The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study

Lotte M Knapen; Rutger H T Koornstra; Johanna H M Driessen; Bas van Vlijmen; Sander Croes; Stein Schalkwijk; Angela Colbers; Winald R Gerritsen; David M Burger; Frank de Vries; Nielka P van Erp

doi:10.1007/s11523-018-0564-3

The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study

Lotte M Knapen, Rutger H T Koornstra, Johanna H M Driessen, Bas van Vlijmen, Sander Croes, Stein Schalkwijk, Angela Colbers, Winald R Gerritsen, David M Burger, Frank de Vries, Nielka P van Erp

Department of Clinical Pharmacy & Toxicology, Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands. [email protected].
Department of Internal Medicine, Hospital Rijnstate, Arnhem, the Netherlands.
Department of Clinical Pharmacy & Toxicology, Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands.
Maastricht University, Department of Internal Medicine, Maastricht, The Netherlands; NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands. Electronic address: [email protected].
Maastricht University Medical Center+, Department of Clinical Pharmacy and Toxicology, Maastricht, The Netherlands; Radboud University Nijmegen Medical Center, Department of Pharmacy, Nijmegen, The Netherlands. Electronic address: [email protected].
Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
The Netherlands MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown.

OBJECTIVES: To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs.

PATIENT AND METHODS: A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012-March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital. Cox regression analysis was used to estimate the risk of progression with full-dose (n = 64) versus reduced-dose vemurafenib (n = 48) and with simultaneous use of vemurafenib and ARAs (n = 35) versus vemurafenib alone (n = 77). Analyses were adjusted for age and sex.

RESULTS: In total, disease progression occurred in 55% of treated patients on vemurafenib, with a median progression-free survival of 6.0 (95% confidence interval [CI] 5.0-6.9) months. Compared to patients on vemurafenib alone, there was no increased risk of progression among patients requiring vemurafenib at a reduced dose or among patients receiving simultaneous therapy with vemurafenib and ARAs. In addition, there was no increased risk of progression among patients who used reduced-dose vemurafenib and ARAs versus those receiving full-dose vemurafenib as sole therapy. However, a tendency for progression was observed among patients who used full-dose vemurafenib and ARAs versus full-dose vemurafenib alone (adjusted hazard ratio [HRa] 2.37; 95% CI 0.97-5.76), which became statistically significant in a sensitivity analysis (HRa 4.56; 95% CI 1.51-13.75).

CONCLUSIONS: There was no association between the use of vemurafenib in a reduced dose or the simultaneous use of vemurafenib and ARAs and the risk of progression. In addition, there was no association between the simultaneous use of vemurafenib in a reduced dose and ARAs and the risk of progression. However, patients tolerating full-dose vemurafenib simultaneously with ARAs might have an increased risk of progression. This finding requires prospective validation.

Original language	English
Pages (from-to)	363-370
Number of pages	8
Journal	Targeted Oncology
Volume	13
Issue number	3
Early online date	11 Apr 2018
DOIs	https://doi.org/10.1007/s11523-018-0564-3
Publication status	Published - Jun 2018

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Knapen, L. M., Koornstra, R. H. T., Driessen, J. H. M., van Vlijmen, B., Croes, S., Schalkwijk, S., Colbers, A., Gerritsen, W. R., Burger, D. M., de Vries, F., & van Erp, N. P. (2018). The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study. Targeted Oncology, 13(3), 363-370. https://doi.org/10.1007/s11523-018-0564-3

@article{870804362fcf4346bea56bf69105444d,

title = "The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study",

abstract = "BACKGROUND: The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown.OBJECTIVES: To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs.PATIENT AND METHODS: A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012-March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital. Cox regression analysis was used to estimate the risk of progression with full-dose (n = 64) versus reduced-dose vemurafenib (n = 48) and with simultaneous use of vemurafenib and ARAs (n = 35) versus vemurafenib alone (n = 77). Analyses were adjusted for age and sex.RESULTS: In total, disease progression occurred in 55% of treated patients on vemurafenib, with a median progression-free survival of 6.0 (95% confidence interval [CI] 5.0-6.9) months. Compared to patients on vemurafenib alone, there was no increased risk of progression among patients requiring vemurafenib at a reduced dose or among patients receiving simultaneous therapy with vemurafenib and ARAs. In addition, there was no increased risk of progression among patients who used reduced-dose vemurafenib and ARAs versus those receiving full-dose vemurafenib as sole therapy. However, a tendency for progression was observed among patients who used full-dose vemurafenib and ARAs versus full-dose vemurafenib alone (adjusted hazard ratio [HRa] 2.37; 95% CI 0.97-5.76), which became statistically significant in a sensitivity analysis (HRa 4.56; 95% CI 1.51-13.75).CONCLUSIONS: There was no association between the use of vemurafenib in a reduced dose or the simultaneous use of vemurafenib and ARAs and the risk of progression. In addition, there was no association between the simultaneous use of vemurafenib in a reduced dose and ARAs and the risk of progression. However, patients tolerating full-dose vemurafenib simultaneously with ARAs might have an increased risk of progression. This finding requires prospective validation.",

author = "Knapen, {Lotte M} and Koornstra, {Rutger H T} and Driessen, {Johanna H M} and {van Vlijmen}, Bas and Sander Croes and Stein Schalkwijk and Angela Colbers and Gerritsen, {Winald R} and Burger, {David M} and {de Vries}, Frank and {van Erp}, {Nielka P}",

year = "2018",

month = jun,

doi = "10.1007/s11523-018-0564-3",

language = "English",

volume = "13",

pages = "363--370",

journal = "Targeted Oncology",

issn = "1776-2596",

publisher = "Springer Paris",

number = "3",

}

Knapen, LM, Koornstra, RHT, Driessen, JHM, van Vlijmen, B, Croes, S, Schalkwijk, S, Colbers, A, Gerritsen, WR, Burger, DM, de Vries, F & van Erp, NP 2018, 'The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study', Targeted Oncology, vol. 13, no. 3, pp. 363-370. https://doi.org/10.1007/s11523-018-0564-3

The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study. / Knapen, Lotte M; Koornstra, Rutger H T; Driessen, Johanna H M et al.
In: Targeted Oncology, Vol. 13, No. 3, 06.2018, p. 363-370.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma

T2 - a Retrospective Cohort Study

AU - Knapen, Lotte M

AU - Koornstra, Rutger H T

AU - Driessen, Johanna H M

AU - van Vlijmen, Bas

AU - Croes, Sander

AU - Schalkwijk, Stein

AU - Colbers, Angela

AU - Gerritsen, Winald R

AU - Burger, David M

AU - de Vries, Frank

AU - van Erp, Nielka P

PY - 2018/6

Y1 - 2018/6

N2 - BACKGROUND: The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown.OBJECTIVES: To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs.PATIENT AND METHODS: A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012-March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital. Cox regression analysis was used to estimate the risk of progression with full-dose (n = 64) versus reduced-dose vemurafenib (n = 48) and with simultaneous use of vemurafenib and ARAs (n = 35) versus vemurafenib alone (n = 77). Analyses were adjusted for age and sex.RESULTS: In total, disease progression occurred in 55% of treated patients on vemurafenib, with a median progression-free survival of 6.0 (95% confidence interval [CI] 5.0-6.9) months. Compared to patients on vemurafenib alone, there was no increased risk of progression among patients requiring vemurafenib at a reduced dose or among patients receiving simultaneous therapy with vemurafenib and ARAs. In addition, there was no increased risk of progression among patients who used reduced-dose vemurafenib and ARAs versus those receiving full-dose vemurafenib as sole therapy. However, a tendency for progression was observed among patients who used full-dose vemurafenib and ARAs versus full-dose vemurafenib alone (adjusted hazard ratio [HRa] 2.37; 95% CI 0.97-5.76), which became statistically significant in a sensitivity analysis (HRa 4.56; 95% CI 1.51-13.75).CONCLUSIONS: There was no association between the use of vemurafenib in a reduced dose or the simultaneous use of vemurafenib and ARAs and the risk of progression. In addition, there was no association between the simultaneous use of vemurafenib in a reduced dose and ARAs and the risk of progression. However, patients tolerating full-dose vemurafenib simultaneously with ARAs might have an increased risk of progression. This finding requires prospective validation.

AB - BACKGROUND: The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown.OBJECTIVES: To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs.PATIENT AND METHODS: A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012-March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital. Cox regression analysis was used to estimate the risk of progression with full-dose (n = 64) versus reduced-dose vemurafenib (n = 48) and with simultaneous use of vemurafenib and ARAs (n = 35) versus vemurafenib alone (n = 77). Analyses were adjusted for age and sex.RESULTS: In total, disease progression occurred in 55% of treated patients on vemurafenib, with a median progression-free survival of 6.0 (95% confidence interval [CI] 5.0-6.9) months. Compared to patients on vemurafenib alone, there was no increased risk of progression among patients requiring vemurafenib at a reduced dose or among patients receiving simultaneous therapy with vemurafenib and ARAs. In addition, there was no increased risk of progression among patients who used reduced-dose vemurafenib and ARAs versus those receiving full-dose vemurafenib as sole therapy. However, a tendency for progression was observed among patients who used full-dose vemurafenib and ARAs versus full-dose vemurafenib alone (adjusted hazard ratio [HRa] 2.37; 95% CI 0.97-5.76), which became statistically significant in a sensitivity analysis (HRa 4.56; 95% CI 1.51-13.75).CONCLUSIONS: There was no association between the use of vemurafenib in a reduced dose or the simultaneous use of vemurafenib and ARAs and the risk of progression. In addition, there was no association between the simultaneous use of vemurafenib in a reduced dose and ARAs and the risk of progression. However, patients tolerating full-dose vemurafenib simultaneously with ARAs might have an increased risk of progression. This finding requires prospective validation.

U2 - 10.1007/s11523-018-0564-3

DO - 10.1007/s11523-018-0564-3

M3 - Article

C2 - 29644577

SN - 1776-2596

VL - 13

SP - 363

EP - 370

JO - Targeted Oncology

JF - Targeted Oncology

IS - 3

ER -

The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study

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