ALK resistance mutations predict lorlatinib efficacy in NSCLC patients progressing on ALK–TKIs
medwireNews: Lorlatinib is more efficacious against non-small-cell lung cancer (NSCLC) with versus without ALK resistance mutations in patients with disease progression after at least one second-generation ALK–tyrosine kinase inhibitor (TKI), suggests research.
Among 139 participants of the registrational phase II study of lorlatinib with ALK translocation-positive NSCLC who had failed to respond to at least one second-generation ALK–TKI, the objective response rate was 40%.
But when Alice Shaw (Massachusetts General Hospital, Boston, USA) and co-researchers compared this rate between the 34 patients with a detectable ALK resistance mutation on plasma genotyping and the 94 without such a mutation, the objective response rate was significantly better for the former group, at 62% versus 32%.The results were similar when mutation status was determined using tissue genotyping, with rates of 69% versus 27%.
Median progression-free survival was also significantly longer in those with ALK mutations on tissue, but not plasma, genotyping, at 11.0 versus 5.4 months, as was duration of response (24.4 vs 4.3 months).
“These data suggest that, in patients who have failed a second-generation ALK TKI, ALK mutations may identify tumors with continued ALK dependency, making them more likely to respond to lorlatinib,” say the researchers in the Journal of Clinical Oncology.
“The absence of an ALK mutation suggests that tumors may have developed ALK-independent mechanisms of resistance, making them less likely to respond to ALK inhibition.”
The team adds that the different results with respect to plasma and tissue genotyping may reflect the current limitations of plasma genotyping.
With this in mind, Shaw and colleagues recommend considering tumor biopsy and genotyping for those without a sensitizing mutation identified in plasma, but they concede that “the absence of ALK mutations, in some cases, may be helpful in estimating the likelihood of response but should not be used to exclude patients from treatment with lorlatinib.”
In contrast to these results in patients with progression after a second-generation ALK–TKI, the 59 patients in the study who had previously been treated with crizotinib had a good objective response to lorlatinib, at around 73%, regardless of ALK mutation status.
“Thus, in patients who have received prior crizotinib as their only ALK TKI, lorlatinib is highly effective regardless of the presence or absence of detectable ALK mutations,” the researchers conclude.
By Catherine Booth
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