Secondary ALK resistance mutations found in 8% of ALK-positive NSCLC samples on genomic profiling

G1202R was the most frequent resistance mutation, at 42.4%

Secondary ALK mutations were detected in 269 of the 3344 ALK-rearranged samples, or 8.0%. The panel covered mutations associated with acquired resistance to first-, second- and third-generation ALK TKIs. After G1202R, the most frequent were I1171N and L1196M, each at 14.9%.

The denominator is all ALK-positive samples in the database, and the abstract does not give the prevalence among samples known to have been collected after TKI exposure. The specimens combined tissue and liquid biopsy, and the abstract does not separate detection rates by specimen type.

A 15% rate of subsequent TKI choices that ran against the resistance profile

To look at treatment after resistance, the authors queried a US-based, de-identified clinico-genomic database derived from electronic health records. They selected patients whose specimens were collected more than 30 days after the start of an ALK TKI. Of the 33 patients included, 5 (15%) went on to receive an ALK TKI that their resistance profile contraindicated.

These five patients had a median real-world progression-free survival (rwPFS) of 4.6 months. Patients given a non-contraindicated TKI had a median rwPFS of 26.4 months. The difference did not reach conventional statistical significance (p = 0.09), and it rests on five patients in one group. The endpoint is real-world PFS, drawn from an EHR-derived database.

Off-target resistance was associated with an rwPFS of 2.7 months

Patients with off-target resistance alterations, as distinct from secondary ALK mutations, had an rwPFS of 2.7 months, which the authors describe as poor. The authors suggest that these patients may represent a poor prognostic subset that could potentially benefit from combination therapy. Which off-target alterations were found is not stated in the abstract.

“The diverse landscape of on- and off-target ALK acquired resistance and variability of post-TKI treatment patterns highlight the importance of repeat NGS testing at progression.”Hofman et al., npj Precision Oncology (2026)

Sequencing at progression as the basis for choosing the next ALK inhibitor

ALK rearrangements predict response to ALK TKIs, but resistance develops in nearly all tumours, and drugs have been designed to overcome specific secondary ALK mutations. The authors’ case for repeat NGS at progression follows from both halves of the study: the spread of mutations seen across a large genomic database, and the small treatment cohort in which a mismatched TKI was given.

The treatment analysis was drawn from a de-identified records database rather than a trial. With 33 patients and a p value of 0.09, it describes an association and cannot establish that matching the TKI to the mutation caused the longer rwPFS.