- Email: [email protected]
Resolving Resistance to Osimertinib Therapy using Afatinib in a NSCLC Patient with an EGFR L718Q Mutation
Journal Pre-proof Resolving Resistance to Osimertinib Therapy using Afatinib in a NSCLC Patient with an EGFR L718Q Mutation Xue Yang, Chuan Huang, Rongrong Chen, Jun Zhao PII:
S1525-7304(19)30345-6
DOI:
https://doi.org/10.1016/j.cllc.2019.12.002
Reference:
CLLC 1061
To appear in:
Clinical Lung Cancer
Received Date: 8 August 2019 Revised Date:
1 December 2019
Accepted Date: 13 December 2019
Please cite this article as: Yang X, Huang C, Chen R, Zhao J, Resolving Resistance to Osimertinib Therapy using Afatinib in a NSCLC Patient with an EGFR L718Q Mutation, Clinical Lung Cancer (2020), doi: https://doi.org/10.1016/j.cllc.2019.12.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Resolving Resistance to Osimertinib Therapy using Afatinib in a NSCLC Patient with an EGFR L718Q Mutation Xue Yang,1 Chuan Huang,2 Rongrong Chen,3 Jun Zhao1,*
1
Key Laboratory of Carcinogenesis and Translational Research (Ministry of
Education), Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing, China 2
Thoracic Surgery Ward (C05), Beijing Hospital, National Center of Gerontology,
Beijing, China 3
Geneplus-Beijing Institute, Beijing, China
*
Corresponding author
Dr. Jun Zhao, MD, Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China Email: [email protected] Tel.: 86-010-88196456
Conflicts of interest The authors declare no conflicts of interest.
Abstract Objectives: Previous studies have demonstrated EGFR L718Q as one of the resistant mechanisms to osimertinib. In vitro studies showed that EGFR L858R/L718Q mutant cancer cells were sensitive to second-generation EGFR-TKI. However, whether second-generation EGFR-TKI could offer equal therapeutic benefits clinically has not yet been reported. Materials and methods: We performed capture-based sequencing on longitudinal plasma samples and pleural effusion samples obtained at various treatment milestones from an advanced lung adenocarcinoma patient undergoing targeted therapy.
Results: The EGFR-mutant patient underwent disease progression after 14 months of osimertinib administration. Targeted NGS sequencing identified a newly emerged EGFR L718Q mutation with remaining EGFR L858R and loss of T790M. Partial response was achieved one month after commencement of afatinib treatment; however, the patient experienced disease progression four months later with the emergence of a KRAS G12A mutation. Conclusions: To the best of our knowledge, this is the first clinical evidence of afatinib’s efficacy targeting concomitant EGFR L858R and L718Q mutations after osimertinib resistance. We also demonstrate that EGFR L718Q might be a potential resistance mechanism. Key words osimertinib resistance, afatinib, L718Q, loss of T790M 1. Introduction Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant efficacy against tumors with both EGFR-TKI-sensitizing and EGFR T790M-resistant mutations. However, some patients eventually develop resistance with EGFR C797S mutation, which is the most common type of EGFR-resistant mutation. Previous studies showed that EGFR L718Q mutations that emerged concurrently with or without T790M mutations accounted for almost 10% of all cases after osimertinib resistance [1-3]. In vitro studies showed that second-generation EGFR-TKI might overcome osimertinib resistance due to concomitant EGFR L858R/L718Q mutations [4, 5]. Herein we report the first unequivocal clinical evidence that afatinib demonstrated significant efficacy in treating patients with concomitant EGFR L858R and L718Q mutations after osimertinib resistance.
2. Case description Adenocarcinoma in the left lower lung was diagnosed in a 69-year-old female with no history of smoking during a routine check-up. She had no symptoms and underwent palliative surgery in the left lower lung along with multiple pleural metastases (pT2N0M1a stage IV). Because the primary lung adenocarcinoma sample harbored EGFR exon 21 L858R, the patient was treated with gefitinib. She achieved stable
disease (SD) based on the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. However, progressive disease (PD) was then identified with new bone lesions, yielding a progression-free survival (PFS) of 38 months. She thereby underwent percutaneous vertebroplasty of the second lumbar vertebra and four cycles of carboplatin-pemetrexed plus bevacizumab, leading to a PFS of 16 months. A cfDNA analysis found an additional EGFR T790M mutation (allelic fraction, AF=2.0%) besides EGFR L858R (AF=36.5%). Treatment with osimertinib initially reduced ostealgia that persisted for 14 months prior to emerging brain metastases and increased pleural effusion. Since the patient showed no symptoms of brain metastases, such as headache, hemiplegia, or psychiatric conditions at that time, radiotherapy was not included in the treatment regimen. Sequencing of pleural effusion revealed EGFR L858R (AF=76.8%) and EGFR L718Q (AF=10.8%) mutations with loss of EGFR T790M (Figure 1). Afatinib, a second-generation EGFR-TKI, was then administered. Symptoms such as dyspnea and ostealgia significantly improved within the first month, and the diameter of the mediastinal lymph node decreased from 20 to 4 mm, indicating a partial response. The patient again experienced PD four months later (Figure 2) with a KRAS G12A (AF=29.6%) mutation.
Discussion Acquired resistance has always been the Achilles’s heel in EGFR-TKI treatment. Recent
studies
revealed
that
osimertinib
resistance
was
associated
with
EGFR-dependent and diverse EGFR-independent genomic alterations. EGFR L718Q mutation, which accounts for 7.3-9.7% of osimertinib resistance [1-3], is located in the p-loop within the ATP binding site of the EGFR kinase domain. A crystallographic model demonstrated that L718Q mutations can cause steric hindrance, reducing the binding affinity of osimertinib [6]. In vitro studies demonstrated that cells with EGFR L718Q alone may respond to first- and second-generation EGFR-TKIs. Cells simultaneously harboring both EGFR L858R/L718Q variants were resistant to osimertinib and gefitinib but were sensitive to second-generation EGFR TKI afatinib when T790M was lost [4]. In this case, we performed capture-based sequencing on longitudinal plasma samples and pleural effusion samples obtained at various treatment milestones from an
advanced lung adenocarcinoma patient undergoing targeted therapy. When osimertinib resistance developed, T790M disappeared while L858R and L718Q concomitant mutations were detected. Other commonly reported genetic alterations in NSCLC such as TP53 mutations in exon 7 and AKT1 amplification were also detected. As AKT1 amplification per se may result in downstream activation of EGFR signaling, we hypothesize that it might essentially reduce EGFR TKIs efficacy. Previous studies have demonstrated that KRAS mutation is a rarely acquired resistance mechanism to first- and third-generation EGFR-TKIs [3]. In our study, KRAS mutation first appeared after afatinib failure. We therefore presumed that KRAS mutation might be a potential resistance mechanism to afatinib, which might be proved by more comprehensive investigations. In summary, this study reports the first clinical evidence of afatinib’s efficacy targeting concomitant EGFR L858R and L718Q mutations after osimertinib resistance. This will be of considerable value to possibly apply second-generation EGFR-TKI
as
a
promising
and
off-the-shelf
medication
for
selected
osimertinib-resistant patients.
Ethics This study was approved by the institutional ethics review committee of Peking University Cancer Hospital and Institute. The enrolled patient provided written consent for specimen collection, genetic analysis, and information authorization for research and publishing purposes.
Acknowledgments This study was supported by the National Key Research and Development Program of China (2016YFC0904900). We thank Mr. Liang Yang, Dr. Zichen Yu, and all of the referring pathologists and specialists for their contribution to this study.
References 1.
Le X, Puri S, Negrao MV, Nilsson MB, Robichaux J, Boyle T, Hicks JK, Lovinger KL, Roarty E, Rinsurongkawong W, Tang M, Sun H, Elamin Y, Lacerda LC, Lewis J, Roth JA, Swisher SG, Lee JJ, William WN, Jr., Glisson BS, Zhang J, Papadimitrakopoulou VA, Gray JE, Heymach JV. Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC. Clin Cancer Res 2018;24: 6195-6203.
2.
Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, Feeney N, Sholl LM, Dahlberg SE, Redig AJ, Kwiatkowski DJ, Rabin MS, Paweletz CP, Thress KS, Janne PA. Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib. JAMA Oncol 2018;4: 1527-1534.
3.
Yang Z, Yang N, Ou Q, Xiang Y, Jiang T, Wu X, Bao H, Tong X, Wang X, Shao YW, Liu Y, Wang Y, Zhou C. Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small Cell Lung Cancer Patients. Clin Cancer Res 2018;24: 3097-3107.
4.
Ercan D, Choi HG, Yun CH, Capelletti M, Xie T, Eck MJ, Gray NS, Jã¤Nne PA. EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors. Clinical Cancer Research 2015;21: 3913-3923.
5.
Liu Y, Li Y, Ou Q, Wu X, Wang X, Shao YW, Ying J. Acquired EGFR L718V mutation mediates resistance to osimertinib in non-small cell lung cancer but retains sensitivity to afatinib. Lung Cancer 2018;118: 1-5.
Figure legends Figure 1 Dynamic monitoring of EGFR and KRAS mutations during multiple treatment milestones with chemotherapy and EGFR TKIs. A. Clonal evolution during treatment. B. Variant allele frequency (VAF) changes throughout treatment. The Y-axis represents the VAF. The VAF at month 54 was determined from plasma cfDNA and the VAFs at months 68 and 72 was were determined from pleural cfDNA. The time points at which medications were administered and NGS were performed are stated across the X-axis.
Figure 2 Clinical responses to afatinib. The patient achieved PR after one month of afatinib administration and experienced significant improvement in pleural effusion, prior to PD after four months of treatment. PR, partial response; PD: progressive disease.
Clinical practice points Osimertinib, the third generation of EGFR-TKI, can overcome resistance to first or second generation of EGFR-TKI with with secondary T790M mutation. However, limited strategies were available after non-small cell lung cancer (NSCLC) patients developed resistance to osimertinib. Clearance of T790M with concomitant EGFR L858R and L718Q mutation had been reported as one of the mechanisms of osimertinib resistance. Here we report the first case of afatinib treatment after osimertinib resistance, and the patient got a partial response in one month but finally progression of disease due to secondary KRAS mutation. Afatinib may be a promising strategy for NSCLC patients who has concomitant EGFR L858R and L718Q mutation after osimertinib resistance.
S1525-7304(19)30345-6
DOI:
https://doi.org/10.1016/j.cllc.2019.12.002
Reference:
CLLC 1061
To appear in:
Clinical Lung Cancer
Received Date: 8 August 2019 Revised Date:
1 December 2019
Accepted Date: 13 December 2019
Please cite this article as: Yang X, Huang C, Chen R, Zhao J, Resolving Resistance to Osimertinib Therapy using Afatinib in a NSCLC Patient with an EGFR L718Q Mutation, Clinical Lung Cancer (2020), doi: https://doi.org/10.1016/j.cllc.2019.12.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Resolving Resistance to Osimertinib Therapy using Afatinib in a NSCLC Patient with an EGFR L718Q Mutation Xue Yang,1 Chuan Huang,2 Rongrong Chen,3 Jun Zhao1,*
1
Key Laboratory of Carcinogenesis and Translational Research (Ministry of
Education), Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing, China 2
Thoracic Surgery Ward (C05), Beijing Hospital, National Center of Gerontology,
Beijing, China 3
Geneplus-Beijing Institute, Beijing, China
*
Corresponding author
Dr. Jun Zhao, MD, Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China Email: [email protected] Tel.: 86-010-88196456
Conflicts of interest The authors declare no conflicts of interest.
Abstract Objectives: Previous studies have demonstrated EGFR L718Q as one of the resistant mechanisms to osimertinib. In vitro studies showed that EGFR L858R/L718Q mutant cancer cells were sensitive to second-generation EGFR-TKI. However, whether second-generation EGFR-TKI could offer equal therapeutic benefits clinically has not yet been reported. Materials and methods: We performed capture-based sequencing on longitudinal plasma samples and pleural effusion samples obtained at various treatment milestones from an advanced lung adenocarcinoma patient undergoing targeted therapy.
Results: The EGFR-mutant patient underwent disease progression after 14 months of osimertinib administration. Targeted NGS sequencing identified a newly emerged EGFR L718Q mutation with remaining EGFR L858R and loss of T790M. Partial response was achieved one month after commencement of afatinib treatment; however, the patient experienced disease progression four months later with the emergence of a KRAS G12A mutation. Conclusions: To the best of our knowledge, this is the first clinical evidence of afatinib’s efficacy targeting concomitant EGFR L858R and L718Q mutations after osimertinib resistance. We also demonstrate that EGFR L718Q might be a potential resistance mechanism. Key words osimertinib resistance, afatinib, L718Q, loss of T790M 1. Introduction Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant efficacy against tumors with both EGFR-TKI-sensitizing and EGFR T790M-resistant mutations. However, some patients eventually develop resistance with EGFR C797S mutation, which is the most common type of EGFR-resistant mutation. Previous studies showed that EGFR L718Q mutations that emerged concurrently with or without T790M mutations accounted for almost 10% of all cases after osimertinib resistance [1-3]. In vitro studies showed that second-generation EGFR-TKI might overcome osimertinib resistance due to concomitant EGFR L858R/L718Q mutations [4, 5]. Herein we report the first unequivocal clinical evidence that afatinib demonstrated significant efficacy in treating patients with concomitant EGFR L858R and L718Q mutations after osimertinib resistance.
2. Case description Adenocarcinoma in the left lower lung was diagnosed in a 69-year-old female with no history of smoking during a routine check-up. She had no symptoms and underwent palliative surgery in the left lower lung along with multiple pleural metastases (pT2N0M1a stage IV). Because the primary lung adenocarcinoma sample harbored EGFR exon 21 L858R, the patient was treated with gefitinib. She achieved stable
disease (SD) based on the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. However, progressive disease (PD) was then identified with new bone lesions, yielding a progression-free survival (PFS) of 38 months. She thereby underwent percutaneous vertebroplasty of the second lumbar vertebra and four cycles of carboplatin-pemetrexed plus bevacizumab, leading to a PFS of 16 months. A cfDNA analysis found an additional EGFR T790M mutation (allelic fraction, AF=2.0%) besides EGFR L858R (AF=36.5%). Treatment with osimertinib initially reduced ostealgia that persisted for 14 months prior to emerging brain metastases and increased pleural effusion. Since the patient showed no symptoms of brain metastases, such as headache, hemiplegia, or psychiatric conditions at that time, radiotherapy was not included in the treatment regimen. Sequencing of pleural effusion revealed EGFR L858R (AF=76.8%) and EGFR L718Q (AF=10.8%) mutations with loss of EGFR T790M (Figure 1). Afatinib, a second-generation EGFR-TKI, was then administered. Symptoms such as dyspnea and ostealgia significantly improved within the first month, and the diameter of the mediastinal lymph node decreased from 20 to 4 mm, indicating a partial response. The patient again experienced PD four months later (Figure 2) with a KRAS G12A (AF=29.6%) mutation.
Discussion Acquired resistance has always been the Achilles’s heel in EGFR-TKI treatment. Recent
studies
revealed
that
osimertinib
resistance
was
associated
with
EGFR-dependent and diverse EGFR-independent genomic alterations. EGFR L718Q mutation, which accounts for 7.3-9.7% of osimertinib resistance [1-3], is located in the p-loop within the ATP binding site of the EGFR kinase domain. A crystallographic model demonstrated that L718Q mutations can cause steric hindrance, reducing the binding affinity of osimertinib [6]. In vitro studies demonstrated that cells with EGFR L718Q alone may respond to first- and second-generation EGFR-TKIs. Cells simultaneously harboring both EGFR L858R/L718Q variants were resistant to osimertinib and gefitinib but were sensitive to second-generation EGFR TKI afatinib when T790M was lost [4]. In this case, we performed capture-based sequencing on longitudinal plasma samples and pleural effusion samples obtained at various treatment milestones from an
advanced lung adenocarcinoma patient undergoing targeted therapy. When osimertinib resistance developed, T790M disappeared while L858R and L718Q concomitant mutations were detected. Other commonly reported genetic alterations in NSCLC such as TP53 mutations in exon 7 and AKT1 amplification were also detected. As AKT1 amplification per se may result in downstream activation of EGFR signaling, we hypothesize that it might essentially reduce EGFR TKIs efficacy. Previous studies have demonstrated that KRAS mutation is a rarely acquired resistance mechanism to first- and third-generation EGFR-TKIs [3]. In our study, KRAS mutation first appeared after afatinib failure. We therefore presumed that KRAS mutation might be a potential resistance mechanism to afatinib, which might be proved by more comprehensive investigations. In summary, this study reports the first clinical evidence of afatinib’s efficacy targeting concomitant EGFR L858R and L718Q mutations after osimertinib resistance. This will be of considerable value to possibly apply second-generation EGFR-TKI
as
a
promising
and
off-the-shelf
medication
for
selected
osimertinib-resistant patients.
Ethics This study was approved by the institutional ethics review committee of Peking University Cancer Hospital and Institute. The enrolled patient provided written consent for specimen collection, genetic analysis, and information authorization for research and publishing purposes.
Acknowledgments This study was supported by the National Key Research and Development Program of China (2016YFC0904900). We thank Mr. Liang Yang, Dr. Zichen Yu, and all of the referring pathologists and specialists for their contribution to this study.
References 1.
Le X, Puri S, Negrao MV, Nilsson MB, Robichaux J, Boyle T, Hicks JK, Lovinger KL, Roarty E, Rinsurongkawong W, Tang M, Sun H, Elamin Y, Lacerda LC, Lewis J, Roth JA, Swisher SG, Lee JJ, William WN, Jr., Glisson BS, Zhang J, Papadimitrakopoulou VA, Gray JE, Heymach JV. Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC. Clin Cancer Res 2018;24: 6195-6203.
2.
Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, Feeney N, Sholl LM, Dahlberg SE, Redig AJ, Kwiatkowski DJ, Rabin MS, Paweletz CP, Thress KS, Janne PA. Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib. JAMA Oncol 2018;4: 1527-1534.
3.
Yang Z, Yang N, Ou Q, Xiang Y, Jiang T, Wu X, Bao H, Tong X, Wang X, Shao YW, Liu Y, Wang Y, Zhou C. Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small Cell Lung Cancer Patients. Clin Cancer Res 2018;24: 3097-3107.
4.
Ercan D, Choi HG, Yun CH, Capelletti M, Xie T, Eck MJ, Gray NS, Jã¤Nne PA. EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors. Clinical Cancer Research 2015;21: 3913-3923.
5.
Liu Y, Li Y, Ou Q, Wu X, Wang X, Shao YW, Ying J. Acquired EGFR L718V mutation mediates resistance to osimertinib in non-small cell lung cancer but retains sensitivity to afatinib. Lung Cancer 2018;118: 1-5.
Figure legends Figure 1 Dynamic monitoring of EGFR and KRAS mutations during multiple treatment milestones with chemotherapy and EGFR TKIs. A. Clonal evolution during treatment. B. Variant allele frequency (VAF) changes throughout treatment. The Y-axis represents the VAF. The VAF at month 54 was determined from plasma cfDNA and the VAFs at months 68 and 72 was were determined from pleural cfDNA. The time points at which medications were administered and NGS were performed are stated across the X-axis.
Figure 2 Clinical responses to afatinib. The patient achieved PR after one month of afatinib administration and experienced significant improvement in pleural effusion, prior to PD after four months of treatment. PR, partial response; PD: progressive disease.
Clinical practice points Osimertinib, the third generation of EGFR-TKI, can overcome resistance to first or second generation of EGFR-TKI with with secondary T790M mutation. However, limited strategies were available after non-small cell lung cancer (NSCLC) patients developed resistance to osimertinib. Clearance of T790M with concomitant EGFR L858R and L718Q mutation had been reported as one of the mechanisms of osimertinib resistance. Here we report the first case of afatinib treatment after osimertinib resistance, and the patient got a partial response in one month but finally progression of disease due to secondary KRAS mutation. Afatinib may be a promising strategy for NSCLC patients who has concomitant EGFR L858R and L718Q mutation after osimertinib resistance.