HER2 Expression Contributes to NSCLC Drug Resistance

By: JNCCN 360 Staff
Posted: Thursday, July 24, 2025

HER2-directed therapy with a tyrosine kinase inhibitor yielded a favorable response when a patient progressed after first-line amivantamab-lazertinib therapy.

HER2 amplification may drive resistance to first-line amivantamab-lazertinib combination therapy in patients with EGFR-mutant non-small cell lung cancer (NSCLC), according to a new preclinical study that was presented at the 2025 AACR Annual Meeting in Chicago. These findings may offer a potential path to targeted interventions for drug-tolerant persisters (DTPs).

In 2024, the FDA approved the combination of amivantamab (a bispecific antibody that targets EGFR and MET) and lazertinib (a third-generation EGFR tyrosine kinase inhibitor) as a first-line therapy for EGFR-mutant NSCLC, based on the MARIPOSA trial. This regimen demonstrated superior progression-free survival compared to osimertinib monotherapy. Despite this advance, the authors noted, mechanisms of acquired resistance, particularly involving DTPs, are not well understood.

The researchers used a patient-derived xenograft (PDX) model created from a treatment-naive tumor with an EGFR exon 19 deletion. Tumor-bearing mice were treated with amivantamab-lazertinib for 10 days, followed by comprehensive multiomics analyses including whole-exome sequencing (WES), bulk and single-cell RNA sequencing (RNA-seq, scRNA-seq), and immunohistochemistry (IHC). A subset of mice was monitored for 30 days after treatment discontinuation to evaluate tumor regrowth and molecular remodeling. 

Key Findings

• WES identified HER2 (ERBB2) amplification in 60% of tumors at 30 days posttreatment (n = 6), compared with controls.
• ERBB2 mRNA levels were significantly increased in both 10-day and 30-day treatment groups. HER2 IHC confirmed protein overexpression at both timepoints.
• DTP clusters exhibited elevated ERBB2 signaling and activation of epigenetic regulators, including histone modification pathways. In later-stage tumors, HER2 signaling was also found to mediate interactions between cancer-associated fibroblasts and tumor cells.
• HER2 expression was significantly induced only by the combination of amivantamab and lazertinib, not by either agent alone.
• A patient who progressed following first-line amivantamab-lazertinib therapy was found to have HER2 amplification (copy number >10). HER2-directed therapy with a tyrosine kinase inhibitor yielded a favorable response, which further validated the preclinical findings.

The researchers concluded that HER2 signaling plays a key role in contributing to drug resistance in EGFR-mutant NSCLC treated with amivantamab and lazertinib. “Our results suggest that targeting the HER2 axis may represent a viable therapeutic strategy for patients who progress following amivantamab-lazertinib combination therapy,” they wrote.

AACR 2025 Annual Meeting

---