Osimertinib Initiation Research Articles

Prognostic Impact of Postoperative Recurrence in Patients With Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.

Mutations in the epidermal growth factor receptor (EGFR) gene are the most common targetable gene alterations in non-small cell lung cancer (NSCLC). In Japan, approximately 40% of patients who undergo surgical resection for non-squamous NSCLC have EGFR mutations. However, no long-term studies have been conducted including a large number of EGFR-positive NSCLC patients with postoperative recurrence (PR). We conducted a retrospective observational study of the data of EGFR-positive NSCLC patients with PR who had undergone surgery at the Shizuoka Cancer Center between October 2002 and November 2017. We evaluated post-recurrence overall survival (PRS) and postoperative overall survival (POS) using the Kaplan-Meier method and identify any associations between the clinical variables at recurrence and PRS using univariate and multivariate analysis. We enrolled 162 patients. The median observation time for PRS was 4.95 years (range, 0.82-13.25) and POS was 5.81 years (range, 2.84-16.71). The median PRS was 5.17 years (95% confidence interval [CI], 3.90-5.61) and POS was 7.07 years (95% CI, 5.88-8.01). Univariate analysis identified male sex (median PRS: 3.32 vs. 5.39 years; p < 0.05), bone metastasis (median PRS: 2.43 vs. 5.33 years; p < 0.05), and central nervous system (CNS) metastasis (median PRS: 3.05 vs. 5.39 years; p < 0.05) and multivariate analysis identified bone metastasis (hazard ratio [HR], 2.01; 95% CI, 1.23-3.28; p < 0.05) and CNS metastasis (HR, 1.84; 95% CI, 1.14-2.98; p < 0.05) as poor prognostic factors. The pattern of recurrence (oligo vs. non-oligo recurrence) was not a prognostic factor. Logistic regression analysis revealed the association between sex and the presence bone/CNS metastasis at recurrence. Our data may help visualize future prospects and determine the timing of osimertinib initiation. New treatment strategies need to be developed for patients with bone/CNS metastasis at the first recurrence.

Real-World Analysis of Post-Progression Treatment Patterns and Outcomes for EGFR Mutation-Positive Patients Treated with First-Line Osimertinib.

Introduction: The use of osimertinib in the first-line (1L) setting is an effective treatment option for sensitizing EGFR-mutations (EGFRm+) and has significantly altered the standard of care practice for EGFRm+ disease in Canada. Unfortunately, acquired resistance to osimertinib is almost universal, and outcomes are disparate. Post-progression treatment patterns and the outcome of real-world Canadian EGFRm+ patients receiving 1L osimertinib were the focus of this retrospective review. Methods: The Glans-Look Lung Cancer Research database was used to identify and collect demographic, clinical, treatment, and outcome data on EGFRm+ patients who received 1L osimertinib in the Canadian province of Alberta between 2018 and 2022. Results: A total of 150 patients receiving 1L osimertinib were identified. In total, 86 developed progressive disease, with 56 (65%) continuing systemic therapy, 73% continuing osimertinib, and 27% switching to second-line (2L) systemic therapy. Patients were similar both in clinical characteristics at 1L osimertinib initiation and patterns of treatment failure at progression; those continuing 1L osimertinib post-progression had a longer time to progression (13.5 vs. 8.8 months, p = 0.05) and subsequent post-osimertinib initiation survival (34.7 vs. 22.8 months, p = 0.11). Conclusions: The continuation of osimertinib post-progression is an effective disease management strategy for select real-world EGFRm+ patients, providing continued clinical benefit, potentially due to different underlying disease pathogenesis.

Effect of early dose reduction of osimertinib on efficacy in the first-line treatment for EGFR-mutated non-small cell lung cancer

SummaryOsimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC.

Osimertinib plus local treatment for brain metastases versus osimertinib alone in patients with EGFR-Mutant Non-Small Cell Lung Cancer

ObjectivesOsimertinib is a standard treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and is highly effective for brain metastases (BMs). However, it is unclear whether local treatment (LT) for BMs prior to osimertinib administration improves survival in EGFR-mutant NSCLC. We aimed to reveal the survival benefit of upfront local treatment (LT) for BMs in patients treated with osimertinib. Materials and MethodsThis multicenter retrospective study included consecutive patients with EGFR mutation (19del or L858R)-positive NSCLC who had BMs before osimertinib initiation between August 2018 and October 2021. We compared overall survival (OS) and central nervous system progression-free survival (CNS-PFS) between patients who received upfront LT for BMs (the upfront LT group), and patients who received osimertinib only (the osimertinib-alone group). Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for potential confounding factors. ResultsOf the 121 patients analyzed, 57 and 64 patients had 19del and L858R, respectively. Forty-five and 76 patients were included in the upfront LT group and the osimertinib-alone groups, respectively. IPTW-adjusted Kaplan–Meier curves showed that the OS of the upfront LT group was significantly longer than that of the osimertinib-alone group (median, 95 % confidence intervals [95 %CI]: Not reached [NR], NR–NR vs. 31.2, 21.7–33.2; p = 0.021). The hazard ratio (HR) for OS and CNS-PFS was 0.37 (95 %CI, 0.16–0.87) and 0.36 (95 %CI, 0.15–0.87), respectively. ConclusionsThe OS and CNS-PFS of patients who received upfront LT for BMs followed by osimertinib were significantly longer than those of patients who received osimertinib alone. Upfront LT for BMs may be beneficial in patients with EGFR-mutant NSCLC treated with osimertinib.

Early dose reduction of osimertinib in advanced EGFR -mutated non-small cell lung cancer.

Osimertinib has become the standard of care for epidermal growth factor receptor ( EGFR )-mutated non-small cell lung cancer (NSCLC). In order to prevent or treat toxicity, the osimertinib dose may be reduced. However, data regarding the impact of dose reduction during treatment are limited. We aimed to compare the efficacy of osimertinib early dose reduction during the first 3 months of treatment with late dose reduction in EGFR -mutated advanced NSCLC. This retrospective study included patients with EGFR -mutated advanced NSCLC who received osimertinib. We constituted two groups: 'early dose reduction' (early) with patients receiving a reduced dose of osimertinib from 80 to 40 mg within the 3 months of osimertinib initiation and 'late dose reduction' (late) with patients receiving a reduced dose after 3 months of full-dose treatment. Thirty-five patients were included, with 17 and 18 patients in the early and late groups, respectively, and a higher median age in the early group (76 vs. 67 years). The real-world progression-free survival (rwPFS) at 1 year was 70.5% in the early group and 88.9% in the late group ( P = 0.31). Median rwPFS was 32.7 and 24.6 months ( P = 0.98), and the median overall survival was 46.9 versus not reached in early and late groups, respectively ( P = 0.17). Central nervous system rwPFS was not different between the early and late groups: 29.8 and 35.8 months, respectively ( P = 0.39). We showed that a reduced dose of osimertinib within the first 3 months of treatment, compared to a later reduced dose, could influence treatment response or patient survival.

Efficacy of osimertinib in patients with EGFR-mutation positive non-small cell lung cancer with malignant pleural effusion.

As an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), osimertinib has emerged as a standard EGFR-mutation positive treatment for non-small cell lung cancer (NSCLC). However, the efficacy of osimertinib for malignant pleural effusion (MPE) remains understudied. This study aimed to evaluate the impact of osimertinib on time to treatment failure (TTF) and overall survival (OS) in patients with EGFR-mutation positive NSCLC, comparing those with and without MPE. This retrospective analysis included patients with advanced or recurrent NSCLC treated with osimertinib at our hospital between April 2016 and June 2021. TTF was defined as the duration from osimertinib initiation to discontinuation, and OS as the duration until death, irrespective of the reason. Among 229 patients receiving osimertinib, 84 had MPE before administration, 39 acquired EGFR exon20 T790M mutation following previous EGFR-TKI therapy, and 45 were EGFR-TKI-naive. Among EGFR-TKI-naive patients, median TTF was 14.8 and 19.8 months for those with and without MPE, respectively (hazard ratio [HR] 1.40; 95% confidence interval [CI]: 0.90-2.18; p = 0.12). Median OS was 32.0 and 42.0 months for patients with and without MPE, respectively (HR 1.43; 95% CI: 0.86-2.38; p = 0.16). Among patients with T790M mutation, median TTF was 12.3 and 13.1 months for patients with and without MPE, respectively (HR 1.03; 95% CI: 0.69-1.55; p = 0.88). Median OS for patients with and without MPE was 23.2 and 24.7 months, respectively (HR 1.09; 95% CI: 0.72-1.67; p = 0.68). Among patients with EGFR-mutation positive NSCLC, the evidence of MPE has little effect on survival with osimertinib.

Predictive significance of circulating tumor DNA against patients with T790M-positive EGFR-mutant NSCLC receiving osimertinib

Circulating tumor DNA (ctDNA) provides molecular information on tumor heterogeneity. The prognostic usefulness of ctDNA after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are limited. Therefore, the present study evaluated ctDNA during osimertinib administration as a second-line or more setting to identify the relationship between EGFR mutation levels and outcomes in patients with advanced non-small cell lung cancer (NSCLC). Forty patients with EGFR T790M-positive NSCLC receiving osimertinib after prior EGFR-TKI treatment were registered. Plasma samples were collected at osimertinib pretreatment, after 1 month of treatment, and at the time of progressive disease (PD). ctDNA analysis was performed by digital polymerase chain reaction. The detection rate of copy numbers of exon 19 deletion, L858R, and T790M in plasma samples was significantly lower 1 month after osimertinib than at pretreatment, and significantly higher at PD than at 1 month, whereas that of C797S was significantly higher at PD than at 1 month. No statistically significant difference was observed in the copy numbers of exon 19 deletion, L858R, T790M, and C797S between complete response or partial response and stable disease or PD. The detection of T790M at PD after osimertinib initiation was a significant independent prognostic factor for predicting shorter prognosis, and the presence of major EGFR mutations at pretreatment and PD was closely linked to worse survival after osimertinib initiation. Molecular testing based on ctDNA is helpful for predicting outcomes of osimertinib treatment in T790M-positive NSCLC after previous EGFR-TKI treatment.

Intracranial Outcomes of De Novo Brain Metastases Treated With Osimertinib Alone in Patients With Newly Diagnosed EGFR-Mutant NSCLC

IntroductionPatients with EGFR-mutant NSCLC have a high incidence of brain metastases. The EGFR-directed tyrosine kinase inhibitor osimertinib has intracranial activity, making the role of local central nervous system (CNS)-directed therapies, such as radiation and surgery, less clear. MethodsPatients with EGFR-mutant NSCLC and brain metastases who received osimertinib as initial therapy after brain metastasis diagnosis were included. Individual lesion responses were assessed using adapted RANO-BM criteria. CNS progression and local progression of brain metastasis from osimertinib start were analyzed using cumulative incidence treating death as a competing risk. Overall survival was estimated using Kaplan-Meier methodology. ResultsThere were 36 patients who had a median interval from brain metastasis diagnosis to first-line osimertinib initiation of 25 days. In total, 136 previously untreated brain metastases were tracked from baseline. Overall, 105 lesions (77.2%) had complete response and 31 had partial response reflecting best objective response of 100%. Best response occurred at a median of 96 days (range: 28–1113 d) from baseline magnetic resonance imaging. This reflects a best objective response rate of 100%. Two-year overall survival was 80%. CNS progression rates at 1-, 2-, and 3-years post-osimertinib were 21%, 32%, and 41%, respectively. Lesion-level local failure was estimated to be 0.7% and 4.7% at 1- and 2-years post-osimertinib, respectively. No clinicodemographic factors including brain metastasis number were associated with post-osimertinib progression. ConclusionsIntracranial response to osimertinib is excellent for patients with EGFR-mutant NSCLC with de novo, previously untreated brain metastases. Very low local failure rates support a strategy of upfront osimertinib alone in selected patients.

BIOM-44. IMPROVED OVERALL SURVIVAL OF RECURRENT GLIOBLASTOMA (GBM) PATIENTS WITH EGFR AMPLIFICATION AND EGFR VIII MUTATIONS TREATED WITH OSIMERTINIB: A RETROSPECTIVE REVIEW

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an overall survival (OS) of 14.6-23 months in clinical trial patients and 11 months for the real world population. There is no uniform standard of care for recurrent GBM (rGBM) patients. EGFR amplification and EGFRvIII mutations are common in GBM and are potential targets with EGFR tyrosine kinase inhibitors (EGFR-TKI). Osimertinib, a third-generation EGFR-TKI, effectively penetrates the blood brain barrier and is FDA-approved for non-small cell lung cancer. We conducted a retrospective review of rGBM patients with EGFR amplification and EGFRvIII mutations who received osimertinib in addition to other therapies such as bevacizumab, irinotecan, tumor-treating fields, and salvage radiation at recurrence. The primary outcome was OS. Secondary outcomes included recurrence free survival (RFS), overall survival after initiation of osimertinib (rOS), and adverse events (AE). Statistical analysis utilized the Kaplan-Meier estimate. AE were defined by the Common Terminology Criteria for Adverse Events Version 5.0. Twenty-seven patients (17 males) with a median age of 59 years (range: 29-75) were identified. All except one patient were IDH1-wild type (92.9%). MGMT promoter statuses included ten methylated (35.71%) and 11 unmethylated patients (39.29%). The median time on osimertinib was 5.1 months. The median OS was 28 months (95% CI 24, NA). Following osimertinib initiation, the median RFS was 6.4 months (95% CI 5.1, NA), and the median rOS was 12 months (95% CI 8.4, NA). AEs included grade I/II rash (44.4%), grade I/II diarrhea (40.7%), grade III leukopenia (18.5%), and grade III thrombocytopenia (11.1%). The data suggests that osimertinib improves the OS of rGBM patients with manageable and reversible AEs. Despite the limitations of a retrospective study and small sample size, osimertinib is a promising targeted therapy for rGBM. Further research is warranted in a clinical trial to evaluate this treatment prospectively.

Abstract 12757: Osimertinib-Associated Cardiotoxicity: Insights Into Echocardiographic Changes and Patients at Increased Risk

Introduction: Osimertinib is a third-generation epidermal growth factor (EGFR) tyrosine kinase inhibitor used in the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). While osimertinib has known cardiotoxicity risks, there is a paucity of detailed transthoracic echocardiographic (TTE) changes and known predictors. Hypothesis: Osimertinib is associated with TTE changes other than reduced EF in patients with NSCLC; further, those with pre-existing cardiac risk factors may be at increased risk of cardiotoxicity. Methods: Single-center retrospective analysis of patients with NSCLC with available TTEs after starting osimertinib between 2007-2022. Cardiac event (any grade ≥2 cardiac common terminology criteria for adverse events [CTCAE]) cumulative incidence was estimated and Fine and Gray regressions performed (adjusting for non-cardiac death as a competing risk). Results: In total, 85 patients were included (mean age was 68 years, 67% female). Median interval between osimertinib initiation and first follow-up TTE was 17.6 months. After a median follow-up of 35 months, 17 patients developed grade ≥2 CTCAE (2-year cumulative incidence, 19.2%; 95% confidence interval [CI]: 11%-29%). These CTCAEs include QTc prolongation (n = 10), EF decline of ≤50% or ≥10% drop from baseline (n = 5), new valvular regurgitation/stenosis on imaging (n = 5), and supraventricular arrhythmia (n = 3). A pre-treatment TTE was available for 38 patients prior to osimertinib initiation. Comparing post- vs pre-osimertinib TTEs, there was significant LVEF decline (58 ± 11% vs 61 ± 8%), increased diastolic dysfunction (40% vs 32%, mitral regurgitation (49% vs 24%), and tricuspid regurgitation (45% vs 24%), all p &lt;0.01. On multivariable analysis, preexisting arrhythmias (hazard ratio [HR] 3.90; 95% CI 1.11-1.13; p = 0.034) and BMI (HR 1.07, 95% CI 1.00-1.14; p = 0.04) were associated with an increased risk of cardiac events. Conclusions: Osimertinib was associated with a nearly 20% 2-year cumulative incidence of cardiac events and multiple echocardiographic changes. BMI is a potential modifiable risk factor to mitigate Osimertinib-associated cardiac events. These findings highlight the need for close surveillance in these higher cardiac-risk patients with NSCLC.

First-line osimertinib for patients with EGFR-mutated advanced non-small cell lung cancer: efficacy and safety during the COVID-19 pandemic.

The FLAURA trial demonstrated improved overall survival (OS) with first-line osimertinib for patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). We studied the efficacy and safety of osimertinib in a cohort treated during the coronavirus disease 2019 (COVID-19) pandemic. Patients diagnosed with EGFR-mutated advanced NSCLC between 11 March 2020 to 31 December 2021 who received first-line osimertinib in British Columbia, Canada were identified retrospectively. Kaplan-Meier curves of OS and progression-free survival (PFS) from the start of osimertinib were plotted. The associations of baseline characteristics with PFS, and development of pneumonitis or dose reductions due to toxicity with OS were evaluated with hazard ratios estimated using univariable and multivariable Cox models. The cohort comprised 231 individuals. 58.7% of patients with de novo advanced NSCLC were initially diagnosed after presentation to the Emergency Room. At osimertinib initiation, 31.6% were aged ≥75 years and 45.5% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Median PFS and OS were 18.0 months [95% confidence interval (CI): 16.1-26.2] and 25.4 months (95% CI: 20.3-not reached), respectively. On multivariable analysis, age ≥75 years (vs. <75), ECOG PS 2/3 (vs. 0/1), ECOG PS 4 (vs. 0/1), current smokers (vs. never smokers), programmed death ligand 1 (PD-L1) expression ≥50% (vs. <1%), and L858R mutation (vs. exon 19 deletion) were associated with shorter PFS. Among 110 patients who progressed, 33.6% received subsequent therapy. A proportion of 16.5% of the cohort developed grade ≥3 adverse events. Pneumonitis from osimertinib (3.9% incidence) was weakly associated with shorter OS (hazard ratio: 2.59, 95% CI: 0.94-7.12, P=0.066); dose reductions were not associated with worse OS. 10.8% of patients developed COVID-19. In a cohort receiving first-line osimertinib during the COVID-19 pandemic, ECOG PS ≥2 was observed in nearly half of patients at treatment initiation contributing to a median OS shorter than in FLAURA. The incidence of severe adverse events was low and dose reduction for drug toxicity did not impact OS. Identifying and reducing barriers to the diagnosis of NSCLC during the COVID-19 pandemic are required.

Dynamics of disease progression during treatment with Osimertinib in patients with EGFR T790M-positive non-small cell lung cancer.

Patterns of treatment failure and subsequent treatment in non-small cell lung cancer (NSCLC) patients treated with osimertinib are scarcely known. We analyzed the disease progression during osimertinib treatment to identify potential treatment strategies. We identified advanced NSCLC patients who commenced osimertinib treatment after progression on previous epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) from June 2014 to November 2018 from electronic records. Patients' tumor characteristics, efficacy outcomes, affected organs from radiology studies, and treatment modalities before and after osimertinib were analyzed. Eighty-four patients were included. At osimertinib initiation, bone (50.0%) and brain (41.9%) were the commonest single metastatic sites, whereas thoracic involvement (73.3%) was more frequent than bone (27.4%) or brain (20.2%) metastasis during disease progression on osimertinib. Oligo-progressive disease (PD) and central nervous system (CNS)-sanctuary PD were observed in 15 (17.9%) and 3 (3.6%) patients, respectively. Most patients without brain metastasis (BM) at osimertinib initiation remained BM-free (46/49, 93.9%), and 60% of patients (21/35) with pre-existing BM showed intracranial disease control despite extracranial PD. The resistance mechanisms to osimertinib were explored in 23 patients (27.4%), and T790M-loss was observed in 14 patients (60.9%) who had worse survival outcomes than those without T790M-loss (progression-free survival, 5.4 vs. 16.5 months, p = 0.02; overall survival, not reached, p = 0.03). PD during osimertinib treatment occurred preferentially in the thorax and pre-existing sites. Extracranial PD prevailed over intracranial PD regardless of baseline BM and prior brain radiation. These results support osimertinib's intracranial efficacy and may guide treatment strategies for EGFR-mutated NSCLC with BM.

Real-world data on efficacy and safety of osimertinib in non-small cell lung cancer patients with EGFR T790M mutation detected by first and repeat rebiopsy.

Osimertinib could effectively target epidermal growth factor receptor (EGFR) T790M resistance mutations in non-small cell lung cancer (NSCLC), indicating that rebiopsy may be particularly important. However, the clinical benefit of repeat rebiopsy in T790M-negative patients with NSCLC detected by the first rebiopsy is still unclear, and data on the efficacy and safety of osimertinib in patients with NSCLC who are T790M-positive patients on a repeat rebiopsy remain rare. We retrospectively collected the clinical data of advanced NSCLC patients with common EGFR mutation who were treated with 1/2-generation (1/2G) EGFR-tyrosine kinase inhibitors (TKIs) in first-line therapy in our center from January 2018 to December 2020. The detection rate of T790M by first and repeat rebiopsy was recorded, and we also analyzed the efficacy and safety of osimertinib for T790M-positive patients. Among 190 common EGFR-mutant patients who received 1/2G EGFR-TKIs with advanced NSCLC in the first-line treatment, 141 patients developed progressive disease. In total, 110 of 141 accepted the first rebiopsy, with a T790M prevalence of 50.9% (56/110). In total, 43 T790M-positive patients who received osimertinib were included in first rebiopsy group. Of 54 T790M-negative patients detected by the first rebiopsy, 28 underwent repeated rebiopsy in subsequent clinical treatment, and 10 (35.7%) T790M-positive cases were confirmed. In total, eight T790M-positive patients treated with osimertinib were included in repeat rebiopsy group. Overall, 66 (60%) of 110 patients acquired a T790M mutation. In patients with the T790M mutation discovered by the first and repeat rebiopsy, osimertinib resulted in median progression-free survival of 7 (95% confidence interval [CI]: 5.3-8.7) and 6 (95% CI: 4.7-7.3) months, respectively (p=.656). The median overall survival since osimertinib initiation for T790M-positive patients at first rebiopsy was 20 (95% CI: 15.1-24.9) months and 19 (95% CI: 16.9-21.1) months, for those at repeated rebiopsy (p=.888). Adverse events of grade 3 or higher were similar in the two groups (25.6% vs. 12.5%, p=.616). There was no treatment-related death in the two groups. Repeat rebiopsy can increase the T790M mutation positivity rate. Osimertinib showed similar efficacy and safety in T790M-positive patients whether detected by the first or repeat rebiopsy.

A real-world pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) events for osimertinib

Osimertinib was a third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), which approved by the US Food and Drug Administration (FDA) in 2015 for treatment of non-small cell lung cancer (NSCLC). Our study was to explore the adverse events (AEs) caused by osimertinib through data mining of the US FDA Adverse Event Reporting System (FAERS), and provide reference for clinical safety. Data of osimertinib were collected from the FAERS database covering the period from first quarter of 2016 to the fourth quarter of 2021. Disproportionality analyses was employed to quantify the associated AE signals of osimertinib and detect the risk signals from the data in the FAERS database. Reporting odds ratio (ROR) was used to detect the risk signals from the data in the FAERS database. The definition relied on system organ class (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA). Totally, 9,704,33 reports were collected from the FAERS database, 10,804 reports of osimertinib were identified as the ‘primary suspected (PS)’ AEs. Osimertinib induced AEs occurred in 27 organ systems. 68 significant disproportionality PTs satisfying with the four algorithms were retained at the same time. Unexpected significant AEs such as scrotal volvulus, hepatic function abnormal, venous thromboembolisms might also occur. The median onset time of osimertinib-associated AEs was 58 days (interquartile range [IQR] 14–212 days), and the majority of the AEs occurred within the first 30 days after osimertinib initiation. Our study found significant new AEs signals of osimertinib and might provide support for clinical monitoring and risk identification of osimertinib.

UNcommon EGFR Mutations: International Case Series on Efficacy of Osimertinib in Real-Life Practice in First-LiNe Setting (UNICORN)

IntroductionApproximately 10% of EGFR mutations (EGFRmuts) are uncommon (ucEGFRmuts). We aimed to collect real-world data about osimertinib for patients with ucEGFRmuts. MethodsThis is a multicenter, retrospective study of ucEGFRmut (exon 20 insertions excluded) metastatic NSCLC treated with osimertinib as first EGFR inhibitor. The Response Evaluation Criteria in Solid Tumors and response assessment in neuro-oncology brain metastases brain objective response rate (ORR) were evaluated by the investigators. Median progression-free survival (mPFS), median overall survival, and median duration of response (mDOR) were calculated from osimertinib initiation. Mutations found at resistance were collected. ResultsA total of 60 patients were included (22 centers, nine countries), with median age of 64 years, 75% females, and 83% Caucasian. The largest subgroups were G719X (30%), L861Q (20%), and de novo Thr790Met (T790M) (15%). The ORR was 61%, mPFS 9.5 months, mDOR 17.4 months, and median overall survival 24.5 months. Regarding patients with no concurrent common mutations or T790M (group A, n = 44), ORR was 60%, mPFS 8.6 months, and mDOR 11 months. For G719X, ORR was 47%, mPFS 8.8 months, and mDOR 9.1 months. For L861Q, ORR was 80%, mPFS 16 months, and mDOR 16 months. For de novo T790M, ORR was 44%, mPFS 12.7 months, and mDOR 46.2 months. Compound EGFRmut including common mutations had better outcome compared with only ucEGFRmut. For 13 patients with a response assessment in neuro-oncology brain metastases–evaluable brain metastases, brain ORR was 46%. For 14 patients, rebiopsy results were analyzed: four patients with additional EGFR mutation (C797S, D585Y, E709K), three with new TP53 mutation, one with c-Met amplification, one with PIK3CA mutation, and one with neuroendocrine transformation. ConclusionsOsimertinib was found to have an activity in ucEGFRmut with a high rate of disease control systemically and intracranially. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest data set of its kind.

Evaluation of Pneumonitis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Receiving Osimertinib and Thoracic Radiotherapy

<h3>Purpose/Objective(s)</h3> In epidermal growth factor receptor mutated (EGFR+) metastatic non-small cell lung cancer (mNSCLC), pneumonitis is a known side effect independently associated with both Osimertinib and thoracic radiotherapy (TRT). The objective of this study was to examine the relationship between concurrent Osimertinib and TRT with regards to pneumonitis, and to observe patterns of practice regarding the cessation of Osimertinib during TRT. <h3>Materials/Methods</h3> In this single institution retrospective cohort study between 2016 and 2020, patients with EGFR+ mNSCLC who received both Osimertinib and TRT were included. TRT was defined as any course of radiotherapy that involved lung parenchyma within the treated field. The primary endpoint was the incidence of symptomatic (CTCAE grade ≥ 2) pneumonitis. Comparisons were made with multivariable Cox proportional hazards regression for both grade ≥ 2 and any grade pneumonitis. <h3>Results</h3> Of the 151 patients receiving Osimertinib during the study period, 41 underwent 147 courses of radiation either during or within 6 months of Osimertinib initiation, with 68 (46.3%) lesions treated with TRT. In total, 5 patients developed RT-related symptomatic pneumonitis (12.2%), of which 1 was grade 4 and another grade 5. Mean (±SD) age at TRT was 65.5 (±12.0) years. Most patients had de novo metastatic disease (n=31; 75.6%), adenocarcinoma histology (n=38; 92.7%), and 16 (39%) were on Osimertinib as first line systemic therapy. The mean (±SD) number of cycles of Osimertinib was 9.6 (±4.3). Median total dose and fractionations were 20 Gy (interquartile range [IQR]: 20-30 Gy) and 5 (IQR: 1-5), respectively. During TRT, Osimertinib was knowingly held in 12 patients (29.3%), most commonly for 1-2 days before and after (n=7; 17.1%) the course of treatment. Osimertinib was knowingly continued during TRT for 5 patients (12.2%), and in 8 patients (19.5%) it was not documented whether the medication was held. Multivariable analysis identified that each additional cycle of Osimertinib was associated with an increased incidence of grade ≥ 2 pneumonitis (hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.15-2.07, p=0.004). Total radiation dose was also associated with increased incidence of any grade of pneumonitis (HR per 5 Gy: 1.38, 95% CI: 1.03-1.86, p=0.031). There was no association with incidence of pneumonitis (any grade) if Osimertinib was continued during TRT (HR: 3.36, 95% CI: 0.13-86.56, p=0.47) or if TRT was given within 6 months of Osimertinib initiation (HR: 0.20, 95% CI: 0.02-2.21, p=0.19). <h3>Conclusion</h3> In patients with EGFR+ mNSCLC treated with Osimertinib and TRT, the risk of symptomatic pneumonitis was moderate, and in 2 instances serious. Patterns on whether to hold Osimertinib during TRT, and for how long, were variable. Symptomatic pneumonitis with TRT was associated with prolonged Osimertinib use. Further research is required to further clarify the safety of the combination of these two treatment modalities.

Analyse de la prise en charge des cancers bronchiques avec mutation du gène de l’EGFR

Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC). Over the past decade, the management of NSCLC-carrying EGFR mutation has evolved considerably with the use of tyrosine kinase inhibitors (TKIs). The main objective of this retrospective study was to analyze the evolution of therapeutic strategies in a cohort of patients with metastatic or locally advanced EGFR- mutated NSCLC. Data on patients with EGFR-mutated NSCLC, eligible for TKIs, and treated between 2010 to 2019 were collected. The main therapeutic strategies adopted following progression under TKIs and the prognostic factors for survival were analyzed. The median age of the 177 patients was included in the cohort was 70years. The majority of patients (77.4%) received TKIs as first-line treatment, while 16.4% received chemotherapy. Osimertinib initiation as second-line treatment was a factor for better prognosis (OR=0.5). Finally, change of chemotherapy line was the main therapeutic strategy adopted for 41.3% of the patients having relapsed under TKIs. Therapeutic management of EGFR-mutated NSCLC patients was in accordance with regional, national and international recommendations. The characterization of progression under TKI therapy has become systematic, allowing better adaption of therapeutic strategies.

Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multicentric Retrospective French Study.

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in first line for the treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC). The identification of related histomolecular resistance mechanisms to first-line osimertinib is a critical step to define the optimal treatment strategy beyond progression. All consecutive patients treated in the first line with osimertinib for advanced EGFR-mutated NSCLC at 10 hospitals in the Greater Paris area between April 2015 and January 2021 were included. Histomolecular data from plasma and tissue samples taken at progression under osimertinib were collected, and all samples were analyzed using DNA next-generation sequencing. Data on objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to treatment discontinuation (TTD) were also collected. Overall, 104 patients were included. Most patients had adenocarcinoma (n=102, 98%) with an exon 19 EGFR deletion (n=54, 52%). Forty-two patients (50%) had central nervous system (CNS) metastasis at the time of osimertinib initiation. ORR was 76%, median PFS and OS were 12.6 months and 52 months, respectively, and TTD was 33 months. At the time of analysis, 44 patients (42%) had tumor progression, and among these patients, 27 (61%) contributive samples were available. The most frequent molecular alterations at progression were mesenchymal epithelial transition factor (MET) amplification (15%; n=4) and EGFR C797S mutation (11%; n=3). Histological transformation was found in one patient (4%). RNA next-generation sequencing was performed in eight patients and showed a CCDC6-RET fusion in one patient (12%). We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation-positive NSCLC. At progression, the most frequent histomolecular alterations were MET amplification and EGFR C797S mutation.

A real-world study of patient characteristics and clinical outcomes in EGFR-mutated lung cancer treated with first-line osimertinib.

e21033 Background: Osimertinib is a third-generation mutation-specific covalent tyrosine kinase inhibitor of epidermal growth factor receptor ( EGFR) that is used for first-line therapy in EGFR-mutated non-small cell lung cancer (NSCLC) based on results of the FLAURA trial. We performed a retrospective analysis of baseline characteristics and clinical outcomes in real-world patients treated with osimertinib. Methods: We queried medical records at our NCI-designated cancer center hospital, Beth Israel Deaconess Medical Center (Boston, MA), for patients with unresectable EGFR-mutated NSCLC treated with first-line osimertinib. 56 patients were identified who initiated treatment with osimertinib from October 2017 to February 2021. Patient demographic information, treatment duration and next generation sequencing data were collected. Patients were determined to be FLAURA-eligible or FLAURA-ineligible based on published FLAURA trial inclusion and exclusion criteria. Time to discontinuation (TTD) of osimertinib was defined as months between osimertinib initiation and discontinuation. Median TTD and median OS were calculated. Results: Of the 56 patients included, 34 (61%) were female; 40 (71%) of patients were White, and 16 (29%) were Asian. 14 (25%) patients had an ECOG performance status of 2-4 at time of osimertinib initiation. Regarding EGFR mutation, 32 (57%) had exon 19 deletion and 16 (29%) had exon 21 L858R mutation. 8 (14%) patients had other EGFR mutations (not included in FLAURA) including: G719X, L861Q, and exon 20 insertion. In total, 25 (45%) patients were determined to be FLAURA-eligible, and 31 (55%) were FLAURA-ineligible. The most frequently occurring exclusionary comorbidities were concurrent active malignancy within two years (n = 9), baseline ECG abnormality (n = 9), and uncontrolled hypertension (n = 6). For clinical outcomes, the median TTD for all patients was 16.9 months (95% CI 12.6 – 35.1), whereas the median TTD was 31.1 months (95% CI 14.9 – NR) in the FLAURA-eligible cohort. Median OS for all patients was 32.0 months (95% CI 15.7 – NR) and not reached for the FLAURA-eligible cohort. No individual characteristic was associated with clinical outcomes using regression analysis. Conclusions: We report a single academic center’s experience with real-world osimertinib use in unresectable EGFR-mutated NSCLC – of which 55% of patients would have been ineligible for inclusion in the practice-changing FLAURA trial. Outcomes in the overall cohort (median TTD and OS) were comparable to the median PFS and OS, respectively, reported in the FLAURA study. Outcomes in our real-world FLAURA-eligible patients were better than previously reported. Our data supports the use of osimertinib in real-word settings and highlights the need for designing registration trials that are more inclusive of patient/disease characteristics seen in routine clinical practice.

Pretreatment Neutrophil-to-Lymphocyte Ratio and Smoking History as Prognostic Factors in Advanced Non-Small Cell Lung Cancer Patients Treated with Osimertinib.

Background The remarkable efficacy of osimertinib in non‒small cell lung cancer (NSCLC) with acquired T790M mutation has been widely documented in clinical trials and real-world practice. However, some patients show primary resistance to this drug. Even patients who initially show a favorable response have inconsistent clinical outcomes later. Therefore, the aim of this study was to identify additional clinical predictive factors for osimertinib efficacy.Methods A prospective cohort of patients with acquired T790M positive stage IV lung adenocarcinoma treated with osimertinib salvage therapy in Hallym University Medical Center were analyzed.Results Sixty-one eligible patients were analyzed, including 38 (62%) women and 39 (64%) who never smoked. Their mean age was 63.3 years. The median follow-up after treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) was 36.0 months (interquartile range, 24.7–50.2 months). The majority (n=45, 74%) of patients were deceased. Based on univariate analysis, low baseline neutrophil-to-lymphocyte ratios (NLR), age ≥50 years, never-smoking history, stage IVA at osimertinib initiation, and prolonged response to previous TKIs (≥10 months) were associated with a significantly longer progression-free survival (PFS). Multivariate analysis showed that never-smoking status (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.30–0.98; p=0.041) and a baseline NLR less than or equal to 3.5 (HR, 0.23; 95% CI, 0.12–0.45; p<0.001) were independently associated with a prolonged PFS with osimertinib.Conclusion Smoking history and high NLR were independent negative predictors of osimertinib PFS in patients with advanced NSCLC developing EGFR T790M resistance after the initial EGFR-TKI treatment.