# Germ-line exon 21 EGFR V831H mutation in advanced NSCLC resistance to almonertinib: a case report

## TL;DR

A rare germ-line EGFR V831H mutation in a lung cancer patient led to rapid resistance to almonertinib, highlighting the need for better treatment strategies for such cases.

## Contribution

This is the first reported case of primary resistance to almonertinib in a patient with a germ-line EGFR V831H mutation and co-occurring KRAS G12V.

## Key findings

- The patient showed primary resistance to almonertinib within 20 days of treatment initiation.
- Rapid disease progression and new brain metastases occurred despite therapy.
- The presence of a germ-line EGFR V831H mutation may confer inherent resistance to third-generation EGFR-TKIs.

## Abstract

Germ-line EGFR mutations are rare, and their clinical significance, particularly regarding response to tyrosine kinase inhibitors (TKIs), remains poorly defined. The EGFR V831H (also known as R831H) mutation is an exceptionally rare variant with constitutive activity, and data on its therapeutic sensitivity are scarce.

We present a detailed case report of a patient with advanced non-small cell lung cancer (NSCLC) harboring a germ-line EGFR V831H mutation. Diagnosis involved imaging, histopathology, and comprehensive genomic profiling of tumor tissue. Germ-line origin was confirmed via Sanger sequencing of normal patient tissue and a familial sample.

A 68-year-old man was diagnosed with stage IIIB lung adenocarcinoma and concurrent latent tuberculosis infection (LTBI). Next-generation sequencing of a lymph node biopsy revealed co-occurring somatic KRAS G12V and an EGFR exon 21 V831H mutation, which was subsequently identified as a germ-line variant. The patient initiated antituberculosis therapy (rifampicin and isoniazid) followed by the third-generation EGFR-TKI almonertinib (110 mg/day).

The disease demonstrated primary resistance to almonertinib, with radiological progression in thoracic lymph nodes observed within 20 days of treatment initiation. The patient died one month later with evidence of new brain metastases.

This case highlights primary resistance to the third-generation EGFR-TKI almonertinib in a patient with NSCLC harboring a germ-line EGFR V831H mutation. The rapid progression suggests that this specific germ-line variant may confer inherent TKI resistance, potentially exacerbated by the presence of a concurrent KRAS G12V mutation and drug-drug interactions between almonertinib and antituberculosis medications. It underscores the clinical challenge of germ-line EGFR mutations and emphasizes the need for further research to establish effective therapeutic strategies for such rare genotypes.