Reversal of Crizotinib Resistance

January 2016

Treatment of NSCLC with EGFR or ALK genetic alterations has been ongoing at MGH Cancer Center and other centers around the U.S. for some time.  Treatment involves the use of tyrosine kinase (TK) inhibitors.  Unfortunately, treatment of patients with the first generation of TK inhibitors can start out being highly effective, however, invariably tumors undergo additional genetic changes such as mutation, resulting in resistance and relapse of their disease.  Clinicians initiate treatment with more potent second or third generation TK inhibitors to achieve patient remission of disease progression in NSCLC.  For ALK rearranged NSCLC, crizotinib was the first generation of ALK inhibitors used to successfully treat patients.  When these patients developed resistance to crizotinib, usually through mutations in the ALK gene, other more potent second generation ALK inhibitors such as ceritinib, alectinib, and brigatinib are used to produce durable responses in these NSCLC patients.  A third generation ALK inhibitor called lorlatinib was recently developed for ALK and ROS1 altered NSCLC and is in early phase study in patients.  In a recent report (January 2016) in the New England Journal of Medicine, Jeff Engelmann, MD, PhD, and colleagues at the MGH cancer center report on a patient whose ALK-rearranged NSCLC had been treated with multiple therapies, including crizotinib and ceritinib, and who, upon relapse was then treated with lorlatinib.  She eventually relapsed on this third generation ALK inhibitor due to a mutation in ALK at amino acid L1198F.  Interestingly, this mutation which had rendered her resistant to lorlatinib actually resensitized her to the first generation ALK inhibitor crizotinib. The publication goes into the details of how this mutation might affect the structure of the ALK protein such that it once again is responsive to crizotinib.
 
Source: New England Journal of Medicine; Shaw, A. et al; Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F; Jan 7, 2016;