Introduction: EGFR-tyrosine kinase inhibitor (TKI)-induced rash can be alleviated with tetracyclines (TCN) and topical corticosteroids (TCS), whereas drugs for acid-related disorders (DARDs) can affect EGFR-TKI absorption. The present study investigated the concomitant use of TCNs, TCSs, and DARDs with EGFR-TKIs in non-small cell lung cancer (NSCLC) and whether these affect patient outcomes. Methods: We retrospectively collected data from all patients (n = 1,498) who had purchased for EGFR-TKIs (erlotinib, gefitinib, and afatinib) in Finland between 2011 and 2020. Overall survival (OS) and time-on-treatment (ToT) were analyzed from the first EGFR-TKI purchase. Results: Early TCN purchases were registered in 298 (19.6%) patients; early TCS and DARD purchases were observed in 154 (10.1%) and 192 (12.9%), while similar percentages were detected in the EGFR mutant cohort. In the entire cohort, early purchase of TCSs and TCNs was associated with improved ToT, OS, and DARDs with inferior outcomes. In the multivariate analysis, TCSs retained their significance in ToT (HR: 0.78; 95% CI: 0.66–0.94), TCNs in OS (HR: 0.73; 95% CI: 0.63–0.84), and DARDs in both (HR: 1.28; 95% CI: 1.091–1.495; HR: 1.19; 95% CI: 1.01–1.41). In the EGFR mutant cohort, similar nonsignificant trends were observed for TCNs, TCSs and DARDs. In the analysis according to EGFR-TKI, erlotinib users had improved outcomes when early TCN or TCS purchases were registered, whereas DARDs were associated with worse outcomes among gefitinib users. Conclusions: Among EGFR-TKI-treated NSCLCs, the use of TCN, TCS, and DARD can affect treatment outcomes that should be considered in optimal patient care.

1.
Manninen
O
,
Puuniemi
L
,
Iivanainen
S
,
Arffman
M
,
Kaarteenaho
R
,
Koivunen
JP
.
Treatment outcomes of non-small cell lung cancers treated with EGFR tyrosine kinase inhibitors: a real-world cohort study
.
Acta Oncol Madr
.
2023
;
62
(
12
):
1
8
.
2.
Kim
ES
,
Hirsh
V
,
Mok
T
,
Socinski
MA
,
Gervais
R
,
Wu
YL
, et al
.
Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial
.
Lancet
.
2008
;
372
(
9652
):
1809
18
.
3.
Zhou
C
,
Wu
YL
,
Chen
G
,
Feng
J
,
Liu
XQ
,
Wang
C
, et al
.
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study
.
Lancet Oncol
.
2011
;
12
(
8
):
735
42
.
4.
Maemondo
M
,
Inoue
A
,
Kobayashi
K
,
Sugawara
S
,
Oizumi
S
,
Isobe
H
, et al
.
Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR
.
N Engl J Med
.
2010
;
362
(
25
):
2380
8
.
5.
Yang
JCH
,
Wu
YL
,
Schuler
M
,
Sebastian
M
,
Popat
S
,
Yamamoto
N
, et al
.
Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials
.
Lancet Oncol
.
2015
;
16
(
2
):
141
51
.
6.
Soria
J-C
,
Ohe
Y
,
Vansteenkiste
J
,
Reungwetwattana
T
,
Chewaskulyong
B
,
Lee
KH
, et al
.
Osimertinib in untreated EGFR -mutated advanced non–small-cell lung cancer
.
N Engl J Med
.
2018
;
378
(
2
):
113
25
.
7.
Ramalingam
SS
,
Vansteenkiste
J
,
Planchard
D
,
Cho
BC
,
Gray
JE
,
Ohe
Y
, et al
.
Overall survival with osimertinib in untreated, EGFR -mutated advanced NSCLC
.
N Engl J Med
.
2020
;
382
(
1
):
41
50
.
8.
Wu
Y-L
,
Mok
TSK
,
Han
J-Y
,
Ahn
M-J
,
Delmonte
A
,
Ramalingam
SS
, et al
.
Overall survival (OS) from the AURA3 phase III study: osimertinib vs platinum-pemetrexed (plt-pem) in patients (pts) with EGFR T790M advanced non-small cell lung cancer (NSCLC) and progression on a prior EGFR-tyrosine kinase inhibitor (TKI)
.
Ann Oncol
.
2019
;
30
:
ix158
.
9.
Mok
TS
,
Wu
Y-L
,
Ahn
M-J
,
Garassino
MC
,
Kim
HR
,
Ramalingam
SS
, et al
.
Osimertinib or platinum–pemetrexed in EGFR t790m–positive lung cancer
.
N Engl J Med
.
2017
;
376
(
7
):
629
40
.
10.
Shah
RR
,
Shah
DR
.
Safety and tolerability of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in oncology
.
Drug Saf
.
2019
;
42
(
2
):
181
98
.
11.
Melosky
B
,
Anderson
H
,
Burkes
RL
,
Chu
Q
,
Hao
D
,
Ho
V
, et al
.
Pan Canadian rash trial: a randomized phase III trial evaluating the impact of a prophylactic skin treatment regimen on epidermal growth factor receptor-tyrosine kinase inhibitor–induced skin toxicities in patients with metastatic lung cancer
.
J Clin Oncol
.
2016
;
34
(
8
):
810
5
.
12.
Arrieta
O
,
Vega-González
MT
,
López-Macías
D
,
Martínez-Hernández
JN
,
Bacon-Fonseca
L
,
Macedo-Pérez
EO
, et al
.
Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients
.
Lung Cancer
.
2015
;
88
(
3
):
282
8
.
13.
Lacouture
ME
,
Keefe
DM
,
Sonis
S
,
Jatoi
A
,
Gernhardt
D
,
Wang
T
, et al
.
A phase II study (ARCHER 1042) to evaluate prophylactic treatment of dacomitinib-induced dermatologic and gastrointestinal adverse events in advanced non-small-cell lung cancer
.
Ann Oncol
.
2016
;
27
(
9
):
1712
8
.
14.
Hofheinz
R-D
,
Deplanque
G
,
Komatsu
Y
,
Kobayashi
Y
,
Ocvirk
J
,
Racca
P
, et al
.
Recommendations for the prophylactic management of skin reactions induced by epidermal growth factor receptor inhibitors in patients with solid tumors
.
Oncologist
.
2016
;
21
(
12
):
1483
91
.
15.
Petrelli
F
,
Borgonovo
K
,
Cabiddu
M
,
Coinu
A
,
Ghilardi
M
,
Lonati
V
, et al
.
Antibiotic prophylaxis for skin toxicity induced by antiepidermal growth factor receptor agents: a systematic review and meta‐analysis
.
Br J Dermatol
.
2016
;
175
(
6
):
1166
74
.
16.
Lacouture
ME
,
Wainberg
ZA
,
Patel
AB
,
Anadkat
MJ
,
Stemmer
SM
,
Shacham-Shmueli
E
, et al
.
Reducing skin toxicities from EGFR inhibitors with topical BRAF inhibitor therapy
.
Cancer Discov
.
2021
;
11
(
9
):
2158
67
.
17.
van Erp
NP
,
Gelderblom
H
,
Guchelaar
H-J
.
Clinical pharmacokinetics of tyrosine kinase inhibitors
.
Cancer Treat Rev
.
2009
;
35
(
8
):
692
706
.
18.
Sim
W
,
Jain
SR
,
Lim
WH
,
Chin
YH
,
Ng
C
,
Syn
N
, et al
.
Interactions between epidermal growth factor receptor tyrosine kinase inhibitors and proton-pump inhibitors/histamine type-2 receptor antagonists in non-small cell lung cancer: a systematic review and meta-analysis
.
Transl Lung Cancer Res
.
2021
;
10
(
8
):
3567
81
.
19.
Peters
S
,
Zimmermann
S
,
Adjei
AA
.
Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug–drug interactions
.
Cancer Treat Rev
.
2014
;
40
(
8
):
917
26
.
20.
Xu
Z-Y
,
Li
J-L
.
Comparative review of drug–drug interactions with epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer
.
Onco Targets Ther
.
2019
;
12
:
5467
84
.
21.
Lee
C-H
,
Shen
M-C
,
Tsai
M-J
,
Chang
J-S
,
Huang
Y-B
,
Yang
Y-H
, et al
.
Proton pump inhibitors reduce the survival of advanced lung cancer patients with therapy of gefitinib or erlotinib
.
Sci Rep
.
2022
;
12
(
1
):
7002
.
22.
Ho
M-C
,
Chung
Y-S
,
Lin
Y-C
,
Hung
M-S
,
Fang
Y-H
.
Combination use of first-line afatinib and proton-pump inhibitors reduces overall survival among patients with EGFFR mutant lung cancer
.
Onco Targets Ther
.
2022
;
15
:
1573
82
.
23.
Alanen
V
,
Iivanainen
S
,
Arffman
M
,
Koivunen
JP
.
Purchase of prophylactic topical corticosteroids is associated with improved survival in NSCLCs treated with EGFR TKI: real-world cohort study
.
Acta Oncol Madr
.
2021
;
60
(
9
):
1100
5
.
24.
Alanen
V
,
Iivanainen
S
,
Arffman
M
,
Koivunen
JP
.
Tetracyclines increase the survival of NSCLC patients treated with EGFR TKIs: a retrospective nationwide registry study
.
ESMO Open
.
2020
;
5
(
5
):
e000864
.
25.
Kim
Y
,
Lee
ES
,
Lee
YS
,
Ahn
MJ
,
Park
K
,
Sun
JM
.
High mortality from viral pneumonia in patients with cancer
.
Infect Dis
.
2019
;
51
(
7
):
502
9
.
26.
Wei
Y-F
,
Lim
C-K
,
Tsai
M-S
,
Huang
M-S
,
Chen
K-Y
.
Intracranial responses to afatinib at different doses in patients with EGFR-mutated non–small-cell lung carcinoma and brain metastases
.
Clin Lung Cancer
.
2019
;
20
(
3
):
e274
83
.
27.
Jänne
PA
,
Yang
JC-H
,
Kim
D-W
,
Planchard
D
,
Ohe
Y
,
Ramalingam
SS
, et al
.
AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer
.
N Engl J Med
.
2015
;
372
(
18
):
1689
99
.
28.
Manninen
O
,
Puuniemi
L
,
Iivanainen
S
,
Arffman
M
,
Kaarteenaho
R
,
Koivunen
JP
.
Treatment outcomes of non-small cell lung cancers treated with EGFR tyrosine kinase inhibitors: a real-world cohort study
.
Acta Oncol Madr
.
2023
;
62
(
12
):
1854
61
.
29.
Jatoi
A
,
Green
EM
,
Rowland
KM
,
Sargent
DJ
,
Alberts
SR
.
Clinical predictors of severe cetuximab-induced rash: observations from 933 patients enrolled in north central cancer treatment group study N0147
.
Oncology
.
2008
;
77
(
2
):
120
3
.
30.
Petrelli
F
,
Borgonovo
K
,
Cabiddu
M
,
Coinu
A
,
Ghilardi
M
,
Lonati
V
, et al
.
Antibiotic prophylaxis for skin toxicity induced by antiepidermal growth factor receptor agents: a systematic review and meta‐analysis
.
Br J Dermatol
.
2016
;
175
(
6
):
1166
74
.
31.
Noguchi
T
,
Sekiguchi
Y
,
Shimada
T
,
Suzuki
W
,
Yokosawa
T
,
Itoh
T
, et al
.
LLPS of SQSTM1/p62 and NBR1 as outcomes of lysosomal stress response limits cancer cell metastasis
.
Proc Natl Acad Sci U S A
.
2023
;
120
(
43
):
e2311282120
.
32.
Zhou
C
,
Tang
K-J
,
Cho
BC
,
Liu
B
,
Paz-Ares
L
,
Cheng
S
, et al
.
Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions
.
N Engl J Med
.
2023
;
389
(
22
):
2039
51
.
33.
Cho
BC
,
Lu
S
,
Felip
E
,
Spira
AI
,
Girard
N
,
Lee
J-S
, et al
.
Amivantamab plus lazertinib in previously untreated EGFR -mutated advanced NSCLC
.
N Engl J Med
.
2024
;
391
(
16
):
1486
98
.
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