Pulse Afatinib for ERBB2 Exon 20 Insertion-Mutated Lung Adenocarcinomas

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Genomic aberrations of the ERBB2 gene are key drivers in ~2% of lung adenocarcinomas.
• Standard daily dosing of ERBB2 tyrosine kinase inhibitors (TKIs), like afatinib, has shown limited efficacy and significant toxicity.
• Achieving effective plasma concentrations with daily dosing has been a challenge for ERBB2 TKIs.

Purpose of the Study:

• To investigate alternative dosing strategies for ERBB2 tyrosine kinase inhibitors (TKIs) to improve tolerability and efficacy.
• To evaluate the toxicity and response of pulse afatinib in lung cancers with ERBB2 mutations.
• To explore the potential of weekly dosing for ERBB2-mutated lung adenocarcinomas.

Main Methods:

• Lung cancer cell lines were profiled against TKIs.
• Retrospective evaluation of toxicity and response to pulse afatinib (280 mg once weekly).
• Analysis of patients with advanced ERBB2-mutated lung adenocarcinomas treated with off-label pulse afatinib.

Main Results:

• An ERBB2 exon 20 insertion-mutated cell line showed a higher 50% inhibitory concentration for afatinib than achieved with daily dosing.
• Pulse afatinib (280 mg weekly) was well-tolerated in three patients, with no rash and minimal diarrhea.
• One patient achieved a partial response for 5 months, and another had stable disease for 11 months.

Conclusions:

• Weekly pulse afatinib demonstrated antitumor activity in ERBB2 exon 20 insertion-mutated lung adenocarcinomas.
• Alternative dosing schemes for ERBB2 TKIs warrant further investigation in clinical trials.
• Future research should explore ERBB2 TKI monotherapy or combination therapies for ERBB2-mutated tumors.