeting HER2-altered NSCLC have had disappointing results. However, compared with HER2 amplification or overexpression, HER2 mutations, especially HER2 exon 20 mutations, are emerging as the most clear targetable driver for HER2-directed therapies in lung cancer. It is reasonable to reconsider modifying the treatment recommendations for lung cancers with HER2 alterations, separate from those for breast cancer.

Second, on the basis of the intricate impact of HER2 aberrations on the therapeutic effects of TKIs, the EGFR mutation status may also be a critical issue. Patients with HER2 alterations who harbor or do not harbor EGFR mutations and who are TKI naïve or show TKI acquired resistance need to be managed differently. Additional clinical studies should explicitly study groups of these patients.

Finally, given the limited effectiveness of anti-HER2 target therapy, additional investigations with new strategies are needed. A combination of agents with different mechanisms might exhibit synergistic effects. A dual anti-HER2 targeted therapy with trastuzumab plus pertuzumab is now under evaluation in a clinical trial ( identifier: NCT03845270). Combination of ADCs and checkpoint inhibitors may also be advantageous. T-DM1 as well as several other ADCs conjugated with anthracycline derivatives, tubulysin, or pyrrolobenzodiazepine dimer (PBD) have shown immunomodulatory effects and synergy with checkpoint inhibitors in animal models.[92–94] Preclinical data have shown that DS-8201a increases T-cell activity and upregulates PD-L1 expression. In addition, the combination of DS-8201a and an anti–PD-1 antibody showed a more pronounced effect than either of the monotherapies,[95] which might lead to a potent regimen.