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

Research output: Contribution to journalArticle

20 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 languageEnglish (US)
Pages (from-to)633-643
Number of pages11
JournalJournal of Thoracic Oncology
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2017

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Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Meta-Analysis
Clinical Trials
Therapeutics
Poisons
Exanthema
Diarrhea
Erlotinib Hydrochloride
gefitinib
BIBW 2992
Pneumonia
Placebos
Drug Therapy
Liver
Enzymes

Keywords

  • EGFR mutation
  • Meta-analysis
  • NSCLC
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

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; Links, Matthew; Bray, Victoria; Gralla, Richard J.; Yang, James Chih Hsin; Lee, Chee Khoon.

In: Journal of Thoracic Oncology, Vol. 12, No. 4, 01.04.2017, p. 633-643.

Research output: Contribution to journalArticle

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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.",
keywords = "EGFR mutation, Meta-analysis, NSCLC, Tyrosine kinase inhibitors",
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T2 - 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

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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.

KW - EGFR mutation

KW - Meta-analysis

KW - NSCLC

KW - Tyrosine kinase inhibitors

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