# Anaplastic Lymphoma Kinase (ALK) Fusion as a Resistance Mechanism to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors With Complete Response After Osimertinib and Alectinib: A Case Report and Literature Review

## TL;DR

A rare resistance mechanism to EGFR inhibitors in lung cancer involves ALK fusion, which can be effectively treated with a combination of targeted therapies.

## Contribution

This case report and literature review highlight ALK fusion as a treatable resistance mechanism to EGFR TKIs in NSCLC.

## Key findings

- ALK fusion was identified in 16 cases as a resistance mechanism to EGFR TKIs, with EML4::ALK being the most common variant.
- Combination therapy with EGFR and ALK TKIs showed a 66.7% objective response rate with good tolerability.
- CNS involvement was common in these cases, and molecular profiling at progression is essential for identifying this resistance mechanism.

## Abstract

Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remains a significant challenge in the management of EGFR-mutant non-small-cell lung cancer (NSCLC). While EGFR T790M mutation and MET amplification are well-established resistance mechanisms, the development of secondary oncogenic fusions such as anaplastic lymphoma kinase (ALK) rearrangements is rare but clinically actionable.

We report a 62-year-old male with EGFR exon 19 deletion-positive NSCLC who initially responded to osimertinib but developed progressive brain metastasis after 13 months of treatment. Next-generation sequencing of the brain metastasis revealed an acquired EML4::ALK fusion while maintaining the original EGFR exon 19 deletion. The patient was treated with a combination of osimertinib and alectinib, achieving a complete response that has been sustained for 12 months without significant toxicity.

Literature review identified 16 reported cases of ALK fusion as a resistance mechanism to EGFR TKIs. The median time to development of ALK fusion resistance was 16 months (range: 6-34 months). Most patients (75%) developed secondary ALK fusion after osimertinib exposure. EML4::ALK was the most common fusion variant (68.8%), though this population showed enrichment for uncommon ALK fusion partners compared to de novo ALK-positive NSCLC. Central nervous system involvement was common (33% of cases). Combination EGFR and ALK TKI therapy demonstrated an objective response rate of 66.7% with good tolerability.

Secondary ALK fusion represents a rare but important resistance mechanism to EGFR TKIs that can be effectively treated with combination targeted therapy. This is particularly clinically relevant as treatment with dual EGFR and ALK TKI has a high response rate with low toxicity in an otherwise treatment-refractory population with poor survival. Comprehensive molecular profiling at progression is essential for identifying this actionable resistance mechanism.