Lorlatinib Resistance Mutation Returns Crizotinib Sensitivity To NSCLC Patient

Changes in sensitivity to crizotinib and lorlatinib in a non-small-cell lung cancer patient reflect expression of a novel anaplastic lymphoma kinase resistance mutation

medwireNews: A patient with anaplastic lymphoma kinase (ALK)-rearranged, metastatic non-small-cell lung cancer has regained sensitivity to crizotinib after the tumour relapsed following sequential lorlatinib treatment, researchers say.

The case study, reported in The New England Journal of Medicine, tracks the mutational status of the 52-year-old woman through treatment with the first-generation ALK crizotinib and – after the development of the ALKC1156Y resistance mutation and failed attempts with the second-generation inhibitor ceritinib, chemotherapy and further crizotinib – with the third-generation inhibitor lorlatinib.

The patient received lorlatinib, a reversible ALK inhibitor that targets leucine at position 1198 in the ALK tyrosine kinase domain, as part of a phase I trial, say Alice Shaw, at Massachusetts General Hospital in Boston, USA, and co-authors.

After 5 weeks of treatment, restaging computed tomography (CT) showed a 41% reduction in tumour burden and the patient continued to do well until 8 months later when her liver metastases progressed. Lorlatinib was discontinued after the patient developed worsening hepatic dysfunction and she was treated with low-dose vinorelbine.

Molecular analysis demonstrated the presence of the double ALKresistance mutation ALKC1156Y–L1198F in the lorlatinib-resistant tumour sample. And the fraction of tumour cells with ALKC1156Y mutation had varied over the patient’s progress, from less than 7% before treatment, to 50% after developing crizotinib resistance and 100% in the lorlatinib-resistant sample.

The team suggests that a minor subclone harbouring C1156Y existed before crizotinib treatment, became enriched during treatment with the drug and then acquired the L1198F mutation under selective pressure from lorlatinib treatment.

Hypothesising that crizotinib could have activity against the ALKL1198F clone, the clinicians restarted crizotinib treatment and the patient experienced a “rapid and dramatic clinical improvement, with resolution of her liver failure”, the researchers report.

Serial CT restaging confirmed a “clinically significant radiologic response that lasted almost 6 months”, they add.

Molecular analysis indicated that L1198F was no longer detectable after the second crizotinib response, “consistent with effective suppression of the C1156Y–L1198F subclone by crizotinib”, the authors say.

Structural analysis confirmed that both the L1198F mutation and the double mutation reduced the binding affinity of lorlatinib to the ALK kinase domain but increased affinity for crizotinib, which the investigators believe suggests that “alterations in drug binding […] are probably the primary mechanism underlying resistance of C1156Y–L1198F to lorlatinib and sensitivity to crizotinib.”

Alice Shaw et al conclude: “These results highlight the clinical usefulness of developing multiple, structurally distinct inhibitors that target the same oncogenic kinase. When resistance develops to one inhibitor, repeat biopsy can provide critical information as to whether sequential therapy with a different inhibitor may be effective.

“Over the course of disease, serial repeat biopsies, as performed in this patient, can not only provide clinically relevant insights but can also offer an invaluable glimpse into the longitudinal evolution of cancer.”


Shaw AT, Friboulet L, Leshchiner I,et al. Resensitization to crizotinib by the lorlatinibALKresistance mutation L1198F. N Engl J Med 2016;374:54-61.DOI: 10.1056/NEJMoa1508887

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