Efficacy and Safety of Ceritinib in Patients (Pts) with Advanced Anaplastic Lymphoma Kinase (Alk)-Rearranged (Alk+) Non-Small Cell Lung Cancer (Nsclc): an Update of Ascend-1

Felip, Enriqueta; Kim, D.; Mehra, Ranee; Tan, D.S.W.; Chow, Laura Q.; Camidge, D. Ross; Vansteenkiste, Johan; Sharma, Sunil; Pas, Tommaso De; Riely, Gregory J.; Solomon, Benjamin J.; Wolf, Juergen; Thomas, Markus; Schüler, Martin; Lui, Goldie Y.L.; Santoro, Armando; Geraldes, Margarida; Boral, Anthony; Yovine, Alejandro; Shaw, Alice T.

doi:10.1093/annonc/mdu349.74

Cited by 34 publications

(30 citation statements)

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“…Given the excellent responses witnessed in crizotinib-treated patients, the main mechanism of crizotinib resistance appears to be ALK dependent, and may be overcome with a more potent ALK inhibitor, such as ceritinib [14]. Updated data from this trial, including 246 patients, showed an ORR of 58.5 % in all patients, with a median duration of response of 9.7 months, time to first response of 6.1 weeks and median PFS of 8.2 months [140]. ASCEND-2 was a single-arm, multicenter phase II trial of 140 patients that evaluated efficacy and safety of ceritinib in ALK-positive NSCLC who progressed after chemotherapy and crizotinib.…”

Section: Clinical Efficacymentioning

confidence: 92%

“…Approximately 58 % of patients taking ceritinib at the recommended starting dose of 750 mg daily required at least one dose reduction [143]. Ceritinib was discontinued entirely in only 7 to 8 % of patients on clinical trial due to adverse events [14,[140][141][142]. Severe interstitial lung disease, which may be related to ceritinib has also been reported, but the incidence is less than 5 %.…”

Section: Clinical Efficacymentioning

confidence: 99%

“…Underlying diabetes may exacerbate this effect. Elevated lipase and fatal pancreatitis have been reported in clinical trials [14,140].…”

Section: Clinical Efficacymentioning

confidence: 99%

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Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

Thompson

Menon

2016

ADMET DMPK

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Discovery of the epidermal growth receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) rearrangements has expanded the therapeutic landscape in non-small cell lung cancer (NSCLC). Survival outcomes for patients with these mutations have improved dramatically with EGFR and ALK tyrosine kinase inhibitors (TKIs). Multiple generations of EGFR and ALK TKIs have been rapidly developed, and patients and clinicians now have several options for first-and second-line treatments. While these small molecule

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Section: Clinical Efficacymentioning

confidence: 92%

Section: Clinical Efficacymentioning

confidence: 99%

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Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

Thompson

Menon

2016

ADMET DMPK

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“…Toxicities included diarrhoea/vomiting, dehydration, hypophosphoraemia and transaminase elevations, with a 57% rate of grade 3-4 toxicity (table 2). This study was subsequently extended to include crizotinib-naïve patients, and results were reported recently [50]. Among the 246 patients included in the study and treated with 750 mg·day −1 ceritinib, 66 had received prior crizotinib.…”

Section: Ceritinibmentioning

confidence: 99%

“…Furthermore, responses were also seen in brain metastases in patients who received prior crizotinib. In the ASCEND-1 study, which included 124 patients with brain metastases (98 pre-treated, 26 therapy-naïve), the overall response rate was 54% and median PFS was 6.9 months [50,51]. On the basis of these preliminary data, ceritinib received FDA approval for ALK + patients who are resistant or intolerant to crizotinib [42], and an exceptional access programme has been approved in other countries.…”

Section: Ceritinibmentioning

confidence: 99%

Therapeutic management of ALK⁺nonsmall cell lung cancer patients

2015

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With therapeutic approaches based on oncogene addiction offering significant anticancer benefit, the identification of anaplastic lymphoma kinase (ALK) rearrangements is a key aspect of the management of lung cancers. The EML4-ALK gene fusion is detected in 4-8% of all lung cancers, predominantly in light smokers or nonsmokers. Crizotinib, the first agent to be approved in this indication, is associated with a median progression-free survival of 10.9 months when given as first-line treatment and 7.7 months when administered after chemotherapy. Median overall survival with crizotinib in the second-line setting is 20.3 months. Second-generation ALK inhibitors are currently being evaluated, with early studies giving impressive results, notably in patients resistant to crizotinib or with brain metastases. Among available chemotherapies, pemetrexed appears to be particularly active in this population. Despite this progress, several questions remain unanswered. What detection strategies should be favoured? What underlies the mechanisms of resistance and what options are available to overcome them? What are the best approaches for progressing patients? This review provides an overview of current data in the literature and addresses these questions. @ERSpublications ALK defines patients who benefit from ALK inhibitors so should be systematically tested in advanced nonsquamous NSCLC http://ow.ly/KQ2oSCopyright ©ERS 2015 This article has supplementary material available from

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New Treatment Options for ALK-Rearranged Non-Small Cell Lung Cancer

Cameron

Solomon

2015

Curr. Treat. Options in Oncol.

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ALK rearrangements are present in 3-5% of patients with non-small cell lung cancer (NSCLC) and after epidermal growth factor receptor (EGFR) mutations represent the second molecular target in NSCLC to be validated through phase III clinical trials. The PROFILE 1014 international multicentre phase III trial demonstrated the superiority of crizotinib over standard chemotherapy, establishing crizotinib as standard first-line therapy for patients with advanced ALK-positive NSCLC and indicating the requirement for ALK testing to guide selection of optimal first-line therapy for non-squamous NSCLC. Despite impressive and durable responses, progression on treatment reflecting the development of acquired resistance is inevitable. There are several mechanisms of resistance including ALK kinase mutation or copy number gain, activation of bypass pathways and potentially pharmacokinetic failure of therapy (most commonly in CNS). A broad array of newer generation ALK inhibitors are in development that appear effective in the crizotinib-resistant setting including in patients with intracranial progression. These agents, including ceritinib and alectinib, have a higher potency against ALK kinase than crizotinib, activity against mutations that confer resistance to crizotinib and potentially improved CNS penetration. While in selected patients, continued therapy with crizotinib after local ablative treatments of oligo-progressive systemic or CNS disease may be an option, for many patients use of a newer generation compound will be effective. First-line treatment with newer generation ALK inhibitors may have potential advantages over sequential treatment after crizotinib; however, the optimal sequence of therapy with ALK inhibitors has not been determined and is being explored in ongoing phase III studies.

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Efficacy and Safety of Ceritinib in Patients (Pts) with Advanced Anaplastic Lymphoma Kinase (Alk)-Rearranged (Alk+) Non-Small Cell Lung Cancer (Nsclc): an Update of Ascend-1

Cited by 34 publications

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Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

Therapeutic management of ALK⁺nonsmall cell lung cancer patients

New Treatment Options for ALK-Rearranged Non-Small Cell Lung Cancer

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Efficacy and Safety of Ceritinib in Patients (Pts) with Advanced Anaplastic Lymphoma Kinase (Alk)-Rearranged (Alk+) Non-Small Cell Lung Cancer (Nsclc): an Update of Ascend-1

Cited by 34 publications

References 0 publications

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

Therapeutic management of ALK+nonsmall cell lung cancer patients

New Treatment Options for ALK-Rearranged Non-Small Cell Lung Cancer

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Product

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Therapeutic management of ALK⁺nonsmall cell lung cancer patients