Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study
Abstract
Background Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer. Methods In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data…
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The low frequency of co-drivers plus marked dependence on the ALK fusion protein could account for prolonged PFS seen with second- and third-generation ALK inhibitors.
“both the rarity of co-drivers and strong addiction to the ALK fusion oncoprotein may account for the long progression-free survival observed in patients with ALK-rearrangements with the potent and selective second and third generation ALK inhibitors alectinib, brigatinib and lorlatinib23, 26, 27.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [27]
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- Authors
- Solomon, B. J., Besse, B., Bauer, T. M., Felip, E., Soo, R. A., Camidge, D. R., Chiari, R., Bearz, A., Lin, C.-C., Gadgeel, S. M., Riely, G. J., Tan, E. H., Seto, T., James, L. P., Clancy, J. S., Abbattista, A., Martini, J.-F., Chen, J., Peltz, G., Thurm, H., Ou, S.-H. I., & Shaw, A. T.
- Affiliations
- Peter MacCallum Cancer Centre (AU)
- Université Paris-Sud (FR)
- Sarah Cannon (US)
- Vall d'Hebron Institute of Oncology (ES)
- National University Hospital (SG)
- University of Colorado Anschutz (US)
- Azienda Ospedaliera di Perugia (IT)
- National Taiwan University Hospital (TW)
- University of Michigan (US)
- Memorial Sloan Kettering Cancer Center (US)
- National Cancer Centre Singapore (SG)
- National Hospital Organization Kyushu Cancer Center (JP)
- Pfizer (United States) (US)
- University of California, Irvine (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Solomon, Benjamin J
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 19
- Issue
- 12
- Pages
- 1654-1667
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W2899668190
- Cited by
- 791
- References
- 27
- Citations by year
- 2026: 47 · 2025: 62 · 2024: 85 · 2023: 109 · 2022: 125 · 2021: 147 · 2020: 123 · 2019: 89 · 2018: 3 · 2017: 1
- FWCI
- 68.13
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-01-01)
- Open access
- closed
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- lorlatinib, ALK-positive non-small cell lung cancer, ROS1-positive non-small cell lung cancer, ALK inhibitors, crizotinib resistance, central nervous system metastasis, treatment-naive patients, previously treated patients, drug safety, antitumour activity
- MeSH terms
- Anaplastic Lymphoma Kinase, Progression-Free Survival, Adult, Aged, Aged, 80 and over, Aminopyridines, Antineoplastic Agents, Brain Neoplasms, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lactams, Lung Neoplasms, Male, Middle Aged, Pyrazoles, Time Factors, Biomarkers, Tumor, Gene Rearrangement, Lactams, Macrocyclic, Tumor Burden, Protein Kinase Inhibitors
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