Mutation in ALK-rearranged lung cancer confers resistance to lorlatinib, restores sensitivity to crizotinib

In a patient with metastatic ALK-rearranged non–small-cell lung cancer (NSCLC), resistance to ALK inhibitors began with a founder ALK C1156Y clone resistant to crizotinib, and progressed to a double-mutant C1156Y-L1198F clone that was resistant to lorlatinib but sensitive again to the less potent, first generation crizotinib, according to a case report published Dec. 23 in the New England Journal of Medicine.

Whole genome sequencing of tumor samples suggested that a minor subclone harboring the C1156Y mutation was enriched during crizotinib treatment, and under selective pressure during lorlatinib treatment, acquired the L1198F mutation that conferred resistance to the potent, third-generation ALK inhibitor lorlatinib but restored sensitivity to crizotinib. The patient relapsed after the second response to crizotinib, and tumor analysis did not detect the L1198F mutation (N Engl J Med. 2015 Dec 23. doi:10.1056/NEJMoa1508887).

“These results highlight the clinical usefulness of developing multiple, structurally distinct inhibitors that target the same oncogenic kinase,” wrote Dr. Alice Shaw, thoracic oncologist at Massachusetts General Hospital and professor at Harvard Medical School, Boston, and colleagues.

“Our results also highlight ALK L1198F as a novel resistance mechanism in ALK-rearranged NSCLC. Remarkably, this substitution changes the exact residue used to enhance selectivity of lorlatinib for ALK over other kinases,” they wrote.

Co-crystal structures of mutant and wild-type ALK kinase domains with bound inhibitors show that the leucine-to-phenylalanine mutation at residue 1198 leads to steric clash with lorlatinib but not with crizotinib. The presence of phenylalanine may result in more favorable binding of crizotinib, which may offset the increased kinase activity due to C1156Y.

The case study analyzed tumor samples from a woman with metastatic ALK-rearranged NSCLC who had received multiple therapies, including crizotinib, ceritinib, and lorlatinib.

Cell survival assays showed that the double mutant ALK C1156Y-L1198F was resistant to lorlatinib, as well as to second-generation ALK inhibitors, and it was sensitive to crizotinib; the single L1198F mutation increased sensitivity to crizotinib. Assays with cell lines expressing additional ALK mutations, including the highly refractory G1202R mutation, demonstrated that in almost all cases, L1198F increased sensitivity to crizotinib but promoted resistance to the other ALK inhibitors.

The study was funded in part by Pfizer. Dr. Shaw reported personal fees from Pfizer, Novartis, Genentech, Roche, and Ariad during the conduct of the study, and personal fees from Blueprint Medicine, Daiichi-Sankyo, and Ignyta outside the submitted work. Several of her coauthors reported ties to industry.

In a patient with metastatic ALK-rearranged non–small-cell lung cancer (NSCLC), resistance to ALK inhibitors began with a founder ALK C1156Y clone resistant to crizotinib, and progressed to a double-mutant C1156Y-L1198F clone that was resistant to lorlatinib but sensitive again to the less potent, first generation crizotinib, according to a case report published Dec. 23 in the New England Journal of Medicine.

Whole genome sequencing of tumor samples suggested that a minor subclone harboring the C1156Y mutation was enriched during crizotinib treatment, and under selective pressure during lorlatinib treatment, acquired the L1198F mutation that conferred resistance to the potent, third-generation ALK inhibitor lorlatinib but restored sensitivity to crizotinib. The patient relapsed after the second response to crizotinib, and tumor analysis did not detect the L1198F mutation (N Engl J Med. 2015 Dec 23. doi:10.1056/NEJMoa1508887).

“These results highlight the clinical usefulness of developing multiple, structurally distinct inhibitors that target the same oncogenic kinase,” wrote Dr. Alice Shaw, thoracic oncologist at Massachusetts General Hospital and professor at Harvard Medical School, Boston, and colleagues.

“Our results also highlight ALK L1198F as a novel resistance mechanism in ALK-rearranged NSCLC. Remarkably, this substitution changes the exact residue used to enhance selectivity of lorlatinib for ALK over other kinases,” they wrote.

Co-crystal structures of mutant and wild-type ALK kinase domains with bound inhibitors show that the leucine-to-phenylalanine mutation at residue 1198 leads to steric clash with lorlatinib but not with crizotinib. The presence of phenylalanine may result in more favorable binding of crizotinib, which may offset the increased kinase activity due to C1156Y.

The case study analyzed tumor samples from a woman with metastatic ALK-rearranged NSCLC who had received multiple therapies, including crizotinib, ceritinib, and lorlatinib.

Cell survival assays showed that the double mutant ALK C1156Y-L1198F was resistant to lorlatinib, as well as to second-generation ALK inhibitors, and it was sensitive to crizotinib; the single L1198F mutation increased sensitivity to crizotinib. Assays with cell lines expressing additional ALK mutations, including the highly refractory G1202R mutation, demonstrated that in almost all cases, L1198F increased sensitivity to crizotinib but promoted resistance to the other ALK inhibitors.

The study was funded in part by Pfizer. Dr. Shaw reported personal fees from Pfizer, Novartis, Genentech, Roche, and Ariad during the conduct of the study, and personal fees from Blueprint Medicine, Daiichi-Sankyo, and Ignyta outside the submitted work. Several of her coauthors reported ties to industry.

In a patient with metastatic ALK-rearranged non–small-cell lung cancer (NSCLC), resistance to ALK inhibitors began with a founder ALK C1156Y clone resistant to crizotinib, and progressed to a double-mutant C1156Y-L1198F clone that was resistant to lorlatinib but sensitive again to the less potent, first generation crizotinib, according to a case report published Dec. 23 in the New England Journal of Medicine.

Whole genome sequencing of tumor samples suggested that a minor subclone harboring the C1156Y mutation was enriched during crizotinib treatment, and under selective pressure during lorlatinib treatment, acquired the L1198F mutation that conferred resistance to the potent, third-generation ALK inhibitor lorlatinib but restored sensitivity to crizotinib. The patient relapsed after the second response to crizotinib, and tumor analysis did not detect the L1198F mutation (N Engl J Med. 2015 Dec 23. doi:10.1056/NEJMoa1508887).

“These results highlight the clinical usefulness of developing multiple, structurally distinct inhibitors that target the same oncogenic kinase,” wrote Dr. Alice Shaw, thoracic oncologist at Massachusetts General Hospital and professor at Harvard Medical School, Boston, and colleagues.

“Our results also highlight ALK L1198F as a novel resistance mechanism in ALK-rearranged NSCLC. Remarkably, this substitution changes the exact residue used to enhance selectivity of lorlatinib for ALK over other kinases,” they wrote.

Co-crystal structures of mutant and wild-type ALK kinase domains with bound inhibitors show that the leucine-to-phenylalanine mutation at residue 1198 leads to steric clash with lorlatinib but not with crizotinib. The presence of phenylalanine may result in more favorable binding of crizotinib, which may offset the increased kinase activity due to C1156Y.

The case study analyzed tumor samples from a woman with metastatic ALK-rearranged NSCLC who had received multiple therapies, including crizotinib, ceritinib, and lorlatinib.

Cell survival assays showed that the double mutant ALK C1156Y-L1198F was resistant to lorlatinib, as well as to second-generation ALK inhibitors, and it was sensitive to crizotinib; the single L1198F mutation increased sensitivity to crizotinib. Assays with cell lines expressing additional ALK mutations, including the highly refractory G1202R mutation, demonstrated that in almost all cases, L1198F increased sensitivity to crizotinib but promoted resistance to the other ALK inhibitors.

The study was funded in part by Pfizer. Dr. Shaw reported personal fees from Pfizer, Novartis, Genentech, Roche, and Ariad during the conduct of the study, and personal fees from Blueprint Medicine, Daiichi-Sankyo, and Ignyta outside the submitted work. Several of her coauthors reported ties to industry.