Osimertinib In Non-small Cell Lung Cancer Patients Research Articles

The impact of EGFR T790M mutation status following the development of Osimertinib resistance on the efficacy of Osimertinib in non-small cell lung cancer: A meta-analysis.

Previous studies have suggested that loss of the EGFR T790M gene mutation may contribute to the development of resistance to Osimertinib in non-small cell lung cancer (NSCLC). This study aims to assess the relationship between the clinical effectiveness of Osimertinib in NSCLC patients and the T790M mutation status following resistance to Osimertinib and examine differences between plasma and tissue tests and between Asian and non-Asian groups. The PubMed, Web of Science, Cochrane, and EMBASE databases were comprehensively searched for studies on the association between T790M mutation status and the efficacy of Osimertinib between January 2014 and November 2023. Meta-analysis was carried out using Review Manager 5.4 software. After evaluating 2727 articles, a total of 14 studies were included in the final analysis. Positive correlations between EGFR T790M mutation status after Osimertinib resistance and longer PFS (HR: 0.44, 95% CI: 0.30-0.66), longer OS (HR: 0.3, 95% CI: 0.10-0.86), longer TTD (HR: 0.69, 95% CI: 0.45-1.07), and improved clinical outcomes including PFS and TTD subgroups (HR: 0.58, 95% CI: 0.47-0.73) were observed. Subgroup analysis revealed that, compared with the blood tests, the results of the T790M mutation tests by the tissue are more significant (HR: 0.24, 95% CI: 0.11-0.52 for tissue tests; HR: 0.47, 95% CI: 0.22-1.00 for plasma tests), and the PFS of Osimertinib were similar for Asian and non-Asian patients (HR: 0.46, 95% CI: 0.31-0.68 for Asians; HR: 0.12, 95% CI: 0.01-1.27 for non-Asians). Persistence of the T790M gene mutation after the development of Osimertinib resistance is associated with higher therapeutic benefits of Osimertinib in NSCLC patients. The results of tissue detection are more significant than those of plasma detection.

Simultaneous Quantitation of Anlotinib and Osimertinib by Isotope-Labeled UHPLC-MS/MS in Human Plasma: Application in NSCLC Patients.

Anlotinib and osimertinib are a class of tyrosine kinase inhibitors for the treatment of malignant tumor. The combination of anlotinib and osimertinib is currently used for treating non-small cell lung cancer (NSCLC) patients. This study aimed to develop a simple and rapid isotope-labeled UHPLC-MS/MS method for the simultaneous determination of anlotinib and osimertinib in human plasma. The analytes were extracted by protein precipitation with acetonitrile and were then separated on a Shim-pack GIST C18 column. The detection was performed on Shimadzu 8050 triple quadruple mass spectrometer in the positive electrospray ionization mode with multiple reaction monitoring. The precursor-to-product ion transitions were m/z 408.10→339.75, 500.25→72.20 and 413.50→344.50 for anlotinib, osimertinib and D5-anlotinib, respectively. Validation is based on US Food and Drug Administration guidelines. The linearity ranges were 0.5-100ng/mL for anlotinib and were 1-500ng/mL for osimertinib with the correlation coefficients (r 2) ≥ 0.99. Accuracy and precision, matrix effect, extraction recovery and stability of anlotinib and osimertinib were acceptable after validation. The UHPLC-MS/MS method was successfully validated and was applied to monitor the concentration of anlotinib and osimertinib in NSCLC patients.

1050P Association of ctDNA quantification with prognosis and early prediction of response to first-line osimertinib in NSCLC patients

Osimertinib is the new standard of care in epidermal growth factor receptor (EGFR)-mutated non-pretreated advanced non-small-cell lung cancer (NSCLC). The MELROSE study, a multicentric, open label, phase II trial (NCT03865511) was designed to identify resistance mechanisms at the time of disease progression in treatment-naive EGFR-mutated NSCLC patients receiving osimertinib. While these analyses are in progress, we explored secondary endpoints including ctDNA analysis.

Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer.

Simple SummaryOsimertinib is a third-generation EGFR tyrosine kinase inhibitor and the standard of care therapy for non-small cell lung cancer patients harboring EGFR-activating mutations. However, even for patients treated with osimertinib, resistance inevitably occurs leading to disease progression. Here, we utilized two osimertinib-resistant cell lines and investigated their RNA profiles. We found that Ras-related protein Rab-32 (RAB32) and thrombospondin 1 (THBS1) were upregulated and associated with resistance in osimertinib-resistant cells as well as in liquid biopsies from patients with disease progression following osimertinib treatment. Moreover, we found RAB32 and THBS1 to be mechanistically linked to activation of the focal adhesion pathway where combination of osimertinib with a FAK inhibitor resulted in a synergistic suppression of viability of osimertinib-resistant cells. Our findings propose a potential therapeutic strategy for overcoming acquired resistance to osimertinib in non-small cell lung cancer.Treatment with the tyrosine kinase inhibitor (TKI) osimertinib is the standard of care for non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR). Osimertinib is also used in T790M-positive NSCLC that may occur de novo or be acquired following first-line treatment with other EGFR TKIs (i.e., gefitinib, erlotinib, afatinib, or dacomitinib). However, patients treated with osimertinib have a high risk of developing resistance to the treatment. A substantial fraction of the mechanisms for resistance is unknown and may involve RNA and/or protein alterations. In this study, we investigated the full transcriptome of parental and osimertinib-resistant cell lines, revealing 131 differentially expressed genes. Knockdown screening of the genes upregulated in resistant cell lines uncovered eight genes to partly confer resistance to osimertinib. Among them, we detected the expression of Ras-related protein Rab-32 (RAB32) and thrombospondin 1 (THBS1) in plasmas sampled at baseline and at disease progression from EGFR-positive NSCLC patients treated with osimertinib. Both genes were upregulated in progression samples. Moreover, we found that knockdown of RAB32 and THBS1 reduced the expression of phosphorylated focal adhesion kinase (FAK). Combination of osimertinib with a FAK inhibitor resulted in synergistic toxicity in osimertinib-resistant cells, suggesting a potential therapeutic drug combination for overcoming resistance to osimertinib in NSCLC patients.

P28-11 The therapeutic efficacy of osimertinib in non-small cell lung cancer with malignant pleural effusion

Osimertinib is one of the standard first-line therapies for epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, little is known about the clinical efficacy of osimertinib in NSCLC patients with malignant pleural effusion (MPE). Here, we evaluated the efficacy of osimertinib on these patients in the first line setting.

Combination of Bevacizumab and Osimertinib in Patients with EGFR T790M-Mutated Non-small Cell Lung Cancer.

Osimertinib may improve the prognosis of patients with epidermal growth factor receptor (EGFR) T790M-mutated non-small cell lung cancer (NSCLC); however, to date, the efficacy and safety of osimertinib plus bevacizumab have not been elucidated. We aimed to investigate the additional effect of bevacizumab plus osimertinibcompared withosimertinib alone in NSCLC patients with EGFR T790M mutation. In this study, 32 patients received osimertinib alone, while 20 patients received osimertinib plus bevacizumab. The median follow-up was 12 months. Overall survival (OS) and progression-free survival (PFS) were estimated and adverse events (AEs) were compared. The overall response rate (ORR) was higher in the combination group than in the osimertinib-alone group (70.0% vs. 43.8%), and the OS (12.8%±7.7% vs. 45.4%±12.0%; p=0.038) and PFS (37.3%±11.9% vs. 55.3%±14.3%; p=0.045) were also significantly improved in patients who underwent osimertinib plus bevacizumab. Furthermore, the incidence of hypertension was significantly higher in the combination arm when compared with osimertinib alone (p=0.003), and the number of other AEs were not significantly increased by adding bevacizumab (all p>0.05). Concomitant use of bevacizumab and osimertinib in NSCLC patients with EGFR T790M mutation may have potential therapeutic effect than osimertinib alone. Further studies with a larger number of patients are warranted to confirm results ofthisstudy.

DDRE-04. EFFECTIVENESS AND SAFETY OF OSIMERTINIB FOR PATIENTS WITH LEPTOMENINGEAL METASTASES FORM NON-SMALL CELL LUNG CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract BACKGROUND the FLAURA study established Osimertinib to be the priority choice for the treatment of metastatic non-small cell lung cancer (NSCLC) harboring mutated epidermal growth factor receptor (EGFR). However, like many previous studies, the FLAURA study excluded patients with symptomatic CNS metastases. Hence, we performed a systematic review and meta-analyses of studies to assess the efficiency and safety of Osimertinib for the treatment of NSCLC with leptomeningeal metastases (LM). METHODS We included studies published between 2010 and 2021 that evaluated the efficacy and toxicity of Osimertinib in NSCLC patients with LM. We searched PubMed, Embase, and oncology meeting abstracts (ASCO, ESMO and WCLC). Primary outcomes were objective response rate (ORR), disease control rate (DCR), any grade 3/4 toxicity rate. We used the random-effects model to generate pooled estimates for proportions. Newcastle-Ottawa Scale (NOS) was used to assess the certainty in the evidence. RESULTS Twelve studies reporting on 367 patients were included in the meta-analysis. Most patients (≥90%) received Osimertinib as at least second line of treatment. The objective response rate was 42% (95% CI, 24%-59%; n = 184), and CNS disease control rate was 90% (95% CI, 85%-94%; n = 154). Intracranial progression free survival and overall survival ranged from 3.7 to 15.6 months, and 11.0 to 18.8 months, respectively. Adverse events were similar with previous studies and Common Terminology Criteria for Adverse Events (version 3.0) grade 3 or higher adverse event rates was acceptable. CONCLUSION This meta-analysis confirmed that for advanced NSCLC with LM harboring EGFR-TKI-sensitizing mutations, Osimertinib showed impressive antitumor activity and acceptable toxicity.

Abstract CT106: Phase I/II study of osimertinib in EGFR exon 20 insertion mutations in non-small cell lung cancer patients: AEX20

Abstract Background EGFR exon 20 insertion gene mutation (ex20ins) accounts for about 4-12% of the total EGFR gene mutations in non-small cell lung cancer (NSCLC) patients. NSCLC patients with EGFR ex20ins is known to be less sensitive to 1st- or 2nd-generation EGFR-TKIs. Although 3rd-generation EGFR-TKI, osimertinib is active against in vitro models of EGFR ex20ins, its efficacy has not yet been fully elucidated. This phase I/II study is conducted to evaluate the clinical efficacy of osimertinib in NSCLC patients with EGFR ex20ins. Method This is a single-arm, multi-center, open-label, non-randomized phase I/II study (UMIN000031929) consisting of stage 1 and stage 2 (Simon's two-stage design). In stage 1, 12 patients receive osimertinib 80mg once daily until they meet the termination criteria, such as, disease progression, severe toxicities, withdrawal etc. In stage 2, 9 patients receive the same dose of osimertinib if more than 1 patient achieve PR or CR in stage 1. At the transition from stage 1 to 2, Independent Data Monitoring Committee (IDMC) will provide recommendation regarding the need for study continuation, termination or dose modification of osimertinib. Patients with advanced or metastatic NSCLC with EGFR ex20ins who have a history of chemotherapy within 0 to 3 regimens are enrolled. Patients with history of EGFR-TKI treatment (gefitinib, erlotinib, afatinib, dacomitinib) can be included if the EGFR-TKI treatment did not show any clinical benefit. Patients with EGFR gene mutations, such as exon 19 deletion, L858R, T790M, G719X, L861Q are excluded. Primary end point is objective response rate (ORR) assessed via Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points are progression-free survival, overall survival, and safety profiles. Blood sampling is obtained at 4-weeks after starting osimertinib to analyze pharmacokinetic parameters. We also perform liquid biopsy for next generation sequencing at before and after acquiring resistance to osimertinib to clarify resistant mechanisms of osimertinib in EGFR ex20ins. We explore the relationship among clinical outcome, side effect, pharmacokinetic parameters and subtype of EGFR ex20ins. Result Recruitment began in June 2018 and by February 2020, 12 patients were enrolled in stage 1 at 6 institutions. Backgrounds of the patients were as follows, the median age was 63 years (range 22-84), female/male 6/6, ECOG PS 0/1 8/4, cStage IIIA/IIIb/IVA/IVB 1/1/2/8. The ORR was 0% (CR/PR 0, SD 8, PD 4), and the DCR was 66.7%. From the result of stage 1, one of the IDMC's recommendations was protocol revision since it is presumed that increasing the dose of osimertinib could be clinically promising. At the conference, the influence of subtype of EGFR ex20ins and blood levels of osimertinib on survival will be evaluated and the results of interim analysis for stage 1 will be presented. Conclusion Regular dose of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. Funding AstraZeneca. Citation Format: Eiki Ichihara, Hiroyuki Yasuda, Yuta Takashima, Yoshitaka Zenke, Shinji Takeuchi, Masahiro Morise, Katsuyuki Hotta, Mineyoshi Sato, Shingo Matsumoto, Azusa Tanimoto, Reiko Matsuzawa, Katsuyuki Kiura, Hideki Terai, Shinnosuke Ikemura, Koichi Goto, Kenzo Soejima. Phase I/II study of osimertinib in EGFR exon 20 insertion mutations in non-small cell lung cancer patients: AEX20 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT106.

Molecular characteristics of EGFR exon 20 uncommon R776H mutation and response to osimertinib in NSCLC patients.

e21001 Background: EGFR R776H is an uncommon exon 20 mutation in non-small cell lung cancer (NSCLC) patients. This mutation was first reported in samples after first generation EGFR TKI treatment as an acquired resistant mutation to first generation of EGFR-TKI. We further analyzed the molecular characteristics of patients with EGFR R776H mutation and its correlation with EGFR TKI therapy. Methods: In this study, a total of 16131 NSCLC patients from multiple centers with NGS data were retrospectively analyzed to study the molecular characteristics and clinical outcomes of patients with EGFR R776H mutation. Results: 44 of the 16131 patients (0.27%) had EGFR R776H mutation, and 28 of them (63.6%) were treatment-naïve while performing the mutation test. TP53 was the most common concomitant mutation in both treatment-naïve (57.1%) and treated (81.3%) patients. EGFR R776H mutation was found to coexist with multiple types EGFR mutation. The common mutations were EGFR L858R (54%) and EGFR G719A/S (25%), but It almost never coexists with 19del (2%). The coexist of EGFR R776H mutation was similar in both treatment-naïve and treated patients. In 16 of treated patients, all had received first - or second-generation EGFR TKI treatment, and the median progression-free survival (PFS) was 9 months. Interestingly, four of them found the presence of not only EGFR R776H but also EGFR T790M. It may be that EGFR R776H and T790M appear together in drug resistance, or it may be that EGFR R776H and EGFR sensitive mutation are not in the same cell clone. Two patients with EGFR R776H received treatment of Osimertinib and achieved partial response. The PFS of two patients in Osimertinib were 11 and 10 months, respectively. Moreover, EGFR C797S mutation was detected in two patients after resistant to Osimertinib. Conclusions: Presence of EGFR R776H mutation was rare in NSCLC patients and our retrospective study provides clinical evidence that Osimertinib could be of benefit and may potentially be an effective treatment strategy to improve survival outcomes in patients with EGFR R776H.

Association between BIM Deletion Polymorphism and Efficacy of Osimertinib in Advanced EGFR T790M NSCLC Patients

BCL-2-like 11 (BIM) deletion polymorphism (BIM-del) has been found to be associated with resistance to first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, and is a poor prognostic factor for non-small-cell lung cancer (NSCLC) patients with EGFR mutations. Nevertheless, the impact of the BIM-del in advanced EGFR T790M NSCLC patients treated with third-generation EGFR-TKI, osimertinib, remains undetermined. The aim of this study is to explore the relationship among BIM-del and therapeutic efficacy of osimertinib in NSCLC patients with EGFR T790M. We totally recruited 137 Chinese Han NSCLC patients with EGFR T790M receiving osimertinib treatment from December 2015 to December 2019. Peripheral blood samples from these patients were collected to detect BIM-del by polymerase chain reaction. Clinical outcomes among patients with and without BIM-del were analyzed by Cox proportional hazards models. BIM-del was detected in 17.5% of all patients (24/137). The majority of patients were no more than 60 years (66%, 91/137), female (57%, 78/137), never smokers (81%, 111/137), ECOG performance status (PS) 0-1 (91%, 124/137), and had central nervous system (CNS) metastases (55%, 75/137). There were no associations between the BIM-del and clinical characteristics including age, sex, histology, smoking status, stage, ECOG PS score, and CNS metastases. Patients with BIM-del had a poor objective response rate compared to those without (29% vs. 57%, P = 0.012). BIM-del was associated with shorter progress free survival (PFS) and overall survival (OS). (PFS, 8.3 vs. 10.4 months, P = 0.042; OS, 14.8 vs. 23.4 months, P = 0.005). Multivariate analysis indicated that BIM-del was the independent prognostic factor for both PFS and OS in NSCLC patients with EGFR T790M receiving osimertinib. BIM-del was associated with inferior efficacy and may serve as a negative predictive biomarker to osimertinib in EGFR T790M NSCLC patients. Genotype analysis of the BIM-del in EGFR mutant patients may be helpful for guiding appropriate treatment.

The Status of the EGFR T790M Mutation is associated with the Clinical Benefits of Osimertinib Treatment in Non-small Cell Lung Cancer Patients: A Meta-Analysis.

Background and Purpose: Pervious studies have demonstrated that the loss of EGFR T790M after Osimertinib treatment may be the cause of Osimertinib resistance. Here, we conducted a meta-analysis to evaluate the association between the persistence of EGFR T790M and the clinical benefits of Osimertinib in non-small cell lung cancer (NSCLC) patients with baseline EGFR T790M mutation.Experimental design and Methods: PUBMED, EMBASE, and Cochrane databases were searched for eligible studies that provided the survival outcomes including overall survival (OS), progression-free survival (PFS) or time to discontinuation (TTD) data for each patient treated with Osimertinib with the status of the T790M mutation tested after Osimertinib resistance. The hazard ratios (HRs) and their 95% confidence intervals (CI) were calculated for each study.Results: In total, eight eligible studies were included in the analysis, among which six studies provided the data on PFS, and the other two studies provided the TTD data. Overall, 312 patients (151 patients with the persistence of T790M) were identified. The persistence of T790M was associated with longer PFS (HR, 0.40; 95% CI, 0.19-0.84; P=0.01) and TTD (HR, 0.54; 95% CI, 0.39-0.76; P=0.0004). Furthermore, overall analysis the survival outcomes including PFS and TTD subgroups also showed preferable clinical benefits for patients with the T790M persistence (HR, 0.57; 95%CI, 0.45-0.73; P<0.00001).Conclusions: Our findings confirm the persistence of T790M is associated with the clinical benefits of Osimertinib in NSCLC patients with baseline EGFR T790M mutation treated with Osimertinib.

Comprehensive analysis of EGFR T790M detection by ddPCR and ARMS-PCR and the effect of mutant abundance on the efficacy of osimertinib in NSCLC patients

Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations often develop systemic disease progression during treatment with EGFR-tyrosine kinase inhibitors (TKIs). Droplet digital polymerase chain reaction (ddPCR) and amplification refractory mutation system (ARMS)-PCR are routinely applied for detection of EGFR mutations, including T790M, which is associated with TKI sensitivity. We compared the efficiency of ddPCR and ARMS-PCR in detecting T790M and explored the association between T790M abundance and osimertinib efficacy. Genomic DNA (gDNA) from tissue and cells in hydrothorax and circulating tumor DNA (ctDNA) from peripheral blood (PB), and clinicopathological data were retrospectively collected from 263 patients who visited Sun Yat-sen University Cancer Center for T790M test. Mean T790M abundance and mutant copy number of cases tested positive by both methods, i.e., the ddPCR+ARMS+ group (19.1%, 636.9), were higher than those in the ddPCR+ARMS- group (0.36%, 12.1), suggesting that ddPCR is more sensitive in detecting samples with low mutant abundance than ARMS-PCR. T790M detection rate was comparable for gDNA and ctDNA samples (44.7% vs. 37.6%, P=0.242); however, gDNA sample tended to show more T790M abundance in ddPCR analysis. T790M coexisted with L858R mutation (8/11) more than with deletions in exon 19 (19del) mutation (3/11) in TKI-naive tumors, while 19del co-occurred as often as L858R in post-TKI tumors. T790M+ patients benefited more from osimertinib and showed longer progression-free survival (PFS) (not achieved vs. 10.1 months, P=0.0399), while lower T790M abundance (<1.065%) was associated with longer PFS (not achieved vs. 8.8 months, P=0.0033). ddPCR has a higher sensitivity than ARMS-PCR, especially in detecting the less abundant T790M. Although detection rates were comparable for ctDNA and gDNA samples, the mutation abundance was higher in gDNA sample. Finally, low T790M abundance was associated with longer PFS in NSCLC patients receiving osimertinib treatment.

MA15.07 Different Responses to Osimertinib in Primary and Acquired EGFR T790M-Mutant NSCLC Patients

Primary EGFR T790M could be occasionally identified by routine molecular testing in tyrosine kinase inhibitor TKI-naive non-small cell lung cancer (NSCLC) patients. This study was aimed to compare clinical characteristics of primary and acquired T790M mutations and their responses to Osimertinib in NSCLC patients. We collected clinical characteristics of patients diagnosed with epidermal growth factor receptor (EGFR) mutation from 2012 to 2017 in Shanghai Chest Hospital. For patients with primary and acquired T790M mutations, the responses to Osimertinib were analyzed. Primary T790M was identified in 1.03% (61/5900) of TKI-naive patients. Acquired T790M was detected in 45.50% (96/211) of TKI-treated patients. T790M always coexisted with sensitizing EGFR mutations. Primary T790M was always coexisted with 21L858R (45/61) whereas acquired T790M was coexisted with 19del (61/96). Among them, 18 patients with primary T790M mutation acquired Osimertinib and 75 patients with acquired T790M mutation received Osimertinib. The median progression-free survival (mPFS) of Osimertinib in primary T790M group was greatly longer than that in acquired T790M group (18.0 months:95% CI:15.0-21.0 VS 10.0months:95% CI:8.3-11.7, P=0.016). The DCR of both groups were 89.3% and 100%. In primary T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 15.7m and 24.0 m, respectively. In acquired T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 11.0m and 10.0m, respectively. Primary and acquired T790M-mutation patients showed different molecular characteristics. Both of them may respond to Osimertinib. However, primary T790M patients showed greater survival benefits from Osimertinib than acquired T790M patients.