G6 Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066

Kwak, E. L.; Camidge, D. Ross; Clark, JeVrey W.; Shapiro, G.; Maki, Robert G.; Ratain, Mark J.; Solomon, Benjamin J.; Bang, Yunkyu; Ou, S.; Salgia, Ravi

doi:10.1016/s1359-6349(09)72045-2

Cited by 85 publications

(109 citation statements)

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“…One lesson from this approach was that the strong signal that eventually led to the rapid approval of crizotinib in ALK+ NSCLC based on its activity in several hundred patients was apparent very early on. Waterfall plots of the first 19 patients and those from over 100 patients had almost identical shapes 65,66 (overall response rate, 53% vs 61%). When the efficacy signals are so strong it is difficult to know how to determine the necessary numbers of patients for a drug approval.…”

Section: Issues In Specific Tumor Typesmentioning

confidence: 87%

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

Venook¹,

Arcila²,

Benson³

et al. 2014

J Natl Compr Canc Netw

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Defining treatment susceptible or resistant populations of cancer patients through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents both opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies because potential patient populations are divided into ever-smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists and information developers.

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Section: Issues In Specific Tumor Typesmentioning

confidence: 87%

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

Venook¹,

Arcila²,

Benson³

et al. 2014

J Natl Compr Canc Netw

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“…(14,15,23) Poor pharmacologic properties of earlier Met inhibitors led to the development of novel compounds, including PF-2341066, which is currently in phase I/II clinical trials for the treatment of several cancer types. (16,24,25) Currently, however, there are no clinical trials specifically evaluating the efficacy of PF-2341066 in OS patients. Moreover, pharmacologic inhibition of Met signaling (using any available Met smallmolecule inhibitor) has not yet been tested in any orthotopic OS xenograft model.…”

Section: Discussionmentioning

confidence: 99%

“…(14,24) PF-2341066 is orally bioavailable, has strong antitumor properties in xenograft models, and is currently in phase I/II clinical trials. (15,25) MNNG is a more malignant derivative of TE85 generated via exposure to N-methyl-N'-nitro-N-nitrosoguanidine. (26) MNNG cells express both the full-length, ligand-dependent Met receptor and the constitutively activated TPR-Met fusion protein generated by a chromosomal translocation between the Tpr and Met genes, (26,27) whereas TE85 cells express only wild-type Met.…”

Section: Histology/immunohistochemistrymentioning

confidence: 99%

The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model

Sampson

Martin

Morris

et al. 2011

Journal of Bone and Mineral Research

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Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Ninety percent of patients who present with metastatic and 30% to 40% of patients with nonmetastatic disease experience relapse, creating an urgent need for novel therapeutic strategies. The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are important for mitosis, motility, and cell survival. Upregulation of Met/HGF signaling via receptor overexpression, amplification, or mutation drives the proliferation, invasiveness, and metastasis of a variety of cancer cells, including OS, prompting the development of Met/HGF inhibitors. OS cells depend on Met overexpression because introduction of dominant-negative Met inhibits in vivo tumorigenicity. Despite the importance of Met/HGF signaling in the development and maintenance of OS, the potential efficacy of pharmacologic Met inhibition in OS has been addressed only in in vitro studies. PF-2341066 is an orally bioavailable, selective ATP-competitive Met inhibitor that showed promising results recently in a phase I clinical trial in non-small cell lung cancer (NSCLC) patients. We tested the ability of PF-2341066 to inhibit malignant properties of osteosarcoma cells in vitro and orthotopic xenograft growth in vivo. In vitro, PF-2341066 inhibited osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF-2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts were inhibited by PF-2341066. PF-2341066 may represent an effective new systemic therapy for localized and potentially disseminated osteosarcoma. ß

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“…Following identification of EML4-ALK, a significant clinical response was noted in two patients with ALK-positive lung adenocarcinoma treated with crizotinib as part of a phase I clinical trial [6]. Further investigation of crizotinib in a phase Ib expansion cohort demonstrated its clinical efficacy in ALKpositive NSCLC, with an overall response rate (ORR) of 60% and a median progression free survival (PFS) of 9.7 months [7].…”

Section: Crizotinib: First-generation Alk Inhibitormentioning

confidence: 99%

Re-Evaluating Progression in an Era of Progress: A Review of First- and Second-Line Treatment Options in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer

Castellanos

Horn

2016

The Oncologist

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The advent of crizotinib, the first small molecule inhibitor against anaplastic lymphoma kinase (ALK), has led to impressive advances in the care of patients with advanced ALK‐rearranged non‐small cell lung cancer. The development of second‐generation ALK inhibitors, starting with the recent U.S. Food and Drug Administration approval of ceritinib, promises to expand the therapeutic landscape for this cohort of patients. With increasing use of molecularly targeted therapy options, it has been observed that disease progression in patients receiving targeted agents has a heterogeneous biology, manifesting as either oligoprogressive or widely progressive disease, which may require development of innovative treatment strategies. This review discusses the first‐ and second‐generation ALK inhibitors approved or in clinical development, as well as the novel challenges and approaches to disease progression in patients on targeted agents. Implications for Practice: The identification of driver mutations in non‐small cell lung cancer (NSCLC), most prominently epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has expanded treatment options for a significant cohort of patients. However, the success of targeted agents has brought new challenges, particularly regarding management of progression. Progression manifests heterogeneously, and management of oligoprogression may differ from diffusely progressive disease. Multiple options for treatment at progression exist, and it is becoming evident that selecting the best avenue of care requires understanding the biology and potential drivers of disease progression. This review discusses the array of treatment options available for patients with ALK‐positive NSCLC, as well as evaluation and treatment of progressive disease.

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G6 Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066

Cited by 85 publications

References 0 publications

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model

Re-Evaluating Progression in an Era of Progress: A Review of First- and Second-Line Treatment Options in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer

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