Brigatinib versus Crizotinib in ALK -Positive Non–Small-Cell Lung Cancer
Open accessAbstract
BACKGROUND: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear. METHODS: In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred. RESULTS: A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow-up was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted. CONCLUSIONS: Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501 .).
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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 [26]
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- Authors
- Camidge, D. R., Kim, H. R., Ahn, M.-J., Yang, J. C.-H., Han, J.-Y., Lee, J.-S., Hochmair, M. J., Li, J. Y.-C., Chang, G.-C., Lee, K. H., Gridelli, C., Delmonte, A., Garcia Campelo, R., Kim, D.-W., Bearz, A., Griesinger, F., Morabito, A., Felip, E., Califano, R., Ghosh, S., Spira, A., Gettinger, S. N., Tiseo, M., Gupta, N., Haney, J., Kerstein, D., & Popat, S.
- Affiliations
- Yonsei University (KR)
- Chungbuk National University (KR)
- From the University of Colorado Cancer Center, Aurora (D.R.C.); Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine (H.R.K.), Samsung Medical Center (M.-J.A.), and Seoul National University Hospital (D.-W.K.), Seoul, National Cancer Center, Goyang (J.-Y.H.), Seoul National University Bundang Hospital, Seongnam (J.-S.L.), and Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju (K.H.L.)...
- Carl von Ossietzky Universität Oldenburg (DE)
- ORCID
- Camidge, D. Ross
- Kim, Hye Ryun
- Ahn, Myung-Ju
- Yang, James Chih-Hsin
- Han, Ji-Youn
- Hochmair, Maximilian J.
- Lee, Ki Hyeong
- Gridelli, Cesare
- Delmonte, Angelo
- Kim, Dong-Wan
- Bearz, Alessandra
- Griesinger, Frank
- Morabito, Alessandro
- Felip, Enriqueta
- Califano, Raffaele
- Ghosh, Sharmistha
- Spira, Alexander
- Gettinger, Scott N.
- Tiseo, Marcello
- Gupta, Neeraj
- Popat, Sanjay
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-11-22
- Volume
- 379
- Issue
- 21
- Pages
- 2027-2039
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2894476389
- Cited by
- 980
- References
- 29
- Citations by year
- 2026: 66 · 2025: 108 · 2024: 111 · 2023: 122 · 2022: 138 · 2021: 163 · 2020: 150 · 2019: 107 · 2018: 14 · 2017: 1
- FWCI
- 81.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
- 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
- brigatinib, crizotinib, anaplastic lymphoma kinase, ALK-positive non-small cell lung cancer, ALK inhibitors, progression-free survival, objective response rate, intracranial response, first-line therapy, brain metastases, head-to-head comparison, targeted therapy, ALK rearrangement
- MeSH terms
- Crizotinib, Anaplastic Lymphoma Kinase, Progression-Free Survival, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Brain Neoplasms, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Organophosphorus Compounds, Pyrimidines, Kaplan-Meier Estimate
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