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Updated: Dec 22, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Patients with NSCLCs Harboring Internal Inversions or Deletion Rearrangements of the ALK Gene Have Durable Responses
Alexa B Schrock1, Russell Madison1, Mark Rosenzweig2
1Foundation Medicine, Department of Clinical Development, Cambridge, MA, USA.
Background:
ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors.
Methods:
Comprehensive genomic profiling (CGP) of DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians.
Results:
We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing identified an EML4-ALK fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an ALK internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that ALK internal deletions removing a portion of the N-terminus are drivers themselves and do not result in ALK fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events.
Conclusion:
Rare internal inversions of ALK appear to be indicative of ALK fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, ALK internal deletions are not associated with ALK fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.
Insights
Rare ALK rearrangements in non-small cell lung cancer (NSCLC) can predict response to ALK inhibitors. Internal inversions indicate ALK fusions, while internal deletions represent distinct targetable drivers, guiding therapy selection.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- Anaplastic lymphoma kinase (ALK) fusions are established drivers in non-small cell lung cancer (NSCLC).
- Patients with NSCLC and ALK rearrangements lacking identified DNA fusion partners also exhibit sensitivity to ALK inhibitors.
- Complex ALK variants require characterization to predict response to ALK-targeted therapies.
Purpose of the Study:
- To characterize complex ALK variants in NSCLC.
- To investigate the association between specific ALK rearrangements and response to ALK inhibitors.
- To identify novel predictive biomarkers for ALK-targeted therapy.
Main Methods:
- Comprehensive genomic profiling (CGP) of DNA from tumor tissue or ctDNA in 39,159 NSCLC patients.
- RNA sequencing for a subset of cases to confirm fusions.
- Clinical data collection from treating physicians regarding treatment and response.
Main Results:
- ALK internal inversions (0.02%) and internal deletions (0.01%) were identified as sole ALK rearrangements.
- Internal inversions were associated with EML4-ALK fusions and durable responses to ALK inhibitors.
- ALK internal deletions, distinct from fusions, likely represent targetable drivers, with one patient responding to multiple ALK inhibitors.
Conclusions:
- Rare ALK internal inversions in DNA suggest ALK fusions detectable by RNA, predicting response to ALK inhibitors.
- ALK internal deletions are not associated with ALK fusions but are likely targetable drivers themselves.
- Supplementing DNA-based CGP with RNA or IHC testing is crucial for precise event resolution and patient stratification for effective therapies.
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