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Accepted Manuscript
Management of non-hematologic toxicities associated with different EGFR TKIs inadvanced NSCLC: a comparison analysis
Antonio Passaro , Massimo di Maio , Ester Del Signore , Bruno Gori , Filippo deMarinis
PII: S1525-7304(14)00080-1
DOI: 10.1016/j.cllc.2014.04.006
Reference: CLLC 274
To appear in: Clinical Lung Cancer
Received Date: 16 January 2014
Revised Date: 6 March 2014
Accepted Date: 8 April 2014
Please cite this article as: Passaro A, di Maio M, Del Signore E, Gori B, de Marinis F, Management ofnon-hematologic toxicities associated with different EGFR TKIs in advanced NSCLC: a comparisonanalysis, Clinical Lung Cancer (2014), doi: 10.1016/j.cllc.2014.04.006.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.
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Management of non-hematologic toxicities associated with different EGFR TKIs in
advanced NSCLC: a comparison analysis.
Antonio Passaro1*, Massimo di Maio2, Ester Del Signore1, Bruno Gori1 and Filippo de
Marinis1
1 Division of Thoracic Oncology, European Institute of Oncology, IEO, Milan, Italy
2 Clinical Trials Unit National Cancer Institute - "G. Pascale" Foundation, Naples, Italy
3 1st Oncological Pulmonary Unit, San Camillo, High Specialization Hospital, Rome, Italy
Corresponding author:
*Antonio Passaro, MD
Division of Thoracic Oncology
European Institute of Oncology, IEO
Via G. Ripamonti, 435, 20141, Milan
Tel: 0294372036 Fax: 0294379235
Email: [email protected]
Running title: Non-hematologic toxicity associated with EGFR TKIs
Numbers of words:
- Abstract: 197
- Manuscript: 2746
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Abstract
Non-hematologic toxicities are frequently observed in patients receiving epidermal growth
factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in advanced non-small-cell
lung cancer (NSCLC). From 2010 to 2013, we evaluated 158 patients diagnosed with
advanced or metastatic NSCLC treated in first-, second- or third-line with the EGFR TKIs
afatinib, erlotinib or gefitinib. We assessed the incidence of cutaneous rash, diarrhoea, and
mucositis/stomatitis by grade (G) at initial assessment (< 30 days) compared to last
assessment after correct management and developed a proposal for a new modality of
evaluation and management of adverse events (AE). The incidence of AE (cutaneous rash,
diarrhoea, and mucositis/stomatitis) classified by grade at the initial assessment, and the re-
evaluation after management demonstrated a reduction of about 95% from the starting
toxicity grade for diarrhoea, 65% for cutaneous rash and approximately 70% for
mucositis/stomatitis. Additionally, our results suggest that the safety profile regarding
cutaneous rash, diarrhoea and mucositis after afatinib, erlotinib and gefitinib treatment
becomes similar after a prompt and correct management. This analysis suggests that
immediate therapeutic approaches and continuous management are required to ensure patient
treatments without severe adverse events (SAEs) that could adversely affect survival and the
quality of life (QoL).
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Introduction
Despite recent advances in the management of advanced non-small cell lung cancer (NSCLC),
the prognosis for these patients remains poor with most only surviving less than 1 year (1).
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have provided a
new therapeutic option for lung cancer (2), and EGFR mutation testing is now a routine
practice for newly diagnosed NSCLC patients (3). EGFR TKIs, such as afatinib, gefitinib and
erlotinib, are recognized as important molecular target agents for the treatment of advanced or
metastatic NSCLC. These molecules have shown patient benefits in first-, second- and third-
line settings, and they improved patients’ progression-free survival, response rate and quality
of life (4-12). According to the indication of the registration trial, erlotinib was the first EGFR
TKI approved for the treatment of advanced, metastatic NSCLC in patients unselected for
EGFR mutations in second- and third-line setting (4). Following the results of the EURTAC
trial (5), erlotinib received also approval to use in patients harbouring EGFR mutations in
first-line setting. Based on the result of the IPASS trial, gefitinib was the first target agent
approved for use (in first or subsequent lines) in patients who express EGFR mutations (7). In
addition to these two important drugs, afatinib is the third EGFR inhibitor showing efficacy in
patients with EGFR mutations, and it was recently approved by the FDA as a front-line
therapy in patients harbouring EGFR mutations following the result of the LUX-Lung 3 trial
(11). Regardless of the clinical setting (first-, second or third-line therapy) these three agents
share a similar mechanism of action and generally are well tolerated with patients displaying
skin rashes and experiencing diarrhoea as the most common adverse events (AEs). However,
a small proportion of NSCLC patients treated with these EGFR TKIs discontinue treatment.
In all randomized clinical trials using EGFR TKIs, data regarding the toxicity response to
correct management are not extensively described, and currently the treatment of cutaneous
toxicities are not yet standardized.
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Materials and methods
Data about adverse events were collected prospectively. All patients enrolled in the study,
received a questionnaire developed to collect daily data about: a) dermatologic adverse
events; b) diarrhea; c) mucositis/stomatitis. Patients were advises to report on this
questionnaire, daily data about AEs, ticking the boxes already prepared and summarized as
follows:
For skin rash
1. Macular o popular eruption or erythema without symptoms
2. Macular o popular eruption or erythema associated with pruritus or other
symptoms
3. Severe, generalized erytroderma o macular, popular or vesicular eruption
4. Generalized exfoliative, ulcerative o blistering skin toxicity.
For diarrhea
Ticking the box for every single stool. Questionnaire was performed to collect at maximum
10 stools per day.
1. Green space: 0-4 stools per day (Box number 1, 2, 3, 4)
2. Yellow space: 4-6 stools per day (Box number 5, 6)
3. Red space: ≥ 7 stool per day (Box number 7, 8, 9, 10)
For mucositis/stomatitis
Patients were advised to describe the symptoms at the first appearance, conferring a
symptomatic evaluation
1. Minimal symptoms associated with normal diet
2. Symptomatic but can eat and swallow modified diet
3. Symptomatic and unable to adequately aliment or hydrate orally
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Patients received instructions to refer to our cancer center, in case of increase of ≥ 7 stool per
day over baseline or persisting of 4/6 stool per day for more of 48 hours for diarrhea, in
presence of severe, generalized erytroderma o macular, popular or vesicular eruption, or in
case of symptomatic and unable to adequately aliment or hydrate orally
Patients were clinically evaluated every 7 days +/- 1 day for the first two cycle of treatment
(first 60 days). After this period, clinical follow-up was scheduled every 30 days +/- 2 days.
Clinical assessment was performed exclusively by three thoracic oncologist of our cancer
center, that utilized standardized clinical and management protocol applied for all patients.
Discussion
From February 2010 to May 2013, 158 patients with advanced or metastatic NSCLC who
received EGFR TKIs (afatinib, erlotinib and gefitinib) were included in our analysis. This
study was designed to assess the differences in non-haematological safety profiles with
comparisons at the time of the first assessment and after reparative management. The primary
analysis evaluated the incidence rate and grade of incidence of skin rashes and diarrhoea at
the time of the first assessment and after management. The secondary analysis included a
comparison among the adverse incidence for the three different drugs at the second-evaluation
time. The first assessment was considered as the time when the toxicity proved the high grade
of evaluation, which was generally revealed during the first 30 days of treatment, and after
management when there was a lower grade of clinical evidence. The toxicity evaluation was
assessed in the first month of treatment every week using the National Cancer Institute
Common Toxicity Criteria (NCI-CTC) for Adverse Events (AEs) version 4.0. We only
considered patients treated as follows: with afatinib, starting dose of 40 mg, once daily for 28
days, following the protocol of the LUX-Lung 1, LUX-Lung 5 and compassionate use; with
erlotinib (150 mg), orally once daily according to the protocol of the BR.21 trial; and, with
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gefitinib (250 mg) orally daily following based on the protocol of the IPASS trial.
EGFR TKIs Toxicities Management
Skin rash
Patients who developed dermatologic AEs, including papulopustular (acneiform) rash,
pruritus, and xerosis, associated with afatinib, erlotinib and gefitinib were treated all with the
same protocol. Depending on the type and severity of the TKIs-associated dermatologic AE,
various treatment interventions were used. Patients developing cutaneous G1 AEs (macular or
papular eruption, or erythema without associated symptoms) were treated with topical
steroids b.i.d. or topical antibiotic b.i.d. (clindamycin 1-2%, erythromycin 1-2% or
metronidazole 1%); for patients with G2 AEs (macular or papular eruption, or erythema with
pruritus or other associated symptoms; localized desquamation or other lesions covering
<50% of body surface area (BSA) we utilized oral antibiotic for 6 weeks (doxycycline 100
mg b.i.d., minocycline 100 mg b.i.d.) associated with topical steroids b.i.d; for G3 AEs
(severe, generalized erythroderma or macular, papular or vesicular eruption; desquamation
covering ≥50% BSA generalized exfoliative, ulcerative or bullous dermatitis) our patients
received oral antibiotics for 6 weeks (doxycycline 100 mg b.i.d., minocycline 100 mg b.i.d)
with topical steroids b.i.d. with interruption of TKIs treatment, resumed when patients
recovers to grade ≤2 (15).
Diarrhoea
Patients with G1 (an increase of < 4 stools per day over baseline) and G2 (4 to 6 stools per
day over baseline) diarrhoea were started with an immediate treatment of loperamide at the
recommended initial dose of 4 mg (two tablets). They continued to take one tablet after each
episode of diarrhoea (up to 20 mg/day) together with dietary modifications incorporating
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bananas, rice, apple sauce and toast (BRAT diet), as well as increasing the amounts of clear
liquids consumed into their daily diet and avoiding foods/drinks that contain lactose or
caffeine. For patients who developed G3 diarrhoea (increase of ≥7 stools per day over
baseline, incontinence, i.v. fluids ≥24 h) we provided hospitalization for aggressive
intravenous fluid replacement, maintained loperamide treatment and discontinued TKIs
therapy (16).
Mucositis / stomatitis
As for patients with dermatologic AEs and diarrhoea, patients with mucositis or stomatitis
were treated all with the same protocol. All patients were advice to follow some basic
indications, ready to prevent the development of mucositis or stomatitis:
- To clean teeth with soft toothbrush after each meal, as well at bedtime
- To rinse the mouth thoroughly three/four times a day, after each meal and at bed-time,
after brushing teeth;
- To maintain adequate oral fluid intake and diet.
- To minimize utilise of alcohol beverage, tobacco and spicy foods
Patients with G1 (minimal symptoms associated with normal diet), follow the standard mouth
care protocol. For patients with G2 (symptomatic but can eat and swallow modified diet),
treatment with chlorhexidine mouthwash twice daily. For patients who developed G3
mucositis (symptomatic and unable to adequately aliment or hydrate orally) we provided (as
reported above) associated with oral decontamination, including antibacterial and antifungal
rinses; topical and systemic pain management, such ad 2% viscous lidocaine and topical
morphine solutions; control of bleeding by use of topical thrombin packs and antifibrinolytic
agents (17-19). Among our patients treated with EGFR TKIs, nobody needed parental or
enteral nutritional support.
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Results
From February 2010 to May 2013, 158 Caucasian patients with advanced NSCLC treated
with EGFR TKIs (52 patients treated with afatinib, 56 treated with erlotinib, and 51 treated
with gefitinib), were enrolled into the study and analysed retrospectively for AEs, skin rash
and diarrhoea.
Skin rash and diarrhoea of any grade were experienced in 83% and 57% of patients treated
with erlotinib, in 63% and 12% of patients receiving gefitinib and in 96% and 76% of patients
treated with afatinib. Mucositis and stomatitis were experienced in 14,5%, 6% and 17% of
patients treated respectively with erlotinib, gefitinib and afatinib.
Out of the 56 patients treated with erlotinib, 41 (73%) were EGFR wild-type, while EGFR
mutational status was unknown in 15 (27%). All 51 patients treated with gefitinib harbouring
EGFR mutations. Out of the 52 patients treated with afatinib, 32 (62%) were EGFR mutated,
12 (23%) were EGFR wild type, and EGFR mutational status was unknown in 8 (15%).
Severe (grade 3) skin toxicity was experienced at the time of first assessment in 6 (11%), 1
(2%) and 10 (20%) of patients treated with erlotinib, gefitinib and afatinib, respectively. In
the whole series of patients, severe skin toxicity was experienced by 8 out of 83 patients with
EGFR mutation, by 7 out of 60 EGFR wild-type patients and by 2 out of 15 patients with
unknown EGFR mutational status. Considering only patients treated with afatinib, severe skin
toxicity was experienced by 7 out of 32 patients with EGFR mutation (21%), by 3 out of 12
EGFR wild-type patients (25%) and by 2 out of 8 patients with unknown EGFR mutational
status.
Severe (grade 3) diarrhoea was experienced in 1 (2%), 0, and 7 (14%) of patients treated with
erlotinib, gefitinib and afatinib, respectively. No patients developed severe
mucositis/stomatitis.
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Time course for AEs onset
The time course for skin rash appearance from the time of starting TKIs was 7 days (95% CI:
5 to 12 days) for afatinib, 9 days (95% CI: 7 to 18 days) for erlotinib, and 14 days (95% CI: 9
to 19 days) for gefitinib. The time course for diarrhoea onset was 13 days (95% CI: 7-18
days) for erlotinib, 18 days (95% CI: 10 to 19 days) for gefitinib and 5 days (95% CI: 4 to 11
days) for patients receiving afatinib. The time course for mucositis/stomatitis appearance from
the time of starting TKIs was 17 days (95% CI: 14 to 19 days) for afatinib, 24 days (95% CI:
22 to 26 days) for erlotinib, and 21 days (95% CI: 18 to 23 days) for gefitinib. About 82% of
all AE were grade 1/2 in severity and 10% were grade ≥3. All patients received prompt and
concomitant treatment management based on the severity grade (as reported above). Dose
reduction of TKI was required in 5% of patients using afatinib 40 mg as a first dose. For
patients treated daily with 150 mg erlotinib dose reduction was required in 4% of patients,
while no dose reduction was required for gefitinib patients. No treatment-related death
occurred in patients treated with the three EGFR TKIs. However, the results collected after
reparative management were similar and did not demonstrate any significant differences. The
results summarized in Table 1 (dermatologic AEs), Table 2 (diarrhoea) and Table 3
(mucositis/stomatitis) shows the comparison of AEs at the time of initial assessment and the
last assessment after management. Most patients had lower grades of AEs at their last
assessment compared with their initial assessment. The last evaluation for the toxicity profile
was similar for the three EGFR TKIs used.
Conclusion
The analysis presented here further examined the safety profile of non-haematological
toxicities, such as skin rashes and diarrhoea, in patients with advanced NSCLC treated with
EGFR TKIs including afatinib, erlotinib and gefitinib as first-, second- and third-line
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treatments. In patients with NSCLC harbouring EGFR mutations, treatment with EGFR TKIs
lasts approximately 10-12 months. Although the safety profiles of the three EGFR TKIs have
significantly fewer side effect than chemotherapy, it change quickly if treated with prompt
and careful management. Based on this rapid improvement, we evaluated the incidence of
grading AEs, which involved a comparison between the first and the last assessments. This
led us to produce a proposed new model of evaluation based on the last assessment,
considered as the time after reparative management, that is needed to better understand the
actual impact of skin rashes and diarrhoea in patients treated with EGFR TKIs. Global
impact of toxicity on patients is actually dependent not only on the worst grade experienced,
but also on its duration. A transient grade 3 adverse event that is completely resolved a few
days after its appearance could be less distressing for the patient that a grade 1 or 2 event
lasting for several weeks. In our retrospective study, we found that AEs characteristics of
EGFR-TKI at the first assessment occurred more frequently in the afatinib and erlotinib group
than in the gefitinib group. However, when these data were re-evaluated considering the last
assessment, the results showed a strong reduction of grading for the afatinib and erlotinib
groups, with grading similar to the gefitinib group. Of course, this result cannot substitute the
evidence that would come from direct, head-to-head comparison of the different drugs.
However, in the absence of direct comparisons, our data suggest that the three different drugs
could be different in terms of worst grade of toxicity, but that this difference is less strong
when considering the whole course of toxicity during the treatment. The AEs, related to TKIs,
evaluated to identify the high grade toxicity, generally occurred during the first 30 days of
treatment; however, data regarding final evaluation that describes the grading of toxicity after
a reparative management are usually missed in the common reports of toxicity, but in our
opinion can be very useful to better describe the impact of treatment toxicity on the patients .
These results underline the importance of early and correct evaluations to identify the real
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incidence of AEs related to TKIs therapy that presents different trends when compared with
chemotherapy-related AEs, which are characterized by cyclic timing of appearance depending
on different kinds of chemotherapy agents. Evaluation of patients treated with EGFR TKIs, it
is needed week during the first months of treatment, because this is the time in when patients
need more attention for yours toxicity; after the first 30 days, toxicity if well managed, cause
less discomfort.
In the era of efficacy comparison for different EGFR TKIs in NSCLC, this is the first study
comparing the safety profile of non-haematological toxicities using afatinib, erlotinib and
gefitinib with a focus on the first and last patient assessments. Although this study was
retrospective, we demonstrated that afatinib and erlotinib were associated with more AEs than
gefitinib only at the onset time of the first analysis. However, the evaluation of AEs at the last
assessment showed that these three drugs present similar safety profiles, which are generally
not required for dose reduction when treated with the correct approach.
Conflict of Interest
None to declare
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Incidence of dermatologic AEs EGFR-TKIs related
Erlotinib 150 mg/daily
Initial assessment Last assessment Definitive Grade
Grade N (%) Lower Equal Worse
1 28 (48%) 1 (0,5%) 24 (41%) 3.48 (6%) 34 (58%)
2 14 (24%) 12 (20%) 1 (0,5%) 1.16 (2%) 10 (16%)
3 6 (11%) 5 ( 9%) 2 (2%) 0% 3 (4%)
4 0.0% 0% 0% 0% 0.0%
Gefitinib 250 mg/daily
Initial Assessment Last assessment Definitive Grade
Grade N (%) Lower Equal Worse
1 26 (53%) 1 (2%) 25 (51%) 0 (0.0%) 31 (63%)
2 6 (12%) 5 (10%) 1 (2%) 0 (0.0%) 1 (2%)
3 1 (2%) 1 (2%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
4 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Afatinib 40 mg/daily
Initial Assessment Last assessment Definitive Grade
Grade N (%) Lower Equal Worse
1 19 (37%) 2 (4%) 16 (31%) 1 (2 %) 25 (50%)
2 20 (39%) 8 (16%) 11 (22%) 1 (2 %) 18 (35%)
3 10 (20%) 8 (16%) 2 (4%) 0 (0.0) 3 (6%)
4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
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Incidence of diarrhea EGFR-TKIs related
Erlotinib 150 mg/daily Initial Assessment Last assessment Definitive grade
Grade N (%) Lower Equal Worse 1 27 (46%) 24 (42%) 3 (4%) 0 (0.0) 3 (2%) 2 20 (10%) 20 (10%) 0 (0.0) 0 (0.0) 0 (0.0) 3 4 (2%) 4 (2%) 0 (0.0) 0 (0.0) 0 (0.0) 4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Gefitinib 250 mg/daily Initial Assessment Last assessment Definitive Grade
Grade N (%) Lower Equal Worse 1 14 (29%) 14 (29%) 0 (0.0) 0 (0.0) 0 (0.0) 2 0 (10 %) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Afatinib 40 mg/daily Initial Assessment Last assessment Definitive Grade
Grade N (%) Lower Equal Worse 1 22 (47%) 19 (37%) 3 (6%) 0 (0.0) 1 (2,5%) 2 12 (23%) 12 (23%) 0 (0.0) 0 (0.0) 0 (0.0) 3 7 (14%) 7 (14%) 0 (0.0) 0 (0.0) 0 (0.0) 4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
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Incidence of mucositis/stomatitis EGFR-TKIs related
Erlotinib 150 mg/daily
Initial assessment Last assessment Definitive Grade
Grade N (%) Lower Equal Worse
1 7 (12,5%) 5 (9 %) 2 (3,5%) 0 (0.0) 3 (3,5%)
2 1 (2%) 1 (2%) 0 (0.0) 0 (0.0) 0 (0.0)
3 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Gefitinib 250 mg/daily
Initial Assessment Last assessment Definitive Grade
Grade N (%) Lower Equal Worse
1 6 (12%) 4 (8%) 2 (4%) 0 (0.0%) 2 (4%)
2 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0%) 0 (0.0)
3 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Afatinib 40 mg/daily
Initial Assessment Last assessment Definitive Grade
Grade N (%) Lower Equal Worse
1 8 (14%) 6 (10%) 2 (3,5%) 0 (0.0) 3 (5%)
2 2 (3.5%) 2 (3.5%) 0 (0.0) 0 (0.0) 0 (0.0)
3 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)