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Routine-dose and High-dose Icotinib in Advanced Non-Small Cell Lung Cancer Patients
harboring EGFR Exon 21 L858R Mutation: the Randomized, Phase II, INCREASE Trial
Running title: High-dose Icotinib in Advanced Non-Small Cell Lung Cancer
Xi Li1,✝, Li Zhang
2,✝, Da Jiang3, Yan Wang
4, Aimin Zang
5, Cuimin Ding
6, Min Zhao
7, Wuyun Su
8,
Yan Zhang9, Diansheng Zhong
10, Jin Wu
11, Cuiying Zhang
12, Guangyu An
13, Xingsheng Hu
4, Gang
Cheng14
, Huaqing Wang15
, Yongqun Li16
, Xiaohui He4, Junli Liu
17, Li Liang
18, Lieming Ding
19, Li
Mao19
, Shucai Zhang1*
1Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing
Tuberculosis and Thoracic Tumor Research Institute, Beijing, China;
2Respiratory Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College
Hospital, Beijing, China;
3Department of Medical Oncology, The Forth Hospital of Hebei Medical University, Tumor
Hospital of Hebei Province, Shijiazhuang, China;
4State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National
Cancer Center and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing, China;
5Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Department of Medical
Oncology, Affiliated Hospital of Hebei University, Baoding, China;
6Department of Respiratory Medicine, The Fourth Hospital of Hebei Medical University,
Shijiazhuang, China;
7Department of Oncology, Hebei Chest Hospital, Shijiazhuang, Hebei, China;
8Department of Medical Oncology, The Affiliated Hospital of Inner Mongolia Medical
University, Hohhot, China;
9Department of Oncology, Affiliated People’s Hospital of Hebei Medical University,
Shijiazhuang, China;
10Department of Oncology, Tianjin Medical University General Hospital, Tianjin, China;
11Department of Head and Neck and Genito-Urinary Oncology, Harbin Medical University
Cancer Hospital, Harbin, China;
12Department of Medical Oncology, People's Hospital of Inner Mongolia Autonomous Region,
Hohhot, China;
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13Department of Medical Oncology, Beijing Chao-Yang Hospital, Capital Medical University,
Beijing, China;
14Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China;
15Department of Respiratory Medicine, Tianjin People‘s Hospital, Tianjin, China;
16Respiratory Department, Sixth Medical Center of PLA General Hospital, Beijing, China;
17Department of Medical Oncology,
Xingtai People's Hospital of Hebei Medical University,
Xingtai, China;
18Department of Oncology, Peking University Third Hospital, Beijing, China;
19Betta Pharmaceutical Co., Ltd., Hangzhou, China.
✝: These authors contributed equally.
*Corresponding author:
Prof. Shucai Zhang, Department of Medical Oncology, Beijing Chest Hospital, Capital Medical
University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 97 Ma Chang,
Tongzhou District, Beijing, 101149, China; Tel: +86-010-89509304; Email:
sczhang6304@163.com
Financial support: This work was supported by Betta pharmaceuticals Co., Ltd.,.
Conflict of Interests: Li Mao and Lieming Ding are employees of Betta Pharmaceuticals which
provided partial funding for the study. Other authors declared no conflict of interests.
Word count: 4147
Tables/figures: 3 figures, 3 tables, 1 supplemental figures.
Statement of translational relevance
Non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon
21 L858R mutation is considered less sensitive to EGFR tyrosine kinase inhibitors, and new
strategies are anticipated to improve the efficacy of targeted therapies among this patient
population. This multicenter phase II randomized clinical trial provides an analysis of
progression-free survival (PFS) in treatment-naïve EGFR-mutant NSCLC patients on high-dose
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icotinib (250mg, thrice daily), as compared with routine-dose icotinib (125mg, thrice daily).
Increasing the dose of icotinib significantly prolonged the median PFS (mPFS) in patients with
exon 21 L858R mutation from 9.2 months to 12.9 months, which was comparable to the mPFS
in patients harboring exon 19 deletion and receiving routine-dose icotinib. This study indicates
that high-dose icotinib could be a better therapeutic option for patients with EGFR exon 21
L858R mutation, which is less responsive to EGFR TKIs than exon 19 deletion during rountine
use of icotinib.
Abstracts
Background: Our primary purpose is to explore safety and efficacy of high-dose icotinib in
comparison with routine-dose icotinib in non-small cell lung cancer (NSCLC) patients harboring
21-L858R mutation.
Patients and Methods: Treatment-naïve, EGFR-mutant (21-L858R or exon 19 deletion at 2:1)
NSCLC patients were enrolled. Patients with 21-L858R mutation were randomized to receive
routine-dose icotinib (125mg, thrice daily; L858R-RD) or high-dose icotinib (250mg, thrice
daily; L858R-HD) , whereas patients with exon 19 deletion received only routine-dose icotinib
(19-Del-RD) until progression, death, or unacceptable toxicity. The primary endpoint was
median progression-free survival (mPFS), assessed by an independent review committee (IRC).
Results: From May, 2015 to November, 2017, 253 patients (86 in L858R-RD; 90 in L858R-HD;
77 in 19-Del-RD) were enrolled. The mPFS in L858R-HD group was similar to that in 19-Del-
RD group (12.9 months and 12.5 months, respectively), and was significantly longer than that in
L858R-RD group (12.9 months vs. 9.2 months, hazard ratio [HR]: 0.75; 95% confidence interval
[CI]: 0.53 to 1.05). A longer but statistically non-significant mPFS was observed between 19-
Del-RD and L858R-RD groups (12.5 months vs. 9.2 months, HR: 0.80; 95% CI: 0.57 to 1.13). A
higher objective response rate (ORR) was observed in L858R-HD group compared to L858R-RD
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group (73% vs. 48%), also between 19-Del-RD and L858R-RD groups (75% vs. 48%). Similar
incidences of grade 3/4 toxicities were observed among the three treatment groups.
Conclusion: High-dose icotinib improved mPFS and ORR in NSCLC patients harboring 21-
L858R mutation with acceptable tolerability, which could be a new therapeutic option for this
patient population.
Keyword: icotinib, high dose, EGFR mutation, exon 21 L858R
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Introduction
Lung cancer, mainly non-small cell lung cancer (NSCLC), remains the most commonly
diagnosed cancer and the leading cause of cancer mortality worldwide, with an estimated 2.1
million new cases and 1.8 million deaths in 2018 [1]. Epidermal growth factor receptor (EGFR)
signaling pathway plays an important role in regulating tumorigenesis and cell survival in cancer
development and progression [2], and NSCLC harboring EGFR mutations is a subtype of lung
cancer with sensitivity to treatment with small molecule EGFR tyrosine kinase inhibitors (EGFR
TKIs). The frequency of EGFR mutations varies among regions worldwide, occurring in
approximately 50% of Asian NSCLC patients and about 10% of Caucasian NSCLC patients [3].
Exon 19 deletion (19-Del) mutation and L858R mutation in exon 21 (21-L858R) are the two
most frequent types of EGFR mutations, which have become the most important determining
factors of clinical response to EGFR TKIs [4-6]. Although these two common mutations could
predict clinical benefits from EGFR TKIs, possible differential sensitivities to EGFR TKIs based
on EGFR mutation types were investigated in retrospective studies and subgroup analysis, and
lower efficacy of EGFR TKIs in patients with 21-L858R mutation than those with 19-Del
mutation was reported [7-11].
So far, EGFR mutations have been extensively studied. Icotinib is a highly specific and
selective EGFR-TKI, which is only approved in China for treatment of NSCLC. It has proven
non-inferior efficacy to gefitinib as second-/third-line treatment in patients with advanced
NSCLC, and superior efficacy as first-line treatment versus chemotherapy in EGFR-mutant
NSCLC patients [12-14]. A randomized study also found that icotinib significantly improved
intracranial progression-free survival (PFS) when compared with whole-brain irradiation (WBI)
in patients with brain metastases and EGFR mutations [15]. However, many questions remain
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unanswered. In particular, few prospective clinical trials have specifically investigated the
differential sensitivities to icotinib between 21-L858R mutation and 19-Del mutation. Recently,
the efficacy of osimertinib in patients harboring the 19-Del mutation was superior to that in
patients harboring the 21-L858R mutation. Therefore, it is worthy to explore whether there is
space for improvement of response to icotinib in patients harboring 21-L858R mutation,
considering previous study has showed NSCLC patients continued to benefit from higher dose
icotinib after progression with routine-dose icotinib [16].
Two phase 1 studies were conducted in 2007 to evaluate the safety and to determine the
maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of oral icotinib twice daily
(100-200mg) and three times daily (75-625mg), respectively. Favorable safety and tolerability
were seen across dose range regardless of administration route. For patients receiving icotinib
twice daily, the objective response rate (ORR) and disease control rate (DCR) were 30.4% and
60.9% in 150mg group, with patients achieved complete regression persisting for 10.3 months,
while no further increase of response was observed in 200mg group [17]. Since the response rate
of icotinib in the twice daily administration regimen was satisfactory compared with that
reported in trials of erlotinib and gefitinib, the research team decided to end the dose escalation;
the highest dose for twicedaily administration is 200mg [17]. For patients receiving icotinib three
times per day, dose expansion was carried out in 100mg (n = 27), 125mg (n = 24) and 150mg (n
= 13) dose levels, and the ORR and DCR for each group were 28% and 84%, 29.2% and 83.3%,
and 46.2% and 76.9%, respectively [18]. The exposure of icotinib increased dose proportionally
between 75mg and 125mg. A little of the saturation profile was observed from 125mg to 150mg
three times daily [19]. Based on the safety, preliminary efficacy, and PK results, 125mg three
times daily was selected as the recommended dose for the confirmative Phase III ICOGEN study
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which was conducted in 2009 [13]. Meanwhile, icotinib was safe and effective over a broad dose
range from 100mg to 500mg thrice daily [20], allowing clinical application with increased dose.
Liu XQ et al. reported that NSCLC patients continued to benefit from higher dose icotinib after
progression with routine dose (125mg thrice daily), and icotinib was well tolerated with 250mg
or 375mg thrice daily [16]. Given the wide therapeutic window of icotinib, increasing the dose of
icotinib might improve the efficacy without incurring novel safety issues in NSCLC patients.
Therefore, a randomized, open-label, phase Ⅱ trial (INCREASE) was conducted to explore the
efficacy and safety of high-dose icotinib (250mg, thrice daily) in treatment-naïve NSCLC
patients harboring 21-L858R mutation.
Methods
Study Design and Patients
The INCREASE study was a randomized, open-label, phase 2 trial conducted at 17 centers in
China. Eligible patients (aged 18-75 years) had histologically confirmed locally advanced or
metastatic (stage IIIB/IV) and previously untreated NSCLC, at least one measurable tumor lesion
(according to Response Evaluation Criteria in Solid Tumor [RECIST] version 1.1), an Eastern
Cooperative Oncology Group performance status (ECOG PS) of 0-2, and adequate organ
(including cardiac, hepatic and renal function) and hematologic functions. Tumor tissue had to
be positive for 19-Del mutation or 21-L858R mutation of EGFR at screening, as assessed by a
central laboratory using the amplification refractory mutation system (ARMS). Patients with
brain metastases were eligible if the disease was asymptomatic or well controlled by
local excision and/or radiotherapy without corticosteroids maintenance. Pregnant or lactating
women were excluded. Complete inclusion/exclusion criteria are provided in the trial protocol
(included in supplementary files).
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This study was performed in accordance with the Declaration of Helsinki and the principles of
Good Clinical Practice. The protocol was approved by the institutional review boards at all
participating sites, and all patients provided written informed consent before their participantion
in the study.
Procedures
Patients harboring 21-L858R mutation were stratified by clinical stage, ECOG PS , smoking
status and brain metastases to receive routine-dose (125mg thrice daily, L858R-RD) or high-dose
icotinib (250mg thrice daily, L858R-HD), and another arm including patients with 19-Del
mutation was served as control group and administered with routine-dose icotinib (125mg thrice
daily, 19-Del-RD). Randomization was done via a computer-supported randomization system.
Both investigators and patients were not masked to treatment assignment. Treatment continued
until radiologically documented disease progression by investigators (RECIST, version 1.1),
unacceptable toxicity, or withdrawal of consent. The dose of icotinib could be reduced by no
more than two dose levels (250mg twice daily and 125mg thrice dail in the high-dose group;
125mg twice daily in the routine-dose group) for adverse events (AEs) management. Dose
interruption for no more than 14 days was allowed to manage treatment-related adverse events
(TRAEs), per the investigator’s judgment.
Tumor assessments were performed by computed tomography at screening (within 28 days
before assignment to treatment), 4 weeks after baseline and every 8 weeks thereafter until
disease progression according to RECIST version 1.1. All scans were assessed by blinded
independent review committee (IRC) and investigators. Objective responses (complete or partial
response) were confirmed > four weeks later after initial response. AEs were assessed throughout
the study and graded according to the National Cancer Institute Common Terminology Criteria
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for Adverse Events (CTCAE) version 4.0. Regular physical (including assessment of symptoms)
and laboratory assessments, as well as electrocardiograms were also evaluated to monitor safety.
Outcomes
The primary endpoint was progression-free survival (PFS), which was defined as the time from
the date of randomization to the date of first documented radiologically confirmed progressive
disease or death of any cause by IRC assessment. Supportive efficacy analyses were performed
based on investigator-assessed PFS. Secondary endpoints were objective response rate (ORR, the
proportion of patients with complete response or partial response), disease control rate (DCR, the
proportion of patients with complete response, partial response, stable disease), overall survival
(OS, the time between the date of randomization to the date of death due to any cause), safety
and tolerability.
Statistical Analysis
In this phase 2 study exploring the efficacy and safety of high-dose icotinib, the sample size was
estimated to detect a difference in proportion of objective response between the L858R-HD
group and the L858R-RD group. In the CONVINCE study, the ORR in patients harboring 21-
L858R mutation and treated with routine-dose icotonib was 47% (unpublished data). Assuming
an ORR of 70% for patients harboring 21-L858R mutation if treated with high-dose icotinib,
which would yield a difference of 23% in proportions. Thus, a total sample size of 162 patients
harboring 21-L858R mutation (81 per treatment arm) would allow us to achieve 85% power at a
two-tailed significance level of 0.05. Taking an anticipated dropout rate (? %) into consideration,
the sample size was initially set at 186 patients harboring 21-L858R mutation, and another 83
patients with 19-Del (receiving routine-dose icotinib) were included as a matching arm.
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Efficacy analyses were conducted in the modified intention-to-treat (mITT) population, which
excluded patients who did not receive any dose of assigned study treatment. Supportive efficacy
analyses were performed in the per-protocol set (PPS), which included patients who had no
major protocol deviation. The safety analyses population was composed of all patients who
received at least one dose of treatment and provided safety data. The Kaplan-Meier method was
used to estimate median PFS and OS, and a two-sided wilcoxon test was performed to compare
the PFS between treatment arms. Cox proportional-hazards model was used to estimate hazard
ratio (HR) and 95% confidence intervals (CIs). ORR and DCR were evaluated and 95% CIs were
calculated. AEs were were assessed in the safety analyses population , and its incidence rates
were compared using Fisher’s exact test. The data cutoff date was May 15, 2019. The p value <
0.05 was considered significant. We used SAS (version 9.3) for all statistical analyses. This
study is registered with ClinicalTrials.gov as NCT02404675.
Results
Patients and Treatments
Between May 22, 2015 and November 15, 2017, a total of 269 patients were enrolled, of which
186 had 21-L858R mutation and were randomly assigned to high-dose ictotinib (L858R-HD;
n=95) and routine-dose icotinib (L858R-RD; n=91). The remaining 83 patients with 19-Del
mutation were enrolled in routine-dose icotinib group (19-Del-RD). Five patients did not receive
any dose of icotinib and 11 patients were not evaluable for safety or efficacy, leaving 253
patients in the mITT population (Figure 1). Additional 8 patients were excluded from the per-
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protocol population (n=245) due to major protocol deviations(Figure 1). Patients’ baseline
characteristics were well balanced among groups in the mITT population (Table 1).
Efficacy
At the data cutoff point, an event of progression or death had occurred in 194 patients in all
groups (L858R-RD: n=65; L858R-HD: n=65; 19-Del-RD: n=64), as assessed by IRC. The
mPFS, assessed by IRC based on the mITT population, in the L858R-HD group was
significantly longer than that in the L858R-RD group (12.9 vs. 9.2 months, HR: 0.75; 95% CI:
0.53-1.05, p<0.05; Figure 2A), and comparable to that in the 19-Del-RD group (12.9 vs. 12.5
months). The mPFS assessed by investigators were roughly in line with IRC assessments, with a
mPFS of 12.9 months in L858-HD group and 9.3 months in L858R-RD group (HR: 0.73, 95%
CI: 0.52-1.03, p<0.05). The IRC-reviewed mPFS in the 19-Del-RD group was 3.3 month longer
than that in the L858R-RD group, but the difference was not statistically significant (12.5 vs. 9.2
months; HR: 0.80; 95% CI, 0.57-1.13; p=0.11; Figure 3A). Whereas, the difference of
investigator-assessed mPFS between L858R-RD group and 19-Del-RD group was statistically
significant in both the mITT population and the per-protocol population (9.3 vs. 12.5 months,
HR: 0.75; 95% CI: 0.53-1.06; p<0.05; 9.1 vs. 12.2 months, HR: 0.68; 95% CI: 0.48-0.96;
p<0.05; respectively).
251 out of 253 patients were evaluable for tumor response. As expected, high-dose icotinib
improved the tumor response in patients with 21-L858R mutation, with a higher ORR than
routine-dose icotinib (73% vs. 48%, p<0.01). Significantly higher response rates were also
observed in 19-Del-RD group than L858R-RD group (75% vs. 48%, p<0.01). No significant
difference in DCR was demonstrated among all groups (99% in the L858R-HD group vs. 97% in
the L858R-RD group vs. 96% in the 19-Del-RD group, p= 0.66, Table 2). At the time of data
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cutoff on May 15, 2019, 71 events of overall survival had occurred and the Kaplan-Meier
estimates of overall survival was shown in the supplementary Figure S1. The final OS analysis
was planed to be conducted when the OS data is approximately 60% mature (approximately 161
deaths).
Subgroup analyses of PFS were conducted according to pre-specified baseline characteristics
without adjustments. The PFS benefits from high-dose ictotinib to patients harboring 21-L858R
mutation were generally consistent across all subgroups, except for the subgroups stratified by
baseline brain metastasis, which favored L858R-HD group significantly (Figure 2B). Similar
results were observed when we compare the PFS between 19-Del-RD group and L858R-RD
group (Figure 3B). Besides, a total of 53 patients had baseline brain metastases in the current
study (L858R-HD group: n=17, 19-Del-RD group: n=20, L858R-RD group: n=16), the mPFS in
L858R-HD group was similar with that in 19-Del-RD group (14.3 vs. 13.4 months, p > 0.05), but
was significantly longer than that in L858R-RD group (14.3 vs. 8.8 months, p = 0.0055). In
addition, we found that a total of 23 patients progressed on brain metastases, including 7 patients
in L858R-HD group, 5 patients in 19-Del-RD group and 11 patients in L858R-RD group,
respectively.
Tolerability
All treatments were well tolerated. Incidence of AEs was similar among all treatment groups.
171 out of 253 patients (67.6%) reported at least one AE related to the study drug, and the most
common TRAEs in all groups were rash (103/253, 40.7%), raised aminotransferase levels
(86/253, 34.0%) and diarrhea (49/253, 19.4%), and others include mucositis, decreased white
blood cell, pruritus, nausea, fatigue, paronychia, conjunctivitis, dry skin, and loss of appetite
(Table 3). Patients in the L858R-HD group experienced significantly more TRAEs than other
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groups (81% vs. 55% in the L858R-RD group vs. 66% in the 19-Del-RD group, p<0.01).
However, the incidences of grade 3/4 TRAEs were similar among all treatment groups (p=0.96).
13 of 253 patients (4 in the L858R-RD group, 5 in the L858R-HD group and 4 in the 19-Del-RD
group) reported grade 3/4 TRAEs, with raised aminotransferase level being the most common
one. One patient in the 19-Del-RD group discontinued study treatment and six patients in the
L858R-HD group required dose interruption due to AEs.
Discussion
In this randomized, open-label, phase II trial, we showed that high-dose icotinib prolonged mPFS
by 3.7 months compared with routine-dose icotinib in treatment-naïve patients with locally
advanced or metastatic NSCLC harboring 21-L858R mutation. The clinical outcomes of high-
dose icotinib in patients with 21-L858R mutation were comparable to the outcomes achieved by
routine-dose icotinib in patients with 19-Del mutation. While the overall TRAEs were higher in
the high-dose icotinib, the incidence of grade 3/4 TRAEs was similar to the routine-dose,
supporting the clinical utility of the high-dose regimen.
19-Del and 21-L858R mutations are the most common subtypes of EGFR mutation, which
consist of 90% of all EGFR mutation-positive NSCLC [21]. Although they are both regarded as
predictors of responses to EGFR TKIs, patients with 19-Del-mutated tumors showed better
clinical outcomes compared to patients with 21-L858R-mutated tumors when treated with EGFR
TKIs [7-11]. A possible explanation is that the kinase activity is mostly dependent on the
conformation of the catalytic domain. The most important TK domain can be divided into an N-
terminal ATP-binding lobe (N-lobe) and a C-terminal substrate-binding lobe (C-lobe) [22]. The
N-lobe constituted by β-sheet and the highly conserved αC-helix, which play a vital role in
conformational changes of the binding pocket. The kinases exist in active or inactive
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conformational state [23] and active and inactive are in a dynamic equilibrium in wild type
EGFR domain. The 19-Del and 21-L858R mutations break the equilibrium and make it incline to
active conformation, but the mechanisms are different. The 21-L858R mutation occurs in the
lower part connected with αC-helix. After L (leucine) mutates to R (arginine), hydrophobic
nucleus cannot be formed and αC-helix stay in the active state. The 19-Del mutation shortens the
upper part connected with αC-helix and activates the conformation via αC-helix rotation. We
deduced that the structures of EGFR with 19-Del mutation are the most strained, which lead to
the highest activity (Figure S2). Additionally, previous in vitro study indicated that several
EGFR TKIs (e.g. erlotinib, gefitinib,afatinib, dacomitinib and osimertinib) had a higher
potency on 19-Del than that on 21-L858R [24]. We analyzed the IC50 of icotinib, which also
showed similar result that the icotinib was more effective for EGFR 19-Del than 21-L858R
(unpublished data). Preclinical study also showed that 19-Del mutant cells are more sensitive to
EGFR TKIs through inhibiting Akt and Erk1/2 signals [25]. Different TKI resistant mechanisms
have been identified between 19 Del and L858R mutations in experimental models [26].
Consistent with previous studies, tumors with EGFR 19-Del mutation were inhibited more
efficiently than those with 21-L858R mutation when treated with routine-dose icotinib in the
present study. These findings suggest that tumors with 19-Del-mutation and 21-L858R-mutation
should be treated differently. In the current study, we found that high-dose icotinib significantly
improved mPFS compared to routine-dose icotinib among patients with 21-L858R-mutant
tumors. The mPFS of 12.9 months in the L858R-HD group was also longer than previously
reported 9.6 months for patients with L858R mutation treated with first-line gefitinib in
WJTOG3405 study [27]. Similar benefits were seen in terms of ORR, with significantly higher
response rate observed in L858R-HD group than L858R-RD group.
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More PFS benefits from high-dose icotinib in patients with baseline brain metastasis were
found according to the subgroup analyses. Moreover, less 21-L858R mutated patients progressed
on brain metastases were found in high-dose icotinib group as compared with rountine-dose
icotinib group. Arbour KC et al. investigated pulse (1200mg)/continuous(50mg)-dose erlotinib in
patients with EGFR-mutant NSCLC and brain metastases, which resulted in a 75% response rate
in brain metastases [28]. A phase 1 dose-escalation study found a significant correlation between
icotinib concentration in the cerebrospinal fluid (CSF) and plasma (R2=0.599, P<0.001), the CSF
penetration rate and intracranial tumor response increased in a dose-dependent manner [29].
These findings support the notion that an increase of icotinib dose may provide a new option for
intracranial tumor control. Moreover, seven EGFR-mutated NSCLC patients with
leptomeningeal metastasis were treated with high-dose gefitinib (750mg, 1000mg), and DLT was
seen in one patient receiving 1000mg gefitinib, with clinical improvement and CSF cytology
clearance in patients with mutation of 19-Del [30]. At present, several second-generation as well
as third-generation EGFR inhibitors have demonstrated robust intracranial activity in clinical
trials that enrolled EGFR mutation-positive NSCLC patients with brain metastases [9,31,32].
Afatinib significantly improved the intracranial efficacy versus chemotherapy, with a PFS of 8.2
months and an ORR of 61-68% reported. However, for patients with 21-L858R mutation, there
was no significant difference in the median intracranial PFS between afatinib and chemotherapy
(6.9 months vs. 9.7 months) [33]. Osimertinib, a third-generation EGFR-TKI developed to
overcome T790M-mediated acquired resistance to first- and second-generation EGFR TKIs, also
achieved consistently encouraging efficacy, irrespective of status with respect to brain metastases
at study entry. The median PFS was 15.2 and 9.6 months with osimertinib and standard EGFR
TKIs (i.e., gefitinib or erlotinib), respectively, in patients with brain metastases [32]. Therefore,
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the median PFS of 14.3 months for patients with baseline brain metastases in the 21-L858R-HD
group was numerically shorter than that observed with osimertinib but longer than those
observed with afatinib, despite lack of direct comparisons and difference of study design.
Recently, high dose osimertinib (160mg, once daily) showed survival benefit and tolerable safety
profile in EGFR T790M positive NSCLC patients with central nervous system (CNS) metastasis
who progressed on prior EGFR TKI [34]. However, a case of congestive heart failure caused by
osimertinib, possibly due to the HER2 inhibition, was reported [35]. Furthermore, rate of QT
prolongation, cardiac failure, CFC and A.fib were higher in osimertinib group compared to other
TKIs and ECG monitoring for QT prolongation and monitoring for symptoms of heart failure
should be considered while using osimertinib [36]. These results suggested that it needs to be
considered carefully for other TKIs to increase dose due to the small sample size or high-dose
TKIs in patients with brain metastasis. Even though whole brain radiation therapy, stereotactic
radiosurgery and brain tumor resection are frequently used for the treatment of brain metastases,
developing more strategies based on available EGFR TKIs would provide more options for
clinicians to personalize treatment strategies. Our previous BRAIN study showed that icotinib
was associated with significantly longer intracranial PFS than whole brain radiation therapy in
patients with EGFR-mutant NSCLC and multiple brain metastases, and indicated that icotinib
might be a reliable first-line therapeutic option for this patient population [15]. However, we
believed the optimal choice depends on the disease characteristics and the profile of patients who
will derive more benefits from high-dose icotinib compared with other therapies needs to be
further investigated.
Currently available EGFR TKIs include icotinib, gefitinib, erlotinib, afatinib, dacomitinib, and
osimertinib, however, the optimal sequence for administration of these drugs is a hot topic in the
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future. The FLAURA trial revealed that untreated EGFR mutation-positive advanced NSCLC
patients treated with osimertinib had a significantly longer PFS (18.9 vs. 10.2 months,) and OS
(38.6 vs 31.8 months) than that with gefitinib or erlotinib [32,37], supporting that osimertinib can
serve as a standard first-line treatment for EGFR-mutated patients [38]. Nevertheless,
osimertinib failed to show OS benefit compared with gefitinib or erlotinib in Asian patients with
advanced EGFR-mutant NSCLC. Moreover, the efficacy of osimertinib in patients harboring the
19-Del mutation was superior compared with that in patients harboring the 21-L858R mutation.
Recently, Zhao et al. reported that osimertinib was associated with the best PFS benefit in
patients with the exon 19 deletion, while gefitinib plus pemetrexed based chemotherapy were
associated with the best PFS in patients with the L858R, indicating the significance of
personalized treatment for patients with different mutation subtype [39]. In addition, mechanisms
of resistance to osimertinib as first-line treatment remain to be fully clarified. For first- and
second-generation EGFR TKIs, the T790M mutation is the most common mechanism of
acquired resistance, and has been detected in up to 50% of patients treated with erlotinib,
gefitinib or afatinib [40,41]. While the phase III FLAURA study indicated that the most common
acquired resistance mechanisms to osimertinib were MET amplification, PIK3CA and KRAS
mutations, HER2 amplification and EGFR C797S mutation [42,43]. Besides, positive response
to icotinib was observed in a metastatic lung adenocarcinoma patient with aquired EGFR L792H
mutation after osimertinib treatment [44]. Consequently, first- or second-generation EGFR TKIs
still have space in the current treatment landscape of EGFR mutation-positive NSCLC.
Compared with gefitinib alone, gefitinib combined with carboplatin plus pemetrexed
significantly prolonged the median OS (50.9 v 38.8 months) in EGFR-mutated NSCLC patients,
which was the best OS benefit so far [45]. Moreover, erlotinib plus bevacizumab was associated
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with the best PFS (19.5 months) in patients with the 21-L858R mutation [46]. Therefore,
improvements in the efficacy (e.g., PFS) of first-line agents are critical for maximizing the
duration of the EGFR signaling inhibition, for which it was meaningful that increasing the dose
of icotinib improved the efficacy in patients harboring 21-L858R mutation based on the findings
from the present INCREASE study. Furthermore, as combined radiotherapy or immunotherapy
with targeted agents has been changing the landscape of cancer treatment, and combination
treatments, especially erlotinib plus bevacizumab, caused more toxicity, the favorable safety
profile of high-dose icotinib would be supportive for future exploration of potential combinations
with other therapies.
In this study, the high-dose icotinib was well tolerated with similar safety profile as reported in
previous trials [12-14]. Rash, diarrhea and elevated aminotransferase levels were still the most
common TRAEs in all groups, most of which were grade 1/2 severity and manageable. No new
safety signal was observed when the dose of icotinib was increased to 250mg. The favorable
safety profile of high-dose icotinib is critical for further investigations that aimed to confirm the
current trend observed.
One limitation of the INCREASE study is that the sample size was determined based on
estimated ORRs, which may limit the power to detect significant differences in mPFS among all
arms. Therefore, the findings should be interpreted with caution. Nevertheless, INCREASE was
designed as an exploratory phase Ⅱ study to evaluate a high-dose icotinib that doubled the
recommended dose in clinical practice and the data actually showed statistically significance in
PFS even though the study was not set up to achieve it with 52% of power initially. We expect
that more statistically significant difference (smaller p values) can be achieved if more subjects
were enrolled or more events were observed in this study, and therefore further studies are
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warranted. Another limitation in our study is lack of biomarker analysis, and we will make best
efforts to collect samples to explore the underlying mechanism in further studies. Additionally,
one of the important clinical questions remains to be determined is if a high-dose icotinib can
also improve treatment outcomes for patients with EGFR 19-Del, which will be further
determined in future studies.
In summary, the INCREASE study demonstrated better efficacy and tolerable toxicities of
high-dose icotinib in NSCLC patients with 21-L858R mutation when compared with routine-
dose. For this patient population, high-dose icotinib may provide a new option in clinical
practice.
Acknowledgements
We would like to acknowledge the patients participating in the INCREASE study, and the
investigators and institutions involved in this study.
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Figure legends
Figure 1. Patient disposition.
Figure 2. (A) Kaplan-Meier estimate of progression-free survival, as assessed by independent
review committee among patients assigned to 21-L858R-HD group and 21-L858R-RD group.
(B) Forest plot of subgroups of patients showing PFS by independent review committee. HR,
hazard ratio; ECOG, Eastern Cooperative Oncology Group. 21-L858R-HD, patients harboring
exon 21 L858R point mutation and receiving high-dose icotinib (250 mg, tid); 21-L858R-RD,
patients harboring exon 21 L858R point mutation and receiving routine-dose icotinib (125 mg,
tid).
Figure 3. (A) Kaplan-Meier estimate of progression-free survival, as assessed by independent
review committee among patients assigned to 19-Del-RD group and 21-L858R-RD group. (B)
Forest plot of subgroups of patients showing PFS by independent review committee. HR, hazard
ratio; ECOG, Eastern Cooperative Oncology Group. 19-Del-RD, patients harboring exon 19
deletion and receiving routine-dose icotinib (250 mg, tid); 21-L858R-RD, patients harboring
exon 21 L858R point mutation and receiving routine-doseicotinib (125 mg, tid).
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Table 1. Baseline demographic and clinical characteristics of patients in the
mITT population
Characteristics 21-L858R-RD 21-L858R-HD 19-Del-RD
No. 86 90 77
Sex
Male/Female (No.) 29/57 37/53 28/49
Age, years
Mean (SD) 59.8 (9.1) 58.9 (8.9) 54.8 (11.5)
Median (range) 61(37-74) 60 (37-76) 57 (26-75)
ECOG PS, No. (%)
0 or 1 81 (94.2%) 87 (96.7%) 69 (89.6%)
2 5 (5.8) 3 (3.3%) 8 (10.4%)
Disease stage
ⅢB, No. (%) 5 (5.8) 4 (4.4) 5 (6.5)
Ⅳ, No. (%) 81 (94.2) 86 (95.6) 72 (93.5)
Smoking history
Never, No. (%) 67 (77.9) 71 (78.9) 56 (72.7)
Ever, No. (%) 19 (22.1) 19 (21.1) 21 (27.3)
Brain metastases
Yes, No. (%) 20 (23.3) 17 (18.9) 16 (20.8)
No, No. (%) 66 (76.7) 73 (81.1) 61 (79.2)
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Table 2. IRC assessed ORR and DCR according to treatment in the mITT
population
21-L858R-RD
(n=86)
21-L858R-HD
(n=90)
19-Del-RD
(n=77) p*
NE 1 (1.2%) 0(0.0%) 1(1.3%)
PR 41 (47.7%) 66 (73.3%) 58 (75.3%)
SD 42 (48.8%) 23 (25.6%) 16 (20.8%)
PD 2 (2.3%) 1 (1.1%) 2 (2.6%)
ORR 41 (47.7%) 66 (73.3%) 58 (75.3%) <0.01
DCR 83 (96.5%) 89 (98.9%) 74 (96.1%) 0.66
*The chi-square test was used; NE: not evaluable.
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Table 3. Treatment related adverse events in the safety population
21-L858R-RD (n=86) 21-L858R-HD (n=90) 19-Del-RD (n=77) P* value for
grade 3-4 Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4
Rash 23
(26.7%)
3
(3.5%)
1
(1.2%)
0
33
(36.7%)
15
(16.7%)
0
0
23
(29.9%)
5
(6.5%)
0
0
0.34
Aminotransferase rise 19
(22.1%)
1
(1.2%)
1
(1.2%)
0
24
(26.7%)
11
(12.2%)
2
(2.2%)
0
19
(24.7%)
7
(9.1%)
1
(1.3%)
1
(1.3%) 0.77
Diarrhea 9
(10.5%)
2
(2.3%))
0
0
23
(25.6%)
3
(3.3%)
0
0
10
(13.0%)
2
(2.6%)
0
0
NA
Mucositis 0
(0.0%)
4
(4.7%)
0
0
5
(5.6%)
3
(3.3%)
2
(2.2%)
0
0
(0.0%)
3
(3.9%)
2
(2.6%)
0
0.18
White blood cell
decreased
2 (2.3%) 1 (1.2%) 0 0 3 (3.3%) 0 0 0 0 2 (2.6%) 0 0 NA
Pruritus 1 (1.2%) 1 (1.2%) 1 (1.2%) 0 0 1 (1.1%) 1 (1.1%) 0 2 (2.6%) 0 0 0 0.48
Nausea 0 0 1 (1.2%) 0 1 (1.1%) 0 0 0 1 (1.3%) 0 0 0 0.34
Fatigue 0 0 0 0 0 0 0 0 1 (1.3%) 0 0 0 NA
Paronychia 0 0 0 0 1 (1.1%) 0 0 0 2 (2.6%) 0 0 0 NA
Conjunctivitis 0 0 0 0 0 1 (1.1%) 0 0 0 0 0 0 NA
Dry skin 0 0 0 0 0 0 0 0 1 (1.3%) 0 0 0 NA
Loss of appetite 0 0 0 0 0 0 0 0 1 (1.3%) 0 0 0 NA
Any adverse events 33
(38.4%)
10
(11.6%)
4
(4.7%)
0
42
(46.7%)
26
(28.9%)
5
(5.6%)
0
32
(41.6%)
15
(19.5%)
3
(3.9%)
1
(1.3%) 0.96
Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria version 4.0; NA: not applicable due to
no patients had grade 3-4 diarrhea. *The fisher’s exact test was used.
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Assessed for eligibility (n=288)
Not meeting inclusion criteria (n=19)
Lost to follow-up (n=0)
Major protocol violation (n=4)
Modified ITT population (n=86)
Allocated to routine-dose icotinib (n= 91)
Randomly assigned and not treated (n=2)
Treated with icotinib but no data were available
(n=3)
Modified ITT population (n=90)
Allocated to high-dose icotinib (n=95)
Randomly assigned and not treated (n=1)
Treated with icotinib but no data were available
(n=4)
Lost to follow-up (n=0)
Major protocol violation (n=3)
Patients with Exon 21 L858R mutations
(n=186) Randomly assigned to treatment
Per-protocol analysis (n=82) Per-protocol analysis (n=87)
Allocated to routine-dose icotinib (n=83)
Not treated (n=2)
Treated with icotinib but no data were available
(n=4)
Patients with Exon 19 deletions (n=83)
Lost to follow-up (n=0)
Major protocol violation (n=1)
Modified ITT population (n=77)
Per-protocol analysis (n=76)
Figure 1
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Published OnlineFirst February 14, 2020.Clin Cancer Res Xi Li, Li Zhang, Da Jiang, et al. Mutation: the Randomized, Phase II, INCREASE TrialCell Lung Cancer Patients harboring EGFR Exon 21 L858R Routine-dose and High-dose Icotinib in Advanced Non-Small
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