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Clin Cancer Res
Clin Cancer Res
Clinical Cancer Research
1078-0432
1557-3265
American Association for Cancer Research

34740925
CCR-21-2595
10.1158/1078-0432.CCR-21-2595
Version of Record
Clinical Trials: Targeted Therapy
A Novel Third-generation EGFR Tyrosine Kinase Inhibitor Abivertinib for EGFR T790M-mutant Non–Small Cell Lung Cancer: a Multicenter Phase I/II Study
Efficacy and Safety of Abivertinib in Patients with T790M+ NSCLC
https://orcid.org/0000-0002-0478-176X
Zhou Qing 1
https://orcid.org/0000-0001-7078-7767
Wu Lin 2
Hu Pei 3
An Tongtong 4
Zhou Jianying 5
Zhang Li 6
Liu Xiao-Qing 7
Luo Feng 8
Zheng Xin 3
Cheng Ying 9
Yang Nong 10
Li Junling 11
Feng Jifeng 12
https://orcid.org/0000-0002-6251-3771
Han Baohui 13
Song Yong 14
Wang Kai 15
Zhang Li 16
Fang Jian 4
Zhao Hong 17
Shu Yongqian 18
Lin Xiao-Yan 19
Chen Zhihong 1
Gan Bin 1
Xu Wan-Hong 20
Tang Wei 20
Zhang Xiaoying 20
Yang Jin-Ji 1
Xu Xiao 21
https://orcid.org/0000-0002-3611-0258
Wu Yi-Long 1*
1 Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
2 Department of Medical Oncology, Second Chest Cancer Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
3 Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
4 Department of Thoracic Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
5 Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
6 Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
7 Department of Lung Cancer, Fifth Medical Center of PLA General Hospital, Beijing, China.
8 Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, China.
9 Division of Thoracic Oncology, Jilin Provincial Cancer Hospital, Changchun, China.
10 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.
11 Department of Medical Oncology, China National Cancer Center/China Cancer Research Foundation/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
12 The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China.
13 Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
14 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
15 Department of Respiratory Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
16 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
17 Oncology Department, Chinese PLA General Hospital, Beijing, China.
18 Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
19 Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, China.
20 ACEA Pharmaceutical Research, Hangzhou, China.
21 ACEA Therapeutics Inc., San Diego, California.
Trial Registration ID: NCT02330367

Prior presentation: Abstracts were accepted in World Conference on Lung Cancer, December 3–8, 2016 and American Society of Clinical Oncology, May 31- June 4, 2019; a poster was presented in American Society of Clinical Oncology, Chicago, 2019.

* Corresponding Author: Yi-Long Wu, Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, No.106 Zhongshan 2nd Road, Guangzhou 510080, China. Phone: 208-387-7855; E-mail: syylwu@live.cn
15 3 2022
14 3 2022
28 6 11271135
16 7 2021
13 9 2021
01 11 2021
©2021 The Authors; Published by the American Association for Cancer Research
2021
American Association for Cancer Research
https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.

Abstract

Purpose:

To establish recommended phase II dose (RP2D) in phase I and evaluate safety and efficacy of abivertinib in patients with EGFR Thr790Met point mutation (T790M)-positive(+) non–small cell lung cancer (NSCLC) with disease progression from prior EGFR inhibitors in phase II.

Patients and Methods:

This multicenter, open-label study included 367 adult Chinese patients. Abivertinib at doses of 50 mg twice a day to 350 mg twice a day was evaluated in phase I in continual 28-day cycles, and the RP2D of 300 mg twice a day was used in phase II in continual 21-day cycles. Primary endpoints include RP2D in phase I and objective response rate (ORR) at RP2D in phase II.

Results:

The RP2D of 300 mg twice a day for abivertinib was established based on pharmacokinetics, efficacy, and safety profiles across doses in phase I. In phase II, 227 patients received RP2D for a median treatment duration of 24.6 weeks (0.43–129). Among 209 response–evaluable patients, confirmed ORR was 52.2% [109/209; 95% confidence interval (CI): 45.2–59.1]. Disease control rate (DCR) was 88.0% (184/209; 95% CI: 82.9–92.1). The median duration of response (DoR) and progression-free survival (PFS) was 8.5 months (95% CI: 6.1–9.2) and 7.5 months (95% CI: 6.0–8.8), respectively. The median overall survival (OS) was 24.9 months [95% CI: 22.4–not reachable (NR)]. All (227/227) patients reported at least 1 adverse event (AE), with 96.9% (220/227) of treatment-related AEs. Treatment-related serious AEs were reported in 13.7% (31/227) of patients. Death was reported in 4.4% (10/227) of patients, and none was deemed as treatment-related.

Conclusions:

Abivertinib of 300 mg twice a day demonstrated favorable clinical efficacy with manageable side effects in patients with EGFR T790M+ NSCLC.

Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer 2017B030314120 High-level Hospital Construction Project DFJH201810 National Science and Technology Infrastructure Program National Key Science Projects Program 2018ZX09301–014–002
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pmcTranslational Relevance

This phase I/II study, investigation of the novel third-generation EGFR tyrosine kinase inhibitor (TKI) abivertinib in 367 Chinese patients with advanced EGFR Thr790Met point mutation (T790M)-positive(+) non–small cell lung cancer (NSCLC), is the first clinical study conducted in the Chinese patients at a large scale to investigate the clinical benefits of abivertinib. Current phase I/II design facilitated immediate recommended phase II dose (RP2D) assessments in an expanded patient population. Abivertinib demonstrated favorable efficacy and tolerable safety profiles in patients.

Introduction

... 

Discussion

This phase I/II study, investigation of the novel third-generation EGFR-TKI abivertinib in 367 Chinese patients with advanced NSCLC, is the first clinical study conducted in the Chinese patients at a large scale to investigate the clinical benefits of abivertinib. In phase I, 300 mg twice a day was selected as the RP2D based on favorable efficacy outcomes and a safety profile comparable with that observed at lower doses with greater steady-state PK parameters. The safety and efficacy of the 300 mg twice a day dose and schedule was further demonstrated in phase II with 227 patients. Abivertinib at 300 mg twice a day was generally well tolerated, with the most common AEs being liver transferase elevation, diarrhea, and rash, which are common with approved EGFR-TKIs and other investigational third-generation agents (9, 15–17). At the dose of 300 mg twice a day, abivertinib treatment resulted in ORR (52.2%) and DCR (88.0%) with significant DoR (8.5 months), PFS (7.5 months), and OS (24.9 months) in patients with EGFR T790M mutation. A substantial efficiency gain in abivertinib efficacy and safety evaluations is obtained by using this two-phase study design, of which a modified three-plus-three dose escalation scheme allowed quick cohort expansion and RP2D determination which was not dependent on MTD of the drug, and also this phase I/II design seamlessly facilitated immediate RP2D assessments in an expanded patient population with less toxicity and favorable efficacy.

Abivertinib demonstrated efficacious effects in overcoming T790M-mediated resistance with the ORR of 52.2%, which is comparable with other third-generation EGFR-TKIs as reported ORRs in the range between 42% and 67% from different studies (10, 15–18). Of the patients included in this study, about 30 had brain metastases. The ORRs for patients with brain metastases or without brain metastasis were 50.0% and 52.5%, respectively and among 159 patients with disease progression, 24.5% of patients were progressed in the CNS as their primary site. Given that the sample size of the patients with brain metastases in this study was small, and the cerebrospinal fluid concentration of the drug has not be systematically analyzed, the efficacy of abivertinib in patients with brain metastases is inconclusive and further study will be warranted. In phase II, abivertinib treatment demonstrated promising effects in PFS and OS with a median PFS of 7.5 months and a median OS of 24.9 months (40% maturity). The subsequent treatment after disease progression includes chemotherapy, rechallenging EGFR-TKIs and Chinese traditional medicines, etc.

In this study with Chinese patients, grade ≥ 3 AE AST/ALT increase occurred more frequently while grade ≥ 3 QT interval prolongation was observed at a similar frequency compared with data previously reported for other TKIs (2–4, 9, 19). However, the majority or AST/ALT increase AEs were mild (grade 1 in severity) and 2 AEs led to treatment discontinuation. The risk factors analysis reflected a relative actual situation for Chinese patients who had a more complicated medication history. The skin rash rate (37% for all grades and 2.2% for grade 3/4) was lower than many first- and second-generation TKIs reported (>70% for all grades and >15% for grade 3/4) probably due to spare target against WT EGFR by abivertinib treatment (2–4). ILD, a warning AE for all TKIs, occurred in 4.8% (13/272) at RP2D in this study; 11 cases (4.0%) were SAEs; 10 cases (3.7%) were grade ≥ 3; one case (0.4%) was fatal. Two cases with grade 2/3 ILD among above 13 cases were re-treated with abivertinib at reduced doses when ILD was recovered to grade 1 till disease progression, suggesting ILD is still controllable by abivertinib treatment. Together, abivertinib treatment in this study demonstrated favorable efficacy and safety profiles in patients with NSCLC patients with EGFR—resistant T790M mutation.

Abivertinib is a pyrrolpyrimidine-based, third-generation EGFR-TKI which is structurally distinct from FDA only approved third-generation TKI osimertinib (12). The molecular structure of a drug may determine its target-binding properties, subsequently the clinical outcomes, and ultimately molecular mechanism upon drug resistance. In recent clinical and nonclinical studies, resistance mechanism of abivertinib was reported to be distinct from that reviewed with osimertinb. Off-target resistance mechanisms involving TP53, MET, ERBB2, and RB1, etc. are thought to be the common resistance mechanisms found by abivertinib treatment as reported from current phase I/II study (43.3%, 13/30 cases; ref. 20), first-in-human study (62.5%, 10/16 cases; ref. 13), and nonclinical studies (BCL-2 and c-MET amplification from in vitro and in vivo results, respectively; ref. 21). EGFR tertiary mutations (8.7%, 4/30 from phase I/II and 0/16 from first-in-human resistance patients) including C797S by abivertinib treatment are much less than osimertinib resistance reported (21%–45%; refs. 13, 20). Moreover, EGFR T790M loss with abivertinib resistance (9.3%, 4/27 from phase I/II and 0/16 from first-in-human resistance patients) was less frequent than reported in osimertinib resistance cohorts (42%–68%), indicating that potential combination therapy, such as abivertinib in combination with drugs targeting bypass pathways, might be explored to overcome the resistance to abivertinib (13, 20). An impressive response was reported in several patients receiving sequential treatment firstly with abivertinib and followed by osimertinib, which suggests that rechallenging third-generation EGFR-TKIs with distinct resistance profile might warrant clinical benefits in patients failed with a third-generation EGFR-TKI (22).

In summary, phase I established abivertinib 300 mg twice a day as RP2D, which is consistent with that previously reported in abivertinib first-in-human study. The clinical efficacy of abivertinib coupled with its safety profile in phase II further confirmed positive clinical outcomes in patients with EGFR T790M+ resistant mutation. Whether the clinical benefits to abivertinib can be expanded in patients with EGFR-TKI–naïve advanced NSCLC will be evaluated in a randomized trial in comparison with gefitinib. In addition, further research into mechanism of acquired resistance with abivertinib and other third-generation EGFR-TKIs and strategies of subsequent treatment will help define the use of these agents in this setting.

Supplementary Material

Supplementary Data Click here for additional data file.

Acknowledgments

This research was supported by Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Y.L. Wu); High-level Hospital Construction Project (Grant No. DFJH201810, to Q. Zhou); and National Science and Technology Infrastructure Program (National Key Science Projects Program, Grant No. 2018ZX09301–014–002, to W.H. Xu, W. Tang, X. Zhang, and X. Xiao).

This study was funded by ACEA Pharmaceutical Research, Hangzhou, China. ACEA Pharmaceutical Research led the design and conduct of the study, monitored it, and provided the study drug. ACEA Pharmaceutical Research, with authors, also participated in the collection, management, analysis, and interpretation of the data. We appreciate the patients, their families, and caregivers for their participation in the study. Medical writing support was provided by Yiqun Zhou, PhD, EME Pharma Consultants, funded by ACEA Therapeutics Inc.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Authors' Disclosures

Q. Zhou reports personal fees from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly and Company, MSD, Pfizer, Sanofi, and Roche outside the submitted work. Y.L. Wu reports grants, personal fees, and other support from AstraZeneca; grants and personal fees from BMS; personal fees and other support from Boehringer Ingelheim and Merck; personal fees from Eli Lilly and Company, Hengrui, MSD, Pfizer, Roche, and Sanofi; and other support from Takeda outside the submitted work. No disclosures were reported by the other authors.

Authors' Contributions

Q. Zhou: Conceptualization, resources, investigation, writing–original draft, writing–review and editing. L. Wu: Resources, investigation, writing–review and editing. P. Hu: Resources, investigation, writing–review and editing. T. An: Resources, investigation, writing–review and editing. J. Zhou: Resources, investigation, writing–review and editing. L. Zhang: Resources, investigation, writing–review and editing. X.Q. Liu: Resources, investigation, writing–review and editing. F. Luo: Resources, investigation, writing–review and editing. X. Zheng: Resources, investigation, writing–review and editing. Y. Cheng: Resources, investigation, writing–review and editing. N. Yang: Resources, investigation, writing–review and editing. J. Li: Resources, investigation, writing–review and editing. J. Feng: Resources, investigation, writing–review and editing. B. Han: Resources, investigation, writing–review and editing. Y. Song: Resources, investigation, writing–review and editing. K. Wang: Resources, investigation, writing–review and editing. L. Zhang: Resources, investigation, writing–review and editing. J. Fang: Resources, investigation, writing–review and editing. H. Zhao: Resources, investigation, writing–review and editing. Y. Shu: Resources, investigation, writing–review and editing. X.Y. Lin: Resources, investigation, writing–review and editing. Z. Chen: Resources, investigation, writing–review and editing. B. Gan: Resources, investigation, writing–review and editing. W.H. Xu: Resources, investigation, writing–review and editing. W. Tang: Resources, investigation, writing–review and editing. X. Zhang: Resources, investigation, writing–review and editing. J.J. Yang: Resources, investigation, writing–review and editing. X. Xu: Resources, investigation, writing–review and editing. Y.L. Wu: Conceptualization, resources, investigation, writing–original draft, writing–review and editing.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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