12 results on '"Keyvanjah, K."'
Search Results
2. 1O Neratinib + capecitabine vs lapatinib + capecitabine in HER2+ metastatic breast cancer previously treated with ≥2 HER2-directed regimens: Exploratory biomarker analyses from phase III NALA trial
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Saura, C., primary, Vivancos, A., additional, Matito, J., additional, Wildiers, H., additional, Brufsky, A.M., additional, Oliveira, M., additional, Waters, S., additional, Hurvitz, S.A., additional, Moy, B., additional, Kim, S-B., additional, Gradishar, W.J., additional, Queiroz, G.S., additional, Cronemberger, E., additional, Bebchuk, J., additional, Keyvanjah, K., additional, Lalani, A.S., additional, Eli, L.D., additional, and Delaloge, S., additional
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- 2020
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3. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial
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Cristina Saura, Suzette Delaloge, Sung Bae Kim, Mafalda Oliveira, Yen-Shen Lu, Bin Yao, John Crown, Ming-Shen Dai, Hong-Tai Chang, Thomas Yau, Takaaki Fujii, Nala Investigators, Daniele Fagnani, Maureen E. Trudeau, Ming-Feng Hou, William J. Gradishar, Johanna Mattson, Marketa Palacova, Barbara Haley, Masato Takahashi, Beverly Moy, Yu-Min Yeh, Richard Bryce, Kiana Keyvanjah, Miki Yamaguchi, Shang Wen Chen, Judith Bebchuk, Adam Brufsky, Norikazu Masuda, Michelino De Laurentiis, Yin-Hsun Feng, Johnson Lin, Toshimi Takano, Sara A. Hurvitz, Hans Wildiers, Yoon Sim Yap, Institut Català de la Salut, [Saura C, Oliveira M] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. SOLTI Breast Cancer Cooperative Group, Barcelona, Spain. [Feng YH, Dai MS, Chen SW] Chi Mei Medical Centre, Liouying, Tainan, Taiwan and Tri-Service General Hospital, Taipei, Taiwan. [Hurvitz SA] University of California Los Angeles/Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA, Vall d'Hebron Barcelona Hospital Campus, Saura, C., Oliveira, M., Feng, Y. -H., Dai, M. -S., Chen, S. -W., Hurvitz, S. A., Kim, S. -B., Moy, B., Delaloge, S., Gradishar, W., Masuda, N., Palacova, M., Trudeau, M. E., Mattson, J., Yap, Y. S., Hou, M. -F., De Laurentiis, M., Yeh, Y. -M., Chang, H. -T., Yau, T., Wildiers, H., Haley, B., Fagnani, D., Lu, Y. -S., Crown, J., Lin, J., Takahashi, M., Takano, T., Yamaguchi, M., Fujii, T., Yao, B., Bebchuk, J., Keyvanjah, K., Bryce, R., and Brufsky, A.
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,Receptor, ErbB-2 ,Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,Quinoline ,Medicaments antineoplàstics - Ús terapèutic ,Kaplan-Meier Estimate ,THERAPY ,Tyrosine-kinase inhibitor ,law.invention ,chemistry.chemical_compound ,ErbB-2 ,0302 clinical medicine ,Randomized controlled trial ,Mama - Càncer ,law ,Antineoplastic Combined Chemotherapy Protocols ,Other subheadings::/therapeutic use [Other subheadings] ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,Brain Neoplasms ,Nausea ,ORIGINAL REPORTS ,Middle Aged ,OPEN-LABEL ,Metastatic breast cancer ,Progression-Free Survival ,3. Good health ,Survival Rate ,TRASTUZUMAB EMTANSINE ,030220 oncology & carcinogenesis ,Neratinib ,Retreatment ,Quinolines ,Female ,Life Sciences & Biomedicine ,Breast Neoplasm ,medicine.drug ,Human ,Diarrhea ,medicine.medical_specialty ,medicine.drug_class ,Clinical Sciences ,Oncology and Carcinogenesis ,Breast Neoplasms ,Lapatinib ,Breast Neoplasms, Male ,Capecitabine ,Brain Neoplasm ,03 medical and health sciences ,Internal medicine ,Breast Cancer ,medicine ,Humans ,Oncology & Carcinogenesis ,Progression-free survival ,COMBINATION ,terapéutica::protocolos clínicos::protocolos antineoplásicos::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Aged ,Science & Technology ,Antineoplastic Combined Chemotherapy Protocol ,RECEPTOR ,business.industry ,Otros calificadores::/uso terapéutico [Otros calificadores] ,Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,medicine.disease ,030104 developmental biology ,chemistry ,Trastuzumab emtansine ,Quality of Life ,NALA Investigators ,business - Abstract
PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.
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- 2020
4. Biomarker Analysis of the Phase III NALA Study of Neratinib + Capecitabine versus Lapatinib + Capecitabine in Patients with Previously Treated Metastatic Breast Cancer.
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Saura C, Matito J, Oliveira M, Wildiers H, Brufksy AM, Waters SH, Hurvitz SA, Moy B, Kim SB, Gradishar WJ, Queiroz GS, Cronemberger E, Wallweber GJ, Bebchuk J, Keyvanjah K, Lalani AS, Bryce R, Vivancos A, Eli LD, and Delaloge S
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- Breast Neoplasms pathology, Correlation of Data, Female, Humans, Neoplasm Metastasis, Retreatment, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Biomarkers, Tumor analysis, Breast Neoplasms chemistry, Breast Neoplasms drug therapy, Capecitabine administration & dosage, Lapatinib administration & dosage, Quinolines administration & dosage
- Abstract
Purpose: Neratinib plus capecitabine (N+C) demonstrated significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized phase III trial comparing N+C with lapatinib + capecitabine (L+C) in 621 patients with HER2-positive (HER2
+ ) metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens in the metastatic setting. We evaluated correlations between exploratory biomarkers and PFS., Patients and Methods: Somatic mutations were evaluated by next-generation sequencing on primary or metastatic samples. HER2 protein expression was evaluated by central IHC, H-score, and VeraTag/HERmark. p95 expression (truncated HER2) was measured by VeraTag. HRs were estimated using unstratified Cox proportional hazards models., Results: Four hundred and twenty samples had successful sequencing: 34.0% had PIK3CA mutations and 5.5% had HER2 (ERBB2) mutations. In the combined patient populations, PIK3CA mutations trended toward shorter PFS [wild-type vs. mutant, HR = 0.81; 95% confidence interval (CI), 0.64-1.03], whereas HER2 mutations trended toward longer PFS [HR = 1.69 (95% CI, 0.97-3.29)]. Higher HER2 protein expression was associated with longer PFS [IHC 3+ vs. 2+, HR = 0.67 (0.54-0.82); H-score ≥240 versus <240, HR = 0.77 (0.63-0.93); HERmark positive vs. negative, HR = 0.76 (0.59-0.98)]. Patients whose tumors had higher HER2 protein expression (any method) derived an increased benefit from N+C compared with L+C [IHC 3+, HR = 0.64 (0.51-0.81); H-score ≥ 240, HR = 0.54 (0.41-0.72); HERmark positive, HR = 0.65 (0.50-0.84)], as did patients with high p95 [p95 ≥2.8 relative fluorescence (RF)/mm2 , HR = 0.66 (0.50-0.86) vs. p95 < 2.8 RF/mm2 , HR = 0.91 (0.61-1.36)]., Conclusions: PIK3CA mutations were associated with shorter PFS whereas higher HER2 expression was associated with longer PFS. Higher HER2 protein expression was also associated with a greater benefit for N+C compared with L+C., (©2021 The Authors; Published by the American Association for Cancer Research.)- Published
- 2021
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5. Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial.
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Hurvitz SA, Saura C, Oliveira M, Trudeau ME, Moy B, Delaloge S, Gradishar W, Kim SB, Haley B, Ryvo L, Dai MS, Milovanov V, Alarcón J, Kalmadi S, Cronemberger E, Souza C, Landeiro L, Bose R, Bebchuk J, Kabbinavar F, Bryce R, Keyvanjah K, and Brufsky AM
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Capecitabine therapeutic use, Central Nervous System, Female, Humans, Quinolines, Treatment Outcome, Breast Neoplasms drug therapy, Receptor, ErbB-2 therapeutic use
- Abstract
Background: Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C)., Materials and Methods: NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m
2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered., Results: Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41-1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59-1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed., Conclusion: These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC., Implications for Practice: In a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)- Published
- 2021
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6. Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens.
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Moy B, Oliveira M, Saura C, Gradishar W, Kim SB, Brufsky A, Hurvitz SA, Ryvo L, Fagnani D, Kalmadi S, Silverman P, Delaloge S, Alarcon J, Kwong A, Lee KS, Ang PCS, Ow SGW, Chu SC, Bryce R, Keyvanjah K, Bebchuk J, Zhang B, Oestreicher N, Bose R, and Chan N
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- Antineoplastic Combined Chemotherapy Protocols adverse effects, Capecitabine adverse effects, Female, Humans, Quinolines, Receptor, ErbB-2 genetics, Breast Neoplasms drug therapy, Quality of Life
- Abstract
Purpose: To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study., Methods: In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan-Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points., Results: Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63-1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32-2.23])., Conclusion: In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC.
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- 2021
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7. Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial.
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Oaknin A, Friedman CF, Roman LD, D'Souza A, Brana I, Bidard FC, Goldman J, Alvarez EA, Boni V, ElNaggar AC, Passalacqua R, Do KTM, Santin AD, Keyvanjah K, Xu F, Eli LD, Lalani AS, Bryce RP, Hyman DM, Meric-Bernstam F, Solit DB, and Monk BJ
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- Administration, Oral, Adult, Diarrhea chemically induced, Diarrhea diagnosis, Diarrhea epidemiology, Female, Humans, Kaplan-Meier Estimate, Middle Aged, Mutation, Nausea chemically induced, Nausea diagnosis, Nausea epidemiology, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local mortality, Progression-Free Survival, Protein Kinase Inhibitors adverse effects, Quinolines adverse effects, Receptor, ErbB-2 genetics, Response Evaluation Criteria in Solid Tumors, Severity of Illness Index, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms mortality, Neoplasm Recurrence, Local drug therapy, Protein Kinase Inhibitors administration & dosage, Quinolines administration & dosage, Receptor, ErbB-2 antagonists & inhibitors, Uterine Cervical Neoplasms drug therapy
- Abstract
Objective: Somatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors., Methods: Patients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety., Results: Sixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations., Conclusions: Neratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population., Trial Registration Number: NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT)., Competing Interests: Declaration of Competing Interest A. Oaknin: has received advisory board honoraria from Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen, Genmab, and Deciphera and travel/accommodation support from Roche, AstraZeneca, and PharmaMar. C.F. Friedman: has received institutional research funding from Bristol-Myers Squibb, Merck, and Genentech, advisory board honoraria from AstraZeneca, and serves on steering committees for the Genentech MyPathway and the Merck LYNK-002 studies (compensation waived). L.D. Roman: has received advisory board honoraria from Tempus Labs and is a consultant for Quantgene. A. D'Souza: has no competing interests. I. Brana: has received institutional research funding from Puma Biotechnology Inc. F. Clement-Bidard: has received advisory board honoraria from Pfizer, Novartis, Eli Lilly, Amgen, and AstraZeneca. J. Goldman: has received institutional research funding from Puma Biotechnology Inc. E. A. Alvarez: has received advisory board honoraria from Eisai Co. Inc. and ArQule Inc. and has been a medical consultant for Tracon Pharmaceuticals, Inc. V. Boni: has received advisory board honoraria from Loxo Oncology and Ideaya. A.C. ElNaggar: has received institutional research funding from Caris Life Sciences and advisory board honoraria from AstraZeneca, Clovis Oncology, Leap Therapeutics, Tesaro/GSK, and AbbVie Pharmaceuticals. R. Passalacqua: has received advisory board/speaker honoraria from Amgen, Astellas, Bayer, BMS, Ipsen, Janssen, Novartis, Sanofi-Aventis, Roche, MSD, and Pierre-Fabre. K.T.M. Do: has received advisory board honoraria from QED Therapeutics. A.D. Santin: has received advisory board honoraria from Merck and Tesaro and has received institutional research funding from Puma Biotechnology Inc., Immunomedics, Tesaro, Boehringer Ingelheim, and Genentech. K. Keyvanjah: is an employee and shareholder of Puma Biotechnology Inc. F. Xu: is an employee and shareholder of Puma Biotechnology Inc. L.D. Eli: is an employee and shareholder of Puma Biotechnology Inc. A.S. Lalani: is an employee and shareholder of Puma Biotechnology Inc. R.P. Bryce: is an employee and shareholder of Puma Biotechnology Inc. D.M. Hyman: has acted in a consulting/advisory role for Atara Biotherapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, and Genentech, and has received institutional research funding from Loxo Oncology, Puma Biotechnology Inc., and AstraZeneca. He is currently employed by Loxo Oncology/Eli Lilly. F. Meric-Bernstam: has received institutional research funding from Novartis, AstraZeneca, Calithera, Aileron, Bayer, Jounce, CytoMx, eFFECTOR, Zymeworks, Puma Biotechnology Inc., Curis, Millennium, Daiichi Sankyo, AbbVie, Guardant Health, Takeda, and GlaxoSmithKline, grants/travel-related fees from Taiho, Genentech, Debiopharm Group, and Pfizer, consultancy fees from Pieris, Dialectica, Sumitomo Dainippon, Samsung Bioepis, Aduro, OrigiMed, Xencor, Jackson Laboratory, Zymeworks, and Parexel International, advisory board fees from Inflection Biosciences, GRAIL, Darwin Health, Clearlight Diagnostics, Spectrum, Mersana, and Seattle Genetics. D.H. Solit: has acted in a consulting/advisory role for Loxo Oncology, Pfizer, Illumina, Vivideon Therapeutics, QED Therapeutics, and Lilly Oncology. B.J. Monk: has received consultancy fees from Puma Biotechnology Inc., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2020
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8. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.
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Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, Kim SB, Moy B, Delaloge S, Gradishar W, Masuda N, Palacova M, Trudeau ME, Mattson J, Yap YS, Hou MF, De Laurentiis M, Yeh YM, Chang HT, Yau T, Wildiers H, Haley B, Fagnani D, Lu YS, Crown J, Lin J, Takahashi M, Takano T, Yamaguchi M, Fujii T, Yao B, Bebchuk J, Keyvanjah K, Bryce R, and Brufsky A
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Brain Neoplasms secondary, Breast Neoplasms metabolism, Breast Neoplasms pathology, Breast Neoplasms therapy, Breast Neoplasms, Male drug therapy, Breast Neoplasms, Male metabolism, Breast Neoplasms, Male pathology, Capecitabine administration & dosage, Diarrhea chemically induced, Female, Humans, Kaplan-Meier Estimate, Lapatinib administration & dosage, Male, Middle Aged, Nausea chemically induced, Progression-Free Survival, Quality of Life, Quinolines administration & dosage, Receptor, ErbB-2 metabolism, Retreatment, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms drug therapy, Breast Neoplasms drug therapy
- Abstract
Purpose: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens., Methods: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m
2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL)., Results: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = . 0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = . 2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = . 043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = . 1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups., Conclusion: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.- Published
- 2020
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9. Pharmacokinetics and safety of neratinib during co-administration with loperamide in healthy subjects.
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Keyvanjah K, Cooke B, Martin D, Di Primeo D, Sterling L, Liang J, Olek E, Rubets I, and Wong A
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- Administration, Oral, Adult, Antidiarrheals pharmacology, Area Under Curve, Drug Administration Schedule, Drug Interactions, Female, Half-Life, Humans, Loperamide pharmacology, Male, Middle Aged, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacokinetics, Quinolines adverse effects, Quinolines pharmacokinetics, Tissue Distribution, Young Adult, Antidiarrheals administration & dosage, Loperamide administration & dosage, Protein Kinase Inhibitors administration & dosage, Quinolines administration & dosage
- Abstract
Purpose: To evaluate the effects of multiple doses of loperamide on the pharmacokinetics and safety of a single oral dose of neratinib., Methods: This was an open-label, two-period, fixed-sequence study. Twenty healthy adult subjects received an oral dose of neratinib 240 mg daily on Days 1-4 of Period 1 followed by a 7-day washout. In Period 2, oral neratinib 240 mg was administered with loperamide 4 mg followed by two further doses of loperamide 2 mg 8 and 16 h later on Days 1-4. Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Safety was monitored throughout the study., Results: A median t
max of ~ 6 h was observed for neratinib during both periods. Apparent clearance and volume of distribution were similar for Periods 1 and 2: mean CLss /F 308.2 and 322.1 L/h; mean Vzτ /F 7995 and 10,318 L, respectively. The half-life of neratinib increased in the presence of loperamide from 18.0 to 22.2 h. Mean exposure was within the same range without and with loperamide administration: Cmax 61.2 ng/mL and 49.5 ng/mL; AUClast 1086 ng h/mL and 1153 ng h/mL, and AUCtau 779 ng h/mL and 745 ng h/mL, respectively. Treatment-emergent adverse events were mainly mild in intensity, with the most frequent events being diarrhea (45%) and constipation (35%)., Conclusions: Neratinib administered alone and concomitantly with multiple oral doses of loperamide is generally safe and well tolerated. Loperamide has minimal effects on neratinib pharmacokinetic parameters.- Published
- 2019
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10. Pharmacokinetics of neratinib during coadministration with lansoprazole in healthy subjects.
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Keyvanjah K, DiPrimeo D, Li A, Obaidi M, Swearingen D, and Wong A
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- Adult, Cross-Over Studies, Female, Healthy Volunteers, Humans, Male, Middle Aged, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors blood, Protein Kinase Inhibitors pharmacokinetics, Proton Pump Inhibitors pharmacology, Quinolines adverse effects, Quinolines blood, Drug Interactions, Lansoprazole pharmacology, Quinolines pharmacokinetics
- Abstract
Aims: To evaluate the effect of lansoprazole, a proton-pump inhibitor, on the absorption, pharmacokinetics, and safety of neratinib, a pan-HER tyrosine kinase inhibitor, in healthy subjects., Methods: This was an open-label, two-period, fixed-sequence study. Fifteen healthy adult subjects received a single oral dose of neratinib 240 mg (Period 1), followed by a washout period, then oral lansoprazole 30 mg once daily for 7 days and a single dose of neratinib 240 mg on Day 5 (Period 2). Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Plasma neratinib concentration-time data were analysed using noncompartmental methods. Geometric mean ratios for AUC
0-t , AUC0-inf , and peak plasma concentrations (Cmax ) for neratinib plus lansoprazole vs. neratinib were used to assess the magnitude of the drug-drug interaction if the 90% confidence intervals were outside 80.00-125.00%., Results: Neratinib geometric least-squares mean (LSM) Cmax was reduced from 84.5 ng ml-1 with neratinib alone to 24.5 ng ml-1 with neratinib plus lansoprazole. The extent of exposure to neratinib was also decreased: geometric LSM AUC0-t was 1478 ng ml-1 h with neratinib vs. 426 ng ml-1 h with neratinib plus lansoprazole, and geometric LSM AUC0-inf was 1557 ng ml-1 h vs. 542 ng ml-1 h, respectively. Mean t½ was similar with both treatments (approximately 14 h). Geometric mean ratios 90% confidence intervals for AUC0-t , AUC0-inf and Cmax fell outside the prespecified equivalence range (80.0-125.0%). Treatment-emergent adverse events, all mild, were reported by five (33%) subjects., Conclusions: Coadministration of lansoprazole with neratinib reduced the rate and extent of neratinib exposure in healthy subjects., (© 2016 The British Pharmacological Society.)- Published
- 2017
- Full Text
- View/download PDF
11. LC-MS/MS assay for the quantitation of the tyrosine kinase inhibitor neratinib in human plasma.
- Author
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Kiesel BF, Parise RA, Wong A, Keyvanjah K, Jacobs S, and Beumer JH
- Subjects
- Chromatography, Liquid methods, Female, Humans, Protein Kinase Inhibitors analysis, Quinolines analysis, Protein Kinase Inhibitors blood, Protein-Tyrosine Kinases antagonists & inhibitors, Quinolines blood, Tandem Mass Spectrometry methods
- Abstract
Neratinib is an orally available tyrosine kinase inhibitor targeting HER2 (ERBB2) and EGFR (ERBB). It is being clinically evaluated for the treatment of breast and other solid tumors types as a single agent or in combination with other chemotherapies. In support of several phase I/II clinical trials investigating neratinib combinations, we developed and validated a novel LC-MS/MS assay for the quantification of neratinib in 100μL of human plasma with a stable isotopic internal standard. Analytes were extracted from plasma using protein precipitation and evaporation of the resulting supernatant followed by resuspension. Chromatographic separation was achieved using an Acquity UPLC BEH Shield RP18 column and a gradient methanol-water mobile phase containing 10% ammonium acetate. An ABI 4000 mass spectrometer and electrospray positive mode ionization were used for detection. The assay was linear from 2 to 1,000ng/mL and proved to be accurate (98.9-106.5%) and precise (<6.2%CV), and met the FDA guidance for bioanalytical method validation. This LC-MS/MS assay will be an essential tool to further define the pharmacokinetics of neratinib., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
12. Soluble KIT correlates with clinical outcome in patients with metastatic breast cancer treated with sunitinib.
- Author
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Keyvanjah K, DePrimo SE, Harmon CS, Huang X, Kern KA, and Carley W
- Subjects
- Adult, Aged, Breast Neoplasms blood, Breast Neoplasms pathology, Female, Humans, Middle Aged, Neoplasm Metastasis, Sunitinib, Treatment Outcome, Antineoplastic Agents therapeutic use, Biomarkers, Tumor blood, Breast Neoplasms drug therapy, Indoles therapeutic use, Proto-Oncogene Proteins c-kit blood, Pyrroles therapeutic use
- Abstract
Background: Sunitinib inhibits vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors, and stem cell factor receptor (KIT). The ability of soluble (s)KIT, VEGF-A, sVEGFR-2, and sVEGFR-3 to predict clinical outcome was analyzed in 61 patients with previously treated metastatic breast cancer (MBC) in a phase II study of sunitinib monotherapy (ClinicalTrials.gov NCT00078000)., Methods: Plasma concentrations of soluble proteins were measured at baseline and during treatment with sunitinib 50 mg/day (4 weeks on treatment, 2 weeks off treatment). Baseline concentrations and maximal percent change during the first two treatment cycles were stratified by median values and evaluated for correlation with median time to tumor progression (TTP) and overall survival (OS). This latter fixed time period was chosen to avoid bias accruing from patients who were on study for longer periods of time., Results: TTP was significantly longer in patients having median or higher maximal percent sKIT change compared with patients with less than the median change (21.7 vs. 7.9 weeks; p < 0.0001). Similarly, OS was significantly longer in patients having median or higher sKIT change versus less than the median change (53.7 vs. 25.7 weeks; p = 0.018). Significant prolongation of OS (62.6 vs. 32.3 weeks; p = 0.032), but not TTP, was observed in patients with a median or higher maximal percent VEGF-A change compared with less than the median change. Maximal percent change of sVEGFR-2 or sVEGFR-3 concentrations and baseline concentrations of all four proteins were not predictive of clinical outcome., Conclusions: This exploratory analysis suggests that changes in sKIT and possibly VEGF-A early during sunitinib treatment may be predictive of clinical outcome in MBC.
- Published
- 2012
- Full Text
- View/download PDF
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