Real-world Afatinib Outcomes in Advanced Non–small Cell Lung Cancer Harboring EGFR Mutations

et al. 2022

Ther Adv Respir Dis

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Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatments for advanced EGFR-mutated non–small cell lung cancer (NSCLC) patients. Osimertinib is an effective therapy for NSCLC patients with acquired resistance due to T790M mutation after first- and second-generation EGFR-TKI treatment. This study aimed to analyze the clinical outcomes of sequential therapy following first-line EGFR-TKIs and the predictive factors of an acquired T790M mutation. Methods: Between January 2014 and December 2018, data from 2190 advanced NSCLC patients with common EGFR mutations (exon 19 deletion and L858R) receiving first- and second-generation EGFR-TKIs in Linkou, Kaohsiung, Chiayi and Keelung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed. Results: Until August 2021, among 1943 patients who experienced progressive disease, 526 underwent T790M mutation tests, and their T790M-positive rate was 53.6%. Exon 19 deletion mutation and progression-free survival (PFS) of >12 months were positively associated with secondary T790M mutation. Different first-line first- and second-generation EGFR-TKI therapies did not affect the appearance of acquired T790M mutations. The median overall survival (OS) was 58.3 [95% confidence interval (CI): 49.0–67.5] months among the patients with T790M mutation who received second-line osimertinib therapy compared with 31.0 (95% CI: 27.5–34.5) months among the patients without T790M mutation who received chemotherapy alone. The multivariate analysis showed that a poor performance status (score: >2), nonadenocarcinoma histology, stage IV cancer, liver metastasis, brain metastasis, PFS while on first-line EGFR-TKIs, and subsequent chemotherapy without third-generation EGFR-TKIs were significant independent unfavorable prognostic factors for OS. Conclusion: This study demonstrated the efficacy of first-line EGFR-TKIs and sequential osimertinib therapy. The results of our study suggest that T790M mutation tests are important for the use of subsequent osimertinib, which yielded favorable survival outcomes.

Section: Discussionmentioning

confidence: 99%

Sequential treatment in advanced non–small cell lung cancer harboring EGFR mutations

Hsu

et al. 2022

Ther Adv Respir Dis

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“…In a previous study, 36.8% of the 36 patients with negative T790M upon the first biopsy showed positive T790M mutation in the second re-biopsy [ 28 ], indicating the benefit of repeated biopsy. In addition, comprehensive genetic testing with a combination of tissue and liquid biopsies can enrich the positive rate for detecting the T790M mutation [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…All 172 study patients were obtained from the Chang Gung Research Database [ 17 , 18 , 19 , 20 ], which is an integrated database with multi-institutional standardized electronic medical records from all branches of Chang Gung Memorial Hospital (CGMH) in Taiwan, including information from the cancer registry. This study included the clinical data of patients from the cancer registry in the Linkou, Kaohsiung, Keelung, and Chiayi branches of CGMH from 2010 to 2018.…”

Section: Methodsmentioning

confidence: 99%

Impact of T790M Mutation Status on Later-Line Osimertinib Treatment in Non-Small Cell Lung Cancer Patients

Tang

et al. 2022

Cancers

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) designed to overcome acquired T790M resistance mutations in non-small cell lung cancer (NSCLC). However, the efficacy of osimertinib in patients without acquired T790M mutations has not been well studied. This study aimed to evaluate the efficacy of osimertinib in patients treated with first- and second-generation EGFR-TKIs followed by later-line osimertinib treatment. Patients: The clinical data and survival outcomes of 172 patients with advanced NSCLC treated with osimertinib following frontline EGFR-TKIs at Chang Gung Memorial Hospital from 2014 to 2018 were retrospectively reviewed. T790M mutations were detected using tissue sequencing and/or liquid biopsy. Results: A total of 172 EGFR-mutated NSCLC patients treated with frontline EGFR-TKI therapy followed by later-line osimertinib were enrolled in the current study and divided into three groups based on the T790M status (positive, negative, or unknown T790M). Patients with NSCLC harboring acquired T790M mutation treated with osimertinib had the best objective response rate (ORR) (52.6%, 25.0%, and 32.0%, p = 0.044), disease control rate (DCR) (79.3%, 41.7%, and 68.0%, p = 0.011), and progression-free survival (PFS, median PFS, 12.6, 3.1, 10.4 months, p = 0.001) among the three groups (positive, negative, and unknown T790M, respectively). However, a marked difference was found between positive and negative T790M mutations but not between positive and unknown T790M mutations. Univariate analysis was performed to identify potential prognostic factors for PFS in 172 patients treated with osimertinib. Lung metastasis (p < 0.001), brain metastasis (p < 0.009), number of metastatic sites (p < 0.001), PFS with frontline EGFR-TKIs (p = 0.03), and T790M status (p = 0.006) were identified as prognostic factors for PFS with osimertinib. Multivariate analysis showed that lung metastasis (p < 0.001) and PFS with frontline EGFR-TKIs and T790M status were independent prognostic factors. Conclusion: This study confirmed the greater efficacy of later-line osimertinib for NSCLC with acquired T790M mutation than for NSCLC without acquired T790M mutation. Detection of the T790M mutation after frontline treatment (first- and second-generation EGFR-TKI) is crucial for prolonging the survival of NSCLC patients harboring EGFR mutation. Osimertinib may be considered an option for NSCLC with unknown T790M mutations, as a certain subpopulation may benefit from osimertinib.

“…Acquired resistance to EGFR-TKI therapies typically develops while the patient is receiving an EGFR-TKI and after a documented response or evidence of disease control [ 25 ]. Among resistance-inducing genes, the EGFR T790M is a rare mutation known to have an important clinical impact and has been identified as the most common mechanism for acquired resistance to EGFR-TKIs, observed in nearly two-thirds of cases that progress following successful EGFR-TKI therapy [ 26 , 27 ]. The poor therapeutic response to EGFR-TKIs is associated with the high allelic frequency of the T790M EGFR mutation [ 28 , 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

EGFR T751_I759delinsN Mutation in Exon19 Detected by NGS but Not by Real-Time PCR in a Heavily-Treated Patient with NSCLC

Chan

2022

IJMS

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The detection of driver gene mutations can determine appropriate treatment strategies for non-small cell lung cancer (NSCLC) by identifying the presence of an effective druggable target. Mutations in the gene encoding the epidermal growth factor receptor (EGFR) are common driver mutations in NSCLC that can be effectively targeted by the use of EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, without the detection of driver mutations, appropriate therapeutic decisions cannot be made. The most commonly applied methods for detecting driver gene mutations are assays based on polymerase chain reaction (PCR). However, the underlying mechanism of PCR-based assays limits the detection of rare mutations. Therefore, patients harboring rare mutations may not receive optimal treatment. We report a heavily-treated patient with NSCLC who harbored a T751_I759delinsN mutation in exon 19 of EGFR that was not detected by real-time PCR but was successfully detected by next-generation sequencing (NGS). The detection of a driver mutation using NGS resulted in the administration of targeted therapy, leading to favorable progression-free survival for the patient. Our report highlights the importance and potential of routine NGS testing among NSCLC patients for whom traditional assays fail to detect driver mutations when determining treatment options.