Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients
Purpose To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC pati...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Kenmotsu, Hirotsugu [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 |
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| Übergeordnetes Werk: |
Enthalten in: Cancer chemotherapy and pharmacology - Berlin : Springer, 1978, 90(2022), 2 vom: 12. Juli, Seite 115-123 |
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| Übergeordnetes Werk: |
volume:90 ; year:2022 ; number:2 ; day:12 ; month:07 ; pages:115-123 |
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| DOI / URN: |
10.1007/s00280-022-04452-0 |
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| Katalog-ID: |
SPR047791624 |
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| 100 | 1 | |a Kenmotsu, Hirotsugu |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients |
| 264 | 1 | |c 2022 | |
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| 500 | |a © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 | ||
| 520 | |a Purpose To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Results Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h ($ AUC_{0-24} $) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound $ AUC_{0-24} $ on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state ($ C_{trough,ss} $) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound $ C_{trough,ss} $ on day 7–15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). Conclusion The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. Clinical trials registration number: UMIN000012862. | ||
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| 650 | 4 | |a Erlotinib |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Exposure–response analysis |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Protein binding |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Kawamura, Takahisa |4 aut | |
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| 700 | 1 | |a Omori, Shota |4 aut | |
| 700 | 1 | |a Nakashima, Kazuhisa |4 aut | |
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| 700 | 1 | |a Murakami, Haruyasu |4 aut | |
| 700 | 1 | |a Yamamoto, Nobuyuki |4 aut | |
| 700 | 1 | |a Takahashi, Toshiaki |4 aut | |
| 700 | 1 | |a Tanigawara, Yusuke |4 aut | |
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10.1007/s00280-022-04452-0 doi (DE-627)SPR047791624 (SPR)s00280-022-04452-0-e DE-627 ger DE-627 rakwb eng Kenmotsu, Hirotsugu verfasserin aut Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 Purpose To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Results Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h ($ AUC_{0-24} $) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound $ AUC_{0-24} $ on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state ($ C_{trough,ss} $) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound $ C_{trough,ss} $ on day 7–15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). Conclusion The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. Clinical trials registration number: UMIN000012862. α (dpeaa)DE-He213 -acid glycoprotein (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Erlotinib (dpeaa)DE-He213 Exposure–response analysis (dpeaa)DE-He213 Protein binding (dpeaa)DE-He213 Non-small cell lung cancer (dpeaa)DE-He213 Imamura, Chiyo K. (orcid)0000-0003-2907-847X aut Kawamura, Takahisa aut Oyakawa, Takuya aut Omori, Shota aut Nakashima, Kazuhisa aut Wakuda, Kazushige aut Ono, Akira aut Taira, Tetsuhiko aut Naito, Tateaki aut Murakami, Haruyasu aut Yamamoto, Nobuyuki aut Takahashi, Toshiaki aut Tanigawara, Yusuke aut Enthalten in Cancer chemotherapy and pharmacology Berlin : Springer, 1978 90(2022), 2 vom: 12. Juli, Seite 115-123 (DE-627)253390435 (DE-600)1458488-8 1432-0843 nnns volume:90 year:2022 number:2 day:12 month:07 pages:115-123 https://dx.doi.org/10.1007/s00280-022-04452-0 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 90 2022 2 12 07 115-123 |
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10.1007/s00280-022-04452-0 doi (DE-627)SPR047791624 (SPR)s00280-022-04452-0-e DE-627 ger DE-627 rakwb eng Kenmotsu, Hirotsugu verfasserin aut Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 Purpose To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Results Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h ($ AUC_{0-24} $) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound $ AUC_{0-24} $ on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state ($ C_{trough,ss} $) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound $ C_{trough,ss} $ on day 7–15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). Conclusion The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. Clinical trials registration number: UMIN000012862. α (dpeaa)DE-He213 -acid glycoprotein (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Erlotinib (dpeaa)DE-He213 Exposure–response analysis (dpeaa)DE-He213 Protein binding (dpeaa)DE-He213 Non-small cell lung cancer (dpeaa)DE-He213 Imamura, Chiyo K. (orcid)0000-0003-2907-847X aut Kawamura, Takahisa aut Oyakawa, Takuya aut Omori, Shota aut Nakashima, Kazuhisa aut Wakuda, Kazushige aut Ono, Akira aut Taira, Tetsuhiko aut Naito, Tateaki aut Murakami, Haruyasu aut Yamamoto, Nobuyuki aut Takahashi, Toshiaki aut Tanigawara, Yusuke aut Enthalten in Cancer chemotherapy and pharmacology Berlin : Springer, 1978 90(2022), 2 vom: 12. Juli, Seite 115-123 (DE-627)253390435 (DE-600)1458488-8 1432-0843 nnns volume:90 year:2022 number:2 day:12 month:07 pages:115-123 https://dx.doi.org/10.1007/s00280-022-04452-0 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 90 2022 2 12 07 115-123 |
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10.1007/s00280-022-04452-0 doi (DE-627)SPR047791624 (SPR)s00280-022-04452-0-e DE-627 ger DE-627 rakwb eng Kenmotsu, Hirotsugu verfasserin aut Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 Purpose To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Results Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h ($ AUC_{0-24} $) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound $ AUC_{0-24} $ on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state ($ C_{trough,ss} $) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound $ C_{trough,ss} $ on day 7–15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). Conclusion The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. Clinical trials registration number: UMIN000012862. α (dpeaa)DE-He213 -acid glycoprotein (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Erlotinib (dpeaa)DE-He213 Exposure–response analysis (dpeaa)DE-He213 Protein binding (dpeaa)DE-He213 Non-small cell lung cancer (dpeaa)DE-He213 Imamura, Chiyo K. (orcid)0000-0003-2907-847X aut Kawamura, Takahisa aut Oyakawa, Takuya aut Omori, Shota aut Nakashima, Kazuhisa aut Wakuda, Kazushige aut Ono, Akira aut Taira, Tetsuhiko aut Naito, Tateaki aut Murakami, Haruyasu aut Yamamoto, Nobuyuki aut Takahashi, Toshiaki aut Tanigawara, Yusuke aut Enthalten in Cancer chemotherapy and pharmacology Berlin : Springer, 1978 90(2022), 2 vom: 12. Juli, Seite 115-123 (DE-627)253390435 (DE-600)1458488-8 1432-0843 nnns volume:90 year:2022 number:2 day:12 month:07 pages:115-123 https://dx.doi.org/10.1007/s00280-022-04452-0 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 90 2022 2 12 07 115-123 |
| allfieldsGer |
10.1007/s00280-022-04452-0 doi (DE-627)SPR047791624 (SPR)s00280-022-04452-0-e DE-627 ger DE-627 rakwb eng Kenmotsu, Hirotsugu verfasserin aut Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 Purpose To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Results Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h ($ AUC_{0-24} $) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound $ AUC_{0-24} $ on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state ($ C_{trough,ss} $) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound $ C_{trough,ss} $ on day 7–15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). Conclusion The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. Clinical trials registration number: UMIN000012862. α (dpeaa)DE-He213 -acid glycoprotein (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Erlotinib (dpeaa)DE-He213 Exposure–response analysis (dpeaa)DE-He213 Protein binding (dpeaa)DE-He213 Non-small cell lung cancer (dpeaa)DE-He213 Imamura, Chiyo K. (orcid)0000-0003-2907-847X aut Kawamura, Takahisa aut Oyakawa, Takuya aut Omori, Shota aut Nakashima, Kazuhisa aut Wakuda, Kazushige aut Ono, Akira aut Taira, Tetsuhiko aut Naito, Tateaki aut Murakami, Haruyasu aut Yamamoto, Nobuyuki aut Takahashi, Toshiaki aut Tanigawara, Yusuke aut Enthalten in Cancer chemotherapy and pharmacology Berlin : Springer, 1978 90(2022), 2 vom: 12. Juli, Seite 115-123 (DE-627)253390435 (DE-600)1458488-8 1432-0843 nnns volume:90 year:2022 number:2 day:12 month:07 pages:115-123 https://dx.doi.org/10.1007/s00280-022-04452-0 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 90 2022 2 12 07 115-123 |
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10.1007/s00280-022-04452-0 doi (DE-627)SPR047791624 (SPR)s00280-022-04452-0-e DE-627 ger DE-627 rakwb eng Kenmotsu, Hirotsugu verfasserin aut Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 Purpose To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Results Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h ($ AUC_{0-24} $) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound $ AUC_{0-24} $ on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state ($ C_{trough,ss} $) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound $ C_{trough,ss} $ on day 7–15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). Conclusion The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. Clinical trials registration number: UMIN000012862. α (dpeaa)DE-He213 -acid glycoprotein (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Erlotinib (dpeaa)DE-He213 Exposure–response analysis (dpeaa)DE-He213 Protein binding (dpeaa)DE-He213 Non-small cell lung cancer (dpeaa)DE-He213 Imamura, Chiyo K. (orcid)0000-0003-2907-847X aut Kawamura, Takahisa aut Oyakawa, Takuya aut Omori, Shota aut Nakashima, Kazuhisa aut Wakuda, Kazushige aut Ono, Akira aut Taira, Tetsuhiko aut Naito, Tateaki aut Murakami, Haruyasu aut Yamamoto, Nobuyuki aut Takahashi, Toshiaki aut Tanigawara, Yusuke aut Enthalten in Cancer chemotherapy and pharmacology Berlin : Springer, 1978 90(2022), 2 vom: 12. Juli, Seite 115-123 (DE-627)253390435 (DE-600)1458488-8 1432-0843 nnns volume:90 year:2022 number:2 day:12 month:07 pages:115-123 https://dx.doi.org/10.1007/s00280-022-04452-0 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 90 2022 2 12 07 115-123 |
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Kenmotsu, Hirotsugu @@aut@@ Imamura, Chiyo K. @@aut@@ Kawamura, Takahisa @@aut@@ Oyakawa, Takuya @@aut@@ Omori, Shota @@aut@@ Nakashima, Kazuhisa @@aut@@ Wakuda, Kazushige @@aut@@ Ono, Akira @@aut@@ Taira, Tetsuhiko @@aut@@ Naito, Tateaki @@aut@@ Murakami, Haruyasu @@aut@@ Yamamoto, Nobuyuki @@aut@@ Takahashi, Toshiaki @@aut@@ Tanigawara, Yusuke @@aut@@ |
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Kenmotsu, Hirotsugu |
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Kenmotsu, Hirotsugu misc α misc -acid glycoprotein misc mutation misc Erlotinib misc Exposure–response analysis misc Protein binding misc Non-small cell lung cancer Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients |
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Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients α (dpeaa)DE-He213 -acid glycoprotein (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Erlotinib (dpeaa)DE-He213 Exposure–response analysis (dpeaa)DE-He213 Protein binding (dpeaa)DE-He213 Non-small cell lung cancer (dpeaa)DE-He213 |
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Kenmotsu, Hirotsugu Imamura, Chiyo K. Kawamura, Takahisa Oyakawa, Takuya Omori, Shota Nakashima, Kazuhisa Wakuda, Kazushige Ono, Akira Taira, Tetsuhiko Naito, Tateaki Murakami, Haruyasu Yamamoto, Nobuyuki Takahashi, Toshiaki Tanigawara, Yusuke |
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prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients |
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Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients |
| abstract |
Purpose To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Results Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h ($ AUC_{0-24} $) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound $ AUC_{0-24} $ on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state ($ C_{trough,ss} $) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound $ C_{trough,ss} $ on day 7–15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). Conclusion The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. Clinical trials registration number: UMIN000012862. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 |
| abstractGer |
Purpose To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Results Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h ($ AUC_{0-24} $) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound $ AUC_{0-24} $ on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state ($ C_{trough,ss} $) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound $ C_{trough,ss} $ on day 7–15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). Conclusion The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. Clinical trials registration number: UMIN000012862. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 |
| abstract_unstemmed |
Purpose To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Results Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h ($ AUC_{0-24} $) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound $ AUC_{0-24} $ on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state ($ C_{trough,ss} $) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound $ C_{trough,ss} $ on day 7–15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). Conclusion The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. Clinical trials registration number: UMIN000012862. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 |
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Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Results Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h ($ AUC_{0-24} $) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound $ AUC_{0-24} $ on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state ($ C_{trough,ss} $) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound $ C_{trough,ss} $ on day 7–15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). Conclusion The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. 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