Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 trial.
Abstract
8003^ Background: ALK+ NSCLC is sensitive to crizotinib (CRZ) but patients (pts) invariably progress. Ceritinib (LDK378) is a novel ALK inhibitor (ALKi) more potent than CRZ in enzymatic and cell-based assays and CRZ-resistant animal models. Prior results from this Phase I study (ASCEND-1) established a MTD of 750 mg/d. Methods: Adult pts with advanced ALK+ cancers received oral ceritinib q.d. After MTD determination, pts were enrolled to expansion groups: ALKi pretreated (PT) NSCLC; ALKi naive NSCLC; non-NSCLC diseases. Results are reported for all NSCLC pts receiving ceritinib at the recommended dose (750 mg/d). Results: 255 pts from 11 countries were treated at 750 mg/d. 246 pts had ALK+ NSCLC, with 4.5 months’ median follow-up; of these, 67% had received ≥2 anticancer therapies; ORR was ≥60% in each subgroup of pts with 0, 1, 2, and 3 prior anticancer regimens. 83 pts were ALKi naïve. All 163 ALKi PT pts had received CRZ – 78% as their last prior therapy – and 92% had progressive disease on prior ALKi. Investigator efficacy assessments are presented for 180 NSCLC pts who received first dose of ceritinib ≥18 wks prior to cut-off (2 Aug 2013). Of all 255 pts, the most common AEs were diarrhea (84%), nausea (77%), vomiting (57%), fatigue (36%), and ALT increased (36%). The most common Grade 3/4 AEs were ALT increased (21%), and AST increased (8%). Ceritinib treatment is ongoing for 58% of pts. During the dosing period dose reductions occurred in 133 pts (52.2%), all due to an AE. Only 24 (9.4%) pts discontinued ceritinib due to an AE. Conclusions: Ceritinib 750 mg/d has rapid, durable and high antitumor activity in ALK+ NSCLC pts, regardless of prior treatment with ALKi, providing effective treatment in this pt population. Clinical trial information: NCT01283516. Endpoint ALKi PT N=121 ALK naive N=59 All N=180 ORR, n (%) [95% CI] 67 (55.4%) [46.1, 64.4] 41 (69.5%) [56.1, 80.8] 108 (60.0%) [52.4, 67.2] DOR (Median [95% CI]) 7.4 mos [5.4, 10.1] NEa [5.6, NE] 9.7 mos [6.9, 11.4] Time to first response (Median [min, max]) 6.1 wks [4.6, 24.1] 6.1 wks [3.0, 24.1] 6.1 wks [3.0, 24.1] PFS (Median [95% CI]) 6.9 mos [5.4, 8.7] NEb [6.7, NE] 7.0 mos [6.2, 10.1] Abbreviation: NE, not estimable. a DOR rate at 12 mos: 71.1% (95% CI: 49.8, 84.6). b PFS rate at 12 mos: 58.1% (95% CI: 41.6, 71.5).
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In the Kim et al study, PFS in the population not pretreated with crizotinib was not estimable at the time of presentation.
“PFS in the population of patients who were not pretreated was not estimable at the time of the presentation.”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [43]
The noncomparative study reported by Kim et al included 163 participants who had received first-line crizotinib and 83 who had not.
“The noncomparative study reported by Kim et al43 included 163 participants who had received first-line crizotinib and 83 who had not.”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [43]
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Masters, G. A., Temin, S., Azzoli, C. G., Giaccone, G., Baker, S., Brahmer, J. R., Ellis, P. M., Gajra, A., Rackear, N., Schiller, J. H., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.62.1342 · Cited by 850 · see citing works
Crinò, L., Ahn, M., de Marinis, F., Groen, H. J. M., Wakelee, H. A., Hida, T., Mok, T. S. K., Spigel, D. R., Felip, E., Nishio, M., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2015.65.5936 · Cited by 350 · see citing works
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Zhang, I., Zaorsky, N. G., Palmer, J. D., Mehra, R., & Lu, J. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00013-3 · Cited by 192 · see citing works
Self-citationALK: a tyrosine kinase target for cancer therapyPreprint
Holla, V., Elamin, Y., Bailey, A. M., Johnson, A. M., Litzenburger, B., Khotskaya, Y., Sanchez, N. S., Zeng, J., Shufean, M. A., Shaw, K. R. M., et al. (2017) · Cold Spring Harbor molecular case studies · doi:10.1101/mcs.a001115 · Cited by 171 · see citing works
Gainor, J. F., Sherman, C. A., Willoughby, K., Logan, J., Kennedy, E., Brastianos, P. K., Chi, A. S., & Shaw, A. T. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000455 · Cited by 168 · see citing works
Self-citationSmall Molecule Kinase Inhibitors for the Treatment of Brain Cancer
Heffron, T. P. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00618 · Cited by 141 · see citing works
Targeted Therapy and Immunotherapy for Lung Cancer
Naylor, E. C., Desani, J., & Chung, P. K. (2016) · Surgical Oncology Clinics of North America · doi:10.1016/j.soc.2016.02.011 · Cited by 125 · see citing works
Guérin, A., Sasané, M., Zhang, J., et al. (2015) · Journal of Medical Economics · doi:10.3111/13696998.2014.1003644 · Cited by 104 · see citing works
Hanna, N. H., Johnson, D. H., Temin, S., & Masters, G. A. (2017) · Journal of Oncology Practice · doi:10.1200/jop.2017.026716 · Cited by 100 · see citing works
Gainor, J. F., Chi, A. S., Logan, J., Hu, R., Oh, K. S., Brastianos, P. K., Shih, H. A., & Shaw, A. T. (2015) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2015.10.010 · Cited by 70 · see citing works
“2: 256-260 ALK inhibitors, the frequency of CNS metastases is approximately 60%.(3,4) Recently, it has also been observed that such relapses may include leptomeningeal and intramedullary metastases.”
BackgroundSelf-citationFuture options for ALK-positive non-small cell lung cancer
Iacono, D., Chiari, R., Metro, G., Bennati, C., Bellezza, G., Cenci, M., Ricciuti, B., Sidoni, A., Baglivo, S., Minotti, V., et al. (2015) · Lung Cancer · doi:10.1016/j.lungcan.2014.12.017 · Cited by 55 · see citing works
“Notably, virtually all ALK-TKIs with clinically available data, including both crizotinib as well as next-generation drugs such as ceritinib, alectinib, and AP26113, have showed some degree of activity against CNS metastases (table 5) [46,51,53,70].”
BackgroundNSCLC: An Update of Driver Mutations, Their Role in Pathogenesis and Clinical Significance.
Black, R. C., & Khurshid, H. (2015) · PubMed · Cited by 52 · see citing works
Yoshida, T., Oya, Y., Tanaka, K., et al. (2016) · Lung Cancer · doi:10.1016/j.lungcan.2016.04.006 · Cited by 47 · see citing works
Cooper, M. R., Chim, H., Chan, H., et al. (2014) · Annals of Pharmacotherapy · doi:10.1177/1060028014553619 · Cited by 42 · see citing works
“Adverse reaction data are based on 255 patients treated with ceritinib 750 mg daily for ALK-positive malignancies (n = 246 NSCLC; n = 9 other ALK-positive diseases).(4,10,12) The most common adverse reactions are listed in Table 2.”
MethodInfluentialHendriks, L. E. L., Schoenmaekers, J. J. A. O., Zindler, J. D., Eekers, D. B. P., Hoeben, A., Ruysscher, D. D., & Dingemans, A. C. (2015) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2015.05.005 · Cited by 41 · see citing works
Ceritinib (LDK378): A Potent Alternative to Crizotinib for ALK-Rearranged Non–Small-Cell Lung Cancer
Li, S., Qi, X., Huang, Y., Liu, D., Zhou, F., & Zhou, C. (2014) · Clinical Lung Cancer · doi:10.1016/j.cllc.2014.09.011 · Cited by 40 · see citing works
Targeted therapies and immunotherapy in non-small-cell lung cancer
Cortinovis, D. L., Abbate, M. I., Bidoli, P., Capici, S., & Canova, S. (2016) · ecancermedicalscience · doi:10.3332/ecancer.2016.648 · Cited by 37 · see citing works
“An update of ASCEND 1 trial [77] was performed and the activity of ceritinib was largely confirmed.”
BackgroundUpdate on systemic therapy of advanced non-small-cell lung cancer
Čufer, T., & Knez, L. (2014) · Expert Review of Anticancer Therapy · doi:10.1586/14737140.2014.940327 · Cited by 37 · see citing works
“In addition to the data showing the benefit of EGFR and ALK inhibition beyond progression [38,39,48,49,57,65], new data show that discontinuation of EGFR TKIs might lead to a rapid, lifethreatening progression in approximately one-quarter of patients [66].”
BackgroundCNS Metastases in Patients With Non–Small-Cell Lung Cancer and ALK Gene Rearrangement
Shi, W., & Dicker, A. P. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.63.9682 · Cited by 34 · see citing works
Ye, M., Zhang, X., Li, N., Zhang, Y., Jing, P., Chang, N., Wu, J., Ren, X., & Zhang, J. (2016) · Oncotarget · doi:10.18632/oncotarget.6935 · Cited by 33 · see citing works
“Another encouraging property for ceritinib is its intracranial efficacy [73].”
BackgroundLiao, B.-C., Lin, C., Shih, J., & Yang, J. C. (2015) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834015590593 · Cited by 27 · see citing works
“The authors concluded that ceritinib therapy had a high rate of durable responses and prolonged PFS in both ALK inhibitor-pretreated group and ALK inhibitornaïve patients [Kim et al. 2014].”
BackgroundPharmacotherapeutic options for treating brain metastases in non-small cell lung cancer
Metro, G., Chiari, R., Ricciuti, B., Rebonato, A., Lupattelli, M., Gori, S., Bennati, C., Castrioto, C., Floridi, P., Minotti, V., et al. (2015) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2015.1094056 · Cited by 26 · see citing works
“Ceritinib [60] Allowed 67/124 (54%) 7/14 (50%) Yes Ceritinib [61] Mandatory (Crizotinib) Not reported 13/33 (39.”
BackgroundPersonalized treatment of EGFR mutant and ALK-positive patients in NSCLC
Somasundaram, A., Socinski, M. A., & Burns, T. F. (2014) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2014.971013 · Cited by 23 · see citing works
“2nM against ALK and has dosages up to 750 mg [90-92].”
BackgroundMatikas, A., Kentepozidis, N. K., Georgoulias, V., & Kotsakis, A. P. (2016) · Clinical Lung Cancer · doi:10.1016/j.cllc.2016.05.006 · Cited by 22 · see citing works
Phase I trials in oncology: a new era has started
Postel-Vinay, S. C., & Soria, J. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu513 · Cited by 22 · see citing works
Felip, E., Concha, Á., de Castro, J., Gómez‐Román, J., Garrido, P., Ramírez, J., Isla, D., Sanz, J., Paz-Ares, L. G., & López‐Ríos, F. (2014) · Clinical & Translational Oncology · doi:10.1007/s12094-014-1248-9 · Cited by 21 · see citing works
“In this study [14], 255 patients were treated with 750 mg/day of this drug.”
Self-citationClarke, J. M., Wang, X., & Ready, N. (2015) · PubMed Central · doi:10.3978/j.issn.2218-6751.2015.05.03 · Cited by 19 · see citing works
“Notable examples recently in lung cancer include both crizotinib and ceritinib which were granted accelerated approval by the FDA for the treatment of ALK rearrangement positive NSCLC based on ORR in single-arm, phase II and I studies, respectively (5,6).”
BackgroundTrials to Overcome Drug Resistance to EGFR and ALK Targeted Therapies – Past, Present, and Future
Spaans, J. N., & Goss, G. D. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00233 · Cited by 18 · see citing works
Perez, C. A., Kanaan, Z., Paintal, A., & Kloecker, G. H. (2015) · OncoTargets and Therapy · doi:10.2147/ott.s67262 · Cited by 16 · see citing works
“Reported adverse events were similar to initial reports.(32) A subgroup analysis of the ASCEND-1 trial set out to delineate interethnic variations in safety and efficacy between Asians (n=82) and Caucasians (n=156).”
Melosky, B. L., Cheema, P. K., Agulnik, J. S., Albadine, R., Bebb, D. G., Blais, N., Burkes, R. L., Butts, C. A., Card, P. B., Chan, A. M. Y., et al. (2018) · Current Oncology · doi:10.3747/co.25.4379 · Cited by 16 · see citing works
Self-citationZhou, F., & Zhou, C. (2015) · 癌症：英文版 · doi:10.1186/s40880-015-0036-4 · Cited by 16 · see citing works
“In light of the striking results of this phase I study, an expansion cohort trial including 180 ALK-rearranged NSCLC receiving ceritinib at the recommended dose (750 mg/day) has been reported at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting and the results were promising [57].”
BackgroundKlempner, S. J., & Ou, S. I. (2015) · PubMed · doi:10.3978/j.issn.2304-3865.2015.05.03 · Cited by 14 · see citing works
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BackgroundCeritinib for the Treatment of Late-Stage (Metastatic) Non–Small Cell Lung Cancer
Massarelli, E., & Papadimitrakopoulou, V. A. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1291 · Cited by 14 · see citing works
“Mechanisms of acquired resistance are heterogeneous andmay evolve dynamically in response to different ALK-TKIs and may be divided into two groups: ALK dominant or ALK nondominant ROS1 fusions Resistance mechanisms ALK dominant Secondary mutations in the ALK gene (L1196M, G1269A, 1151T-ins, L1152R, C1156Y, G1202R, S12…”
BackgroundInfluentialCanadian Consensus: Inhibition of Alk-Positive Tumours in Advanced Non-Small-Cell Lung Cancer
Melosky, B. L., Agulnik, J. S., Albadine, R., et al. (2016) · Current Oncology · doi:10.3747/co.23.3120 · Cited by 13 · see citing works
Self-citationMitchell, J. M., Flight, R. M., Lane, A. N., & Moseley, H. (2021) · Metabolites · doi:10.3390/metabo11110740 · Cited by 13 · see citing works
Targeting EGFR and ALK in NSCLC: Current Evidence and Future Perspective
Bennati, C., Paglialunga, L., Ricciuti, B., Metro, G., Marcomigni, L., Gili, A., & Crinò, L. (2016) · Lung Cancer Management · doi:10.2217/lmt-2016-0005 · Cited by 12 · see citing works
Gentzler, R. D., Yentz, S. E., Johnson, M. L., RADEMAKER, A. W., & Patel, J. D. (2014) · Cancer · doi:10.1002/cncr.28956 · Cited by 10 · see citing works
The Future of Targeted Therapies for Brain Metastases
Berghoff, A. S., & Preusser, M. (2015) · Future Oncology · doi:10.2217/fon.15.127 · Cited by 8 · see citing works
First-line treatment of advanced ALK-positive non-small-cell lung cancer
Dy, G. K., Gandhi, S., Chen, H., et al. (2015) · Lung Cancer Targets and Therapy · doi:10.2147/lctt.s63491 · Cited by 9 · see citing works
“In a subset analysis, 124 out of total population of 246 had brain metastases at study entry.(41) Among these 124 patients, 98 had been treated by an ALK inhibitor before, and 26 were ALK inhibitor treatment-naïve.”
Martinez, R. (2019) · JACC Heart Failure · doi:10.1016/j.jchf.2018.12.003 · Cited by 8 · see citing works
Carnio, S., Novello, S., Bironzo, P., & Scagliotti, G. V. (2014) · Expert Review of Anticancer Therapy · doi:10.1586/14737140.2014.949245 · Cited by 7 · see citing works
“Treatment was reasonably tolerated and the most common AEs included diarrhea (84%), nausea (77%), vomiting (57%), fatigue (36%), and ALT increased (36%) [66].”
BackgroundWorley, S. L. (2014) · PubMed · Cited by 6 · see citing works
Kuribayashi, H., Abe, S., Kuse, N., et al. (2015) · International Cancer Conference Journal · doi:10.1007/s13691-015-0231-9 · Cited by 6 · see citing works
Profile of ceritinib in the treatment of ALK+ metastatic non-small-cell lung cancer
Kim, E. S., & Burns, M. (2015) · Lung Cancer Targets and Therapy · doi:10.2147/lctt.s69114 · Cited by 5 · see citing works
Leprieur, E. G., Fallet, V., & Wislez, M. (2015) · Bulletin du Cancer · doi:10.1016/j.bulcan.2015.09.007 · Cited by 5 · see citing works
López‐Ríos, F., de Castro, J., Concha, Á., Garrido, P., Gómez‐Román, J., Isla, D., Ramírez, J., Paz-Ares, L. G., Sanz‐Ortega, J., & Felip, E. (2014) · Revista Española de Patología · doi:10.1016/j.patol.2014.10.005 · Cited by 5 · see citing works
Self-citationAn Efficient Synthesis of Ceritinib (LDK378) Using a Sandmeyer Reaction
Liu, H., Li, Y., Wang, D., et al. (2015) · Journal of Chemical Research · doi:10.3184/174751915x14381780373834 · Cited by 3 · see citing works
[Advances in treatment of brain metastases from primary non-small cell lung cancer].
Lin, G., Xu, H., & Huang, C. (2014) · Europe PMC (PubMed Central) · doi:10.3779/j.issn.1009-3419.2014.12.10 · Cited by 2 · see citing works
Ricciuti, B., Brambilla, M., Giglio, A. D., et al. (2017) · Journal of Radiation Oncology · doi:10.1007/s13566-017-0293-8 · Cited by 1 · see citing works
Safety and efficacy of targeted agents monotherapy in advanced NSCLC
Zhang, Q., & Wu, Y.-L. L. C. (2015) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2016.1101340 · Cited by 1 · see citing works
“9 months, regardless of ethnicity or prior treatment with crizotinib.[61,62] For patients with brain metastases, ceritinib 750 mg/day was efficacious whether ALK inhibitor-pretreated (ORR: 50%; PFS: 6.”
Background[Current status of targeted therapy for anaplastic lymphoma kinase in non-small cell lung cancer].
Ma, L., & Zhang, S. (2014) · PubMed · doi:10.3779/j.issn.1009-3419.2014.12.05
Agents in the preclinical development stage for non-small cell lung cancer
Sacco, P. C., Sgambato, A., Casaluce, F., Maione, P., Rossi, A., Palazzolo, G., Napolitano, A., & Gridelli, C. (2015) · Expert Review of Anticancer Therapy · doi:10.1586/14737140.2015.1092875
“Thus, the second-generation ALK inhibitors have been developed and among these, ceritinib has been approved in USA by the US FDA and in Europe by the EMA for the treatment of patients with disease progression or intolerance to crizotinib [20].”
BackgroundSgambato, A., Casaluce, F., Rossi, A., Maione, P., Sacco, P. C., Ciardiello, F., & Gridelli, C. (2015) · Clinical Investigation · doi:10.4155/cli.14.121
ASCO 2014 – 50 Jahre onkologische Forschung auf höchstem Niveau
Junker, A. (2014) · Der Onkologe · doi:10.1007/s00761-014-2749-4
Towards Manageable Toxicities From Targeted Lung Cancer Treatment
Mohindra, N. A., & Patel, J. D. (2015) · Lung Cancer Management · doi:10.2217/lmt.15.30
Achievements in targeted therapies
Bironzo, P., Mele, T., & Novello, S. (2015) · European Respiratory Society eBooks · doi:10.1183/2312508x.10010714
Treatment After Crizotinib Resistance in ALK+ Non-Small-Cell Lung Cancer
Kazaz, S. N. (2017) · International Journal of Hematology and Oncology · doi:10.4999/uhod.171786
- Authors
- Kim, D.-W., Mehra, R., Tan, D. S.-W., Felip, E., Chow, L. Q. M., Camidge, D. R., Vansteenkiste, J. F., Sharma, S., De Pas, T., Riely, G. J., Solomon, B. J., Wolf, J., Thomas, M., Schuler, M. H., Liu, G., Santoro, A., Geraldes, M., Boral, A., Yovine, A. J., & Shaw, A. T.
- Affiliations
- Seoul National University Hospital (KR)
- Fox Chase Cancer Center (US)
- National Cancer Centre Singapore (SG)
- Vall d'Hebron Hospital Universitari (ES)
- University of Washington (US)
- University of Colorado Cancer Center (US)
- Universitair Ziekenhuis Leuven (BE)
- University of Utah (US)
- Instituto Europeo di Oncologia, Milan, Italy
- Memorial Sloan Kettering Cancer Center (US)
- Peter MacCallum Cancer Centre (AU)
- University Hospital Cologne (DE)
- Heidelberg University (DE)
- University Hospital Essen, University Duisburg-Essen, Essen, Germany and German Cancer Consortium, Heidelberg, Germany
- Princess Margaret Cancer Centre (CA)
- IRCCS Humanitas Research Hospital (IT)
- Novartis (United States) (US)
- Novartis Institutes for BioMedical Research, Cambridge, MA
- Novartis (Switzerland) (CH)
- Massachusetts General Hospital (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2014-05-20
- Volume
- 32
- Issue
- 15_suppl
- Pages
- 8003-8003
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2245637869
- Cited by
- 57
- References
- 0
- Citations by year
- 2021: 1 · 2019: 1 · 2018: 1 · 2017: 4 · 2016: 9 · 2015: 27 · 2014: 14
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- 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, anaplastic lymphoma kinase, ALK-positive non-small cell lung cancer, ALK inhibitors, crizotinib resistance, objective response rate, progression-free survival, overall survival, adverse events, diarrhea, elevated liver enzymes, recommended dose, targeted therapy, oral anticancer drugs
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