3rd-gen TKI proven effective in treatment-resistant EGFR-mutant lung cancer with brain metastasis: study

A clinical study has confirmed the efficacy of the third-generation tyrosine kinase inhibitor (TKI), lazertinib, in patients with metastatic EGFR-variant non-small cell lung cancer (NSCLC) with brain metastases, who had previously failed to respond to conventional treatments.

Professors Kim Hye-ryun and Hong Min-hee from Yonsei Cancer Center at Severance Hospital, along with Kang Jin-hyoung from Seoul St. Mary’s Hospital, Choi Yoon-ji from Korea University Anam Hospital, and Ahn Hee-kyung from Gachon University Gil Medical Center, said on Aug. 19 that 55.3 percent of the patients treated with lazertinib demonstrated a significant reduction in brain tumors. 

The study, led by the Korean Cancer Study Group (KCSG), involved multiple institutions, including Yonsei Cancer Center, Seoul St. Mary’s Hospital, Seoul National University Hospital, and Seoul National University Bundang Hospital.

EGFR mutations, frequently observed in NSCLC, activate signaling pathways that promote tumor growth. Tyrosine kinase, a key enzyme in this signaling process, becomes the target of TKIs. However, brain metastases present a major treatment challenge due to the blood-brain barrier (BBB), which limits the effectiveness of earlier generations of TKIs. 

In this context, third-generation TKIs like lazertinib provide a potential treatment option for patients with central nervous system (CNS) metastases.

The study enrolled 40 patients who had failed previous treatment with first and second-generation TKIs, such as gefitinib, erlotinib, or afatinib. Lazertinib demonstrated substantial CNS activity in these patients, showing a 55.3 percent intracranial objective response rate (ORR), including those with leptomeningeal metastases. 

Patients with the T790M mutation—a common cause of resistance to earlier therapies—achieved an 80 percent ORR, while those without the mutation saw a response rate of 42.9 percent.

The progression-free survival (PFS) for all patients was 15.8 months, with no significant differences between T790M-positive and negative groups, which had PFS periods of 15.2 and 15.4 months, respectively. Adverse effects were mild, confirming the drug’s safety profile.

Professor Kim said, “This study demonstrates lazertinib's potential as a new treatment strategy for EGFR-positive NSCLC patients with brain metastases, regardless of T790M mutation status." 

The full study detailing these findings is published in JAMA Oncology (Impact Factor 28.4).