The Experts below are selected from a list of 4587 Experts worldwide ranked by ideXlab platform

Peter N. Morcos - One of the best experts on this subject based on the ideXlab platform.

Dong-wan Kim - One of the best experts on this subject based on the ideXlab platform.

  • brigatinib versus crizotinib in advanced ALK Inhibitor naive ALK positive non small cell lung cancer second interim analysis of the phase iii alta 1l trial
    Journal of Clinical Oncology, 2020
    Co-Authors: Ross D Camidge, James Chihhsin Yang, Hye Ryun Kim, Myungju Ahn, Ji Youn Han, M J Hochmair, Ki Hyeong Lee, Angelo Delmonte, Maria Rosario Garcia Campelo, Dong-wan Kim
    Abstract:

    PURPOSEBrigatinib, a next-generation anaplastic lymphoma kinase (ALK) Inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizo...

  • 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
    Lancet Oncology, 2016
    Co-Authors: Dong-wan Kim, Laura Quan Man Chow, Enriqueta Felip, Daniel Shaoweng Tan, Ranee Mehra, Johan Vansteenkiste, Sunil Sharma, Tommaso De Pas, Ross D Camidge, Gregory J Riely
    Abstract:

    Summary 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.

  • first line crizotinib versus pemetrexed cisplatin or pemetrexed carboplatin in patients pts with advanced ALK positive non squamous non small cell lung cancer nsclc results of a phase iii study profile 1014
    Journal of Clinical Oncology, 2014
    Co-Authors: Tony Mok, Enriqueta Felip, Kazuhiko Nakagawa, Benjamin Solomon, Dong-wan Kim, Tarek Mekhail, Federico Cappuzzo, Jolanda Paolini, Tiziana Usari, J Tursi
    Abstract:

    8002 Background: The efficacy of the oral ALK Inhibitor crizotinib as 1st-line treatment for advanced ALK-positive NSCLC compared with standard chemotherapy is unknown. A multicenter, randomized op...

  • ceritinib in advanced anaplastic lymphoma kinase ALK rearranged ALK non small cell lung cancer nsclc results of the ascend 1 trial
    Journal of Clinical Oncology, 2014
    Co-Authors: Dong-wan Kim, Laura Quan Man Chow, Enriqueta Felip, Daniel Shaoweng Tan, Ranee Mehra, Johan Vansteenkiste, Sunil Sharma, Tommaso De Pas, Ross D Camidge, Gregory J Riely
    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-b...

  • ceritinib in ALK rearranged non small cell lung cancer
    The New England Journal of Medicine, 2014
    Co-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 Pas
    Abstract:

    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...

Elena Guerini - One of the best experts on this subject based on the ideXlab platform.

  • alectinib exposure response er in ALK Inhibitor naive ALK positive nsclc patients pooled analysis across phase iii studies
    Journal of Clinical Oncology, 2019
    Co-Authors: Kevin Smart, Elena Guerini, Walter Bordogna, Alice T. Shaw, Felix Jaminion, Joy C. Hsu, Caicun Zhou, Tony Mok, Nicolas Frey, Peter N. Morcos
    Abstract:

    e20575Background: Alectinib superiority to crizotinib has been demonstrated in ALK-Inhibitor naive ALK-positive NSCLC patients (pts) in Phase III studies conducted in Japanese (J-ALEX; JapicCTI-132...

  • exposure response analysis of alectinib in crizotinib resistant ALK positive non small cell lung cancer
    Cancer Chemotherapy and Pharmacology, 2018
    Co-Authors: Peter N. Morcos, Elena Guerini, Walter Bordogna, Bogdana Balas, Eveline Nueesch, Felix Jaminion, Joy C. Hsu, Francois Mercier
    Abstract:

    Purpose Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) Inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess alectinib dose selection.

  • population pharmacokinetics poppk and exposure response er analyses bridge j alex to the global population with an alectinib alc 600mg bid dosing regimen
    Journal of Clinical Oncology, 2017
    Co-Authors: Joy C. Hsu, Elena Guerini, Peter N. Morcos, Bogdana Balas, Felix Jaminion, A Zeaiter, Tomohiro Tanaka, Sophie Golding, Nicolas Frey
    Abstract:

    e20616Background: J-ALEX showed superiority of ALC 300mg BID vs crizotinib (CRIZ) in Japanese ALK Inhibitor naive ALK-positive NSCLC patients (pts). PopPK and ER analyses were used to bridge J-ALEX...

  • clinical drug drug interactions through cytochrome p450 3a cyp3a for the selective ALK Inhibitor alectinib
    Clinical pharmacology in drug development, 2017
    Co-Authors: Peter N. Morcos, Elena Guerini, Georgina Dall, Luigi De Petris, Santiago Viteri, Katrijn Bogman, Walter Bordogna, Yumi Cleary, Li Yu, Meret Martinfacklam
    Abstract:

    The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) Inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small-cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from three fixed-sequence studies evaluating drug–drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is co-administered with CYP3A Inhibitors or inducers, or for co-administered CYP3A substrates. This article is protected by copyright. All rights reserved

  • clinical drug drug interactions through cytochrome p450 3a cyp3a for the selective ALK Inhibitor alectinib
    Clinical pharmacology in drug development, 2017
    Co-Authors: Peter N. Morcos, Elena Guerini, Georgina Dall, Luigi De Petris, Santiago Viteri, Meret Martinfacklam, Katrijn Bogman, Walter Bordogna, Yumi Cleary, Alex Phipps
    Abstract:

    The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) Inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A Inhibitors or inducers or for coadministered CYP3A substrates.

Walter Bordogna - One of the best experts on this subject based on the ideXlab platform.

  • alectinib exposure response er in ALK Inhibitor naive ALK positive nsclc patients pooled analysis across phase iii studies
    Journal of Clinical Oncology, 2019
    Co-Authors: Kevin Smart, Elena Guerini, Walter Bordogna, Alice T. Shaw, Felix Jaminion, Joy C. Hsu, Caicun Zhou, Tony Mok, Nicolas Frey, Peter N. Morcos
    Abstract:

    e20575Background: Alectinib superiority to crizotinib has been demonstrated in ALK-Inhibitor naive ALK-positive NSCLC patients (pts) in Phase III studies conducted in Japanese (J-ALEX; JapicCTI-132...

  • circulating free dna as a prognostic biomarker in patients with advanced ALK nsclc treated with alectinib from the global phase iii alex trial
    Journal of Clinical Oncology, 2019
    Co-Authors: Rafal Dziadziuszko, Walter Bordogna, Peter N. Morcos, Ross D Camidge, Tony Mok, Solange Peters, Johannes Noe, Malgorzata Nowicka, Vlatka Smoljanovic, Alice T. Shaw
    Abstract:

    9053Background: Circulating free DNA (cfDNA) released predominantly by tumors into the blood correlates with tumor load, but correlation with outcomes after ALK Inhibitor treatment is poorly unders...

  • exposure response analysis of alectinib in crizotinib resistant ALK positive non small cell lung cancer
    Cancer Chemotherapy and Pharmacology, 2018
    Co-Authors: Peter N. Morcos, Elena Guerini, Walter Bordogna, Bogdana Balas, Eveline Nueesch, Felix Jaminion, Joy C. Hsu, Francois Mercier
    Abstract:

    Purpose Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) Inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess alectinib dose selection.

  • clinical drug drug interactions through cytochrome p450 3a cyp3a for the selective ALK Inhibitor alectinib
    Clinical pharmacology in drug development, 2017
    Co-Authors: Peter N. Morcos, Elena Guerini, Georgina Dall, Luigi De Petris, Santiago Viteri, Katrijn Bogman, Walter Bordogna, Yumi Cleary, Li Yu, Meret Martinfacklam
    Abstract:

    The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) Inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small-cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from three fixed-sequence studies evaluating drug–drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is co-administered with CYP3A Inhibitors or inducers, or for co-administered CYP3A substrates. This article is protected by copyright. All rights reserved

  • clinical drug drug interactions through cytochrome p450 3a cyp3a for the selective ALK Inhibitor alectinib
    Clinical pharmacology in drug development, 2017
    Co-Authors: Peter N. Morcos, Elena Guerini, Georgina Dall, Luigi De Petris, Santiago Viteri, Meret Martinfacklam, Katrijn Bogman, Walter Bordogna, Yumi Cleary, Alex Phipps
    Abstract:

    The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) Inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A Inhibitors or inducers or for coadministered CYP3A substrates.

Ross D Camidge - One of the best experts on this subject based on the ideXlab platform.

  • brigatinib versus crizotinib in advanced ALK Inhibitor naive ALK positive non small cell lung cancer second interim analysis of the phase iii alta 1l trial
    Journal of Clinical Oncology, 2020
    Co-Authors: Ross D Camidge, James Chihhsin Yang, Hye Ryun Kim, Myungju Ahn, Ji Youn Han, M J Hochmair, Ki Hyeong Lee, Angelo Delmonte, Maria Rosario Garcia Campelo, Dong-wan Kim
    Abstract:

    PURPOSEBrigatinib, a next-generation anaplastic lymphoma kinase (ALK) Inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizo...

  • circulating free dna as a prognostic biomarker in patients with advanced ALK nsclc treated with alectinib from the global phase iii alex trial
    Journal of Clinical Oncology, 2019
    Co-Authors: Rafal Dziadziuszko, Walter Bordogna, Peter N. Morcos, Ross D Camidge, Tony Mok, Solange Peters, Johannes Noe, Malgorzata Nowicka, Vlatka Smoljanovic, Alice T. Shaw
    Abstract:

    9053Background: Circulating free DNA (cfDNA) released predominantly by tumors into the blood correlates with tumor load, but correlation with outcomes after ALK Inhibitor treatment is poorly unders...

  • brigatinib versus crizotinib in ALK positive non small cell lung cancer
    The New England Journal of Medicine, 2018
    Co-Authors: Ross D Camidge, James Chihhsin Yang, Hye Ryun Kim, Myungju Ahn, Ji Youn Han, M J Hochmair, Ki Hyeong Lee, Jong Seok Lee, Gee Chen Chang, Cesare Gridelli
    Abstract:

    Abstract 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 o...

  • 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
    Lancet Oncology, 2016
    Co-Authors: Dong-wan Kim, Laura Quan Man Chow, Enriqueta Felip, Daniel Shaoweng Tan, Ranee Mehra, Johan Vansteenkiste, Sunil Sharma, Tommaso De Pas, Ross D Camidge, Gregory J Riely
    Abstract:

    Summary 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.

  • ceritinib in advanced anaplastic lymphoma kinase ALK rearranged ALK non small cell lung cancer nsclc results of the ascend 1 trial
    Journal of Clinical Oncology, 2014
    Co-Authors: Dong-wan Kim, Laura Quan Man Chow, Enriqueta Felip, Daniel Shaoweng Tan, Ranee Mehra, Johan Vansteenkiste, Sunil Sharma, Tommaso De Pas, Ross D Camidge, Gregory J Riely
    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-b...