Lazertinib-amivantamab combo shows superior efficacy in treating atypical EGFR-mutated lung cancer

A new clinical study conducted by Severance Hospital has demonstrated that a combination therapy of lazertinib (product name: Leclaza) and amivantamab (product name: Rybrevant) offers superior efficacy compared to lazertinib monotherapy for treating non-small cell lung cancer (NSCLC) with atypical EGFR mutations.

Approximately 30–40 percent of NSCLC patients exhibit EGFR mutations, with 90 percent of these mutations classified as L858R and exon 19 deletions. The remaining cases involve atypical EGFR mutations, including G719X, S768I, and L861Q, with some patients exhibiting multiple mutations simultaneously.

While the second-generation EGFR-targeting therapy afatinib has received FDA approval for atypical EGFR mutations, its efficacy remains limited for certain mutations, and alternative options are scarce when resistance develops. The third-generation EGFR inhibitor osimertinib has also demonstrated effectiveness, but its efficacy varies depending on the specific mutation type.

In response, the research team, led by Professors Hong Min-hee of the Division of Medical Oncology and Yun Mi-ran at Severance Biomedical Science Institute, explored a novel therapeutic approach targeting both EGFR mutations and MET alterations, a key resistance mechanism to EGFR inhibitors.

Researchers Oh Seung-yeon of the Department of Medical Science at Yonsei University College of Medicine and Park Se-won of the JEUK Institute for Cancer Research also participated in the study.

They investigated a combination of lazertinib, a third-generation EGFR inhibitor, and amivantamab, a bispecific EGFR-MET antibody, to overcome the limitations of current treatments.

Preclinical studies were conducted using mouse-derived cell lines engineered to express EGFR mutations, patient-derived organoids (PDOs), and patient-derived cells (PDCs). The combination therapy exhibited a significantly stronger tumor-suppressing effect than EGFR inhibitors alone.

In PDO experiments, researchers evaluated the half-maximal inhibitory concentration (IC50), the drug concentration required to reduce EGFR phosphorylation activity, which drives cancer growth.

The IC50 values for monotherapy and combination therapy were 19.5 nanomolar (nM) and 3 nM, respectively, indicating that the combination therapy achieved the same inhibitory effect with nearly six times lower drug concentration.

Also, cancer cell growth was arrested in the G1 phase, the preparatory stage before cell division, and the study confirmed the activation of antibody-dependent cellular cytotoxicity (ADCC), a mechanism by which immune cells target and eliminate cancer cells, using PDCs derived from patients resistant to monotherapy,

Animal studies further supported the durability of combination therapy in suppressing tumor growth. While tumor regrowth occurred immediately after discontinuing monotherapy, the combination therapy maintained tumor suppression for approximately 90 days post-treatment cessation.

The researchers noted that lazertinib enhanced the expression of target receptors, thereby boosting amivantamab’s efficacy.

In clinical applications, about 40 percent of patients experienced tumor shrinkage, and the progression-free survival (PFS) duration extended beyond 16 months—substantially longer than monotherapy outcomes.

"Combination therapy activates antibody-dependent cellular cytotoxicity, enabling immune cells to eliminate cancer cells and overcoming resistance to existing treatments," Professor Hong said. "This study not only provides supporting evidence for last year’s atypical cohort study presented at the American Society of Clinical Oncology (ASCO) but also identifies MET mutation expression levels as a potential biomarker for predicting treatment response."

The results of the research were published in Cell Reports Medicine.