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Central nervous system efficacy of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small cell lung cancer: a pooled analysis from two phase 2 studies

BMC Medicine volume 21, Article number: 164 (2023) Cite this article

Abstract

Background

Furmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies.

Methods

This was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1.

Results

A total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4–8.3), 11.6 months (95% CI 8.3–13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively.

Conclusions

Furmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC.

Trial registration

Both studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018.

Peer Review reports

Background

Epidermal growth factor receptor (EGFR) sensitizing mutations were the most frequent driven alterations detected in non-small cell lung cancer (NSCLC), especially in Asian patients with lung adenocarcinoma [1, 2]. Treatment with first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) had prolonged the median progression-free survival (PFS) to 9.2–14.7 months in EGFR mutated advanced NSCLC patients [3,4,5,6,7], which was superior to chemotherapy and changed the treatment landscape of NSCLC dramatically. Nevertheless, resistance would inevitably occur and the most common reason for first- and second-generation EGFR TKI treatment failure was a secondary EGFR T790M mutation.

Several covalent pyrimidine-based third-generation EGFR TKIs such as osimertinib and rociletinib were developed to act against EGFR T790M mutation [8, 9]. Osimertinib was the first approved third-generation EGFR TKI for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR 19Del or L858R mutations and for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR TKI therapy by the US Food and Drug Administration (FDA) [10,11,12,13].

Brain metastases (BM) were commonly reported in patients with NSCLC and were associated with poor survival outcomes [14]. Compared with unselected patients, NSCLC patients with EGFR sensitizing mutations were found to have a higher incidence of BM [15]. Therefore, it is crucial to develop EGFR TKIs with central nervous system (CNS) activity and to evaluate the CNS efficacy in clinical studies irrespective of treatment lines.

Furmonertinib (AST2818) is a brain penetrant pan-EGFR TKI developed by Shanghai Allist Pharmaceuticals Co., Ltd, Shanghai, China. It has a trifluoroethoxypyridine-based molecule structure and can irreversibly inhibit EGFR T790M mutation with high selectivity [16]. In preclinical studies, the concentration of furmonertinib and its main active metabolite in the brain was higher than that in the plasma, indicating that furmonertinib had the potential to treat CNS metastases [16]. In a phase 2b study, the CNS objective response rate (ORR) of furmonertinib 80 mg orally once daily in EGFR T790M mutated NSCLC patients was 66% and the median CNS-PFS was 11.6 months [17]. In the phase 3 FURLONG study, furmonertinib was associated with higher PFS and CNS-PFS compared with gefitinib in EGFR sensitizing mutation positive, untreated, CNS metastatic patients [18, 19]. These data had demonstrated the CNS efficacy of furmonertinib 80 mg orally once daily, but the evidence of other doses for CNS metastases was lacking. Here we report the CNS efficacy of different doses of furmonertinib in EGFR T790M mutated, CNS metastatic NSCLC patients, along with the exploratory genetic analysis. FURLONG study was excluded in this analysis because it was a first-line study (patients with common EGFR sensitizing mutations without T790M mutation), whereas the pooled analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]) was focused on furmonertinib in pre-treated patients with T790M mutation.

Methods

Study design and procedures

This was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). Both studies were open-label, single-arm, multi-center study, which conducted in 14 and 46 hospitals in the People’s Republic of China, respectively. Eligible patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily in the phase 2a study and received furmonertinib 80 mg orally once daily in the phase 2b study, both until disease progression or any other cessation criterion was met.

Blood samples were collected at baseline and six weeks after treatment for exploratory genetic analysis. The genetic analysis was done with next-generation sequencing (NGS, Tongshu Biotech, Shanghai, China), a target panel of 556 genes with mean sequencing depths of more than 7000 times, detailed information could be found in a previous publication [17].

Patients

For detailed information on patient inclusion and exclusion criteria, please refer to two previous publications by Shi Y et al. [16, 17]. Briefly, eligible patients in both studies were aged at least 18 years old, with locally advanced or metastatic NSCLC diagnosed histologically or cytologically, had measurable diseases as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had radiologically documented disease progression on first- or second-generation EGFR TKIs, with EGFR T790M mutation confirmed using tumor tissue by the central lab, with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2. Patients with asymptomatic, stable CNS metastases which did not require steroids for four weeks or more before the first dose of furmonertinib were allowed for enrolment.

Assessments

Tumor assessments were done every six weeks for the first 48 weeks, and then every 12 weeks until disease progression. Baseline brain scans (computerized tomography or magnetic resonance imaging) were mandated for all patients at study entry. Subsequent brain imaging was required with the same method used at baseline when clinically indicated and in patients with confirmed CNS metastases.

The patients with baseline CNS metastases according to an independent review center (IRC) constituted this analysis. Patients were grouped based on the doses of furmonertinib. The endpoints in this report included CNS-ORR, CNS disease control rate (DCR), CNS-PFS, and CNS duration of response (DoR) of each group. Patients with measurable or non-measurable CNS lesions were defined as CNS full analysis set (cFAS). Patients with measurable CNS lesions were defined as CNS evaluable-for-response set (cEFR). All the CNS measurements were assessed by an IRC according to the RECIST version 1.1.

CNS-ORR was defined as the proportion of patients who achieved complete response (CR) or partial response (PR) in CNS lesions with subsequent confirmation. CNS-DCR was defined as the proportion of patients who were assessed as CR, PR, or stable disease in CNS lesions. CNS-PFS was defined as the time from the date of the first dose of furmonertinib to the date of documented CNS disease progression or death with any reason, whichever came first. CNS-DoR was defined as the time from the date of first documented CNS-ORR to the date of CNS disease progression or all-cause death, whichever came first.

An exploratory analysis of circulating tumor DNA (ctDNA) was also conducted to reveal more biological information during the study. The analysis included qualitative detection of biomarkers in ctDNA at baseline, plasma EGFR T790M mutation clearance rate after six weeks of treatment, and their predictive roles in CNS efficacy of furmonertinib.

Statistical analysis

The determination of sample size of the two studies could be found in published articles by Shi Y et al. [16, 17]. In this pooled analysis, the CNS-ORR and CNS-DCR were calculated on the basis of the confirmed best response of CNS lesions during the study, and the two-sided confidence intervals (CIs) were performed with Clopper-Person exact method. For time-to-event endpoints (CNS-PFS and CNS-DoR), Kaplan–Meier method was used to determine the median values and corresponding two-sided 95% CIs. Hazard ratios (HRs) of CNS-PFS were calculated using COX proportional hazards model, corresponding p values and two-sided 95% CIs were calculated using Wald test. All the statistical analyses were done with SAS (version 9.4, SAS Institute Inc., Cary, NC, USA).

Results

Patients

A total of 116 patients were enrolled in the phase 2a study from June 1, 2017 to July 24, 2018, of which 45 (39%) patients with CNS metastases at baseline were included in this analysis. Two hundred and twenty patients were enrolled in the phase 2b study from June 4 to December 8 in 2018, and 87 (40%) patients with CNS metastatic at baseline were analyzed in this report. In total, 132 patients with measurable or non-measurable CNS lesions constituted the cFAS and 52 patients with measurable CNS lesions were included in the cEFR population. In the cFAS, three patients received furmonertinib 40 mg orally once daily, 99 patients received furmonertinib 80 mg orally once daily, 23 patients received furmonertinib 160 mg orally once daily, and seven patients received furmonertinib 240 mg orally once daily. In the cEFR, the numbers of patients who were assigned to the groups of furmonertinib 40 mg, 80 mg, 160 mg, and 240 mg orally once daily were one, 34, 13, and four, respectively (Fig. 1). Fifty-five per cent (72/132) of the patients had more than three CNS lesions at baseline. Detailed patient baseline characteristics in the cFAS were shown in Table 1.

Fig. 1
figure 1

Study flowchart of furmonertinib. CNS, central nervous system. cFAS, CNS full analysis set. cEFR, CNS evaluable-for-response set

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Table 1 Patients’ baseline characteristics in the cFAS
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Efficacy

The data cut-off date of this analysis was January 29, 2020. The median follow-up time was 13.5 months (range 0.1–26.1). In the cEFR population, CNS objective response was achieved in zero, 22 (65%), 11 (85%), and one (25%) patient(s) while CNS disease control was documented in zero, 33 (97%), 13 (100%), and four (100%) patient(s) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively (Table 2, Fig. 2A). The only patient who was assessed as progressive disease (PD) as the best response in CNS lesions was in the lowest dose group (40 mg orally once daily group). The benefit of CNS objective response was consistent in different subgroups (Fig. 2B). In nine patients received brain radiotherapy owing to CNS metastases before enrolment, CNS-ORR was 56% and CNS-DCR was 100%. The median CNS-DoR was 9.7 months (95% CI 6.9-not available [NA]) in the 80 mg orally once daily group and not reached (NR) in the 160 mg and 240 mg orally once daily group, respectively (Fig. 3A). The proportion of patients estimated to be remaining in response at 12 months after the onset of response was 42.6% (95% CI 19.6–64.0%), 88.9% (95% CI 43.3–98.4%), and 100% (95% CI 100–100%) in the 80 mg, 160 mg, and 240 mg orally once daily group, respectively.

Table 2 Best CNS response in the cEFR population
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Fig. 2
figure 2

A Waterfall plot for the best percentage change of furmonertinib in CNS lesions in the cEFR. The dashed lines at 20% and -30% indicate the thresholds for PD and PR, respectively. One patient in 80 mg orally once daily group was not evaluable. B Forest plot of subgroup of patients having objective response of furmonertinib in the cEFR. The reference line at 65% represented the overall CNS-ORR. CNS, central nervous system. cEFR, CNS evaluable-for-response set. PD, progressive disease. PR, partial response. ORR, objective response rate. DCR, disease control rate. CI, confidence interval. EGFR, epidermal growth factor receptor

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Fig. 3
figure 3

CNS-DoR and CNS-PFS in each group of furmonertinib. A CNS-DoR in the cEFR; B CNS-PFS in the cFAS. CNS, central nervous system. DoR, duration of response. PFS, progression-free survival. cEFR, CNS evaluable-for-response set. cFAS, CNS full analysis set. NA, not available. NR, not reached. CI, confidence interval

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In the cFAS population, three (100%), 53 (54%), eight (35%), and one (14%) patient(s) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group had progressed in CNS lesions or died at the data cut-off date, respectively. The corresponding median CNS-PFS was 2.8 months (95% CI 1.4–8.3), 11.6 months (95% CI 8.3–13.8), 19.3 months (95% CI 5.5-NA), and NR (95% CI 2.8 months-NA), respectively (Fig. 3B). CNS-PFS rate at 12 months was 0, 50% (95% CI 38–60%), 64% (95% CI 37–82%), 86% (95% CI 33–98%) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively.

Exploratory analysis

Of the 132 patients with CNS metastases at baseline enrolled in the phase 2a and 2b studies, 119 patients provided plasma samples for ctDNA testing, and 93 (78%) of these patients were at 80 mg orally once daily dose. Ninety-nine (83%) patients harboured plasma gene alterations in addition to EGFR mutations, including six (5%) patients with tumor suppressor gene (PTEN, TP53, or RB1) mutations and 93 (78%) patients with oncogenic driver gene (ALK, BRAF, ERBB2, KRAS, MET, RET, or ROS1) alterations or amplificated EGFR irrespective of tumor suppressor gene mutations. The median CNS-PFS was 11.6 months (95% CI 8.4–13.8) in patients with additional plasma gene alterations and NR (95% CI 9.9 months-NA) in patients who harboured only plasma EGFR mutations (HR 2.21 [95% CI 0.95–5.17], p = 0.06; Fig. 4A) based on all doses. In the 80 mg orally once daily group (n = 93), the median CNS-PFS was 10.5 months (95% CI 8.3–13.7) and NR (95% CI 9.9 months-NA) in patients with and without additional plasma gene alterations, respectively (HR 2.40 [95% CI 1.02–5.64], p = 0.04; Fig. 4B).

Fig. 4
figure 4

CNS-PFS of patients with and without additional plasma gene alterations at baseline. A All doses of furmonertinib; B Eighty mg orally once daily of furmonertinib. Plasma gene alterations in addition to EGFR mutations including tumor suppressor gene (PTEN, TP53, or RB1) mutations and oncogenic driver gene (ALK, BRAF, ERBB2, KRAS, MET, RET, ROS1, or amplificated EGFR) alterations. CNS, central nervous system. PFS, progression-free survival. CI, confidence interval. NR, not reached. NA, not available. HR, hazard ratio

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Among the 119 patients who underwent ctDNA detection at baseline, 84 (71%) patients were plasma EGFR T790M mutation positive. Among these 84 patients, their ctDNA was re-evaluated after six weeks of treatment. The plasma EGFR T790M mutation was undetectable in 71 (85%) patients at week six (Additional file 1: Figure S1). The clearance rates of plasma EGFR T790M mutation were similar between different doses, except for the not-calculatable result in the 40 mg orally once daily group (Additional file 2: Table S1). Among the 84 patients with detectable EGFR T790M at baseline, their median CNS-PFS was 13.2 months (n = 71, 95% CI 8.4–19.3) in patients with plasma EGFR T790M mutation cleared and 10.5 months (n = 13, 95% CI 8.4-NA) in patients still harbouring plasma EGFR T790M mutation after six weeks of treatment (HR 0.87 [95% CI 0.37–2.08], p = 0.77; Additional file 3: Figure S2).

Discussion

In this post-hoc, pooled analysis of two phase 2 studies, furmonertinib 80–240 mg orally once daily was effective in treating CNS metastatic NSCLC patients with EGFR T790M mutation. Numerically better response and longer median CNS-PFS were observed in patients treated by furmonertinib 160 mg orally once daily with limited cases, which warranted further investigation.

CNS metastases represented a risk factor for poor prognosis in EGFR mutated NSCLC patients treated with first- or second-generation EGFR TKIs [20]. Third-generation EGFR TKIs were effective in treating EGFR T790M mutated NSCLC, but the median PFS and median overall survival (OS) of CNS metastatic patients were still shorter compared with patients without CNS metastases. In a pooled analysis of AURA extension and AURA2 studies, the median PFS treated with osimertinib was 8.2 months (95% CI 6.9–9.7) in CNS metastatic group and 12.4 months (95% CI 9.8–13.8) in CNS non-metastatic group. Similarly, the median OS was 20.3 months (95% CI 17.5–23.6) in CNS metastatic patients and 30.7 months (95% CI 27.5–36.4) in CNS non-metastatic patients [21]. In the phase 3 AURA3 study, the median PFS with osimertinib was 8.5 months (95% CI 6.8–12.3) in CNS metastatic patients and 10.8 months (95% CI 8.3–12.5) in CNS non-metastatic patients [11]. The median OS with osimertinib was 19.2 months (95% CI 16.1–24.3) in patients with CNS metastases and 31.8 months (95% CI 26.6–35.9) in patients without CNS metastases [22]. These results indicated that there were unmet medical needs in EGFR T790M mutated, CNS metastatic NSCLC patients.

Several studies explored higher doses or dose escalations of EGFR TKIs to enhance the disease management of CNS metastases. A phase 1 study showed that pulse/continuous-dose erlotinib (1200 mg on days 1–2 and 50 mg on days 3–7 weekly) produced a 75% CNS response rate in EGFR mutated lung cancer patients with untreated brain metastases [23]. In the BLOOM study, osimertinib 160 mg orally once daily resulted in a leptomeningeal lesions ORR of 62% and a median PFS of 8.6 months in treated EGFR mutated NSCLC with leptomeningeal metastases [24]. In a subcohort analysis with 11 patients from a phase 2 study, the dose escalation of osimertinib to 160 mg orally once daily post intracranial progression on osimertinib 80 mg orally once daily still showed a 54% intracranial response rate and a median intracranial PFS of 8.1 months [25]. Two other reports also indicated the potential of dose escalation of osimertinib in the treatment of CNS progression after the failure on standard dose [26, 27]. Our analysis added to the evidence for the CNS efficacy of higher dose of EGFR TKIs in CNS metastatic, EGFR mutated NSCLC patients. However, all of these studies should be interpreted with caution due to the small sample size or the post-hoc or retrospective nature, and larger prospective studies are warranted. Several studies are ongoing to further investigate the efficacy of higher doses of furmonertinib (NCT05465343, NCT05379803) and aumolertinib (NCT04870190) in patients with CNS metastases.

The predictive role of baseline plasma gene alterations in addition of EGFR mutations was explored in some studies. The BENEFIT study showed that EGFR mutated NSCLC patients with concurrent alterations of tumor-suppressor genes or oncogenes were associated with shorter median PFS when treated with gefitinib [28]. In the phase 2b study of furmonertinib, median PFS was numerically shorter in patients with additional gene alterations besides EGFR mutations (including tumor suppressor genes [TP53, RB1, or PTEN], oncogenes [ALK, MET, ERBB2, KRAS, BRAF, RET, ROS1, or amplificated EGFR]) than those without at baseline [17]. Similarly, this analysis showed poor predictive effects of accompanying plasma gene alterations on CNS-PFS in patients with EGFR T790M mutated NSCLC, indicating that additional gene alterations could also be a potential biomarker in CNS efficacy analysis.

The clearance of plasma EGFR T790M mutation after treatment was supposed to predict a better outcome in EGFR mutated NSCLC patients. In the osimertinib arm of the AURA3 study, median PFS was significantly longer in patients with plasma EGFR mutation clearance at week three than those without (10.9 months [95% CI 8.3–12.7] versus 5.7 months [95% CI 4.1–9.7], HR 0.5 [95% CI 0.3–0.8], p = 0.0022) [29]. In the FLAURA study, patients with non-detectable plasma EGFR mutations at week three also showed meaningfully longer median PFS than those detected (13.5 months [95% CI 11.1–15.2] versus 9.5 months [95% CI 7.0–10.9], HR 0.57 [95% CI 0.4–0.7], p < 0.0001) [30]. However, these studies did not evaluate the relationship between plasma EGFR mutation clearance and CNS outcomes. In this analysis, after six weeks of treatment with furmonertinib, plasma EGFR T790M clearance was tested and 85% (71/84) patients with plasma EGFR T790M clearance did not show a superior CNS-PFS than those without. Additionally, although patients taking higher doses of furmonertinib seemed to have better CNS clinical outcomes, the plasma EGFR T790M clearance rate was similar in different groups. These results indicated that plasma EGFR T790M clearance might not serve as a predictive biomarker in CNS efficacy of furmonertinib and the possible mechanisms warranted further exploration.

There were some limitations of this report. First, this was a post-hoc analysis which did not exam the statistical difference among different groups, and whether higher doses of furmonertinib could bring better outcomes required further investigation. Second, the efficacy of furmonertinib 240 mg orally once daily did not show a promising ORR possibly due to the small sample size, although the median CNS-PFS was NR with furmonertinib 240 mg orally once daily, and all the patients with 160 mg or 240 mg orally once daily furmonertinib achieved CNS disease control. Third, the definition of CNS-PFS in this pooled post-hos analysis was consistent with previous published CNS analysis of third-generation EGFR TKIs including AURA extension and AURA2 pooled [31], FLAURA [32], FURLONG [19], however, the observed treatment benefit in the CNS-PFS analysis might be influenced as patients did not continue to receive brain scans following disease progression (irrespective of site of progression) or discontinuation from study with no CNS progression or death were censored at date last evaluable CNS assessment.

Conclusions

In summary, this is an analysis reporting the CNS efficacy of furmonertinib with different doses in EGFR T790M mutated NSCLC patients and reveals that furmonertinib of 80 mg orally once daily or higher is effective in CNS metastatic patients. The higher dose of furmonertinib is promising in treating CNS metastases and several studies are ongoing.

Availability of data and materials

The data underlying this article will be shared on reasonable request to the corresponding author.

Abbreviations

EGFR:

Epidermal growth factor receptor

TKI:

Tyrosine kinase inhibitor

CNS:

Central nervous system

NSCLC:

Non-small cell lung cancer

NA:

Not available

PFS:

Progression-free survival

FDA:

Food and Drug Administration

BM:

Brain metastases

ORR:

Objective response rate

NGS:

Next-generation sequencing

RECIST:

Response Evaluation Criteria in Solid Tumors

ECOG:

Eastern Cooperative Oncology Group

PS:

Performance status

IRC:

Independent review center

DCR:

Disease control rate

DoR:

Duration of response

cFAS:

CNS full analysis set

cEFR:

CNS evaluable-for-response set

CR:

Complete response

PR:

Partial response

ctDNA:

Circulating tumor DNA

CI:

Confidence interval

HR:

Hazard ratios

PD:

Progressive disease

NR:

Not reached

OS:

Overall survival

NE:

Not evaluated

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Acknowledgements

We thank the patients and their families who participated in this study, all the hospitals that contributed to patient recruitment, and participating study teams. Medical writing assistance for this manuscript was provided by Anna Yao from Medical Insight funded by Shanghai Allist Pharmaceuticals Co., Ltd, Shanghai, China. We thank Dr. Liling Huang and Dr. Tongji Xie (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College) for editorial assistance.

Funding

These two studies (NCT03127449 and NCT03452592) were funded by Shanghai Allist Pharmaceuticals Co., Ltd, Shanghai, China and partly supported by China National Major Project for New Drug Innovation (2017ZX09304015, 2018ZX09301014009, and 2019ZX09201-002). Shanghai Allist Pharmaceuticals Co., Ltd, Shanghai, China provided furmonertinib and collaborated with academic authors regarding the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, Beijing, 100021, China

    Xingsheng Hu & Yuankai Shi

  2. Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Oncology Institute, Beijing, China

    Shucai Zhang

  3. Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, China

    Zhiyong Ma

  4. Department of Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China

    Jifeng Feng

  5. Thoracic Medicine Department II, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

    Lin Wu

  6. Department of Respiratory Medicine, Taizhou Hospital of Zhejiang Province, Taizhou, China

    Dongqing Lv

  7. Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Jianying Zhou

  8. Department of Medical Oncology, Nantong Cancer Hospital, Nantong, China

    Xiaodong Zhang

  9. Department of Thoracic Oncology, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Li Liu

  10. Department of Respiratory Oncology, Guangxi Medical University Affiliated Tumor Hospital, Nanning, China

    Qitao Yu

  11. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Wangjun Liao

  12. Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China

    Yiping Zhang

  13. Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou, China

    Xiang Wang

  14. Department of Oncology, Jilin Cancer Hospital, Changchun, China

    Ying Cheng

  15. Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China

    Hongrui Niu

  16. Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing, China

    Ziping Wang

  17. Department of Oncology, Army Medical Centre of People’s Liberation Army, Chongqing, China

    Dong Wang

  18. Department of Oncology, Fujian Cancer Hospital, Fuzhou, China

    Cheng Huang

  19. Department of Pulmonary Medicine, Cancer Hospital of Xinjiang Medical University, Urumqi, China

    Chunling Liu

  20. Department of Respiratory and Critical Care Medicine, The Second Hospital of Anhui University, Hefei, China

    Hui Zhao

  21. Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong, China

    Jian Feng

  22. Department of Oncology, Liuzhou People’s Hospital, Liuzhou, China

    Jingzhang Li

  23. Department of Respiratory Medicine, Sir Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China

    Kejing Ying

  24. Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

    Nong Yang

  25. The People’s Liberation Army Cancer Center, Jinling Hospital, Nanjing, China

    Shukui Qin

  26. Shanghai Allist Pharmaceutical Technology Co., Ltd, , Shanghai, China

    Jie Hu, Fei Liu, Yong Jiang & Nan Ge

Authors
  1. Xingsheng Hu
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  2. Shucai Zhang
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  30. Yuankai Shi
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Contributions

YS and YJ were responsible for the conceptualization, methodology, software and validation. YS, XH, SZ, ZM, JF1 (Jifeng Feng), LW, DL, JZ, XZ, LL, QY, WL, YZ, XW, YC, HN, ZW, DW, CH, CL, HZ, JF2 (Jian Feng), JL, KY, NY and SQ were responsible for data curation, investigation and resources. YS, JH, FL, YJ and NG were responsible for formal analysis. YS, JH, FL and YJ were responsible for supervision and project administration. YS, FL and NG wrote the original draft. All authors contributed to and approved the final version of the manuscript.

Corresponding author

Correspondence to Yuankai Shi.

Ethics declarations

Ethics approval and consent to participate

Both studies were conducted in accordance with the Good Clinical Practice guidelines and the Declaration of Helsinki. Studies were approved by the institutional review board of the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (approval number of phase 2a study of furmonertinib: 17–057/1312, approval number of phase 2a study of furmonertinib: 18–008/1472), along with all participating institutions. Written informed consent forms were obtained from each patient before enrolment.

Consent for publication

Not applicable.

Competing interests

JH, FL, YJ and NG are employees and shareholders of Shanghai Allist Pharmaceuticals Co., Ltd, Shanghai, China. No other competing interests were reported.

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Supplementary Information

Additional file 1: Figure S1.

VAF of plasma EGFR T790M mutation at baseline and at week six.

Additional file 2: Table S1.

Plasma EGFR T790M mutation clearance after six weeks of treatment.

Additional file 3: Figure S2.

Central nervous system progression-free survival of patients with and without plasma EGFR T790M mutation clearance after six weeks of treatment.

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Hu, X., Zhang, S., Ma, Z. et al. Central nervous system efficacy of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small cell lung cancer: a pooled analysis from two phase 2 studies. BMC Med 21, 164 (2023). https://doi.org/10.1186/s12916-023-02865-z

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Keywords

BMC Medicine

ISSN: 1741-7015

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