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Daniel Shaoweng Tan - One of the best experts on this subject based on the ideXlab platform.
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Ceritinib efficacy and safety in treatment naive asian patients with advanced alk rearranged nsclc an ascend 4 subgroup analysis
JTO Clinical and Research Reports, 2021Co-Authors: Daniel Shaoweng Tan, Sarayut Lucien Geater, Chun-ming Tsai, Te Chun Hsia, Jun Chen, Meng-chih Lin, Virote Sriuranpong, Cheng-ta Yang, Paramita Sen, Fabrice BranleAbstract:Abstract Introduction In the phase 3 ASCEND-4 study, Ceritinib exhibited improved progression-free survival (PFS) by Blinded Independent Review Committee (BIRC) assessment versus the standard first-line chemotherapy in patients with advanced ALK-rearranged NSCLC. Here, we assessed the efficacy and safety of Ceritinib in the subgroup of Asian patients from the ASCEND-4 trial. Methods Treatment-naive patients with stage IIIB or IV ALK-rearranged nonsquamous NSCLC were randomized in a one-to-one ratio to receive either oral Ceritinib 750 mg/day (fasted) daily or intravenous chemotherapy ([cisplatin 75 mg/m2 or carboplatin area under the curve 5–6 plus pemetrexed 500 mg/m2] every three wk, followed by pemetrexed maintenance). The primary end point was PFS by BIRC assessment. Results Of 376 randomized patients, 158 (42.0%) were Asian (Ceritinib arm: N = 76; chemotherapy arm: N = 82). The median time from randomization to the cutoff date (June 24, 2016) was 18.3 months (range = 13.5–34.2) in the Asian subgroup. The median PFS (by BIRC assessment) was 26.3 months (95% confidence interval [CI]: 8.6–not estimable) and 10.6 months (95% CI: 6.7–15.0), with an estimated 34% risk reduction in PFS (hazard ratio = 0.66, 95% CI: 0.41–1.05) in the Ceritinib arm versus chemotherapy arm. The most common adverse events of any grade were diarrhea (85.5%), increased alanine aminotransferase and vomiting (73.7% each), and increased aspartate aminotransferase and nausea (69.7% each) in the Ceritinib arm, and nausea (49.3%), vomiting (42.7%), and anemia (40.0%) in the chemotherapy arm. Conclusion Ceritinib was effective and safe in treatment-naive Asian patients with advanced ALK-rearranged NSCLC. The findings were largely consistent with that of the overall study population.
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comparative efficacy of Ceritinib and crizotinib as initial alk targeted therapies in previously treated advanced nsclc an adjusted comparison with external controls
Journal of Thoracic Oncology, 2016Co-Authors: Daniel Shaoweng Tan, Zheng-yi Zhou, António Araújo, Jie Zhang, James Signorovitch, Xiaopeng Cai, Geoffrey LiuAbstract:Introduction Crizotinib and Ceritinib have been developed to treat advanced or metastatic NSCLC by inhibiting anaplastic lymphoma receptor tyrosine kinase gene (ALK). No randomized trial has compared these treatments head-to-head. We compared efficacy outcomes between patients receiving Ceritinib and an external control group receiving crizotinib, both as initial ALK-targeted therapies for previously treated advanced or metastatic ALK-positive NSCLC. Methods Individual patient data for the Ceritinib-treated patients were drawn from two single-arm trials (ASCEND-1 and ASCEND-3); published summary data for the crizotinib-treated patients were extracted from three trials (PROFILE 1001, PROFILE 1005, and PROFILE 1007). To adjust for cross-trial differences, average baseline characteristics were matched using propensity score weighting. Overall survival (OS), progression-free survival (PFS), and overall response rate were then compared between treatment groups. Results Before matching, the Ceritinib-treated patients (n = 189) were significantly different from the crizotinib-treated patients (n = 557) in the distribution of race and number of prior regimens. After matching, all available baseline characteristics were balanced. Compared with crizotinib, Ceritinib was associated with longer OS (hazard ratio = 0.59, 95% confidence interval: 0.46-0.75) and longer PFS (median 13.8 versus 8.3 months, hazard ratio = 0.52, 95% confidence interval: 0.44-0.62) in Cox proportional hazards models. The 12-month OS was 82.6% with Ceritinib and 66.0% with crizotinib in a Kaplan-Meier analysis (log-rank p Conclusions In an adjusted comparison across separate clinical trials, Ceritinib was associated with prolonged OS and PFS compared with crizotinib when used as initial ALK-targeted therapy for previously treated ALK-positive NSCLC.
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Comparative Efficacy of Ceritinib and Crizotinib as Initial ALK–Targeted Therapies in Previously Treated Advanced NSCLC: An Adjusted Comparison with External Controls
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2016Co-Authors: Daniel Shaoweng Tan, Zheng-yi Zhou, António Araújo, Jie Zhang, James Signorovitch, Xiaopeng Cai, Geoffrey LiuAbstract:Introduction Crizotinib and Ceritinib have been developed to treat advanced or metastatic NSCLC by inhibiting anaplastic lymphoma receptor tyrosine kinase gene (ALK). No randomized trial has compared these treatments head-to-head. We compared efficacy outcomes between patients receiving Ceritinib and an external control group receiving crizotinib, both as initial ALK-targeted therapies for previously treated advanced or metastatic ALK-positive NSCLC. Methods Individual patient data for the Ceritinib-treated patients were drawn from two single-arm trials (ASCEND-1 and ASCEND-3); published summary data for the crizotinib-treated patients were extracted from three trials (PROFILE 1001, PROFILE 1005, and PROFILE 1007). To adjust for cross-trial differences, average baseline characteristics were matched using propensity score weighting. Overall survival (OS), progression-free survival (PFS), and overall response rate were then compared between treatment groups. Results Before matching, the Ceritinib-treated patients (n = 189) were significantly different from the crizotinib-treated patients (n = 557) in the distribution of race and number of prior regimens. After matching, all available baseline characteristics were balanced. Compared with crizotinib, Ceritinib was associated with longer OS (hazard ratio = 0.59, 95% confidence interval: 0.46-0.75) and longer PFS (median 13.8 versus 8.3 months, hazard ratio = 0.52, 95% confidence interval: 0.44-0.62) in Cox proportional hazards models. The 12-month OS was 82.6% with Ceritinib and 66.0% with crizotinib in a Kaplan-Meier analysis (log-rank p Conclusions In an adjusted comparison across separate clinical trials, Ceritinib was associated with prolonged OS and PFS compared with crizotinib when used as initial ALK-targeted therapy for previously treated ALK-positive NSCLC.
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Genetic landscape of ALK+ non-small cell lung cancer (NSCLC) patients (pts) and response to Ceritinib in ASCEND-1.
Journal of Clinical Oncology, 2016Co-Authors: Daniel Shaoweng Tan, Dong-wan Kim, Ranee Mehra, Laura Q.m. Chow, Michael Thomas, Serafino Pantano, Ying Wang, Sebastian Szpakowski, A. Yovine, Sunil SharmaAbstract:9064Background: To better understand genetic determinants of response to Ceritinib, tumor biopsies from NSCLC pts treated with Ceritinib in ASCEND-1 (NCT01283516) were analyzed by next-generation s...
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whole body and intracranial efficacy of Ceritinib in alk inhibitor alki naive patients pts with alk rearranged alk nsclc and baseline bl brain metastases bm results from ascend 1 and 3
Journal of Clinical Oncology, 2016Co-Authors: Enriqueta Felip, Daniel Shaoweng Tan, Makoto Nishio, Dong-wan Kim, Ranee Mehra, Keunchil Park, Tony Mok, Sergey Orlov, Giorgio V Scagliotti, David R SpigelAbstract:e20520Background: Here we present efficacy outcomes in ALK+ NSCLC pts with BL BM treated with the selective oral ALKi Ceritinib in the ASCEND-1 (ph1; NCT01283516) and ASCEND-3 (ph2; NCT01685138) trials. Methods: ALKi-naive pts with ALK+ NSCLC and stable BL BM received Ceritinib 750 mg/d. Efficacy analyses (by blinded independent review committee [BIRC]) assessed whole body responses for ASCEND-1 and -3 according to RECIST 1.0 and 1.1 criteria, respectively. Pooled intracranial responses were evaluated by BIRC (ASCEND-1, retrospectively; ASCEND-3, prospectively) in pts with measureable BL BM (RECIST 1.1). Results: Of 26 and 50 ALKi-naive pts with BL BM enrolled in ASCEND-1 and -3, respectively, 88.5% and 100% had prior chemotherapy and 57.7% and 54.0% had prior brain radiotherapy (RT); median times from prior RT to first Ceritinib dose were 4.6 and 2.7 mo. Ceritinib showed whole body and intracranial efficacy (Table). The most common AEs (ASCEND-1; ASCEND-3) were nausea (84.6%; 78.0%), diarrhea (92.3%; 76....
Tommaso De Pas - One of the best experts on this subject based on the ideXlab platform.
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Molecular and clinical features of second-generation anaplastic lymphoma kinase inhibitors: Ceritinib.
Future oncology (London England), 2017Co-Authors: Tommaso De Pas, Laura Pala, Chiara Catania, Fabio ConfortiAbstract:The discovery of ALK rearrangement in non-small-cell lung cancer (NSCLC) triggered rapid clinical development of a family of specific drugs targeting this alteration, called ALK inhibitors. Despite high rate of responses, the vast majority of patients treated with first-generation ALK inhibitor crizotinib will ultimately develop disease progression. The second-generation ALK inhibitor, Ceritinib, is an oral, small-molecule that inhibits the ALK kinase activity with a potency 20-fold greater than crizotinib, being able to tackle some of the principal mechanisms of resistance to crizotinib. Evidences from five large prospective clinical trials have so far showed impressive activity of Ceritinib in ALK inhibitor pretreated and naive NSCLC patients. This review will focus on the preclinical and clinical data available regarding Ceritinib pharmacology, clinical efficacy and safety profile.
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Ceritinib in asian versus caucasian patients pts with advanced anaplastic lymphoma kinase alk rearranged alk nsclc subgroup analysis of the ascend 1 trial
Journal of Clinical Oncology, 2014Co-Authors: Daniel Shaoweng Tan, Enriqueta Felip, Alice T. Shaw, Ranee Mehra, Laura Q.m. Chow, Johan Vansteenkiste, Sunil Sharma, Tommaso De Pas, Ross D Camidge, Gregory J RielyAbstract:8078^ Background: Prior results from the first-in-human phase I study (ASCEND-1) of the novel ALK inhibitor (ALKi) Ceritinib (LDK378), demonstrated high response rates in crizotinib (CRZ)-naive and CRZ-resistant patients, and established 750 mg/day as maximum tolerated dose. As inter-ethnic variations can lead to differences in treatment response in Asian vs Caucasian pts, we report here a subgroup analysis of the data for pts with ALK+ NSCLC receiving Ceritinib at 750 mg/day. Methods: In ASCEND-1, adult pts with advanced ALK+ cancers received oral Ceritinib once daily. Investigator assessment of efficacy is presented for pts who received a first dose of Ceritinib ≥18 wks prior to the cut-off date (2 Aug 2013). Results: 246 pts with ALK+ NSCLC (82 Asian, 156 Caucasian, 8 other) received Ceritinib 750 mg/day with median follow-up of 4.5 months (mos). 67% of patients had received ≥2 prior anticancer therapies. Between Asian and Caucasian pts baseline demographics were similar but ALKi pretreatment had been ...
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Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer
The New England journal of medicine, 2014Co-Authors: Alice T. Shaw, Enriqueta Felip, Daniel Shaoweng Tan, Dong-wan Kim, Ranee Mehra, Laura Q.m. Chow, D. Ross Camidge, Johan Vansteenkiste, Sunil Sharma, Tommaso De PasAbstract:BackgroundNon–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. MethodsIn this phase 1 study, we administered oral Ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of Ceritinib. Tumor biopsies were performed before Ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. ResultsA total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of Ceritinib was 750 mg once daily; dose-l...
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Ceritinib in alk rearranged non small cell lung cancer
The New England Journal of Medicine, 2014Co-Authors: Alice T. Shaw, Laura Quan Man Chow, Enriqueta Felip, Daniel Shaoweng Tan, Dong-wan Kim, Ranee Mehra, Johan Vansteenkiste, Sunil Sharma, Ross D Camidge, Tommaso De PasAbstract:BackgroundNon–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. MethodsIn this phase 1 study, we administered oral Ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of Ceritinib. Tumor biopsies were performed before Ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. ResultsA total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of Ceritinib was 750 mg once daily; dose-l...
Enriqueta Felip - One of the best experts on this subject based on the ideXlab platform.
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The accelerated path of Ceritinib: Translating pre-clinical development into clinical efficacy
Cancer Treatment Reviews, 2017Co-Authors: Lucio Crinò, Enriqueta Felip, Ravi Salgia, Laura Quan Man ChowAbstract:Abstract The discovery of anaplastic lymphoma kinase ( ALK )-rearranged non–small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved—Ceritinib and alectinib—and others that are in development—brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK -positive ( ALK +) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for Ceritinib penetration across the blood-brain barrier. In clinical trials, Ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor–pre-treated and –naive NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of Ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK + NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK -mutation–driven tumors.
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whole body and intracranial efficacy of Ceritinib in alk inhibitor alki naive patients pts with alk rearranged alk nsclc and baseline bl brain metastases bm results from ascend 1 and 3
Journal of Clinical Oncology, 2016Co-Authors: Enriqueta Felip, Daniel Shaoweng Tan, Makoto Nishio, Dong-wan Kim, Ranee Mehra, Keunchil Park, Tony Mok, Sergey Orlov, Giorgio V Scagliotti, David R SpigelAbstract:e20520Background: Here we present efficacy outcomes in ALK+ NSCLC pts with BL BM treated with the selective oral ALKi Ceritinib in the ASCEND-1 (ph1; NCT01283516) and ASCEND-3 (ph2; NCT01685138) trials. Methods: ALKi-naive pts with ALK+ NSCLC and stable BL BM received Ceritinib 750 mg/d. Efficacy analyses (by blinded independent review committee [BIRC]) assessed whole body responses for ASCEND-1 and -3 according to RECIST 1.0 and 1.1 criteria, respectively. Pooled intracranial responses were evaluated by BIRC (ASCEND-1, retrospectively; ASCEND-3, prospectively) in pts with measureable BL BM (RECIST 1.1). Results: Of 26 and 50 ALKi-naive pts with BL BM enrolled in ASCEND-1 and -3, respectively, 88.5% and 100% had prior chemotherapy and 57.7% and 54.0% had prior brain radiotherapy (RT); median times from prior RT to first Ceritinib dose were 4.6 and 2.7 mo. Ceritinib showed whole body and intracranial efficacy (Table). The most common AEs (ASCEND-1; ASCEND-3) were nausea (84.6%; 78.0%), diarrhea (92.3%; 76....
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Ceritinib in asian versus caucasian patients pts with advanced anaplastic lymphoma kinase alk rearranged alk nsclc subgroup analysis of the ascend 1 trial
Journal of Clinical Oncology, 2014Co-Authors: Daniel Shaoweng Tan, Enriqueta Felip, Alice T. Shaw, Ranee Mehra, Laura Q.m. Chow, Johan Vansteenkiste, Sunil Sharma, Tommaso De Pas, Ross D Camidge, Gregory J RielyAbstract:8078^ Background: Prior results from the first-in-human phase I study (ASCEND-1) of the novel ALK inhibitor (ALKi) Ceritinib (LDK378), demonstrated high response rates in crizotinib (CRZ)-naive and CRZ-resistant patients, and established 750 mg/day as maximum tolerated dose. As inter-ethnic variations can lead to differences in treatment response in Asian vs Caucasian pts, we report here a subgroup analysis of the data for pts with ALK+ NSCLC receiving Ceritinib at 750 mg/day. Methods: In ASCEND-1, adult pts with advanced ALK+ cancers received oral Ceritinib once daily. Investigator assessment of efficacy is presented for pts who received a first dose of Ceritinib ≥18 wks prior to the cut-off date (2 Aug 2013). Results: 246 pts with ALK+ NSCLC (82 Asian, 156 Caucasian, 8 other) received Ceritinib 750 mg/day with median follow-up of 4.5 months (mos). 67% of patients had received ≥2 prior anticancer therapies. Between Asian and Caucasian pts baseline demographics were similar but ALKi pretreatment had been ...
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Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer
The New England journal of medicine, 2014Co-Authors: Alice T. Shaw, Enriqueta Felip, Daniel Shaoweng Tan, Dong-wan Kim, Ranee Mehra, Laura Q.m. Chow, D. Ross Camidge, Johan Vansteenkiste, Sunil Sharma, Tommaso De PasAbstract:BackgroundNon–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. MethodsIn this phase 1 study, we administered oral Ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of Ceritinib. Tumor biopsies were performed before Ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. ResultsA total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of Ceritinib was 750 mg once daily; dose-l...
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Ceritinib in alk rearranged non small cell lung cancer
The New England Journal of Medicine, 2014Co-Authors: Alice T. Shaw, Laura Quan Man Chow, Enriqueta Felip, Daniel Shaoweng Tan, Dong-wan Kim, Ranee Mehra, Johan Vansteenkiste, Sunil Sharma, Ross D Camidge, Tommaso De PasAbstract:BackgroundNon–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. MethodsIn this phase 1 study, we administered oral Ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of Ceritinib. Tumor biopsies were performed before Ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. ResultsA total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of Ceritinib was 750 mg once daily; dose-l...
Luc Friboulet - One of the best experts on this subject based on the ideXlab platform.
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p glycoprotein mediates Ceritinib resistance in anaplastic lymphoma kinase rearranged non small cell lung cancer
EBioMedicine, 2016Co-Authors: Ryohei Katayama, Justin F Gainor, Luc Friboulet, Noriko Yanagitani, Takuya Sakashita, Hironori Ninomiya, Atsushi Horiike, Noriko Motoi, Akito DobashiAbstract:The anaplastic lymphoma kinase (ALK) fusion oncogene is observed in 3%-5% of non-small cell lung cancer (NSCLC). Crizotinib and Ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI) active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect. To date, various secondary mutations or bypass pathway activation-mediated resistance have been identified, but large parts of the resistance mechanism are yet to be identified. Here, we report the discovery of p-glycoprotein (P-gp/ABCB1) overexpression as a Ceritinib resistance mechanism in ALK-rearranged NSCLC patients. P-gp exported Ceritinib and its overexpression conferred Ceritinib and crizotinib resistance, but not to PF-06463922 or alectinib, which are next-generation ALK inhibitors. Knockdown of ABCB1 or P-gp inhibitors sensitizes the patient-derived cancer cells to Ceritinib, in vitro and in vivo. P-gp overexpression was identified in three out of 11 cases with in ALK-rearranged crizotinib or Ceritinib resistant NSCLC patients. Our study suggests that alectinib, PF-06463922, or P-gp inhibitor with Ceritinib could overcome the Ceritinib or crizotinib resistance mediated by P-gp overexpression.
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progression free and overall survival in alk positive nsclc patients treated with sequential crizotinib and Ceritinib
Clinical Cancer Research, 2015Co-Authors: Justin F Gainor, Daniel Shaoweng Tan, Tomasso De Pas, Benjamin Solomon, Aziah Ahmad, Chiara Lazzari, Filippo De Marinis, Gianluca Spitaleri, Katherine Schultz, Luc FribouletAbstract:Purpose: Anaplastic lymphoma kinase ( ALK ) rearrangements are important therapeutic targets in non–small cell lung cancer (NSCLC) that confer sensitivity to the ALK inhibitors crizotinib and Ceritinib. To determine the outcome of sequential treatment with crizotinb and Ceritinib, we retrospectively evaluated a cohort of ALK-positive patients treated with both agents. Experimental Design: We identified 73 ALK-positive NSCLC patients treated with crizotinib followed by Ceritinib at four institutions. Medical records were reviewed to determine overall survival (OS) and progression-free survival (PFS) on crizotinib and Ceritinib. Results: Among 73 ALK-positive patients, the median PFS (mPFS) on crizotinib was 8.2 months [95% confidence interval (CI), 7.4–10.6]. The median interval from crizotinib discontinuation to initiation of Ceritinib was 25 days (range, 1–694). The mPFS on Ceritinib was 7.8 months (6.5–9.1). Among 53 patients with no interval therapies between crizotinib and Ceritinib, the mPFS on Ceritinib was similar at 7.8 months (5.4–9.8). The median combined PFS for sequential treatment with crizotinib and Ceritinib was 17.4 months (15.5–19.4). Among 23 patients who underwent post-crizotinib/pre-Ceritinib biopsies, there was no difference in PFS on Ceritinib between patients with or without ALK resistance mutations (mPFS 5.8 vs. 6.5 months, respectively; P = 0.510). In the overall study population, median OS was 49.4 months (35.5–63.1). Conclusions: Ceritinib has significant antitumor activity in ALK-positive NSCLC—even when crizotinib immediately precedes treatment with Ceritinib (median combined PFS 17.0 months). Additional studies are necessary to further define the impact of specific ALK resistance mutations on duration of response to Ceritinib. Clin Cancer Res; 1–8. ©2015 AACR.
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the alk inhibitor Ceritinib overcomes crizotinib resistance in non small cell lung cancer
Cancer Discovery, 2014Co-Authors: Luc Friboulet, Justin F Gainor, Ryohei Katayama, Christian C Lee, Adam S Crystal, Pierreyves Michellys, Mark M Awad, Noriko Yanagitani, Sungjoon Kim, Annemarie Culazzo PferdekamperAbstract:Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, Ceritinib (LDK378) in the setting of crizotinib resistance. Interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of crizotinib-resistant NSCLC patients revealed that Ceritinib potently overcomes crizotinib resistance mutations. In particular, Ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T and S1206Y mutations, and a co-crystal of Ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that Ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations were identified in 5 out of 11 biopsies from patients with acquired resistance to Ceritinib. Altogether our results demonstrate that Ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of Ceritinib in patients with crizotinib-resistant disease.
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The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non–Small Cell Lung Cancer
Cancer discovery, 2014Co-Authors: Luc Friboulet, Justin F Gainor, Ryohei Katayama, Christian C Lee, Adam S Crystal, Pierreyves Michellys, Mark M Awad, Noriko Yanagitani, Sungjoon KimAbstract:Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, Ceritinib (LDK378) in the setting of crizotinib resistance. Interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of crizotinib-resistant NSCLC patients revealed that Ceritinib potently overcomes crizotinib resistance mutations. In particular, Ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T and S1206Y mutations, and a co-crystal of Ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that Ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations were identified in 5 out of 11 biopsies from patients with acquired resistance to Ceritinib. Altogether our results demonstrate that Ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of Ceritinib in patients with crizotinib-resistant disease.
Sunil Sharma - One of the best experts on this subject based on the ideXlab platform.
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Genetic landscape of ALK+ non-small cell lung cancer (NSCLC) patients (pts) and response to Ceritinib in ASCEND-1.
Journal of Clinical Oncology, 2016Co-Authors: Daniel Shaoweng Tan, Dong-wan Kim, Ranee Mehra, Laura Q.m. Chow, Michael Thomas, Serafino Pantano, Ying Wang, Sebastian Szpakowski, A. Yovine, Sunil SharmaAbstract:9064Background: To better understand genetic determinants of response to Ceritinib, tumor biopsies from NSCLC pts treated with Ceritinib in ASCEND-1 (NCT01283516) were analyzed by next-generation s...
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Ceritinib in asian versus caucasian patients pts with advanced anaplastic lymphoma kinase alk rearranged alk nsclc subgroup analysis of the ascend 1 trial
Journal of Clinical Oncology, 2014Co-Authors: Daniel Shaoweng Tan, Enriqueta Felip, Alice T. Shaw, Ranee Mehra, Laura Q.m. Chow, Johan Vansteenkiste, Sunil Sharma, Tommaso De Pas, Ross D Camidge, Gregory J RielyAbstract:8078^ Background: Prior results from the first-in-human phase I study (ASCEND-1) of the novel ALK inhibitor (ALKi) Ceritinib (LDK378), demonstrated high response rates in crizotinib (CRZ)-naive and CRZ-resistant patients, and established 750 mg/day as maximum tolerated dose. As inter-ethnic variations can lead to differences in treatment response in Asian vs Caucasian pts, we report here a subgroup analysis of the data for pts with ALK+ NSCLC receiving Ceritinib at 750 mg/day. Methods: In ASCEND-1, adult pts with advanced ALK+ cancers received oral Ceritinib once daily. Investigator assessment of efficacy is presented for pts who received a first dose of Ceritinib ≥18 wks prior to the cut-off date (2 Aug 2013). Results: 246 pts with ALK+ NSCLC (82 Asian, 156 Caucasian, 8 other) received Ceritinib 750 mg/day with median follow-up of 4.5 months (mos). 67% of patients had received ≥2 prior anticancer therapies. Between Asian and Caucasian pts baseline demographics were similar but ALKi pretreatment had been ...
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Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer
The New England journal of medicine, 2014Co-Authors: Alice T. Shaw, Enriqueta Felip, Daniel Shaoweng Tan, Dong-wan Kim, Ranee Mehra, Laura Q.m. Chow, D. Ross Camidge, Johan Vansteenkiste, Sunil Sharma, Tommaso De PasAbstract:BackgroundNon–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. MethodsIn this phase 1 study, we administered oral Ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of Ceritinib. Tumor biopsies were performed before Ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. ResultsA total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of Ceritinib was 750 mg once daily; dose-l...
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Ceritinib in alk rearranged non small cell lung cancer
The New England Journal of Medicine, 2014Co-Authors: Alice T. Shaw, Laura Quan Man Chow, Enriqueta Felip, Daniel Shaoweng Tan, Dong-wan Kim, Ranee Mehra, Johan Vansteenkiste, Sunil Sharma, Ross D Camidge, Tommaso De PasAbstract:BackgroundNon–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. MethodsIn this phase 1 study, we administered oral Ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of Ceritinib. Tumor biopsies were performed before Ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. ResultsA total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of Ceritinib was 750 mg once daily; dose-l...