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

Author Manuscript Published OnlineFirst on February 14, 2020; DOI: 10.1158/1078-0432.CCR-19-3064 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

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 Zhang2,✝, Da Jiang3, Yan Wang4, Aimin Zang5, Cuimin Ding6, Min Zhao7, Wuyun Su8, Yan Zhang9, Diansheng Zhong10, Jin Wu11, Cuiying Zhang12, Guangyu An13, Xingsheng Hu4, Gang Cheng14, Huaqing Wang15, Yongqun Li16, Xiaohui He4, Junli Liu17, Li Liang18, Lieming Ding19, 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;

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: [email protected]

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.

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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

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

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

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

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

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).

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

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.

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-

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

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

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

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.

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,

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

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

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

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.

References 1. Bray F, Ferlay J, Soerjomataram I,et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6):394-424. 2. Sharma SV, Bell DW, Settleman J et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007; 7(3):169-181. 3. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 2015; 5(9):2892-2911.

4. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009; Suppl 1:S24-31. 5. Lee VH, Tin VP, Choy TS et al. Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first-line tyrosine kinase inhibitor in metastatic non-small-cell lung cancer. J Thorac Oncol 2013; 8(9):1148-1155. 6. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350(21):2129-2139. 7. Jackman DM, Yeap BY, Sequist LV et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006; 12(13):3908-3914. 8. Patel N, Wu P, Zhang H et al. Comparison of gefitinib as first- and second-line therapy for advanced lung adenocarcinoma patients with positive exon 21 or 19 del epidermal growth factor receptor mutation. Cancer Manag Res 2017; 9:243-248. 9. Sequist LV, Yang JC, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31(27):3327-3334. 10. Yang JC, Wu YL, Schuler M 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):141-151. 11. Seto T, Kato T, Nishio M et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol 2014; 15(11):1236-1244. 12. Shi Y, Zhang L, Liu X et al. Icotinib versus gefitinib in previously treated advanced non- small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol 2013; 14(10):953-961. 13. Shi YK, Wang L, Han BH et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol 2017; 28(10):2443-2450. 14. Hu X, Han B, Gu A et al. A single-arm, multicenter, safety-monitoring, phase IV study of icotinib in treating advanced non-small cell lung cancer (NSCLC). Lung Cancer 2014; 86(2):207-212. 15. Yang JJ, Zhou C, Huang Y et al. Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial. Lancet Respir Med

2017; 5(9):707-716. 16. Liu XQ, Wang W, Tang C et al. Higher dose icotinib in treating non-small cell lung cancer patients who progressed with conventional dose of icotinib. Ann Oncol 2014; 25: iv426- iv470. 17. Wang H, Zhang L, Wang Y, et al. Phase I trial of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in Chinese patients with non-small cell lung cancer. Chinese medical journal 2011; 124(13): 1933-1938. 18. Shentu J, Wu G, Liu J, et al. An open label, dose escalation, phase I trial to evaluate the tolerability and antitumor activity of icotinib in patients with advanced non-small-cell lung cancer[C]//JOURNAL OF THORACIC ONCOLOGY. 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA: LIPPINCOTT WILLIAMS & WILKINS 2013; 8: S1191-S1191. 19. Zhao Q, Shentu J, Xu N, et al. Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors. Lung cancer 2011; 73(2): 195-202. 20. Liu J, Wu L, Wu G et al. A Phase I study of the safety and pharmacokinetics of higher-dose icotinib in patients with advanced non-small cell lung cancer. Oncologist 2016; 21(11):1294- 1295. 21. Rosell R, Moran T, Queralt C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361(10):958-967. 22. Robinson, D, Wu, Y, Lin, S. The protein tyrosine kinase family of the human genome. Oncogene 2000; 19: 5548-5557. 23. Kumar A, Petri E T, Halmos B, et al. The Structure and Clinical Relevance of the EGF Receptor in Human Cancer. Journal of Clinical Oncolog 2008; 26(10):1742. 24. Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014; 4(9):1046-1061. 25. Zhu JQ, Zhong WZ, Zhang GC et al. Better survival with EGFR exon 19 than exon 21 mutations in gefitinib-treated non-small cell lung cancer patients is due to differential inhibition of downstream signals. Cancer Lett 2008; 265(2):307-317. 26. Ke EE, Zhou Q, Zhang QY et al. A Higher Proportion of the EGFR T790M Mutation May Contribute to the Better Survival of Patients with Exon 19 Deletions Compared with Those with L858R. J Thorac Oncol 2017; 12:1368-1375. 27. Mitsudomi T, Morita S, Yatabe Y et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010; 11(2):121-128.

28. Arbour KC, Kris MG, Riely GJ et al. Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor-mutant lung cancers and brain metastases. Cancer 2018; 124(1):105-109. 29. Zhou L, He J, Xiong W et al. Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: Results of phase I dose-escalation study. Lung Cancer 2016; 96:93-100. 30. Jackman D M, Cioffredi L A, Jacobs L, et al. A phase I trial of high dose gefitinib for patients with leptomeningeal metastases from non-small cell lung cancer. Oncotarget 2015; 6(6): 4527. 31. Wu YL, Zhou C, Hu CP et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15(2):213-222. 32. Soria JC, Ohe Y, Vansteenkiste J et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018; 378(2):113-125. 33. Schuler M, Wu YL, Hirsh V et al. First-Line Afatinib versus Chemotherapy in Patients with Non-Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases. J Thorac Oncol 2016; 11(3):380-390. 34. Ahn M, Park S, Hong S, et al. MA21.10 Phase II Study of 160mg of Osimertinib in EGFR T790M Positive NSCLC with Brain or Leptomeningeal Metastases Who Progressed on Prior EGFR TKI. Journal of Thoracic Oncology 2019; 14(10): S338. 35. Watanabe H, Ichihara E, Kano H, et al. Congestive Heart Failure During Osimertinib Treatment for Epidermal Growth Factor Receptor (EGFR)-mutant Non-small Cell Lung Cancer (NSCLC). Internal Medicine 2017; 56(16): 2195-2197. 36. Anand K, Ensor J, Trachtenberg B, et al. Osimertinib-induced cardiotoxicity: a retrospective review of the FDA adverse events reporting system (FAERS). JACC: CardioOncology 2019; 1(2): 172-178. 37. Ramalingam S S, Gray J E, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. Ann Oncol 2019; 30: 914-+.

38. Cho BC, Chewaskulyong B, Lee KH et al. Osimertinib versus Standard of Care EGFR TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC: FLAURA Asian Subset. J Thorac Oncol 2019; 14(1):99-106. 39. Zhao Y, Liu J, Cai X, et al. Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis. bmj 2019; 367: l5460. 40. Takeda M, Nakagawa K. First- and Second-Generation EGFR-TKIs Are All Replaced to

Osimertinib in Chemo-Naive EGFR Mutation-Positive Non-Small Cell Lung Cancer? Int J Mol Sci 2019; 20(1):146. 41. Wu SG, Liu YN, Tsai MF et al. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget 2016; 7(11):12404-12413. 42. Ramalingam SS, Cheng Y, Zhou C et al. Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study. In Proceedings of the ESMO 2018 Congress, Munich, Germany, 19-23 October 2018. 43. Ramalingam SS, Yang JC, Lee CK et al. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2018; 36(9):841- 849. 44. Wang J, Chen J. Positive response to Icotinib in metastatic lung adenocarcinoma with acquiring EGFR Leu792H mutation after AZD9291 treatment: a case report. BMC cancer 2019; 19(1): 131. 45. Hosomi Y, Morita S, Sugawara S, et al. Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study. Journal of Clinical Oncology 2019: JCO. 19.01488. 46. Zhou Q, Wu Y L, Cheng Y, et al. 1480O CTONG 1509: Phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR-mutated NSCLC. Ann Oncol 2019, 30(Supplement_5): mdz260. 002.

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).

Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 14, 2020; DOI: 10.1158/1078-0432.CCR-19-3064 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 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)

21-L858R-RD 21-L858R-HD 19-Del-RD p* (n=86) (n=90) (n=77) 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.

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 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4 grade 3-4 23 3 1 0 33 15 0 0 23 5 0 0 Rash 0.34 (26.7%) (3.5%) (1.2%) (36.7%) (16.7%) (29.9%) (6.5%) 19 1 1 0 24 11 2 0 19 7 1 1 Aminotransferase rise 0.77 (22.1%) (1.2%) (1.2%) (26.7%) (12.2%) (2.2%) (24.7%) (9.1%) (1.3%) (1.3%) 9 2 0 0 23 3 0 0 10 2 0 0 Diarrhea NA (10.5%) (2.3%)) (25.6%) (3.3%) (13.0%) (2.6%) 0 4 0 0 5 3 2 0 0 3 2 0 Mucositis 0.18 (0.0%) (4.7%) (5.6%) (3.3%) (2.2%) (0.0%) (3.9%) (2.6%) White blood cell 2 (2.3%) 1 (1.2%) 0 0 3 (3.3%) 0 0 0 0 2 (2.6%) 0 0 NA decreased 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 33 10 4 0 42 26 5 0 32 15 3 1 Any adverse events 0.96 (38.4%) (11.6%) (4.7%) (46.7%) (28.9%) (5.6%) (41.6%) (19.5%) (3.9%) (1.3%) 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.

Assessed for eligibility (n=288) Figure 1

Not meeting inclusion criteria (n=19)

Patients with Exon 19 deletions Patients with Exon 21 L858R mutations (n=83) (n=186) Randomly assigned to treatment

Allocated to routine-dose icotinib (n=83) Allocated to routine-dose icotinib (n= 91) Allocated to high-dose icotinib (n=95) Not treated (n=2) Randomly assigned and not treated (n=2) Randomly assigned and not treated (n=1) Treated with icotinib but no data were available Treated with icotinib but no data were available Treated with icotinib but no data were available (n=4) (n=3) (n=4)

Modified ITT population (n=77) Modified ITT population (n=86) Modified ITT population (n=90)

Lost to follow-up (n=0) Lost to follow-up (n=0) Lost to follow-up (n=0)

Major protocol violation (n=1) Major protocol violation (n=4) Major protocol violation (n=3)

Per-protocol analysis (n=76) Per-protocol analysis (n=82) Per-protocol analysis (n=87)

Figure 2

Figure 3

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

Xi Li, Li Zhang, Da Jiang, et al.

Clin Cancer Res Published OnlineFirst February 14, 2020.

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