Resensitization to Crizotinib in ALK-Mutated Lung Cancer: A Case Study

Summary and Comment |
January 21, 2016

Resensitization to Crizotinib in ALK-Mutated Lung Cancer: A Case Study

  1. Anne S. Tsao, MD

When the patient relapsed after treatment with lorlatinib, a new mutation enhanced binding to crizotinib.

  1. Anne S. Tsao, MD

Non–small-cell lung cancer (NSCLC) patients with ALK-rearrangements are a unique population whose resistance mechanisms to current ALK inhibitors are largely unknown. Investigators now present an industry-funded case report on a patient with metastatic ALK-rearranged NSCLC who became resistant to front-line crizotinib due to a C1156Y mutation. The patient did not respond to ceritinib, AUY922 (heat shock protein 90 inhibitor), carboplatin-pemetrexed, or a rechallenge of crizotinib, but was sensitive to lorlatinib for 8 months. A repeat biopsy identified the ALK C1156Y mutation and a new ALK L1198F from the same allele that was sensitive again to crizotinib.

Findings were as follows:

  • C1156Y is a known resistance mutation to crizotinib.

  • ALK L1198F, a gain-of-function mutation in anaplastic thyroid cancer, now appears to confer sensitivity to crizotinib in ALK-rearranged NSCLC.

  • ALK C1156Y was present in <7% of the pretreatment tumor, 50% of the crizotinib-resistant tumor, and 100% of the lorlatinib-resistant tumor; L1198F was found only in the lorlatinib-resistant tumor.

  • Clonal analysis suggests that a minor subclone with C1156Y existed prior to crizotinib treatment, arose during crizotinib therapy, and after lorlatinib treatment acquired the L1198F mutation under selective pressure.

  • After the patient progressed on crizotinib the third time, a rebiopsy showed that ALK L1198F was absent; indicating that crizotinib can target the C1156Y-L1198F dual subclone.

  • Ba/F3 cell line data showed that C1156Y-L1198F mutations confer resistance to lorlatinib, ceritinib, alectinib, and brigatinib, but are sensitive to crizotinib. Cocrystal structure analysis indicates that the L1198F mutation has greater binding to crizotinib that overcomes the C1156Y increased kinase activity.

Comment

This case report leads us to a greater understanding of the resistance mechanisms in ALK-NSCLC and, more important, demonstrates that patients who acquire the L1198F mutation can be rechallenged with crizotinib. Also, the C1156Y-L1198F dual mutation leads to a crizotinib-sensitive phenotype, since the L1198F enhanced binding overcomes the resistance from C1156Y.

Editor Disclosures at Time of Publication

  • Disclosures for Anne S. Tsao, MD at time of publication Consultant / Advisory board Genetech; Roche; Medimmune; Novartis; Astellas; Boehringer-Ingelheim; Eli Lilly Speaker’s bureau Genetech; Roche; Medimmune; Novartis; Astellas; Boehringer-Ingelheim; Eli Lilly Grant / Research support Department of Defense; SWOG Leadership positions in professional societies American Medical Association (Member); American Association of Cancer Research (Member); American Society of Clinical Oncology (Member); AACR-Women in Cancer Research (Member); International Mesothelioma Interest Group (Member); SWOG (Member); International Association for the Study of Lung Cancer (Communications Committee Chair); American Radium Society (Chair); RTOG (Member)

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