Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non–Small Cell Lung Cancer

Pei Ni Ding; Sarah J. Lord; Val Gebski; Matthew Links; Victoria Bray; Richard J. Gralla; James Chih Hsin Yang; Chee Khoon Lee

doi:10.1016/j.jtho.2016.11.2236

Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non–Small Cell Lung Cancer

Pei Ni Ding, Sarah J. Lord, Val Gebski, Matthew Links, Victoria Bray, Richard J. Gralla, James Chih Hsin Yang, Chee Khoon Lee^*

^*Corresponding author for this work

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

135 Citations (Scopus)

Abstract

Introduction

Gefitinib, erlotinib, and afatinib are tyrosine kinase inhibitors (TKIs) used for treatment of advanced EGFR-mutated NSCLC. Estimating differences in toxicity between these EGFR TKIs is important for personalizing treatment.

Methods

We performed a meta-analysis of randomized trials that compared EGFR TKI therapy against chemotherapy or placebo. We extracted data from the EGFR TKI arm for indirect comparisons to estimate the relative risk for toxic death, grade 3 to 4 (G3/4) adverse events (AEs), and discontinuation of treatment because of AE for each EGFR TKI.

Results

Sixteen trials included 2535 patients with mutated or wild-type EGFR. Toxic deaths were rare (1.7%), with pneumonitis being most frequent cause and no significant differences between EGFR TKIs. Overall, 40% of patients experienced G3/4 AEs. The risk for G3/4 AEs was lower with gefitinib (29.1%) than with erlotinib (54.1%) or afatinib (42.1%) (p < 0.01). Discontinuation of treatment because of AEs occurred in 7.7% of patients, with no significant differences between EGFR TKIs. Diarrhea (in 53.3% of cases) and rash (in 66.5%) were the most frequent AEs. The risk for rash was higher with afatinib (84.8%) than with erlotinib (62.0%) or gefitinib (62.0%) (p < 0.01). The risk for diarrhea was higher with afatinib (91.7%) than with erlotinib (42.4%) or gefitinib (44.4%) (p < 0.01). The risk for increased liver enzyme levels was higher with gefitinib (61.7%) than with erlotinib (17.8%) or afatinib (20.1%) (p < 0.01). A risk-benefit contour was used to assess the trade-off between efficacy and toxicity for different EGFR TKIs.

Conclusions

EGFR TKIs are well tolerated, with less than 10% of patients discontinuing treatment because of AEs. The profile of and risk for toxicities vary between EGFR TKIs and can be used to inform the selection of treatment.

Original language	English
Pages (from-to)	633-643
Number of pages	11
Journal	Journal of Thoracic Oncology
Volume	12
Issue number	4
DOIs	https://doi.org/10.1016/j.jtho.2016.11.2236
Publication status	Published - 1 Apr 2017
Externally published	Yes

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Cite this

Ding, P. N., Lord, S. J., Gebski, V., Links, M., Bray, V., Gralla, R. J., Yang, J. C. H., & Lee, C. K. (2017). Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non–Small Cell Lung Cancer. Journal of Thoracic Oncology, 12(4), 633-643. https://doi.org/10.1016/j.jtho.2016.11.2236

@article{09a40c23f21c4bb3acb612d36b28b1cb,

title = "Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non–Small Cell Lung Cancer",

abstract = "Introduction Gefitinib, erlotinib, and afatinib are tyrosine kinase inhibitors (TKIs) used for treatment of advanced EGFR-mutated NSCLC. Estimating differences in toxicity between these EGFR TKIs is important for personalizing treatment. Methods We performed a meta-analysis of randomized trials that compared EGFR TKI therapy against chemotherapy or placebo. We extracted data from the EGFR TKI arm for indirect comparisons to estimate the relative risk for toxic death, grade 3 to 4 (G3/4) adverse events (AEs), and discontinuation of treatment because of AE for each EGFR TKI. Results Sixteen trials included 2535 patients with mutated or wild-type EGFR. Toxic deaths were rare (1.7%), with pneumonitis being most frequent cause and no significant differences between EGFR TKIs. Overall, 40% of patients experienced G3/4 AEs. The risk for G3/4 AEs was lower with gefitinib (29.1%) than with erlotinib (54.1%) or afatinib (42.1%) (p < 0.01). Discontinuation of treatment because of AEs occurred in 7.7% of patients, with no significant differences between EGFR TKIs. Diarrhea (in 53.3% of cases) and rash (in 66.5%) were the most frequent AEs. The risk for rash was higher with afatinib (84.8%) than with erlotinib (62.0%) or gefitinib (62.0%) (p < 0.01). The risk for diarrhea was higher with afatinib (91.7%) than with erlotinib (42.4%) or gefitinib (44.4%) (p < 0.01). The risk for increased liver enzyme levels was higher with gefitinib (61.7%) than with erlotinib (17.8%) or afatinib (20.1%) (p < 0.01). A risk-benefit contour was used to assess the trade-off between efficacy and toxicity for different EGFR TKIs. Conclusions EGFR TKIs are well tolerated, with less than 10% of patients discontinuing treatment because of AEs. The profile of and risk for toxicities vary between EGFR TKIs and can be used to inform the selection of treatment.",

author = "Ding, {Pei Ni} and Lord, {Sarah J.} and Val Gebski and Matthew Links and Victoria Bray and Gralla, {Richard J.} and Yang, {James Chih Hsin} and Lee, {Chee Khoon}",

note = "Publisher Copyright: {\textcopyright} 2016 International Association for the Study of Lung Cancer",

year = "2017",

month = apr,

day = "1",

doi = "10.1016/j.jtho.2016.11.2236",

language = "English",

volume = "12",

pages = "633--643",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

publisher = "Lippincott Williams & Wilkins",

number = "4",

}

Ding, PN, Lord, SJ, Gebski, V, Links, M, Bray, V, Gralla, RJ, Yang, JCH & Lee, CK 2017, 'Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non–Small Cell Lung Cancer', Journal of Thoracic Oncology, vol. 12, no. 4, pp. 633-643. https://doi.org/10.1016/j.jtho.2016.11.2236

Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non–Small Cell Lung Cancer. / Ding, Pei Ni; Lord, Sarah J.; Gebski, Val et al.
In: Journal of Thoracic Oncology, Vol. 12, No. 4, 01.04.2017, p. 633-643.

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

TY - JOUR

T1 - Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non–Small Cell Lung Cancer

AU - Ding, Pei Ni

AU - Lord, Sarah J.

AU - Gebski, Val

AU - Links, Matthew

AU - Bray, Victoria

AU - Gralla, Richard J.

AU - Yang, James Chih Hsin

AU - Lee, Chee Khoon

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Introduction Gefitinib, erlotinib, and afatinib are tyrosine kinase inhibitors (TKIs) used for treatment of advanced EGFR-mutated NSCLC. Estimating differences in toxicity between these EGFR TKIs is important for personalizing treatment. Methods We performed a meta-analysis of randomized trials that compared EGFR TKI therapy against chemotherapy or placebo. We extracted data from the EGFR TKI arm for indirect comparisons to estimate the relative risk for toxic death, grade 3 to 4 (G3/4) adverse events (AEs), and discontinuation of treatment because of AE for each EGFR TKI. Results Sixteen trials included 2535 patients with mutated or wild-type EGFR. Toxic deaths were rare (1.7%), with pneumonitis being most frequent cause and no significant differences between EGFR TKIs. Overall, 40% of patients experienced G3/4 AEs. The risk for G3/4 AEs was lower with gefitinib (29.1%) than with erlotinib (54.1%) or afatinib (42.1%) (p < 0.01). Discontinuation of treatment because of AEs occurred in 7.7% of patients, with no significant differences between EGFR TKIs. Diarrhea (in 53.3% of cases) and rash (in 66.5%) were the most frequent AEs. The risk for rash was higher with afatinib (84.8%) than with erlotinib (62.0%) or gefitinib (62.0%) (p < 0.01). The risk for diarrhea was higher with afatinib (91.7%) than with erlotinib (42.4%) or gefitinib (44.4%) (p < 0.01). The risk for increased liver enzyme levels was higher with gefitinib (61.7%) than with erlotinib (17.8%) or afatinib (20.1%) (p < 0.01). A risk-benefit contour was used to assess the trade-off between efficacy and toxicity for different EGFR TKIs. Conclusions EGFR TKIs are well tolerated, with less than 10% of patients discontinuing treatment because of AEs. The profile of and risk for toxicities vary between EGFR TKIs and can be used to inform the selection of treatment.

AB - Introduction Gefitinib, erlotinib, and afatinib are tyrosine kinase inhibitors (TKIs) used for treatment of advanced EGFR-mutated NSCLC. Estimating differences in toxicity between these EGFR TKIs is important for personalizing treatment. Methods We performed a meta-analysis of randomized trials that compared EGFR TKI therapy against chemotherapy or placebo. We extracted data from the EGFR TKI arm for indirect comparisons to estimate the relative risk for toxic death, grade 3 to 4 (G3/4) adverse events (AEs), and discontinuation of treatment because of AE for each EGFR TKI. Results Sixteen trials included 2535 patients with mutated or wild-type EGFR. Toxic deaths were rare (1.7%), with pneumonitis being most frequent cause and no significant differences between EGFR TKIs. Overall, 40% of patients experienced G3/4 AEs. The risk for G3/4 AEs was lower with gefitinib (29.1%) than with erlotinib (54.1%) or afatinib (42.1%) (p < 0.01). Discontinuation of treatment because of AEs occurred in 7.7% of patients, with no significant differences between EGFR TKIs. Diarrhea (in 53.3% of cases) and rash (in 66.5%) were the most frequent AEs. The risk for rash was higher with afatinib (84.8%) than with erlotinib (62.0%) or gefitinib (62.0%) (p < 0.01). The risk for diarrhea was higher with afatinib (91.7%) than with erlotinib (42.4%) or gefitinib (44.4%) (p < 0.01). The risk for increased liver enzyme levels was higher with gefitinib (61.7%) than with erlotinib (17.8%) or afatinib (20.1%) (p < 0.01). A risk-benefit contour was used to assess the trade-off between efficacy and toxicity for different EGFR TKIs. Conclusions EGFR TKIs are well tolerated, with less than 10% of patients discontinuing treatment because of AEs. The profile of and risk for toxicities vary between EGFR TKIs and can be used to inform the selection of treatment.

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U2 - 10.1016/j.jtho.2016.11.2236

DO - 10.1016/j.jtho.2016.11.2236

M3 - Article

C2 - 28007626

AN - SCOPUS:85015858896

SN - 1556-0864

VL - 12

SP - 633

EP - 643

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

IS - 4

ER -

Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non–Small Cell Lung Cancer

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