Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial
Open accessAbstract
Background ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood-brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK-rearranged NSCLC.Methods ASCEND-1 was an open-label, phase 1 trial that recruited patients from 20 academic hospitals or cancer centres in 11 countries in Europe, North America, and Asia-Pacific. Eligible patients were aged 18 years or older with ALK-rearranged locally advanced or metastatic cancer that had progressed despite standard therapy (or for which no effective standard therapy existed), who had at least one measurable lesion at baseline. The primary objective (to determine the maximum tolerated dose) has been reported previously. This updated analysis includes all patients with ALK-rearranged NSCLC given oral ceritinib at the recommended dose of 750 mg/day in the dose-escalation and expansion phases. Here we report the secondary outcomes of overall response, duration of response, and progression-free survival, analysed in all patients who received at least one 750 mg dose of ceritinib. Exploratory analyses included retrospective analysis of intracranial activity by independent neuroradiologists, in patients with untreated or locally treated neurologically stable brain metastases at baseline. Safety was assessed in all patients who received at least one dose of ceritinib. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516.Findings Between Jan 24, 2011, and July 31, 2013, 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK-rearranged NSCLC. At data cutoff (April 14, 2014), median follow-up was 11·1 months (IQR 6·7-15·2) and 147 (60%) patients had discontinued treatment, 98 (40%) as a result of disease progression. An overall response was reported in 60 (72% [95% CI 61-82]) of 83 ALK inhibitor-naive patients and 92 (56% [49-64]) of 163 ALK inhibitor-pretreated patients. Median duration of response was 17·0 months (95% CI 11·3-non-estimable [NE]) in ALK inhibitor-naive patients and 8·3 months (6·8-9·7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18·4 months (95% CI 11·1-NE) in ALK inhibitor-naive patients and 6·9 months (5·6-8·7) in ALK inhibitor-pretreated patients. Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment, intracranial disease control was reported in 15 (79% [95% CI 54-94]) of 19 ALK inhibitor-naive patients and in 49 (65% [54-76]) of 75 ALK inhibitor-pretreated patients. Of these 94 patients, 11 had measurable brain lesions and no previous radiotherapy to the brain, six of whom achieved a partial intracranial response. Serious adverse events were recorded in 117 (48%) of 246 patients. The most common grade 3-4 laboratory abnormalities were increased alanine aminotransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]). The most common grade 3-4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6%) patients. Two on-treatment deaths during the study were deemed to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis.Interpretation The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib. A confirmatory phase 2 clinical trial is ongoing to assess ceritinib activity in patients with ALK-rearranged NSCLC and brain or leptomeningeal metastases.Funding Novartis Pharmaceuticals Corporation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A retrospective review of 94 ALK-rearranged NSCLC patients with brain metastases in a phase I ceritinib expansion study found intracranial disease control rates of 65.3% in crizotinib-pretreated patients and 78.9% in TKI-naive patients.
“Retrospective review of 94 ALK-rearranged NSCLC patients with brain metastases in a phase I expansion study of ceritinib, of which 75 were ALK inhibitor-pretreated, revealed an intracranial disease control rate (DCR) of 65.3% in crizotinib-pretreated patients and 78.9% in TKI-naive patients [139].”
From Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2016) · cites this paper as [139]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer
Kwak, E. L., Bang, Y., Camidge, D. R., Shaw, A. T., Solomon, B., Maki, R. G., Ou, S. I., Dezube, B. J., Janne, P. A., Costa, D. B., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1006448 · Cited by 4,442 · see citing works
Self-citationPao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., Kris, M. G., & Varmus, H. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020073 · Cited by 3,527 · see citing works
Self-citationCrizotinib versus Chemotherapy in Advanced <i>ALK</i> -Positive Lung Cancer
Shaw, A. T., Kim, D.-W., Nakagawa, K., Seto, T., Crinó, L., Ahn, M.-J., De Pas, T., Besse, B., Solomon, B. J., Blackhall, F., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1214886 · Cited by 3,381 · see citing works
Self-citationScagliotti, G. V., Parikh, P., von Pawel, J., Biesma, B., Vansteenkiste, J., Manegold, C., Serwatowski, P., Gatzemeier, U., Digumarti, R., Zukin, M., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.0375 · Cited by 3,203 · see citing works
Self-citationFirst-Line Crizotinib versus Chemotherapy in <i>ALK</i> -Positive Lung Cancer
Solomon, B. J., Mok, T., Kim, D.-W., Wu, Y.-L., Nakagawa, K., Mekhail, T., Felip, E., Cappuzzo, F., Paolini, J., Usari, T., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408440 · Cited by 3,190 · see citing works
Self-citationCrizotinib in <i>ROS1</i>-Rearranged Non–Small-Cell Lung Cancer
Shaw, A. T., Ou, S.-H. I., Bang, Y.-J., Camidge, D. R., Solomon, B. J., Salgia, R., Riely, G. J., Varella-Garcia, M., Shapiro, G. I., Costa, D. B., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1406766 · Cited by 1,964 · see citing works
Self-citationUsing Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs
Kris, M. G., Johnson, B. E., Berry, L. D., Kwiatkowski, D. J., Iafrate, A. J., Wistuba, I. I., Varella-Garcia, M., Franklin, W. A., Aronson, S. L., Su, P.-F., et al. (2014) · JAMA · doi:10.1001/jama.2014.3741 · Cited by 1,724 · see citing works
Self-citationCeritinib in <i>ALK</i> -Rearranged Non–Small-Cell Lung Cancer
Shaw, A. T., Kim, D.-W., Mehra, R., Tan, D. S. W., Felip, E., Chow, L. Q. M., Camidge, D. R., Vansteenkiste, J., Sharma, S., De Pas, T., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1311107 · Cited by 1,495 · see citing works
Self-citationMechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers
Katayama, R., Shaw, A. T., Khan, T. M., Mino-Kenudson, M. A., Solomon, B., Halmos, B., Jessop, N. A., Wain, J. C., Yeo, A. T., Benes, C. H., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003316 · Cited by 1,316 · see citing works
Self-citationCamidge, D. R., Bang, Y., Kwak, E. L., Iafrate, A. J., Varella‐Garcia, M., Fox, S. B., Riely, G. J., Solomon, B., Ou, S. I., Kim, D., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70344-3 · Cited by 1,271 · see citing works
Self-citationDoebele, R. C., Pilling, A. B., Aisner, D. L., Kutateladze, T. G., Le, A. T., Weickhardt, A. J., Kondo, K. L., Linderman, D. J., Heasley, L. E., Franklin, W. A., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2906 · Cited by 1,064 · see citing works
Self-citationThe ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non–Small Cell Lung Cancer
Friboulet, L., Li, N., Katayama, R., Lee, C. C., Gainor, J. F., Crystal, A., Michellys, P., Awad, M. M., Yanagitani, N., Kim, S., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0846 · Cited by 847 · see citing works
Self-citationGadgeel, S. M., Gandhi, L., Riely, G. J., Chiappori, A., West, H., Azada, M. C., Morcos, P. N., Lee, R.-M., Garcia, L., Yu, L. J., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70362-6 · Cited by 702 · see citing works
Self-citationWeickhardt, A. J., Scheier, B., Burke, J. M., Gan, G., Lu, X., Bunn, P. A., Aisner, D. L., Gaspar, L. E., Kavanagh, B. D., Doebele, R. C., et al. (2012) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3182745948 · Cited by 684 · see citing works
Self-citationCosta, D. B., Shaw, A. T., Ou, S. I., Solomon, B., Riely, G. J., Ahn, M., Zhou, C., Shreeve, S. M., Selaru, P., Polli, A., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.0539 · Cited by 603 · see citing works
Self-citationCSF Concentration of the Anaplastic Lymphoma Kinase Inhibitor Crizotinib
Costa, D. B., Kobayashi, S. S., Pandya, S. S., Yeo, W.-L., Shen, Z., Tan, W., & Wilner, K. D. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.34.1313 · Cited by 601 · see citing works
Brain metastases in patients with EGFR -mutated or ALK -rearranged non-small-cell lung cancers
Rangachari, D., Yamaguchi, N., VanderLaan, P. A., Folch, E. E., Mahadevan, A., Floyd, S., Uhlmann, E. J., Wong, E. T., Dahlberg, S. E., Huberman, M. S., et al. (2015) · Lung Cancer · doi:10.1016/j.lungcan.2015.01.020 · Cited by 539 · see citing works
Nguyen, K.-S. H., Kobayashi, S., & Costa, D. B. (2009) · Clinical Lung Cancer · doi:10.3816/clc.2009.n.039 · Cited by 437 · see citing works
Ou, S.-H. I., Janne, P. A., Bartlett, C. H., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdt572 · Cited by 219 · see citing works
Tanizaki, J., Okamoto, I., Okabe, T., Sakai, K., Tanaka, K., Hayashi, H., Kaneda, H., Takezawa, K., Kuwata, K., Yamaguchi, H., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0392 · Cited by 155 · see citing works
Malik, S. M., Maher, V. E., Bijwaard, K. E., Becker, R. L., Zhang, L., Tang, S. W., Song, P., Liu, Q., Marathe, A., Gehrke, B. J., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-3077 · Cited by 140 · see citing works
Metro, G., Lunardi, G., Floridi, P., et al. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000468 · Cited by 110 · see citing works
Mok, T. S. K., Kim, D., Wu, Y.-L. L. C., Solomon, B., Nakagawa, K., Mekhail, T. M., Felip, E., Cappuzzo, F., Paolini, J., Usari, T., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.32.15_suppl.8002 · Cited by 84 · see citing works
Self-citationFelip, E., Orlov, S., Park, K., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.33.15_suppl.8060 · Cited by 78 · see citing works
Self-citationSong, Z., Wang, M., & Zhang, A. (2015) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2014.12.007 · Cited by 77 · see citing works
Mok, T. S. K., Spigel, D. R., Felip, E., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.33.15_suppl.8059 · Cited by 77 · see citing works
Self-citationManaging Treatment–Related Adverse Events Associated with Alk Inhibitors
Rothenstein, J. M., & Letarte, N. (2014) · Current Oncology · doi:10.3747/co.21.1740 · Cited by 68 · see citing works
Biology of brain metastases and novel targeted therapies: Time to translate the research
Fokas, E., Steinbach, J., & Rödel, C. M. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.10.005 · Cited by 55 · see citing works
On the Merits and Limitations of Whole-Brain Radiation Therapy
Khan, A. J., & Dicker, A. P. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.46.0410 · Cited by 37 · see citing works
Arrondeau, J., & Sas, L. (2014) · Cited by 28 · see citing works
Lukas, R. V., Lesniak, M. S., & Salgia, R. (2014) · CNS Oncology · doi:10.2217/cns.13.66 · Cited by 16 · see citing works
Kerstein, D., Gettinger, S. N., Gold, K., et al. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv128.06 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Novello, S., Barlesi, F., Califano, R., Cufer, T., Ekman, S., Levra, M. G., Kerr, K., Popat, S., Reck, M., Senan, S., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw326 · Cited by 2,631 · see citing works
Self-citationSoria, J.-C., Tan, D. S. W., Chiari, R., Wu, Y.-L., Paz-Ares, L., Wolf, J., Geater, S. L., Orlov, S., Cortinovis, D., Yu, C.-J., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)30123-x · Cited by 1,151 · see citing works
Self-citationSolomon, 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., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30649-1 · Cited by 791 · see citing works
Self-citationToward a More Precise Future for Oncology
Murciano-Goroff, Y. R., Taylor, B. S., Hyman, D. M., & Schram, A. M. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.03.014 · Cited by 48 · see citing works
- Authors
- Kim, D.-W., Mehra, R., Tan, D. S. W., Felip, E., Chow, L. Q. M., Camidge, D. R., Vansteenkiste, J., Sharma, S., De Pas, T., Riely, G. J., Solomon, B. J., Wolf, J., Thomas, M., Schuler, M., Liu, G., Santoro, A., Sutradhar, S., Li, S., Szczudlo, T., Yovine, A., & Shaw, A. T.
- Affiliations
- Seoul National University Hospital (KR)
- Fox Chase Cancer Center (US)
- National Cancer Centre Singapore (SG)
- Vall d'Hebron Institut de Recerca (ES)
- University of Washington (US)
- University of Colorado Denver (US)
- KU Leuven (BE)
- Huntsman Cancer Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Peter MacCallum Cancer Centre (AU)
- University Hospital Cologne (DE)
- University Hospital Heidelberg (DE)
- Princess Margaret Cancer Centre (CA)
- IRCCS Humanitas Research Hospital (IT)
- Novartis (Switzerland) (CH)
- Massachusetts General Hospital (US)
- Corresponding author
- Shaw, Alice T
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 17
- Issue
- 4
- Pages
- 452-463
- ISSN
- 1470-2045 (ISSN-L)
- PMC
- PMC5063047
- OpenAlex
- W2295354328
- Cited by
- 471
- References
- 32
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 22 · 2023: 36 · 2022: 39 · 2021: 39 · 2020: 38 · 2019: 52 · 2018: 71 · 2017: 96 · 2016: 60 · 2015: 1 · 2014: 1
- FWCI
- 83.17
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-05-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
- Lirias (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Institutes of Health (5R01CA164273)
- Novartis Pharmaceuticals Corporation
- 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
- ceritinib, ALK-positive non-small cell lung cancer, ALK inhibitors, crizotinib resistance, brain metastases, intracranial activity, blood-brain barrier penetration, overall response rate, progression-free survival, duration of response, safety, maximum tolerated dose, dose escalation, metastatic disease
- MeSH terms
- Anaplastic Lymphoma Kinase, Adult, Aged, Blood-Brain Barrier, Carcinoma, Non-Small-Cell Lung, Female, Humans, Male, Middle Aged, Pyrimidines, Sulfones, Gene Rearrangement, Disease-Free Survival, Drug Resistance, Neoplasm, Receptor Protein-Tyrosine Kinases, Protein Kinase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
