99 results on '"Wilner KD"'
Search Results
2. Sufficiency of Single-Arm Studies to Support Registration of Targeted Agents in Molecularly Selected Patients with Cancer: Lessons from the Clinical Development of Crizotinib.
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Selaru, P, Tang, Y, Huang, B, Polli, A, Wilner, KD, Donnelly, E, and Cohen, DP
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DRUG approval ,CRIZOTINIB ,ANAPLASTIC lymphoma kinase ,NON-small-cell lung carcinoma ,CANCER treatment ,CLINICAL trials - Abstract
The article offers information on aspects of regulatory approval processes for registering molecularly targeted agents (MTAs) such as crizotinib, a drug for treating advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). It discusses the benefits offered by prospective single-arm clinical trial for future registration of MTA monotherapies for diseases such as rare tumors. It mentions the history of crizotinib along with various studies about the drug.
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- 2016
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3. Current Status of Targeted Therapy for Anaplastic Lymphoma Kinase-Rearranged Non-Small Cell Lung Cancer.
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Solomon, B, Wilner, KD, and Shaw, AT
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ANAPLASTIC lymphoma kinase ,LUNG cancer ,PROTEIN-tyrosine kinases ,CLINICAL trials ,CANCER chemotherapy ,ENZYME inhibitors - Abstract
The identification of chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene in ~3-5% of non-small cell lung cancer (NSCLC) tissues and the demonstration that the first-in-class ALK tyrosine kinase inhibitor, crizotinib, can effectively target these tumors represent a significant advance in the evolution of personalized medicine for NSCLC. Single-arm studies demonstrating rapid and durable responses in the majority of ALK-positive NSCLC patients treated with crizotinib have been followed by a randomized phase III clinical trial in which superiority of crizotinib over chemotherapy was seen in previously treated ALK-positive NSCLC patients. However, despite the initial responses, most patients develop acquired resistance to crizotinib. Several novel therapeutic approaches targeting ALK-positive NSCLC are currently under evaluation in clinical trials, including second-generation ALK inhibitors, such as LDK378, CH5424802 (RO5424802802), and AP26113, and heat shock protein 90 inhibitors.Clinical Pharmacology & Therapeutics (2013); 95 1, 15-23 advance online publication 13 November 2013. doi:10.1038/clpt.2013.200 [ABSTRACT FROM AUTHOR]
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- 2014
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4. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification.
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Ou SH, Kwak EL, Siwak-Tapp C, Dy J, Bergethon K, Clark JW, Camidge DR, Solomon BJ, Maki RG, Bang YJ, Kim DW, Christensen J, Tan W, Wilner KD, Salgia R, Iafrate AJ, Ou, Sai-Hong Ignatius, Kwak, Eunice L, Siwak-Tapp, Christina, and Dy, Joni
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- 2011
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5. Pharmacokinetics, safety, and tolerability of intramuscular ziprasidone in healthy volunteers.
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Miceli JJ, Wilner KD, Swan SK, and Tensfeldt TG
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Little has been published regarding the pharmacokinetics of the intramuscular (IM) formulation of Ziprasidone. The authors report results from 2 early phase I studies in healthy volunteers: a trial of single 5-, 10-, or 20-mg IM doses of ziprasidone in 24 subjects and an open-label 3-way crossover trial of 5-mg intravenous (IV), 5-mg IM, and 20-mg oral ziprasidone in 12 subjects. Absorption of IM ziprasidone was rapid (Tmax < 1 hour). The IM pharmacokinetic profile was consistent between studies and linear, with dose-related increases in exposure observed. The mean IM elimination t(1/2) was short and approximately 2.5 hours. The mean bioavailability for the 5-mg IM ziprasidone dose was approximately 100%. Adverse events were generally mild to moderate, and no subjects were discontinued from the study. No significant effects on renal function or other laboratory values were noted. These results support the use of IM ziprasidone in treating acutely agitated patients with schizophrenia. [ABSTRACT FROM AUTHOR]
- Published
- 2005
6. Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers.
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Wilner KD, Rushing M, Walden C, Adler R, Eskra J, Noveck R, and Vargas R
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Celecoxib is a novel cyclooxygenase-2-specific inhibitor for the management of acute pain, primary dysmenorrhea, and the signs and symptoms of arthritis. This double-blind, placebo-controlled study in 16 healthy volunteers evaluated whether celecoxib alters the effect of concomitant aspirin on platelet function. Volunteers received celecoxib (400 mg/day) or placebo for 4 days. On day 5, they also received a single 325 mg dose of aspirin with either 200 mg celecoxib or placebo. Thromboxane and platelet aggregation response to adenosine 5'-diphosphate (ADP), collagen, and arachidonic acid were measured before the first dose of celecoxib or placebo (baseline) and before dosing and 2 and 8 hours post dose on day 5. There was no significant difference in thromboxane inhibition between the two groups (percent inhibition: placebo 99.4%, celecoxib 99.0%; p = 0.555). There was also no significant difference in the effect of aspirin on platelet aggregation due to ADP, collagen, or arachidonic acid between the groups. Therefore, these data indicate that celecoxib does not alter the effects of aspirin on platelet function. [ABSTRACT FROM AUTHOR]
- Published
- 2002
7. Final Overall Survival, Safety, and Quality of Life Results From a Phase 2 Study of Crizotinib in East Asian Patients With ROS1 -Positive Advanced NSCLC.
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Wu YL, Lu S, Yang JC, Zhou J, Seto T, Ahn MJ, Su WC, Yamamoto N, Kim DW, Paolini J, Usari T, Iadeluca L, Wilner KD, and Goto K
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Introduction: Crizotinib provided meaningful clinical benefit in the initial analysis of a phase 2 study in East Asian patients with advanced ROS1 -positive NSCLC (NCT01945021). Nevertheless, overall survival (OS) data were immature. Here, we present the final OS, quality of life (QoL), and safety data after an additional 3 years of follow-up., Methods: In this phase 2, open-label, single-arm trial, East Asian patients with ROS1 -positive advanced NSCLC who had received less than or equal to three systemic therapies previously were treated with crizotinib 250 mg twice daily on a continuous daily dosing schedule in 28-day cycles. The OS (secondary end point) was analyzed for the total population, by country, and by number of previous chemotherapy regimens. QoL and safety were also evaluated., Results: With a median duration of follow-up of 56.1 months, the median OS was 44.2 months (95% confidence interval: 32.0-not reached) for the total population (N = 127). Differences in median OS were observed among individual countries and with number of previous regimens. The improvement in QoL found in the previous analysis was maintained with the extended follow-up. Treatment-related adverse events led to crizotinib dose reductions or permanent treatment discontinuations in 17.3% and 2.4%, respectively, of the patients., Conclusions: This is the largest trial of an ALK/ROS1 inhibitor to treat patients with ROS1 -positive advanced NSCLC and provides a new benchmark for OS in East Asian patients. The QoL and safety profile with long-term follow-up were consistent with previous reports and support the continued use of crizotinib in the treatment of patients with ROS1 -positive advanced NSCLC., (© 2022 The Authors.)
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- 2022
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8. Encorafenib plus binimetinib in patients with BRAF V600 -mutant non-small cell lung cancer: phase II PHAROS study design.
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Riely GJ, Ahn MJ, Felip E, Ramalingam SS, Smit EF, Tsao AS, Alcasid A, Usari T, Wissel PS, Wilner KD, and Johnson BE
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- Adult, Aged, Benzimidazoles administration & dosage, Carbamates administration & dosage, Carcinoma, Non-Small-Cell Lung pathology, Female, Humans, Lung Neoplasms pathology, Male, Middle Aged, Mutation, Sulfonamides administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Proto-Oncogene Proteins B-raf genetics
- Abstract
BRAF
V600 oncogenic driver mutations occur in 1-2% of non-small-cell lung cancers (NSCLCs) and have been shown to be a clinically relevant target. Preclinical/clinical evidence support the efficacy and safety of BRAF and MEK inhibitor combinations in patients with NSCLC with these mutations. We describe the design of PHAROS, an ongoing, open-label, single-arm, phase II trial evaluating the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with metastatic BRAFV600 -mutant NSCLC, as first- or second-line treatment. The primary end point is objective response rate, based on independent radiologic review (per RECIST v1.1); secondary objectives evaluated additional efficacy end points and safety. Results from PHAROS will describe the antitumor activity/safety of encorafenib plus binimetinib in patients with metastatic BRAFV600 -mutant NSCLC.- Published
- 2022
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9. Crizotinib in Patients With MET-Amplified NSCLC.
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Camidge DR, Otterson GA, Clark JW, Ignatius Ou SH, Weiss J, Ades S, Shapiro GI, Socinski MA, Murphy DA, Conte U, Tang Y, Wang SC, Wilner KD, and Villaruz LC
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- Crizotinib pharmacology, Crizotinib therapeutic use, Humans, In Situ Hybridization, Fluorescence, Mutation, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins genetics, Retrospective Studies, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Protein-Tyrosine Kinases genetics
- Abstract
Introduction: MET amplification is a rare, potentially actionable, primary oncogenic driver in patients with NSCLC., Methods: The influence of MET amplification on the clinical activity of the ALK, ROS1, and MET inhibitor, crizotinib (250 mg twice daily), was examined in patients with NSCLC (NCT00585195) who were enrolled into high (≥4 MET-to-CEP7 ratio), medium (>2.2 to <4 MET-to-CEP7 ratio), or low (≥1.8 to ≤2.2 MET-to-CEP7 ratio) amplification categories. Retrospective next-generation sequencing profiling was performed on archival tumor tissue. End points included objective response rate (ORR), duration of response, and progression-free survival., Results: A total of 38 patients with a MET-to-CEP7 ratio greater than or equal to 1.8 by local fluorescence in situ hybridization testing received crizotinib. All patients were response-assessable, among whom 21, 14, and 3 had high, medium, and low MET amplification, respectively. ORRs of 8 of 21 (38.1%), 2 of 14 (14.3%), and 1 of 3 (33.3%), median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival values of 6.7, 1.9, and 1.8 months were observed for those with high, medium, and low MET amplification, respectively. MET amplification gene copy number greater than or equal to 6 was detected by next-generation sequencing in 15 of 19 (78.9%) analyzable patients. Of these 15 patients, objective responses were observed in six (40%), two of whom had concurrent MET exon 14 alterations. No responses were observed among five patients with concurrent KRAS, BRAF, or EGFR mutations., Conclusions: Patients with high-level, MET-amplified NSCLC responded to crizotinib with the highest ORR. Use of combined diagnostics for MET and other oncogenes may potentially identify patients most likely to respond to crizotinib., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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10. Outcomes in patients with lung cancer treated with crizotinib and erlotinib in routine clinical practice: A post-authorization safety cohort study conducted in Europe and in the United States.
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Ehrenstein V, Huang K, Kahlert J, Bahmanyar S, Karlsson P, Löfling L, Nunes AP, Enger C, Bezemer ID, Kuiper JG, Hoti F, Juuti R, Korhonen P, Mo J, Schachterle SE, Wilner KD, Rørth M, and Sørensen HT
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- Anaplastic Lymphoma Kinase, Cohort Studies, Crizotinib adverse effects, Erlotinib Hydrochloride adverse effects, Humans, United States epidemiology, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms drug therapy, Lung Neoplasms epidemiology
- Abstract
Purpose: We examined safety outcomes of interest (SOI) and overall survival (OS) among lung cancer patients initiating crizotinib and erlotinib in routine clinical practice., Methods: This descriptive cohort study used routinely collected health data in Denmark, Finland, Sweden, the Netherlands, and the United States (US) during 2011-2017, following crizotinib commercial availability in each country. Among crizotinib or erlotinib initiators, we reported baseline characteristics and incidence rates and cumulative incidences of the SOI - hepatotoxicity, pneumonitis/interstitial lung disease, QT interval prolongation-related events, bradycardia, vision disorders, renal cysts, edema, leukopenia, neuropathy, photosensitivity, malignant melanoma, gastrointestinal perforation, cardiac failure and OS. Results from the European Union (EU) countries were combined using meta-analysis; results from the US were reported separately., Results: There were 456 patients in the crizotinib cohort and 2957 patients in the erlotinib cohort. Rates of the SOI per 1000 person-years in the crizotinib cohort ranged from 0 to 65 in the EU and from 0 to 374 in the US. Rates of the SOI per 1000 person-years in the erlotinib cohort ranged from 0 to 91 in the EU and from 3 to 394 in the US. In the crizotinib cohort, 2-year OS was ~50% in both EU and US. In the erlotinib cohort, 2-year OS was 21% in the EU and 35% in the US., Conclusions: This study describes clinical outcomes among lung cancer patients initiating crizotinib or erlotinib in routine clinical practice. Differences between SOI rates in EU and US may be partially attributable to differences in the underlying databases., (© 2021 John Wiley & Sons Ltd.)
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- 2021
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11. Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Performance Status Work Group.
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Magnuson A, Bruinooge SS, Singh H, Wilner KD, Jalal S, Lichtman SM, Kluetz PG, Lyman GH, Klepin HD, Fleury ME, Hirsch B, Melemed A, Arnaldez FI, Basu Roy U, Schenkel C, Sherwood S, and Garrett-Mayer E
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- Biomedical Research, Clinical Decision-Making, Clinical Trials as Topic methods, Disease Management, Humans, Medical Oncology methods, Research Design, Clinical Trials as Topic standards, Medical Oncology standards, Neoplasms diagnosis, Neoplasms therapy
- Abstract
Purpose: Performance status (PS) is one of the most common eligibility criteria. Many trials are limited to patients with high-functioning PS, resulting in important differences between trial participants and patient populations with the disease. In addition, existing PS measures are subjective and susceptible to investigator bias., Experimental Design: A multidisciplinary working group of the American Society of Clinical Oncology and Friends of Cancer Research evaluated how PS eligibility criteria could be more inclusive. The working group recommendations are based on a literature search, review of trials, simulation study, and multistakeholder consensus. The working group prioritized inclusiveness and access to investigational therapies, while balancing patient safety and study integrity., Results: Broadening PS eligibility criteria may increase the number of potentially eligible patients for a given clinical trial, thus shortening accrual time. It may also result in greater participant diversity, potentially reduce trial participant and patient disparities, and enable clinicians to more readily translate trial results to patients with low-functioning PS. Potential impact on outcomes was explored through a simulation trial demonstrating that when the number of Eastern Cooperative Oncology Group PS2 participants was relatively small, the effect on the estimated HR and power was modest, even when PS2 patients did not derive a treatment benefit., Conclusions: Expanding PS eligibility criteria to be more inclusive may be justified in many cases and could result in faster accrual rates and more representative trial populations. See related commentary by Giantonio, p. 2369 ., (©2021 American Association for Cancer Research.)
- Published
- 2021
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12. Safety and efficacy of first-line dacomitinib in Asian patients with EGFR mutation-positive non-small cell lung cancer: Results from a randomized, open-label, phase 3 trial (ARCHER 1050).
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Cheng Y, Mok TS, Zhou X, Lu S, Zhou Q, Zhou J, Du Y, Yu P, Liu X, Hu C, Lu Y, Zhang Y, Lee KH, Nakagawa K, Linke R, Wong CH, Tang Y, Zhu F, Wilner KD, and Wu YL
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- Disease-Free Survival, ErbB Receptors genetics, Humans, Mutation, Protein Kinase Inhibitors adverse effects, Quinazolinones, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
Objectives: To compare efficacy and safety of dacomitinib versus gefitinib as first-line therapy for EGFR mutation-positive advanced NSCLC in Asian patients enrolled in the ongoing ARCHER 1050 trial., Materials and Methods: In this ongoing, randomized, open-label, phase 3 trial (NCT01774721), eligible patients with newly diagnosed advanced EGFR mutation-positive NSCLC were randomized (1:1) to receive oral dacomitinib 45 mg/day or oral gefitinib 250 mg/day. Randomization, by a central computer system, was stratified by race and EGFR mutation type (exon 19 deletion mutation/exon 21 L858R substitution mutation). The primary endpoint was PFS by blinded independent review., Results: Of 346 Asian patients, 170 were randomized to dacomitinib and 176 to gefitinib. The hazard ratio (HR) for PFS with dacomitinib versus gefitinib was 0.509 (95 % confidence interval [CI]: 0.391-0.662; 1-sided p < 0.0001; median 16.5 months [95 % CI: 12.9-18.4] vs. 9.3 months [95 % CI: 9.2-11.0]). HR for OS with dacomitinib versus gefitinib was 0.759 (95 % CI: 0.578-0.996; median 37.7 months [95 % CI: 30.2-44.7] vs. 29.1 months [95 % CI: 25.6-36.0]). The OS benefit was still maintained in those patients who had a stepwise dose reduction of dacomitinib (to 30 and 15 mg/day). The most common adverse events (AEs) were diarrhea (154 [90.6 %] patients), paronychia (110 [64.7 %]), dermatitis acneiform (96 [56.5 %]), and stomatitis (87 [51.2 %]) with dacomitinib, and diarrhea (100 [56.8 %]), alanine aminotransferase increased (81 [46.0 %]), and aspartate aminotransferase increased (75 [42.6 %]) with gefitinib. Treatment-related serious AEs were reported in 16 (9.4 %) and 8 (4.5 %) patients treated with dacomitinib and gefitinib, respectively., Conclusion: First-line dacomitinib was associated with significant prolongation of PFS and improved OS compared with gefitinib in Asian patients with EGFR mutation-positive advanced NSCLC. The AE profiles of dacomitinib and gefitinib in Asian patients were consistent with the overall ARCHER 1050 population., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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13. Updated Overall Survival in a Randomized Study Comparing Dacomitinib with Gefitinib as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations.
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Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Chawla A, Rosell R, Corral J, Migliorino MR, Pluzanski A, Noonan K, Tang Y, Pastel M, Wilner KD, and Wu YL
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- Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung metabolism, Dose-Response Relationship, Drug, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, ErbB Receptors metabolism, Female, Gefitinib administration & dosage, Humans, Lung Neoplasms diagnosis, Lung Neoplasms metabolism, Male, Mutation, Protein Kinase Inhibitors administration & dosage, Quinazolinones administration & dosage, Survival Analysis, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Gefitinib pharmacology, Lung Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Quinazolinones pharmacology
- Abstract
Background: ARCHER 1050, an ongoing, randomized, open-label, phase III trial of dacomitinib versus gefitinib in newly diagnosed patients with advanced non-small-cell lung cancer (NSCLC) and an EGFR-activating mutation, reported significant improvement in overall survival (OS) with dacomitinib., Objective: This paper reports an updated OS analysis of ARCHER 1050 after an extended follow-up., Patients and Methods: In this multinational, multicenter trial, adults (aged ≥ 18 years or ≥ 20 years in Japan and Korea) with newly diagnosed NSCLC and EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and no history of central nervous system metastases, were randomized 1:1 to receive dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225). Randomization was stratified by race and EGFR mutation type. An ad hoc updated analysis of OS was conducted at the protocol-defined cut-off of 48 months from first dosing of the last enrolled patient (13 May 2019)., Results: After a median follow-up of 47.9 months, 133 (58.6%) patients had died in the dacomitinib arm and 152 (67.6%) in the gefitinib arm. The hazard ratio (HR) for OS was 0.748 (95% CI 0.591-0.947; two-sided P = 0.0155); median OS was 34.1 months with dacomitinib versus 27.0 months with gefitinib. The HR for OS in patients with dose reduction(s) in the dacomitinib arm (n = 154) compared with all patients in the gefitinib arm was 0.554 (95% CI 0.420-0.730); median OS was 42.5 months for patients with dose reduction(s) in the dacomitinib arm. The most common adverse events were diarrhea (87.7%), paronychia (61.7%), dermatitis acneiform (49.3%), and stomatitis (43.6%) with dacomitinib, and diarrhea (55.8%) and alanine aminotransferase increased (40.2%) with gefitinib., Conclusions: The OS benefit from first-line treatment with dacomitinib versus gefitinib was maintained after extended follow-up in patients with advanced NSCLC with EGFR-activating mutations. CLINICALTRIALS.GOV: NCT01774721 (registered 24 January 2013).
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- 2021
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14. Indirect analysis of first-line therapy for advanced non-small-cell lung cancer with activating mutations in a Japanese population.
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Nakagawa K, Matsumura K, Scory T, Farris MS, Larkin-Kaiser KA, Kikkawa H, Ivanova JI, and Wilner KD
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- Antineoplastic Combined Chemotherapy Protocols pharmacology, Bayes Theorem, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung mortality, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Gain of Function Mutation, Humans, Japan epidemiology, Lung Neoplasms diagnosis, Lung Neoplasms genetics, Lung Neoplasms mortality, Neoplasm Staging, Network Meta-Analysis, Progression-Free Survival, Protein Kinase Inhibitors pharmacology, Randomized Controlled Trials as Topic, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use
- Abstract
Background: Five EGFR -tyrosine kinase inhibitors ( EGFR TKIs) are currently available in the first-line setting for non-small-cell lung cancer (NSCLC) in Japan. The aim here was to compare the relative efficacy of EGFR TKIs in the Japanese population. Materials & methods: A systematic review identified randomized controlled trials examining the efficacy of first-line EGFR TKIs. A Bayesian network meta-analysis was used to assess these EGFR TKI comparisons for progression-free survival (PFS). Results: A total of seven randomized controlled trials were identified and considered for network meta-analysis. Dacomitinib showed a trend toward improved PFS versus all comparators. Conclusion: Dacomitinib demonstrated a trend toward improved PFS and therefore, should be considered one of the standard first-line therapies for Japanese patients diagnosed with EGFR+ non-small-cell lung cancer.
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- 2021
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15. Network meta analysis of first-line therapy for advanced EGFR mutation positive non-small-cell lung cancer: updated overall survival.
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Farris M, Larkin-Kaiser KA, Scory T, Boyne D, Wilner KD, Pastel M, Cappelleri JC, and Ivanova JI
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- Acrylamides pharmacology, Acrylamides therapeutic use, Afatinib pharmacology, Afatinib therapeutic use, Aniline Compounds pharmacology, Aniline Compounds therapeutic use, Bayes Theorem, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung mortality, Disease-Free Survival, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Erlotinib Hydrochloride pharmacology, Erlotinib Hydrochloride therapeutic use, Gain of Function Mutation, Gefitinib pharmacology, Gefitinib therapeutic use, Humans, Lung Neoplasms diagnosis, Lung Neoplasms genetics, Lung Neoplasms mortality, Neoplasm Staging, Network Meta-Analysis, Protein Kinase Inhibitors pharmacology, Quinazolinones pharmacology, Randomized Controlled Trials as Topic, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Quinazolinones therapeutic use
- Abstract
Aim: To update overall survival (OS) results from a previous network meta analysis comparing the relative clinical efficacy of epidermal growth factor receptor-targeted tyrosine kinase inhibitors ( EGFR TKIs) for EGFR mutation positive ( EGFR +) advanced non-small-cell lung cancer (NSCLC). Materials & methods: A Bayesian network meta analysis was conducted using updated/mature randomized controlled trial OS results in response to first-line EGFR TKI therapies. Results: Dacomitinib showed a numerical improvement of OS relative to other EGFR TKIs: afatinib (hazard ratio [HR]: 0.87; 95% credible interval [CrI]: 0.61-1.24), erlotinib (HR: 0.79; 95% CrI: 0.44-1.42), gefitinib (HR: 0.75; 95% CrI: 0.59-0.95) and osimertinib (HR: 0.94; 95% CrI: 0.68-1.29). Conclusion: Dacomitinib should be considered as a first-line treatment option for patients diagnosed with advanced EGFR + NSCLC.
- Published
- 2020
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16. Ophthalmological assessment of crizotinib in advanced non-small-cell lung cancer.
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Solomon BJ, Kim EE, Winter M, Monti K, Tang Y, Wilner KD, Wang S, and Ou SI
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- Crizotinib therapeutic use, Humans, Intraocular Pressure, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Objectives: During crizotinib clinical evaluation, visual disturbances, generally of grade 1 severity, were frequently reported adverse events (AE). Consequently, ophthalmologic assessments were included in a patient subgroup enrolled in PROFILE 1001 (NCT00585195), a phase 1, open-label, single-arm trial of crizotinib in patients with advanced non-small-cell lung cancer and are reported here., Materials and Methods: At least 30 patients were required to undergo ophthalmologic assessments, including: best-corrected visual acuity (BCVA), refractive error, pupil size, slit-lamp anterior segment biomicroscopy, intraocular inflammation, intraocular pressure, retinal fundoscopic exams, fundus photography, ocular characteristics, and optical coherence tomography (OCT). Scheduled assessments included those at baseline, Cycle 1 Day 15, Cycle 3 Day 1 (C3D1), annually during treatment, and end of treatment (28 days after last crizotinib dose)., Results: Thirty-three patients completed all required ophthalmologic assessments through C3D1, and 22 (66.7 %) had abnormal findings on ≥1 ophthalmologic test. Clinically important changes were ≥2-line loss in BCVA in 10 patients (30.3 %), >±1.25-diopter change in refractive error in 3 patients (9.1 %), >±2-mm change pupillary diameter change in 3 patients (9.1 %), and >50 μm increase in OCT center point thickness in 7 patients (21.2 %). Three patients (15 %) reported clinically significant abnormalities in anterior segment biomicroscopy (grade 1 cataract [n = 2], grade 1 Visual Impairment [n = 1]). No permanent treatment discontinuations were associated with ophthalmologic findings changes. Twenty-four patients (72.7 %) reported ≥1 ocular all-causality treatment-emergent AE (TEAE); none required dose reduction or permanent discontinuation, but 2 required temporary dosing interruption. Although TEAEs and ophthalmologic findings may not have occurred concurrently, of 24 patients with ≥1 all-causality ocular TEAE, 18/24 (75.0 %) had ≥1 abnormal ophthalmologic finding and 6/24 (25 %) had none; and of 9 patients without an all-causality ocular TEAE, 4/9 (44.4 %) had ≥1 abnormal ophthalmologic finding and 5/9 (55.6 %) had none. Of the 18 patients with ≥1 abnormal ophthalmologic finding, 9 (50 %) had preexisting ocular conditions., Conclusion: During crizotinib treatment, ophthalmologic changes from baseline did not appear to be associated with patient-reported ocular TEAEs. Abnormal ophthalmologic findings occurred in the context of preexisting conditions for a number of patients. No ophthalmologic changes from baseline or ocular all-causality TEAEs required permanent treatment discontinuation., (Copyright © 2020. Published by Elsevier B.V.)
- Published
- 2020
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17. Effect of the patient information brochure in communicating the risks associated with crizotinib treatment to patients with non-small cell lung cancer (NSCLC) in Europe.
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Huang K, Madison T, Wehler B, Tiseo M, Wilner KD, and Mo J
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- Adolescent, Adult, Aged, Cross-Sectional Studies, Europe, Female, Health Communication, Humans, Male, Middle Aged, Surveys and Questionnaires, Young Adult, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Crizotinib therapeutic use, Lung Neoplasms drug therapy, Pamphlets, Patient Education as Topic, Protein Kinase Inhibitors therapeutic use
- Abstract
Crizotinib (XALKORI
® ) is indicated for anaplastic lymphoma kinase-positive and ROS1-positive advanced non-small cell lung cancer. This study evaluated the distribution of the crizotinib patient information brochure (PIB) in Europe and patient knowledge of the key messages in the PIB. A cross-sectional survey was conducted in 10 European countries among patients who received crizotinib to ascertain whether each patient received and read the PIB, and his/her knowledge of its key messages on hepatotoxicity, interstitial lung disease/pneumonitis, QTc prolongation, bradycardia, and vision disorders. Of the 341 patients contacted, 40 responded (11.7%), and 39 patients were eligible. A total of 77% of respondents acknowledged receiving the PIB, of which, 93% reported reading it. Knowledge of the individual side effects ranged from 36% to 85%, and precautions for use ranged from 56% to 67%. Understanding the reasons for calling a physician ranged from 54% to 85%. Knowledge of each of the 6 key side effects was greater among readers of the PIB compared to non-readers or respondents who did not recall receiving the PIB. Approximately three-quarters of survey respondents recalled receiving the crizotinib PIB and respondents who read the PIB were more knowledgeable of the key side effects of crizotinib than those who did not read or receive. Caution should be taken in generalizing these results because of the potential for selection bias and small sample size. These survey results suggest that the crizotinib PIB may be an effective risk communication tool for crizotinib-treated patients in Europe., (© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2020
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18. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration.
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Drilon A, Clark JW, Weiss J, Ou SI, Camidge DR, Solomon BJ, Otterson GA, Villaruz LC, Riely GJ, Heist RS, Awad MM, Shapiro GI, Satouchi M, Hida T, Hayashi H, Murphy DA, Wang SC, Li S, Usari T, Wilner KD, and Paik PK
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Crizotinib pharmacology, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Antineoplastic Agents therapeutic use, Crizotinib therapeutic use, Exons genetics, Lung Neoplasms drug therapy, Mutation genetics, Proto-Oncogene Proteins c-met genetics
- Abstract
MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs)
1 . These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition2 . Crizotinib is a multikinase inhibitor with potent activity against MET3 . The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC.- Published
- 2020
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19. Dose-escalation trial of the ALK, MET & ROS1 inhibitor, crizotinib, in patients with advanced cancer.
- Author
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Clark JW, Camidge DR, Kwak EL, Maki RG, Shapiro GI, Chen I, Tan W, Randolph S, Christensen JG, Ozeck M, Tang Y, Wilner KD, and Salgia R
- Subjects
- Antineoplastic Agents pharmacokinetics, Biomarkers, Tumor metabolism, Crizotinib pharmacokinetics, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms metabolism, Neoplasms pathology, Prognosis, Tissue Distribution, Anaplastic Lymphoma Kinase antagonists & inhibitors, Antineoplastic Agents therapeutic use, Crizotinib therapeutic use, Neoplasms drug therapy, Protein-Tyrosine Kinases antagonists & inhibitors, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins c-met antagonists & inhibitors
- Abstract
Aim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily-300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced ≥1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195.
- Published
- 2020
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20. Systematic review and network meta-analysis of first-line therapy for advanced EGFR -positive non-small-cell lung cancer.
- Author
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Franek J, Cappelleri JC, Larkin-Kaiser KA, Wilner KD, and Sandin R
- Subjects
- Bayes Theorem, Carcinoma, Non-Small-Cell Lung metabolism, Disease-Free Survival, ErbB Receptors metabolism, Humans, Lung Neoplasms metabolism, Network Meta-Analysis, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use
- Abstract
Here, we compare the relative clinical efficacy of EGFR -targeted tyrosine kinase inhibitors ( EGFR TKIs) for EGFR -positive advanced non-small-cell lung cancer (NSCLC). The authors systematically searched 11 electronic databases from January 2004 to August 2018 for randomized controlled trials measuring clinical efficacy of first-line TKI therapies. Clinical efficacy outcomes included overall survival and progression-free survival. Bayesian network meta-analysis was used to assess the relative efficacy of first-line EGFR TKIs for overall survival and progression-free survival. This network meta-analysis showed that dacomitinib and osimertinib resulted in improved efficacy outcomes compared with afatinib, erlotinib and gefitinib. Both osimertinib and dacomitinib should be considered as standard first-line treatment options for patients diagnosed with advanced EGFR -positive non-small-cell lung cancer.
- Published
- 2019
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21. Clinical implications of an analysis of pharmacokinetics of crizotinib coadministered with dexamethasone in patients with non-small cell lung cancer.
- Author
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Lin S, Nickens DJ, Patel M, Wilner KD, and Tan W
- Subjects
- Anaplastic Lymphoma Kinase genetics, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols pharmacology, Clinical Trials as Topic, Crizotinib pharmacokinetics, Cytochrome P-450 CYP3A Inducers administration & dosage, Cytochrome P-450 CYP3A Inducers pharmacology, Dexamethasone pharmacology, Drug Interactions, Gene Rearrangement, Humans, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Carcinoma, Non-Small-Cell Lung drug therapy, Crizotinib administration & dosage, Dexamethasone administration & dosage, Lung Neoplasms drug therapy
- Abstract
Purpose: Dexamethasone is a systemic corticosteroid and a known cytochrome P450 (CYP)3A inducer. Crizotinib is a selective tyrosine kinase inhibitor of ALK, ROS1, and MET and a substrate of CYP3A. This post hoc analysis characterized the use of concomitant CYP3A inducers with crizotinib and estimated the effect of dexamethasone use on crizotinib pharmacokinetics at steady state., Methods: This analysis used data from four clinical studies (PROFILE 1001, 1005, 1007, and 1014) including 1690 patients with non-small cell lung cancer with ALK or ROS1 rearrangements treated with crizotinib at 250 mg twice daily. Frequency and reasons for use of concomitant CYP3A inducers, including dexamethasone, with crizotinib were characterized. Multiple steady-state trough concentrations (C
trough,ss ) of crizotinib were measured for each patient. A linear mixed-effects model was used for within-patient comparison of crizotinib Ctrough,ss between dosing of crizotinib alone and crizotinib coadministered with dexamethasone consecutively for ≥ 21 days., Results: Dexamethasone was the most commonly used CYP3A inducer (30.4%). A total of 15 patients had crizotinib Ctrough,ss for both crizotinib dosing with and without dexamethasone. The adjusted geometric mean ratio of crizotinib Ctrough,ss following coadministration with dexamethasone relative to crizotinib without dexamethasone, as a percentage, was 98.2% (90% confidence interval, 79.1-122.0%)., Conclusions: Crizotinib plasma exposure following coadministration with dexamethasone was similar to that when crizotinib was administered without dexamethasone, indicating dexamethasone has no effect on crizotinib exposure or efficacy. Other CYP3A inducers with similar potency would likewise have no clinically relevant effect on crizotinib exposure.- Published
- 2019
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22. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001.
- Author
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Shaw AT, Riely GJ, Bang YJ, Kim DW, Camidge DR, Solomon BJ, Varella-Garcia M, Iafrate AJ, Shapiro GI, Usari T, Wang SC, Wilner KD, Clark JW, and Ou SI
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cohort Studies, Female, Follow-Up Studies, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Middle Aged, Prognosis, Retrospective Studies, Survival Rate, Carcinoma, Non-Small-Cell Lung drug therapy, Crizotinib therapeutic use, Gene Rearrangement, Lung Neoplasms drug therapy, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics
- Abstract
Background: In the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1-rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor activity, overall survival (OS) and safety data (additional 46.2 months follow-up) for patients with ROS1-rearranged advanced NSCLC from PROFILE 1001., Patients and Methods: ROS1 status was determined by FISH or reverse transcriptase-polymerase chain reaction. All patients received crizotinib at a starting dose of 250 mg twice daily., Results: Fifty-three patients received crizotinib, with a median duration of treatment of 22.4 months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% [95% confidence interval (CI), 58% to 83%], including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7 months; 95% CI, 15.2-45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3 months (95% CI, 15.2-39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6 months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4 months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48 months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment., Conclusions: These findings serve as a new benchmark for OS in ROS1-rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup., Trial Registration Number: ClinicalTrials.gov identifier NCT00585195., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)
- Published
- 2019
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23. Renal Effects of Crizotinib in Patients With ALK-Positive Advanced NSCLC.
- Author
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Camidge DR, Kim EE, Usari T, Polli A, Lewis I, and Wilner KD
- Subjects
- Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Creatinine blood, Female, Glomerular Filtration Rate drug effects, Humans, Lung Neoplasms blood, Lung Neoplasms enzymology, Lung Neoplasms pathology, Male, Retrospective Studies, Anaplastic Lymphoma Kinase metabolism, Antineoplastic Agents pharmacology, Crizotinib pharmacology, Kidney drug effects, Lung Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology
- Abstract
Introduction: We retrospectively analyzed the effects of crizotinib on serum creatinine and creatinine-based estimated glomerular filtration rate (eGFR) in patients with anaplastic lymphoma kinase-positive advanced NSCLC across four trials (NCT00585195, NCT00932451, NCT00932893, and NCT01154140)., Methods: Changes from baseline data in serum creatinine and eGFR, calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based equation, were assessed over time. eGFR was graded using standard chronic kidney disease criteria., Results: Median serum creatinine increased from 0.79 mg/dL at baseline to 0.93 mg/dL after 2 weeks of treatment (median percentage increase from baseline, 21.2%), was stable from week 12 (0.96 mg/dL) to week 104 (1.00 mg/dL), and decreased to 0.90 mg/dL at 28 days after last dose (median percentage increase from baseline, 13.1%). Median eGFR decreased over time (96.42, 80.23, 78.06 and 75.45 mL/min/1.73 m
2 at baseline, week 2, week 12, and week 104, respectively) and increased to 83.02 mL/min/1.73 m2 at 28 days after the last dose. Median percentage decrease from baseline was 14.9%, 17.0%, and 10.4% at week 2, week 12, and 28 days after last dose of crizotinib, respectively. Overall, 12.6% of patients had a shift from eGFR grade less than or equal to 3a (≥45 mL/min/1.73 m2 ) at baseline to greater than or equal to 3b (<45 mL/min/1.73 m2 ) post-baseline., Conclusions: Crizotinib resulted in a decline in creatinine-based estimates of renal function mostly over the first 2 weeks of treatment. However, there was minimal evidence of cumulative effects with prolonged treatment and these changes were largely reversible following treatment discontinuation, consistent with previous reports suggesting this may be predominantly an effect on creatinine secretion as opposed to true nephrotoxicity., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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24. Comparison of cardiovascular effects of crizotinib and chemotherapy in ALK-positive advanced non-small-cell lung cancer.
- Author
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Wilner KD, Usari T, Polli A, and Kim EE
- Subjects
- Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Cardiotoxicity, Clinical Trials, Phase III as Topic, Follow-Up Studies, Heart Failure metabolism, Heart Failure pathology, Humans, Lung Neoplasms metabolism, Lung Neoplasms pathology, Prognosis, Prospective Studies, Randomized Controlled Trials as Topic, Anaplastic Lymphoma Kinase metabolism, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carcinoma, Non-Small-Cell Lung drug therapy, Crizotinib adverse effects, Heart Failure chemically induced, Lung Neoplasms drug therapy, Protein Kinase Inhibitors adverse effects
- Abstract
Aim: We analyzed cardiac function in two Phase III studies of previously treated (PROFILE 1007) or untreated (PROFILE 1014) ALK-positive advanced non-small-cell lung cancer., Patients & Methods: Adverse events associated with cardiac failure were compared between treatment arms in each study separately. Cardiac function was assessed prospectively by multigated acquisition scans or echocardiograms., Results: In PROFILE 1007 and 1014, incidence of cardiac failure adverse events was 0% (crizotinib) versus 0.6% (chemotherapy) and 2.3% versus 0.6%, respectively. In crizotinib versus chemotherapy arms, respectively, >20% left ventricular ejection fraction decreases occurred in 0/19 (0%) versus 1/16 (6.3%) patients from PROFILE 1007 and 4/150 (2.7%) versus 10/150 (6.7%) patients from PROFILE 1014., Conclusion: These analyses did not reveal any clinically meaningful changes in myocardial function with crizotinib in patients with ALK-positive non-small-cell lung cancer. Clinicaltrials.gov identifier: PROFILE 1007, NCT00932893; PROFILE 1014, NCT01154140.
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- 2019
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25. Results of PROFILE 1029, a Phase III Comparison of First-Line Crizotinib versus Chemotherapy in East Asian Patients with ALK-Positive Advanced Non-Small Cell Lung Cancer.
- Author
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Wu YL, Lu S, Lu Y, Zhou J, Shi YK, Sriuranpong V, Ho JCM, Ong CK, Tsai CM, Chung CH, Wilner KD, Tang Y, Masters ET, Selaru P, and Mok TS
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols pharmacology, Asian People, Carcinoma, Non-Small-Cell Lung pathology, Crizotinib pharmacology, Female, Humans, Lung Neoplasms pathology, Male, Middle Aged, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Crizotinib therapeutic use, Lung Neoplasms drug therapy
- Abstract
Introduction: The phase III randomized PROFILE 1014 study demonstrated superiority of crizotinib to first-line chemotherapy in prolonging progression-free survival (PFS) in previously untreated patients with ALK receptor tyrosine kinase gene (ALK)-positive advanced nonsquamous NSCLC. This result was consistent with that in the smaller subset of East Asian patients in PROFILE 1014. The subsequent study reported here prospectively evaluated crizotinib in a larger East Asian patient population., Methods: In this open-label phase III study (PROFILE 1029), patients were randomized 1:1 to receive orally administered crizotinib 250 mg twice daily continuously (3-week cycles) or intravenously administered chemotherapy (pemetrexed 500 mg/m
2 , plus cisplatin 75 mg/m2 , or carboplatin [at a dose to produce area under the concentration-time curve of 5-6 mg·min/mL]) every 3 weeks for a maximum of six cycles. PFS confirmed by independent radiology review was the primary end point., Results: Crizotinib significantly prolonged PFS (hazard ratio, 0.402; 95% confidence interval [CI]: 0.286-0.565; p < 0.001). The median PFS was 11.1 months with crizotinib and 6.8 months with chemotherapy. The objective response rate was 87.5% (95% CI: 79.6-93.2%) with crizotinib versus 45.6% (95% CI: 35.8-55.7%) with chemotherapy (p < 0.001). The most common adverse events were increased transaminase levels, diarrhea, and vision disorders with crizotinib and leukopenia, neutropenia, and anemia with chemotherapy. Significantly greater improvements from baseline in patient-reported outcomes were seen in crizotinib-treated versus chemotherapy-treated patients., Conclusions: First-line crizotinib significantly improved PFS, objective response rate, and patient-reported outcomes compared with standard platinum-based chemotherapy in East Asian patients with ALK-positive advanced NSCLC, which is similar to the results from PROFILE 1014. The safety profiles of crizotinib and chemotherapy were consistent with those previously published., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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26. Correlation of extent of ALK FISH positivity and crizotinib efficacy in three prospective studies of ALK-positive patients with non-small-cell lung cancer.
- Author
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Soria JC, Ho SN, Varella-Garcia M, Iafrate AJ, Solomon BJ, Shaw AT, Blackhall F, Mok TS, Wu YL, Pestova K, Wilner KD, Polli A, Paolini J, Lanzalone S, Green S, and Camidge DR
- Subjects
- Adult, Aged, Aged, 80 and over, Anaplastic Lymphoma Kinase metabolism, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Crizotinib pharmacology, Drug Resistance, Neoplasm, Female, Humans, In Situ Hybridization, Fluorescence, Lung pathology, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Middle Aged, Progression-Free Survival, Prospective Studies, Protein Kinase Inhibitors pharmacology, Randomized Controlled Trials as Topic, Young Adult, Anaplastic Lymphoma Kinase analysis, Carcinoma, Non-Small-Cell Lung drug therapy, Crizotinib therapeutic use, Lung Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use
- Abstract
Background: In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small sample sizes., Patients and Methods: Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively., Results: Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells; of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17)., Conclusions: Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.
- Published
- 2018
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27. Final Overall Survival Analysis From a Study Comparing First-Line Crizotinib Versus Chemotherapy in ALK-Mutation-Positive Non-Small-Cell Lung Cancer.
- Author
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Solomon BJ, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Tang Y, Wilner KD, Blackhall F, and Mok TS
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carboplatin administration & dosage, Carboplatin adverse effects, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung genetics, Cisplatin administration & dosage, Cisplatin adverse effects, Crizotinib adverse effects, Female, Humans, Lung Neoplasms enzymology, Lung Neoplasms genetics, Male, Middle Aged, Mutation, Pemetrexed administration & dosage, Pemetrexed adverse effects, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Survival Rate, Anaplastic Lymphoma Kinase genetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Crizotinib administration & dosage, Lung Neoplasms drug therapy
- Abstract
Purpose The phase III PROFILE 1014 trial compared crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) -positive advanced nonsquamous non-small-cell lung cancer. Here, we report the final overall survival (OS) results. Patients and Methods Patients were randomly assigned to receive oral crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m
2 plus cisplatin 75 mg/m2 or carboplatin (area under the concentration-time curve of 5 to 6 mg·mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover. Results Median follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053; two-sided P = .0978). Median OS was not reached (NR) with crizotinib (95% CI, 45.8 months to NR) and 47.5 months with chemotherapy (95% CI, 32.2 months to NR). Survival probability at 4 years was 56.6% (95% CI, 48.3% to 64.1%) with crizotinib and 49.1% (95% CI, 40.5% to 57.1%) with chemotherapy. After crossover adjustment, there was an improvement in OS that favored crizotinib (hazard ratio, 0.346; 95% bootstrap CI, 0.081 to 0.718). The longest OS was observed in crizotinib-treated patients who received a subsequent ALK tyrosine kinase inhibitor. No new safety signals were identified. Conclusion The final analysis of the PROFILE 1014 study provides a new benchmark for OS in patients with ALK-rearranged non-small-cell lung cancer and highlights the benefit of crizotinib for prolonging survival in this patient population.- Published
- 2018
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28. Crizotinib versus Chemotherapy in Asian Patients with ALK-Positive Advanced Non-small Cell Lung Cancer.
- Author
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Nishio M, Kim DW, Wu YL, Nakagawa K, Solomon BJ, Shaw AT, Hashigaki S, Ohki E, Usari T, Paolini J, Polli A, Wilner KD, and Mok T
- Subjects
- Anaplastic Lymphoma Kinase, Carcinoma, Non-Small-Cell Lung genetics, Crizotinib, Docetaxel, Drug Administration Schedule, Female, Humans, Intention to Treat Analysis, Kaplan-Meier Estimate, Lung Neoplasms genetics, Male, Pemetrexed adverse effects, Pyrazoles adverse effects, Pyridines adverse effects, Survival Analysis, Taxoids adverse effects, Treatment Outcome, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Pemetrexed administration & dosage, Pyrazoles administration & dosage, Pyridines administration & dosage, Receptor Protein-Tyrosine Kinases genetics, Taxoids administration & dosage
- Abstract
Purpose: Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of crizotinib in Asian subpopulations of two global phase III trials., Materials and Methods: This analysis evaluated previously treated and untreated patients in two randomized, openlabel phase III trials of crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and "as-treated" populations for efficacy and safety endpoints, respectively., Results: In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p < 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p < 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p < 0.05). The most common treatment-emergent adverse events (any grade)with crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity., Conclusion: These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.
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- 2018
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29. Phase II Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced Non-Small-Cell Lung Cancer.
- Author
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Wu YL, Yang JC, Kim DW, Lu S, Zhou J, Seto T, Yang JJ, Yamamoto N, Ahn MJ, Takahashi T, Yamanaka T, Kemner A, Roychowdhury D, Paolini J, Usari T, Wilner KD, and Goto K
- Subjects
- Administration, Oral, Aged, Carcinoma, Non-Small-Cell Lung ethnology, Carcinoma, Non-Small-Cell Lung pathology, China, Crizotinib administration & dosage, Female, Gene Rearrangement, Humans, In Situ Hybridization, Fluorescence, Japan, Kaplan-Meier Estimate, Lung Neoplasms ethnology, Lung Neoplasms pathology, Male, Middle Aged, Protein Kinase Inhibitors administration & dosage, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Republic of Korea, Taiwan, Treatment Outcome, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Crizotinib therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Protein Kinase Inhibitors therapeutic use
- Abstract
Purpose Approximately 1% to 2% of non-small-cell lung cancers (NSCLCs) harbor a c-ros oncogene 1 ( ROS1) rearrangement. Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and MET, has shown marked antitumor activity in a small expansion cohort of patients with ROS1-positive advanced NSCLC from an ongoing phase I study. We assessed the efficacy and safety of crizotinib in the largest cohort of patients with ROS1-positive advanced NSCLC. Patients and Methods This phase II, open-label, single-arm trial enrolled East Asian patients with ROS1-positive (assessed through validated AmoyDx assay [Amoy Diagnostics, Xiamen, China] at three regional laboratories) advanced NSCLC who had received three or fewer lines of prior systemic therapies. Patients were to receive oral crizotinib at a starting dose of 250 mg twice daily and continued treatment until Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1-defined progression (by independent radiology review [IRR]), unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR) by IRR. Results In the efficacy and safety analyses, 127 patients were included, with 49.6% still receiving treatment at data cutoff. ORR by IRR was 71.7% (95% CI, 63.0% to 79.3%), with 17 complete responses and 74 partial responses. ORRs were similar irrespective of the number of prior lines of therapy, and responses were durable (median duration of response, 19.7 months; 95% CI, 14.1 months to not reached). Median progression-free survival by IRR was 15.9 months (95% CI, 12.9 to 24.0 months). No new safety signals associated with crizotinib were reported. Conclusion This study demonstrated clinically meaningful benefit and durable responses with crizotinib in East Asian patients with ROS1-positive advanced NSCLC. Crizotinib was generally well tolerated, with a safety profile consistent with previous reports.
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- 2018
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30. Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer.
- Author
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Durairaj C, Ruiz-Garcia A, Gauthier ER, Huang X, Lu DR, Hoffman JT, Finn RS, Joy AA, Ettl J, Rugo HS, Zheng J, Wilner KD, and Wang DD
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols blood, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Breast Neoplasms blood, Breast Neoplasms physiopathology, Double-Blind Method, Female, Heart Rate drug effects, Humans, Letrozole, Middle Aged, Nitriles administration & dosage, Nitriles blood, Nitriles pharmacokinetics, Piperazines administration & dosage, Piperazines blood, Piperazines pharmacokinetics, Pyridines administration & dosage, Pyridines blood, Pyridines pharmacokinetics, Triazoles administration & dosage, Triazoles blood, Triazoles pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Electrocardiography drug effects
- Abstract
The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent.
- Published
- 2018
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31. Interstitial Lung Disease Associated With Crizotinib in Patients With Advanced Non-Small Cell Lung Cancer: Independent Review of Four PROFILE Trials.
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Yoneda KY, Scranton JR, Cadogan MA, Tassell V, Nadanaciva S, Wilner KD, and Stollenwerk NS
- Subjects
- Adult, Aged, Aged, 80 and over, Asian People ethnology, Crizotinib, Female, Humans, Incidence, Japan ethnology, Lung Diseases, Interstitial epidemiology, Lung Diseases, Interstitial mortality, Male, Middle Aged, Randomized Controlled Trials as Topic, Retrospective Studies, White People ethnology, Young Adult, Antineoplastic Agents adverse effects, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Diseases, Interstitial chemically induced, Lung Neoplasms drug therapy, Pyrazoles adverse effects, Pyridines adverse effects
- Abstract
Introduction: Interstitial lung disease (ILD) is a rare, but potentially serious, side effect associated with crizotinib, a tyrosine kinase inhibitor for anaplastic lymphoma kinase-positive (ALK
+ ) advanced non-small cell lung cancer. Our objective was to determine the incidence and nature of ILD associated with crizotinib in 4 PROFILE trials (ClinicalTrials.gov identifiers, NCT00585195, NCT00932451, NCT00932893, and NCT01154140)., Materials and Methods: Grade ≥ 3 respiratory adverse events (AEs) and serious AEs (SAEs) and any grade AEs/SAEs reported as pneumonitis, ILD, or radiation pneumonitis in trials PROFILE 1001, PROFILE 1005, PROFILE 1007, and PROFILE 1014 were evaluated by an expert independent review committee that included a pulmonologist, medical oncologist, and radiologist. Events were designated as disease progression, de novo ILD possibly or probably related to crizotinib, exacerbation or recurrence of pre-existing ILD, concurrent illness, other toxicity not thought to be related to ILD, or inconclusive., Results: The independent review committee evaluated 446 events (in 368 of 1669 patients who had received crizotinib therapy). They classified these events as follows: progressive disease, 77; de novo ILD, 20; pre-existing ILD, 3; concurrent illness, 9; other toxicities, 310; and inconclusive, 27. The incidence of de novo ILD was 1.2% overall, 1.3% in whites, and 1.2% overall in Asians, but greater at 3.7% in Japanese patients. The median onset of ILD from the initiation of crizotinib therapy was 23 days (range, 3-763 days). The mortality rate due to ILD was 50%. Survival was improved if crizotinib was discontinued on presentation of ILD (9 of 14 patients) compared with discontinued later or continued (1 of 6 patients)., Conclusion: ILD associated with crizotinib, although rare, can occur at any time and requires close monitoring., (Published by Elsevier Inc.)- Published
- 2017
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32. Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer.
- Author
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Blackhall F, Ross Camidge D, Shaw AT, Soria JC, Solomon BJ, Mok T, Hirsh V, Jänne PA, Shi Y, Yang PC, Pas T, Hida T, Carpeño JC, Lanzalone S, Polli A, Iyer S, Reisman A, Wilner KD, and Kim DW
- Abstract
Purpose: Crizotinib is a potent, orally administered tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We report final results from PROFILE 1005, the largest clinical trial to date for an ALK inhibitor in ALK-positive NSCLC., Patients and Methods: PROFILE 1005 (NCT00932451) was a multicenter, single-arm phase 2 trial of the efficacy, safety and tolerability of crizotinib (250 mg twice daily; 3 week continuous treatment cycles) in patients with ALK-positive NSCLC after failure of ≥1 lines of systemic treatment for locally advanced/metastatic disease. Patients' tumour ALK status was initially determined by a central laboratory until a protocol amendment permitted enrolment of patients based on locally determined ALK status. Co-primary endpoints were objective response rate (ORR), evaluated using Response Evaluation Criteria in Solid Tumours V.1.1 and adverse events (AEs). Cancer-specific patient-reported outcomes (PROs) were also assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 and its lung cancer module QLQ-LC13., Results: 1069 patients were enrolled; 1066 received crizotinib. The as-treated population comprised 908 and 158 patients, in whom tumour positive ALK - status was determined centrally (± locally) or locally only, respectively. At baseline, a majority of patients were <65 years (84%), 66% were never smokers and 46% were Asian. Derived investigator-assessed ORR was 54% (95% CI 51 to 57) and 41% (95% CI 33 to 49) in the central-testing and local-testing subgroups, respectively. The most common treatment-related AEs in the overall population (any grade) were vision disorder (58%), nausea (51%), diarrhoea (47%) and vomiting (47%). PRO scores demonstrated clinically meaningful improvement in lung cancer symptoms and global quality of life., Conclusion: The efficacy, safety and PRO profiles of crizotinib in this cohort of 1066 patients with ALK-positive NSCLC are consistent with previous reports., Trial Registration Number: Phase 2 trial (NCT00932451); Results., Competing Interests: Competing interests: We have already uploaded ICMJE form of each authors when Ann Oncol submission
- Published
- 2017
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33. Clinical Implications of the Pharmacokinetics of Crizotinib in Populations of Patients with Non-Small Cell Lung Cancer.
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Wang E, Nickens DJ, Bello A, Khosravan R, Amantea M, Wilner KD, Parivar K, and Tan W
- Subjects
- Aged, Asian People, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung drug therapy, Crizotinib, Female, Humans, Lung Neoplasms blood, Lung Neoplasms drug therapy, Male, Protein Kinase Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyridines therapeutic use, Carcinoma, Non-Small-Cell Lung metabolism, Lung Neoplasms metabolism, Protein Kinase Inhibitors pharmacokinetics, Pyrazoles pharmacokinetics, Pyridines pharmacokinetics
- Abstract
Purpose: We assessed the effect of baseline patient demographic and disease characteristics on the crizotinib pharmacokinetic parameters oral clearance (CL/F), volume of distribution (V2/F), and area under the curve at steady state (AUC
ss ) following multiple crizotinib 250-mg twice-daily dosing in patients with ALK-positive cancer., Experimental Design: A pharmacokinetic model was fit to data from 1,214 patients. We identified statistically significant covariates (P ≤ 0.001) by evaluating their effects on CL/F and V2/F and estimated their magnitudes., Results: Age, Eastern Cooperative Oncology Group performance status, aspartate aminotransferase (AST) levels, albumin levels, and smoking status had no effect on CL/F or V2/F. Statistically significant covariates were Asian race and female sex for CL/F and V2/F and body weight, creatinine clearance (CLcr), and total bilirubin for CL/F only. The model predicted that CL/F would be 9% lower or higher in a 40-kg or a 100-kg patient, respectively; 16% lower in patients with CLcr 30 mL/minute; 23% lower in Asians; and 11% lower in females than the reference patient (65-kg non-Asian male; baseline CLcr, 91.6 mL/minute; total bilirubin, 0.41 mg/dL). The effect of total bilirubin on CL/F was small. V2/F was 23% lower in Asians than non-Asians and females than males. Effects of all significant covariates on AUCss were not predicted to be clinically relevant., Conclusions: Crizotinib at a 250-mg twice-daily starting dose appears to be appropriate for all patients irrespective of age, sex, race, body weight, mild or moderate renal impairment, or hepatic function (in the range evaluated: bilirubin ≤ 2.1 mg/dL or AST ≤124 U/L). Clin Cancer Res; 22(23); 5722-8. ©2016 AACR., (©2016 American Association for Cancer Research.)- Published
- 2016
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34. Intracranial Efficacy of Crizotinib Versus Chemotherapy in Patients With Advanced ALK-Positive Non-Small-Cell Lung Cancer: Results From PROFILE 1014.
- Author
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Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, Nakagawa K, Wu YL, Mekhail T, Paolini J, Tursi J, Usari T, Wilner KD, Selaru P, and Mok TS
- Subjects
- Adult, Aged, Anaplastic Lymphoma Kinase, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms enzymology, Brain Neoplasms genetics, Carboplatin administration & dosage, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cisplatin administration & dosage, Crizotinib, Drug Administration Schedule, Female, Humans, Lung Neoplasms enzymology, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Middle Aged, Pemetrexed administration & dosage, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases biosynthesis, Receptor Protein-Tyrosine Kinases genetics, Young Adult, Brain Neoplasms drug therapy, Brain Neoplasms secondary, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Protein Kinase Inhibitors administration & dosage, Pyrazoles administration & dosage, Pyridines administration & dosage
- Abstract
Purpose: Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer., Patients and Methods: Patients were randomly assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) or carboplatin at area under the curve 5 to 6, every 3 weeks for ≤ six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed., Results: Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P < .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P < .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P < .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P < .001; median, 10.9 v 7.0 months, respectively)., Conclusion: Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low., (© 2016 by American Society of Clinical Oncology.)
- Published
- 2016
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35. Sufficiency of Single-Arm Studies to Support Registration of Targeted Agents in Molecularly Selected Patients with Cancer: Lessons from the Clinical Development of Crizotinib.
- Author
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Selaru P, Tang Y, Huang B, Polli A, Wilner KD, Donnelly E, and Cohen DP
- Subjects
- Antineoplastic Agents therapeutic use, Crizotinib, Drug Approval, Humans, Neoplasms genetics, Treatment Outcome, Drug Discovery, Neoplasms drug therapy, Pyrazoles therapeutic use, Pyridines therapeutic use
- Published
- 2016
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36. Factors associated with sinus bradycardia during crizotinib treatment: a retrospective analysis of two large-scale multinational trials (PROFILE 1005 and 1007).
- Author
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Ou SH, Tang Y, Polli A, Wilner KD, and Schnell P
- Subjects
- Adrenergic beta-Antagonists therapeutic use, Adult, Aged, Aged, 80 and over, Blood Pressure, Bradycardia diagnosis, Bradycardia drug therapy, Bradycardia mortality, Carcinoma, Non-Small-Cell Lung complications, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Clinical Trials as Topic, Crizotinib, Female, Heart Rate, Humans, Lung Neoplasms complications, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Middle Aged, Multicenter Studies as Topic, Neoplasms complications, Neoplasms drug therapy, Prognosis, Retrospective Studies, Risk Factors, Young Adult, Antineoplastic Agents adverse effects, Bradycardia etiology, Protein Kinase Inhibitors adverse effects, Pyrazoles adverse effects, Pyridines adverse effects
- Abstract
Decreases in heart rate (HR) have been described in patients receiving crizotinib. We performed a large retrospective analysis of HR changes during crizotinib therapy. HRs from vital-sign data for patients with anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer enrolled in PROFILE 1005 and the crizotinib arm of PROFILE 1007 were analyzed. Sinus bradycardia (SB) was defined as HR <60 beats per minute (bpm). Magnitude and timing of HR changes were assessed. Potential risk factors for SB were investigated by logistic regression analysis. Progression-free survival (PFS) was evaluated according to HR decrease by <20 versus ≥ 20 bpm within the first 50 days of starting treatment. For the 1053 patients analyzed, the mean maximum postbaseline HR decrease was 25 bpm (standard deviation 15.8). Overall, 441 patients (41.9%) had at least one episode of postbaseline SB. The mean precrizotinib treatment HR was significantly lower among patients with versus without postbaseline SB (82.2 bpm vs. 92.6 bpm). The likelihood of experiencing SB was statistically significantly higher among patients with a precrizotinib treatment HR <70 bpm. PFS was comparable among patients with or without HR decrease of ≥ 20 bpm within the first 50 days of starting crizotinib. Decrease in HR is very common among patients on crizotinib. The likelihood of experiencing SB was statistically significantly higher among patients with a precrizotinib treatment HR <70 bpm. This is the first large-scale report investigating the association between treatment with a tyrosine kinase inhibitor and the development of bradycardia. HRs should be closely monitored during crizotinib treatment., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2016
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37. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases.
- Author
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Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, Zhou C, Shreeve SM, Selaru P, Polli A, Schnell P, Wilner KD, Wiltshire R, Camidge DR, and Crinò L
- Subjects
- Adult, Aged, Anaplastic Lymphoma Kinase, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Brain Neoplasms secondary, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung secondary, Cranial Irradiation, Crizotinib, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Magnetic Resonance Imaging, Male, Middle Aged, Radiosurgery, Randomized Controlled Trials as Topic, Retrospective Studies, Tomography, X-Ray Computed, Treatment Outcome, Antineoplastic Agents therapeutic use, Brain Neoplasms drug therapy, Carcinoma, Non-Small-Cell Lung drug therapy, Gene Rearrangement, Lung Neoplasms pathology, Protein Kinase Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyridines therapeutic use, Receptor Protein-Tyrosine Kinases genetics
- Abstract
Purpose: Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied., Patients and Methods: Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1)., Results: At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases., Conclusion: Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib., (© 2015 by American Society of Clinical Oncology.)
- Published
- 2015
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38. Complex renal cysts associated with crizotinib treatment.
- Author
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Schnell P, Bartlett CH, Solomon BJ, Tassell V, Shaw AT, de Pas T, Lee SH, Lee GK, Tanaka K, Tan W, Tang Y, Wilner KD, Safferman A, and Han JY
- Subjects
- Adult, Aged, Crizotinib, Female, Humans, Male, Middle Aged, Randomized Controlled Trials as Topic, Retrospective Studies, Risk Factors, Tomography, X-Ray Computed, Treatment Outcome, Antineoplastic Agents adverse effects, Carcinoma, Non-Small-Cell Lung drug therapy, Kidney Diseases, Cystic chemically induced, Lung Neoplasms drug therapy, Protein Kinase Inhibitors adverse effects, Pyrazoles adverse effects, Pyridines adverse effects
- Abstract
An apparent causal association between crizotinib treatment and renal cyst development emerged during clinical trials in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Serious adverse event (SAE) reports of renal cysts from a safety database of 1375 patients from four clinical trials were reviewed. A blinded, retrospective, independent radiologic review (IRR) was performed using scans from patients on study for ≥ 6 months in three clinical trials; risk factors for renal cyst development were assessed. Among 17 patients with renal cysts reported as SAEs, evidence of invasion into adjacent structures was noted in seven patients, with no evidence of malignancy found. These patients generally did not require dose reductions, none required permanent crizotinib discontinuation due to this AE, and most continued treatment with clinical benefit. In the blinded IRR, among 255 crizotinib-treated patients, 22%, 3%, and 2% had preexisting simple cysts, complex cysts, or both, respectively. At the 6-month tumor assessment, 9% of all patients had acquired new cysts, and 2% of patients with preexisting cysts had developed new cysts and enlargements (>50%) of preexisting simple cysts. Asians appeared to have an increased risk of developing new cysts on treatment; Koreans in particular had 5.18 times higher odds of developing cysts than non-Asians (95% confidence interval, 1.51-17.78; P = 0.05). Crizotinib treatment appears to be associated with an increased risk of development and progression of renal cysts in patients with ALK-positive NSCLC. While close monitoring is recommended, dosing modification was not generally necessary, allowing patients to remain on crizotinib treatment., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2015
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39. First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
- Author
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Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, and Blackhall F
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma mortality, Adult, Aged, Anaplastic Lymphoma Kinase, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carboplatin administration & dosage, Carcinoma, Non-Small-Cell Lung mortality, Cisplatin administration & dosage, Crizotinib, Disease-Free Survival, Female, Glutamates administration & dosage, Guanine administration & dosage, Guanine analogs & derivatives, Humans, Kaplan-Meier Estimate, Lung Neoplasms mortality, Male, Middle Aged, Pemetrexed, Protein Kinase Inhibitors adverse effects, Pyrazoles adverse effects, Pyridines adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyridines therapeutic use, Receptor Protein-Tyrosine Kinases antagonists & inhibitors
- Abstract
Background: The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown., Methods: We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review., Results: Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life., Conclusions: Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).
- Published
- 2014
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40. Crizotinib in ROS1-rearranged non-small-cell lung cancer.
- Author
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Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, and Iafrate AJ
- Subjects
- Administration, Oral, Adult, Aged, Carcinoma, Non-Small-Cell Lung genetics, Crizotinib, Disease-Free Survival, Female, Gene Rearrangement, Humans, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Lung Neoplasms genetics, Male, Middle Aged, Protein Kinase Inhibitors adverse effects, Proto-Oncogene Mas, Pyrazoles adverse effects, Pyridines adverse effects, Treatment Outcome, Vision Disorders chemically induced, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics, Pyrazoles therapeutic use, Pyridines therapeutic use
- Abstract
Background: Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET., Methods: We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays., Results: The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC., Conclusions: In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
- Published
- 2014
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41. Patient-reported outcomes and quality of life in PROFILE 1007: a randomized trial of crizotinib compared with chemotherapy in previously treated patients with ALK-positive advanced non-small-cell lung cancer.
- Author
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Blackhall F, Kim DW, Besse B, Nokihara H, Han JY, Wilner KD, Reisman A, Iyer S, Hirsh V, and Shaw AT
- Subjects
- Anaplastic Lymphoma Kinase, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung genetics, Crizotinib, Docetaxel, Humans, Lung Neoplasms enzymology, Lung Neoplasms genetics, Pemetrexed therapeutic use, Quality of Life, Receptor Protein-Tyrosine Kinases genetics, Receptor Protein-Tyrosine Kinases metabolism, Self Report, Taxoids therapeutic use, Treatment Outcome, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyridines therapeutic use
- Abstract
Introduction: The main objective of the current post hoc analysis was to compare patient-reported outcomes between crizotinib (N = 172) and chemotherapy subgroups (pemetrexed [N = 99] and docetaxel [N = 72]) in previously treated patients with advanced ALK-positive non-small-cell lung cancer, in PROFILE 1007 study (Pfizer; NCT0093283)., Methods: Patient-reported outcomes were assessed at baseline, day 1 of each cycle, and end of treatment. General health status was measured using the EuroQol-5D visual analog scale and health utility index scores were assessed using the EuroQol-5D descriptive system. Functioning, lung cancer symptoms, and global quality of life (QOL) were assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and the QLQ-LC13 lung cancer module. Repeated measures mixed-effects analyses compared overall scores and change from baseline scores, controlling for baseline scores., Results: The overall mean EQ-5D health utility index scores (95% CI) on treatment were significantly greater (p < 0.05) for crizotinib (0.82 [0.79-0.85]) than for chemotherapy (0.73 [0.70-0.77]; 0.74 [0.70-0.79] for pemetrexed and 0.66 [0.58-0.74] for docetaxel). A significantly greater improvement from baseline was observed with crizotinib versus pemetrexed and versus docetaxel treatment groups for general health status, physical functioning, global QOL, dyspnea, fatigue, and pain. Improvement rates for fatigue, cough, pain, dyspnea, and global QOL were significantly greater on crizotinib compared with pemetrexed and docetaxel, respectively. Worsening rates for diarrhea and constipation were higher with crizotinib., Conclusion: The benefits of crizotinib in improving symptoms and QOL are demonstrated regardless of whether the comparator is pemetrexed or docetaxel.
- Published
- 2014
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42. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
- Author
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Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, and Jänne PA
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Carcinoma, Non-Small-Cell Lung mortality, Crizotinib, Disease-Free Survival, Docetaxel, Female, Glutamates adverse effects, Glutamates therapeutic use, Guanine adverse effects, Guanine analogs & derivatives, Guanine therapeutic use, Humans, Kaplan-Meier Estimate, Lung Neoplasms mortality, Male, Middle Aged, Pemetrexed, Protein Kinase Inhibitors adverse effects, Pyrazoles adverse effects, Pyridines adverse effects, Quality of Life, Taxoids adverse effects, Taxoids therapeutic use, Young Adult, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyridines therapeutic use
- Abstract
Background: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown., Methods: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival., Results: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy., Conclusions: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).
- Published
- 2013
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43. Acquired resistance to crizotinib from a mutation in CD74-ROS1.
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Awad MM, Katayama R, McTigue M, Liu W, Deng YL, Brooun A, Friboulet L, Huang D, Falk MD, Timofeevski S, Wilner KD, Lockerman EL, Khan TM, Mahmood S, Gainor JF, Digumarthy SR, Stone JR, Mino-Kenudson M, Christensen JG, Iafrate AJ, Engelman JA, and Shaw AT
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma pathology, Crizotinib, Fatal Outcome, Female, Humans, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Middle Aged, Mutation, Protein Conformation, Protein-Tyrosine Kinases chemistry, Proto-Oncogene Proteins chemistry, Structure-Activity Relationship, Adenocarcinoma genetics, Drug Resistance genetics, Lung Neoplasms genetics, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics, Pyrazoles therapeutic use, Pyridines therapeutic use, Translocation, Genetic
- Abstract
Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), has also recently shown efficacy in the treatment of lung cancers with ROS1 translocations. Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment. We performed a biopsy of a resistant tumor and identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
- Published
- 2013
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44. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma.
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Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, Yu JQ, Vallabhajosula S, Schoder H, English P, Neuberg DS, Martin P, Millenson MM, Ely SA, Courtney R, Shaik N, Wilner KD, Randolph S, Van den Abbeele AD, Chen-Kiang SY, Yap JT, and Shapiro GI
- Subjects
- Adult, Aged, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Female, Humans, Lymphoma, Mantle-Cell blood, Lymphoma, Mantle-Cell diagnosis, Lymphoma, Mantle-Cell metabolism, Male, Middle Aged, Piperazines administration & dosage, Piperazines adverse effects, Piperazines pharmacokinetics, Prognosis, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors therapeutic use, Pyridines administration & dosage, Pyridines adverse effects, Pyridines pharmacokinetics, Substrate Specificity, Treatment Outcome, Lymphoma, Mantle-Cell drug therapy, Piperazines therapeutic use, Pyridines therapeutic use
- Abstract
Mantle cell lymphoma (MCL) carries an unfavorable prognosis and requires new treatment strategies. The associated t(11:14) translocation results in enhanced cyclin D1 expression and cyclin D1-dependent kinase activity to promote cell-cycle progression. A pharmacodynamic study of the selective CDK4/6 inhibitor PD0332991 was conducted in 17 patients with relapsed disease, using 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and 3-deoxy-3[(18)F]fluorothymidine (FLT) positron emission tomography (PET) to study tumor metabolism and proliferation, respectively, in concert with pre- and on-treatment lymph node biopsies to assess retinoblastoma protein (Rb) phosphorylation and markers of proliferation and apoptosis. Substantial reductions in the summed FLT-PET maximal standard uptake value (SUV(max)), as well as in Rb phosphorylation and Ki-67 expression, occurred after 3 weeks in most patients, with significant correlations among these end points. Five patients achieved progression-free survival time of > 1 year (range, 14.9-30.1+ months), with 1 complete and 2 partial responses (18% objective response rate; 90% confidence interval, 5%-40%). These patients demonstrated > 70%, > 90%, and ≥ 87.5% reductions in summed FLT SUV(max) and expression of phospho-Rb and Ki67, respectively, parameters necessary but not sufficient for long-term disease control. The results of the present study confirm CDK4/6 inhibition by PD0332991 at a well-tolerated dose and schedule and suggest clinical benefit in a subset of MCL patients. This study is registered at www.clinicaltrials.gov under identifier NCT00420056.
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- 2012
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45. ROS1 rearrangements define a unique molecular class of lung cancers.
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Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak EL, Clark JW, Carbone DP, Ji H, Engelman JA, Mino-Kenudson M, Pao W, and Iafrate AJ
- Subjects
- Adenocarcinoma genetics, Adult, Aged, Aged, 80 and over, Anaplastic Lymphoma Kinase, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung mortality, Crizotinib, Drug Screening Assays, Antitumor, Female, Humans, In Situ Hybridization, Fluorescence, Lung Neoplasms drug therapy, Lung Neoplasms mortality, Male, Middle Aged, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Pyrazoles pharmacology, Pyrazoles therapeutic use, Pyridines pharmacology, Pyridines therapeutic use, Receptor Protein-Tyrosine Kinases genetics, Retrospective Studies, Treatment Outcome, Carcinoma, Non-Small-Cell Lung genetics, Gene Rearrangement, Lung Neoplasms genetics, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics
- Abstract
Purpose: Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non-small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement., Patients and Methods: Using a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status. In vitro studies assessed the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib. The clinical response of one patient with ROS1-rearranged NSCLC to crizotinib was investigated as part of an expanded phase I cohort., Results: Of 1,073 tumors screened, 18 (1.7%) were ROS1 rearranged by FISH, and 31 (2.9%) were ALK rearranged. Compared with the ROS1-negative group, patients with ROS1 rearrangements were significantly younger and more likely to be never-smokers (each P < .001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade. ROS1-positive and -negative groups showed no difference in overall survival. The HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 showed evidence of sensitivity to crizotinib. The patient treated with crizotinib showed tumor shrinkage, with a near complete response., Conclusion: ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib shows in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC.
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- 2012
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46. Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor.
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Chi AS, Batchelor TT, Kwak EL, Clark JW, Wang DL, Wilner KD, Louis DN, and Iafrate AJ
- Subjects
- Brain Neoplasms diagnostic imaging, Brain Neoplasms genetics, Brain Neoplasms pathology, Crizotinib, Female, Gene Amplification, Glioblastoma diagnostic imaging, Glioblastoma genetics, Glioblastoma pathology, Humans, Middle Aged, Proto-Oncogene Proteins c-met genetics, Radiography, Brain Neoplasms drug therapy, Epithelial-Mesenchymal Transition drug effects, Glioblastoma drug therapy, Pyrazoles therapeutic use, Pyridines therapeutic use
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- 2012
- Full Text
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47. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer.
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Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, Shaik MN, Wilner KD, O'Dwyer PJ, and Schwartz GK
- Subjects
- Administration, Oral, Adult, Aged, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents toxicity, Area Under Curve, Cyclin-Dependent Kinases antagonists & inhibitors, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Neutropenia chemically induced, Piperazines pharmacokinetics, Piperazines toxicity, Pyridines pharmacokinetics, Pyridines toxicity, Treatment Outcome, Young Adult, Antineoplastic Agents administration & dosage, Maximum Tolerated Dose, Neoplasms drug therapy, Piperazines administration & dosage, Pyridines administration & dosage
- Abstract
Purpose: To identify the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the first-in-class, oral CDK4/6 inhibitor PD 0332991 administered once daily for 21 of 28 days (3/1 schedule) in patients with retinoblastoma protein (Rb)-positive advanced solid tumors and to describe pharmacokinetic-pharmacodynamic relationships relative to drug effects., Experimental Design: This open-label phase I study (NCT00141297) enrolled patients who received PD 0332991 orally in six dose-escalation cohorts in a standard 3 + 3 design., Results: Forty-one patients were enrolled. DLTs were observed in five patients (12%) overall; at the 75, 125, and 150 mg once daily dose levels. The MTD and recommended phase II dose of PD 0332991 was 125 mg once daily. Neutropenia was the only dose-limiting effect. After cycle 1, grade 3 neutropenia, anemia, and leukopenia occurred in five (12%), three (7%), and one (2%) patient(s), respectively. The most common non-hematologic adverse events included fatigue, nausea, and diarrhea. Thirty-seven patients were evaluable for tumor response; 10 (27%) had stable disease for ≥4 cycles of whom six derived prolonged benefit (≥10 cycles). PD 0332991 was slowly absorbed (median T(max), 5.5 hours), and slowly eliminated (mean half-life was 25.9 hours) with a large volume of distribution (mean, 2,793 L). The area under the concentration-time curve increased linearly with dose. Using an E(max) model, neutropenia was shown to be proportional to exposure., Conclusions: PD 0332991 warrants phase II testing at 125 mg once daily, at which dose neutropenia was the sole significant toxicity., (©2011 AACR.)
- Published
- 2012
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48. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib.
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Lennerz JK, Kwak EL, Ackerman A, Michael M, Fox SB, Bergethon K, Lauwers GY, Christensen JG, Wilner KD, Haber DA, Salgia R, Bang YJ, Clark JW, Solomon BJ, and Iafrate AJ
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Cohort Studies, Crizotinib, ErbB Receptors genetics, Esophageal Neoplasms drug therapy, Esophageal Neoplasms pathology, Female, Genes, erbB-2, Humans, Male, Middle Aged, Proto-Oncogene Mas, Stomach Neoplasms drug therapy, Stomach Neoplasms pathology, Adenocarcinoma genetics, Esophageal Neoplasms genetics, Gene Amplification, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-met antagonists & inhibitors, Proto-Oncogene Proteins c-met genetics, Pyrazoles therapeutic use, Pyridines therapeutic use, Stomach Neoplasms genetics
- Abstract
Purpose: Amplification of the MET proto-oncogene in gastroesophageal cancer (GEC) may constitute a molecular marker for targeted therapy. We examined a GEC cohort with follow-up and reported the clinical response of four additional patients with MET-amplified tumors to the small molecule inhibitor crizotinib as part of an expanded phase I cohort study., Patients and Methods: From 2007 to 2009, patients with GEC were genetically screened as a consecutive series of 489 tumors (stages 0, I, and II, 39%; III, 25%; IV, 36%; n = 222 esophageal, including n = 21 squamous carcinomas). MET, EGFR, and HER2 amplification status was assessed by using fluorescence in situ hybridization., Results: Ten (2%) of 489 patients screened harbored MET amplification; 23 (4.7%) harbored EGFR amplification; 45 (8.9%) harbored HER2 amplification; and 411 (84%) were wild type for all three genes (ie, negative). MET-amplified tumors were typically high-grade adenocarcinomas that presented at advanced stages (5%; n = 4 of 80). EGFR-amplified tumors showed the highest fraction of squamous cell carcinoma (17%; n = 4 of 23). HER2, MET, and EGFR amplification were, with one exception (MET and EGFR positive), mutually exclusive events. Survival analysis in patients with stages III and IV disease showed substantially shorter median survival in MET/EGFR-amplified groups, with a rank order for all groups by median survival (from most to least aggressive): MET (7.1 months; P < .001) less than EGFR (11.2 months; P = .16) less than HER2 (16.9 months; P = .89) when compared with the negative group (16.2 months). Two of four patients with MET-amplified tumors treated with crizotinib experienced tumor shrinkage (-30% and -16%) and experienced progression after 3.7 and 3.5 months., Conclusion: MET amplification defines a small and aggressive subset of GEC with indications of transient sensitivity to the targeted MET inhibitor crizotinib (PF-02341066).
- Published
- 2011
- Full Text
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49. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.
- Author
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Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, Shapiro GI, Costa DB, Ou SH, Butaney M, Salgia R, Maki RG, Varella-Garcia M, Doebele RC, Bang YJ, Kulig K, Selaru P, Tang Y, Wilner KD, Kwak EL, Clark JW, Iafrate AJ, and Camidge DR
- Subjects
- Adult, Aged, Anaplastic Lymphoma Kinase, Australia, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Clinical Trials, Phase I as Topic, Crizotinib, Female, Humans, Kaplan-Meier Estimate, Lung Neoplasms enzymology, Lung Neoplasms genetics, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Middle Aged, Multicenter Studies as Topic, Patient Selection, Proportional Hazards Models, Receptor Protein-Tyrosine Kinases genetics, Retrospective Studies, Risk Assessment, Risk Factors, Survival Rate, Time Factors, Treatment Outcome, United States, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Gene Rearrangement, Lung Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyridines therapeutic use, Receptor Protein-Tyrosine Kinases antagonists & inhibitors
- Abstract
Background: ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period., Methods: We examined overall survival in patients with advanced, ALK-positive NSCLC who enrolled in the phase 1 clinical trial of crizotinib, focusing on the cohort of 82 patients who had enrolled through Feb 10, 2010. For comparators, we identified 36 ALK-positive patients from trial sites who were not given crizotinib (ALK-positive controls), 67 patients without ALK rearrangement but positive for EGFR mutation, and 253 wild-type patients lacking either ALK rearrangement or EGFR mutation. To assess differences in overall survival, we assessed subsets of clinically comparable ALK-positive and ALK-negative patients., Findings: Among 82 ALK-positive patients who were given crizotinib, median overall survival from initiation of crizotinib has not been reached (95% CI 17 months to not reached); 1-year overall survival was 74% (95% CI 63-82), and 2-year overall survival was 54% (40-66). Overall survival did not differ based on age, sex, smoking history, or ethnic origin. Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls given any second-line therapy (median overall survival not reached [95% CI 14 months to not reached] vs 6 months [4-17], 1-year overall survival 70% [95% CI 50-83] vs 44% [23-64], and 2-year overall survival 55% [33-72] vs 12% [2-30]; hazard ratio 0·36, 95% CI 0·17-0·75; p=0·004). Survival in 56 crizotinib-treated, ALK-positive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy (median overall survival not reached [95% CI 17 months to not reached] vs 24 months [15-34], 1-year overall survival 71% [95% CI 58-81] vs 74% [61-83], and 2-year overall survival 57% [40-71] vs 52% [38-65]; p=0·786), whereas survival in 36 crizotinib-naive, ALK-positive controls was similar to that in 253 wild-type controls (median overall survival 20 months [95% CI 13-26] vs 15 months [13-17]; p=0·244)., Interpretation: In patients with advanced, ALK-positive NSCLC, crizotinib therapy is associated with improved survival compared with that of crizotinib-naive controls. ALK rearrangement is not a favourable prognostic factor in advanced NSCLC., Funding: Pfizer Inc, V Foundation for Cancer Research., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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50. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1).
- Author
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Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, Courtney R, and O'Dwyer PJ
- Subjects
- Adult, Aged, Drug Administration Schedule, Female, Humans, Lymphoma, Non-Hodgkin drug therapy, Male, Maximum Tolerated Dose, Middle Aged, Piperazines adverse effects, Piperazines pharmacokinetics, Pyridines adverse effects, Pyridines pharmacokinetics, Retinoblastoma Protein analysis, Cyclin-Dependent Kinases antagonists & inhibitors, Neoplasms drug therapy, Piperazines administration & dosage, Pyridines administration & dosage
- Abstract
Background: This phase I, open-label, first-in-human study determined dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo., Methods: A total of 33 patients with retinoblastoma protein-positive advanced solid tumours or non-Hodgkin's lymphoma refractory to standard therapy or for which no therapy was available received PD 0332991 once daily (QD) for 14 days followed by 7 days off treatment (21-day cycles; Schedule 2/1)., Results: Six patients had DLTs (18%; four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non-haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild-moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (≥10 cycles in three cases). PD 0332991 was slowly absorbed (mean T(max) 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure., Conclusion: PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study.
- Published
- 2011
- Full Text
- View/download PDF
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