ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung Cancer

Abstract

PURPOSE Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical activity in advanced ALK-positive non–small-cell lung cancer, including in patients who have failed prior ALK TKIs. Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that ALK resistance mutations may represent a biomarker of response in previously treated patients. PATIENTS AND METHODS Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non–small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK mutation–focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to ALK mutation status. RESULTS Approximately one quarter of patients had ALK mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, the efficacy of lorlatinib was comparable among patients with and without ALK mutations using plasma or tissue genotyping. In contrast, in patients who had failed 1 or more second-generation ALK TKIs, objective response rate was higher among patients with ALK mutations (62% v 32% [plasma]; 69% v 27% [tissue]). Progression-free survival was similar in patients with and without ALK mutations on the basis of plasma genotyping (median, 7.3 months v 5.5 months; hazard ratio, 0.81) but significantly longer in patients with ALK mutations identified by tissue genotyping (median, 11.0 months v 5.4 months; hazard ratio, 0.47). CONCLUSION In patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with ALK mutations compared with patients without ALK mutations. Tumor genotyping for ALK mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib.

Short progression‐free survival of ALK inhibitors sensitive to secondary mutations in ALK‐positive NSCLC patients

“…Recently, the phase II study of lorlatinib has been reported . The cohort with at least one secondary mutation in the baseline tumor biopsy had a PFS of 11.0 months, while the cohort with no secondary mutation in the baseline biopsy had a PFS of 5.4 months . This result suggests that the PFS in the current study was relatively short; however, the previous cohorts included patients treated with not only second‐generation ALK‐TKIs, but also crizotinib as pretreatment of lorlatinib.…”

“…If a new treatment strategy (i.e., combination treatment with a next generation ALK‐TKI and agents targeting the bypass track) that overcomes this resistance mechanism is established, then the prognosis of ALK‐TKI refractory patients will be remarkably improved in comparison to the existing treatment. Recently, the phase II study of lorlatinib has been reported . The cohort with at least one secondary mutation in the baseline tumor biopsy had a PFS of 11.0 months, while the cohort with no secondary mutation in the baseline biopsy had a PFS of 5.4 months .…”

Liquid biopsy in oncology: a consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

“…Many studies have been published that demonstrate that ctDNA can be used for emergency monitoring of resistant clones during exposure to a predetermined targeted treatment strategy such as T790M mutation following treatment with EGFR tyrosine kinase inhibitors (TKIs), resistance mutations to ALK in patients carrying the translocation after exposure to ALK inhibitors [59], ESR1 mutations [60,61], PIK3CA in breast cancer patients treated with different treatment strategies, or KRAS mutations in colorectal carcinoma patients treated with anti-EGFR drugs [62][63][64]. Once again, a good example of how detecting one of the most common mechanisms of resistance (T790M) to first-generation or second-generation inhibitor drugs has been implemented in the context of clinical practice is advanced NSCLC with EGFR mutations, detected in ctDNA using Cobas® with a moderate sensitivity.…”

Targeted Therapy for Non-Small Cell Lung Cancer

“…203 Note ctDNA NGS is principally being developed in monitoring for response and resistance to treatment given a lower sensitivity (77%) in detecting ALK rearrangements. 204,205 An additional consideration for NGS in diagnostic evaluation of ALK rearrangement is the ability to evaluate for other mutations concurrently. While targetable mutations are generally mutually exclusive, the presence of comutations at diagnosis may provide predictive and potentially prognostic information.…”