Results of a First-In-Human Phase I Study of the Alk Inhibitor LDK378 in Advanced Solid Tumors

Shaw, Alice T.; Camidge, D. Ross; Felip, E.; Sharma, Shringi; Tan, D.S.W.; Kim, D.; Pas, Tomasso De; Vansteenkiste, J.; Santoro, Armando; Liu, G.; Goldwasser, Meredith A.; Dai, David L.; Boral, Anthony; Mehra, Ranee

doi:10.1016/s0923-7534(20)33016-7

Cited by 16 publications

(4 citation statements)

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“…Compound 15b also showed an improved profile in terms of in vivo glucose homeostasis over 4 when examined in mouse OGTT experiments. For these reasons, compound 15b was chosen to move into development and is currently being evaluated in ALK-positive patients where it has displayed substantial preliminary antitumor clinical activity …”

Section: Discussionmentioning

confidence: 99%

Synthesis, Structure–Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical Trials

et al. 2013

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The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

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Section: Discussionmentioning

confidence: 99%

Synthesis, Structure–Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical Trials

et al. 2013

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“…In a dose-escalation Phase I study single arm, the maximum tolerating dose (MTD), safety, pharmacokinetics and preliminary antitumor activity of LDK378 have been investigated in ALK-positive solid tumors of any type. After MTD determination (750 mg once daily in 59 patients) [53], 255 patients from 11 countries were enrolled to expansion groups: ALK inhibitor (ALKi) pretreated NSCLC (163 patients), ALKi naïve NSCLC (83 patients) and non-NSCLC disease (9 patients) [54]. Out of 246 ALK-positive NSCLC patients, 67.5% had received ≥2 anticancer therapies: ORR was ≥60% in each subgroup of patients with 0, 1, 2 and 3 prior anticancer regimens.…”

Section: Beyond Crizotinib: From Mechanisms Of Resistance To Second Gmentioning

confidence: 99%

The treatment of advanced non-small-cell lung cancer with anaplastic lymphoma kinase genetic alterations: reality and hopes

Sgambato¹,

Casaluce²,

Rossi³

et al. 2015

Clinical Investigation

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Targeted therapies based on molecular diagnostics have opened a new era of personalized medicine in lung cancer treatment. Recently, anaplastic lymphoma kinase (ALK) fusion gene emerged as an important biomarker for identifying a small proportion of non-small-cell lung cancer (NSCLC) patients that will benefit from ALK kinase inhibitor crizotinib, like EGFR activating mutations and EGFR tyrosine kinase inhibitors. Despite the remarkable initial responses, acquired resistance to crizotinib develops within a year and promising second generation of ALK inhibitors are in current development to overcome it. This review will focus on the basic molecular pathology of ALK gene rearrangement in NSCLC, current testing methods, treatment strategies against ALK-positive and crizotinib-resistant NSCLCs.

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“…Next generation ALK inhibitors such as CH5424802 demonstrate preclinical activity against cancer cells harboring EML4-ALK gene fusions and have activity against many of the resistance mutations identified in the ALK kinase domain (39). Early preclinical data with LDK378, AP26113, and CH5424802 suggest that these drugs have activity in both crizotinib naïve and crizotinib-resistant patients and each drug has anecdotal data for response of brain metastases (44)(45)(46). Next generation ALK inhibitors might be the optimal choice for ALK-dominant resistance where tumors still rely predominantly on ALK signaling as the oncogenic mutation.…”

Section: Acquired Resistance To Crizotinib In Alk-positive Nsclcmentioning

confidence: 99%

Acquired Resistance to Targeted Therapies in Advanced Non-Small Cell Lung Cancer: New Strategies and New Agents

West

Oxnard

2013

American Society of Clinical Oncology Educational Book

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Although the transition to molecularly defined patient subgroups in advanced non-small cell lung cancer (NSCLC) often leads to dramatic and prolonged responses to an inhibitor of an identified oncogenic mutation, acquired resistance eventually ensues. The optimal approach to management in that setting remains the subject of ongoing research, although it is possible to identify several points that distinguish it from traditional tenets based on conventional chemotherapy. Such patients are not equivalent to those who have progressed on first-line chemotherapy, and consideration of initiation of chemotherapy-based regimens as if the patient were being treated first line in the absence of an oncogenic mutation is a reasonable consideration. Acquired resistance is often partial; therefore, continued treatment with the same targeted therapy or another agent against the same target is a strategy favored by many experts, in part to minimize the risk of “rebound progression” that may occur when the targeted therapy is withdrawn. Progression within the central nervous system (CNS) may occur because of poor penetration of the systemic targeted therapy into the CNS, rather than true cellular resistance to the therapy itself; accordingly, local therapy for “brain only” progression with sustained targeted therapy for extracranial disease can be associated with prolonged disease control. Finally, patients with acquired resistance to a targeted therapy are ideal candidates for clinical trials when available, particularly when repeat biopsies of progressing lesions can help elucidate mechanisms of resistance and thereby lead to histologically and molecularly informed treatment decisions.

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Results of a First-In-Human Phase I Study of the Alk Inhibitor LDK378 in Advanced Solid Tumors

Cited by 16 publications

References 0 publications

The treatment of advanced non-small-cell lung cancer with anaplastic lymphoma kinase genetic alterations: reality and hopes

Acquired Resistance to Targeted Therapies in Advanced Non-Small Cell Lung Cancer: New Strategies and New Agents

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