Resensitization to Crizotinib via Acquisition of Lorlatinib ALK Resistance Mutation Reported in Patient With NSCLC
As reported by Shaw et al in The New England Journal of Medicine, a woman with metastatic ALK-rearranged non–small cell lung cancer (NSCLC) who had received multiple prior therapies, including the first- and second-generation ALK inhibitors crizotinib (Xalkori) and ceritinib (Zykadia), regained response to crizotinib after experiencing disease progression on the third-generation ALK inhibitor lorlatinib. The mechanism of resensitization appears to be acquisition of the lorlatinib ALK resistance mutation L1198F.
Treatment Course
The patient had an initial response to crizotinib lasting 18 months; disease progression and identification of the crizotinib C1156Y resistance mutation was followed by ceritinib treatment and subsequent heat shock protein 90 inhibitor treatment with continued disease progression. Chemotherapy with carboplatin/pemetrexed (Alimta) then produced a 6-month response; relapse was followed by crizotinib again, with no response.
The patient then received lorlatinib and exhibited a 41% reduction in tumor burden at first restaging computed tomography at 5 weeks; clinical benefit was maintained for 8 months, followed by worsening liver metastases and hepatic dysfunction and discontinuation of lorlatinib. She received a single dose of low-dose vinorelbine at 22.5 mg/m2 and had further clinical deterioration and impending liver failure over the next 5 days.
Identification of Mutant and Its Effect
Molecular testing revealed a double-mutant subclone consisting of C1156Y, which was previously detected in the post-crizotinib biopsy, and L1198F. The structure of the ALK kinase domain suggested that crizotinib could be active against the compound mutant; the findings indicated that the L1198F substitution conferred resistance to lorlatinib via steric interference with the drug, but enhanced binding to crizotinib, eliminating the effect of C1156Y and resensitizing resistant cells to crizotinib.
Restarting of crizotinib resulted in rapid and dramatic clinical improvement, with resolution of liver failure. The patient continued to receive full-dose crizotinib and also received intermittent low-dose vinorelbine, although chemotherapy was frequently interrupted, dose reduced, and finally discontinued due to neutropenia. The investigators stated that it was unlikely that vinorelbine was the cause of the dramatic recovery.
The investigators concluded: “Overall, these results suggest that detailed knowledge of structure and functional features of drug targets can be exploited in strategies for drug design and lead to clinically relevant predictions of drug activity…. [T]he 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.”
The study was funded by Pfizer, the National Cancer Institute, the National Foundation for Cancer Research, Be a Piece of the Solution, and Lungstrong.
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