Positive Epidermal Growth Factor Receptor Mutation Research Articles

100P Physician perceptions of testing practices in patients with early and advanced stage EGFR mutation-positive (EGFRm) NSCLC: A global survey

Prevalence of EGFRm in NSCLC is estimated to be approximately 30%, although this varies by country and region. This global survey investigated physician behaviours related to genetic testing patterns in early (I/II/IIIa) and advanced (IIIb/IIIc/IV) stage NSCLC.

13P Durvalumab + chemotherapy in patients (pts) with advanced EGFR mutation-positive (EGFRm) NSCLC whose disease progressed on first-line (1L) osimertinib: An ORCHARD study interim analysis

Osimertinib is third generation, irreversible, CNS-active EGFR-TKI, and preferred 1L treatment in pts with advanced EGFRm NSCLC. Pts on 1L osimertinib may develop treatment resistance and experience disease progression. The ongoing phase II, open-label, biomarker-directed platform study ORCHARD (NCT03944772) aims to characterise resistance mechanisms and evaluate novel therapy combinations in pts who progressed on 1L osimertinib. This interim analysis reports results of durvalumab + chemotherapy in pts with no biomarker-detected resistance mechanisms or for whom biomarker-directed study treatments were not available.

Bone metastases tend to increase in non-small cell lung cancer with epidermal growth factor receptor mutation

BackgroundIncreased understanding in molecular pathology of advanced non-small cell lung cancer (NSCLC) over the past decades has led to personalized treatment approaches being advocated. Epidermal growth factor receptor (EGFR) mutation that often occurs in NSCLC can be identified using immunohistochemical examinations. Moreover, clarifying the relationship between computed tomography (CT) and EGFR mutation of NSCLC might inform therapeutic decision-making. The purpose of this study was to determine the relationship between metastatic sites on primary chest CT-scan and EGFR mutation in NSCLC lung cancer patients. MethodsAn cross-sectional design using secondary data was conducted, involving 76 NSCLC patients. EGFR mutations were determined by immunohistochemical examination and metastatic sites by chest CT-scan with contrast. The collected metastatic sites comprised hilar and mediastinal lymphadenopathy, pulmonary nodules, and bone, liver, spleen and suprarenal metastases. A Chi square test was used to analyze the data. ResultsThis study revealed that the highest NSCLC stage was IVb, found in 39 samples (51.3%), while 34 (44.7%) subjects had EGFR mutation. There was no statistically significant difference between metastatic site and positive EGFR mutation, although positive bone metastases (54.8%) tend to have more numerous positive EGFR mutations compared to negative bone metastases (37.7%) (p=0.142). ConclusionsPatients with positive bone metastases tend to have higher positive EGFR mutation compared to negative bone metastases in NSCLC lung cancer patients. Prospective studies evaluating patients with EGFR mutation for bone metastases should be considered. This can provide information on therapeutic decision-making to obtain good clinical outcomes.

Osimertinib plus platinum–pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study

BackgroundThe phase III FLAURA2 (NCT04035486) study will evaluate efficacy and safety of first-line osimertinib with platinum–pemetrexed chemotherapy versus osimertinib monotherapy in epidermal growth factor receptor mutation-positive (EGFRm) advanced/metastatic non-small-cell lung cancer (NSCLC). The safety run-in, reported here, assessed the safety and tolerability of osimertinib with chemotherapy prior to the randomized phase III evaluation.Patients and methodsPatients (≥18 years; Japan: ≥20 years) with EGFRm locally advanced/metastatic NSCLC received oral osimertinib 80 mg once daily (QD), with either intravenous (IV) cisplatin 75 mg/m2 or IV carboplatin target area under the curve 5, plus pemetrexed 500 mg/m2 every 3 weeks (Q3W) for four cycles. Maintenance was osimertinib 80 mg QD with pemetrexed 500 mg/m2 Q3W until progression/discontinuation. The primary objective was to evaluate safety and tolerability of the osimertinib–chemotherapy combination.ResultsThirty patients (15 per group) received treatment [Asian, 73%; female, 63%; median age (range) 61 (45-84) years]. Adverse events (AEs) were reported by 27 patients (90%): osimertinib–carboplatin–pemetrexed, 100%; osimertinib–cisplatin–pemetrexed, 80%. Most common AEs were constipation (60%) with osimertinib–carboplatin–pemetrexed and nausea (60%) with osimertinib–cisplatin–pemetrexed. In both groups, 20% of patients reported serious AEs. No specific pattern of AEs leading to dose modifications/discontinuations was observed; one patient discontinued all study treatments including osimertinib due to pneumonitis (study-specific discontinuation criterion). Hematologic toxicities were as expected and manageable.ConclusionsOsimertinib–chemotherapy combination had a manageable safety and tolerability profile in EGFRm advanced/metastatic NSCLC, supporting further assessment in the FLAURA2 randomized phase.

European and US Real-World Treatment Patterns in Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Retrospective Medical Record Review.

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line (1L) therapy for EGFR mutation-positive (EGFRm) advanced/metastatic non-small cell lung cancer (NSCLC).ObjectiveOur objective was to describe real-world treatment patterns and T790M testing practices in patients with 1L disease progression (Europe/USA) following treatment with first- or second-generation EGFR-TKIs.MethodsThis was a retrospective, non-interventional medical record review of patients with EGFRm locally advanced/metastatic NSCLC from routine clinical practice (EGFR-TKI initiation: 1 January 2015 to 31 December 2017; follow-up: last available medical record). Endpoints were demographic/clinical characteristics, incidence of central nervous system (CNS) metastases/leptomeningeal disease, second-line (2L) treatment, T790M mutation testing, and osimertinib treatment prevalence.ResultsAmong 469 patients, 73% (n = 341/469) progressed on 1L EGFR-TKI treatment. Of those who progressed, 74% (n = 252/341) were tested for T790M, with 50% (n = 126/252) testing positive; 75% (n = 94/126) of T790M-positive patients received osimertinib (mostly 2L). Of the patients with progression, 24% (n = 83/341) did not receive 2L treatment, and 88% (n = 73/83) of these patients died. At diagnosis of advanced disease, 9% of patients (n = 41) had CNS metastases; at EGFR-TKI initiation, 14% of patients (n = 68) had CNS metastases. Over the study period, 11% of patients (n = 42) developed CNS metastases not detected at NSCLC diagnosis.ConclusionsRates of resistance mutation testing and subsequent utilization of recommended 2L therapies could be improved. As more targeted therapies are developed, it will be crucial to improve the molecular testing rates to ensure patients receive appropriate, effective, and timely treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-021-00261-8.

Thoracic stereotactic body radiation therapy plus first-line tyrosine kinase inhibitors for patients with epidermal growth factor receptor-mutant polymetastatic non-small-cell lung cancer: A propensity-matched retrospective study.

The role of thoracic stereotactic body radiation therapy (SBRT) in addition to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant polymetastatic non-small-cell lung cancer (NSCLC) has not been well established. This retrospective study aimed to evaluate the efficacy and safety of EGFR-TKIs with thoracic SBRT for the treatment of this patient group.Polymetastatic NSCLC was defined as having >5 metastatic lesions. Patients with polymetastatic NSCLC harboring positive EGFR mutations after initial TKI therapy for at least 8 weeks were eligible for SBRT between August 2016and August 2019. Eligible patients were treated with thoracic SBRT, and TKIs were administered for the duration of SBRT and continued after SBRT until they were considered ineffective. The control group was treated with TKI monotherapy. Propensity score matching (ratio of 1:4) was used to account for differences in baseline characteristics. Progression-free survival (PFS), overall survival, and treatment safety were evaluated.In total, 136 patients were included in the study population. Among them, 120 patients received TKIs alone, and 16 patients received TKIs with thoracic SBRT. The baseline characteristics did not significantly differ between the two cohorts after propensity score matching. The median PFS was 17.8 months in the thoracic SBRT group and 10.8 months in the control group (P = .033). In the multivariate analysis, a Cox regression model showed that thoracic SBRT was an independent statistically significant positive predictor of improved survival, with a hazard ratio of 0.54 (P = .046). We recorded no severe toxic effects or grade 4 to 5 toxicities.Real-world data demonstrate that thoracic SBRT significantly extends PFS in EGFR-mutant polymetastatic NSCLC patients with tolerable toxicity. Given these results, randomized studies are warranted.

Treatment Patterns in Patients with Locally Advanced or Metastatic Non-Small-Cell Lung Cancer Treated with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors: Analysis of US Insurance Claims Databases.

BackgroundMost patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC) acquire resistance to first-line (1L) first- or second-generation (1G/2G) EGFR-TKIs; therefore, it is important to optimize 1L treatment to improve patient outcomes.ObjectiveTo retrospectively examine treatment patterns in locally advanced/metastatic NSCLC using MarketScan® Commercial and Medicare Supplemental Databases (all US census regions).Patients and methodsAdults with a lung cancer diagnosis code between 1 January 2015–31 March 2018 were analyzed from diagnosis (index) through a variable-length follow-up. Patients had ≥ 1 pharmacy claim for 1G/2G EGFR-TKIs on or within 60 days post-index. Data were stratified by presence or absence of central nervous system (CNS) metastases (30 days pre-index through study end).Results578 patients were included (median age 63 years, 64% female). Median follow-up was 13.5 months. The most frequently prescribed 1L EGFR-TKI was erlotinib (414/578, 72%). Median time to 1L treatment discontinuation was 8.2 (95% confidence interval (CI) 6.9, 9.0) months in patients diagnosed with CNS metastases at any time, and 7.7 (95% CI 6.9, 8.9) months in patients without CNS metastases. 270/578 patients (47%) discontinued 1L EGFR-TKIs; 209/270 (77%) initiated second-line (2L) therapy, most frequently osimertinib (96/209, 46%).ConclusionsIn an analysis of US claims data, nearly half of patients discontinued 1L EGFR-TKIs, and 46% who initiated 2L received osimertinib. As nearly a quarter of patients who discontinued 1L EGFR-TKIs did not receive 2L treatment, this study highlights the need for optimal 1L treatment in EGFRm locally advanced/metastatic NSCLC.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-021-00272-5.

1239P ORCHARD osimertinib + savolitinib interim analysis: A biomarker-directed phase II platform study in patients (pts) with advanced non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib

Most pts with epidermal growth factor receptor mutation-positive (EGFRm) NSCLC treated with osimertinib, a third-generation, irreversible, CNS-active EGFR-tyrosine kinase inhibitor (TKI), eventually develop resistance. MET alterations are common resistance mechanisms to osimertinib. The phase II ORCHARD platform study (NCT03944772) aims to characterise 1L osimertinib resistance mechanisms and identify optimal post-progression therapies. This interim analysis reports use of osimertinib + savolitinib, an oral, potent and highly selective MET-TKI, in adults with EGFRm advanced NSCLC and MET alterations (MET amplification / MET exon 14 skipping). Pts were allocated to treatment cohorts after disease progression on 1L osimertinib, based on molecular profiling of a tumour biopsy with NGS. Pts whose tumours harbour MET alterations were allocated to osimertinib 80 mg qd + savolitinib 300 or 600 mg qd. Primary endpoint: investigator assessed objective response rate (ORR; RECIST v1.1). Other endpoints include duration of response and safety / tolerability. Interim data cut-off (DCO): Jan 2021. Of 20 pts that received osimertinib + savolitinib, median duration on prior 1L osimertinib was 414 (197–1722) days. At DCO, 17 pts were evaluable for confirmed response. ORR was 41% (n=7; 80% CI: 25, 59); 7 pts (41%) had partial response, 7 (41%) had stable disease and 1 (6%) had disease progression as their best response; 2 pts (12%) were not evaluable. Overall, 6 / 20 pts (30%) reported a grade ≥3 adverse event (AE), most commonly pneumonia and decreased neutrophil count (each n=2; 10%); 6 / 20 pts (30%) reported a serious AE. Three pts (15%) discontinued combination treatment due to AEs. No deaths due to AEs were reported. Osimertinib + savolitinib showed preliminary activity in pts with MET alterations after 1L osimertinib. Based on interim efficacy, enrolment will continue to 30 pts as pre-specified per protocol. The safety profile was acceptable and consistent with known profiles of osimertinib / savolitinib. Further exploration of this combination is underway in the SAVANNAH study (NCT03778229).

Real-world Treatment Patterns in Patients with EGFR Mutation-positive NSCLC Receiving a First-Line, First- or Second-generation EGFR Tyrosine Kinase Inhibitor in South Korea and Taiwan

Introduction: The preferred first-line (1L) treatment for epidermal growth factor receptor (EGFR) mutation-positive (EGFRm) advanced/metastatic non-small lung cancer (NSCLC) are EGFR-tyrosine kinase inhibitors (TKIs). However, most patients treated with 1L first- or second-generation (1G/2G) EGFR-TKIs acquire resistance; the EGFR T790M mutation is observed in ~30–50% of patients. We report real-world NSCLC treatment and T790M testing patterns in South Korea and Taiwan. Methods: Retrospective medical record review of EGFRm advanced/metastatic NSCLC patients from routine practice. 1G/2G EGFR-TKI initiation 1 January 2015–31 December 2017 (follow-up end date: last available medical record or August 2019). Study measures: demographic/disease characteristics, 1L/2L treatment, T790M testing. Results: In South Korea, 70% (164/235) and in Taiwan 89% (89/100) experienced 1L disease progression (median [range] follow-up: 22 [2.3–50.7] months). Of those with disease progression, 68% (111/164) and 62% (55/89) had T790M testing in South Korea and Taiwan, respectively. In South Korea, 43% (48/111) were T790M-positive with 88% (n=42/48) receiving osimertinib (mostly 2L). In Taiwan, 18% (10/55) were T790M-positive; 100% received osimertinib. Overall, 73% (120/164) and 63% (63/100) in South Korea and Taiwan, respectively, received 2L therapy, predominantly pemetrexed-containing regimens. Among patients with disease progression, 9% (14/164) and 24% (21/89) died before receiving 2L therapy in South Korea and Taiwan, respectively. Conclusion: In both countries, <70% with 1L disease progression were tested for T790M at any point from NSCLC diagnosis, suggesting resistance mutation testing could be improved. Treatment/testing patterns may have changed in both countries since study initiation due to osimertinib reimbursement changes beginning December 2017.

Savolitinib ± Osimertinib in Japanese Patients with Advanced Solid Malignancies or EGFRm NSCLC: Ph1b TATTON Part C

BackgroundPreliminary data suggest that combining savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), with osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor-TKI (EGFR-TKI), may overcome MET-based resistance to EGFR-TKIs.ObjectiveTo investigate the safety and tolerability of savolitinib in Japanese patients with advanced solid malignancies.Patients and MethodsIn Part C of the phase Ib, multi-arm, open-label, multicenter TATTON study, two cohorts of Japanese adult patients were evaluated across six study centers in Japan. Patients with advanced solid malignancies received oral savolitinib monotherapy 400 mg once daily (qd), escalating to 600 mg; patients with advanced EGFR mutation-positive (EGFRm) non-small-cell lung carcinoma (NSCLC) who progressed on prior EGFR-TKI received oral osimertinib 80 mg+savolitinib 300/400/600 mg qd combination therapy. Primary endpoints: safety/tolerability of savolitinib±osimertinib, and maximum tolerated dose(s) (MTD) definition.ResultsSeventeen patients received monotherapy; 12 received combination. Dose-limiting toxicities (DLTs): with monotherapy, 400 mg, none reported; 600 mg, n = 3/9 evaluable patients (33%) reported DLTs (grade 3 and 4 alanine aminotransferase and aspartate transaminase increased, and grade 4 drug-induced liver injury). With combination: 400 mg, 1/6 (17%) reported DLTs (grade 2 fatigue, nausea, and myalgia); 300 mg, none reported; 600 mg, 3/4 (75%) reported DLTs (grade 2 pyrexia, grade 3 skin reaction, and anaphylactic shock). Grade ≥3 adverse events were reported in 41% of patients receiving monotherapy and 33% receiving combination. TATTON is no longer recruiting patients.ConclusionsThe MTD of savolitinib was 400 mg qd in both cohorts. Data demonstrate an acceptable safety profile for savolitinib alone, or with osimertinib.Trial registration: Clinicaltrials.gov; NCT02143466; 21 May 2014.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00806-5.

Efficacy and acquired resistance for EGFR-TKI plus thoracic SBRT in patients with advanced EGFR-mutant non\u2013small-cell\u2002lung\u2002cancer: a propensity-matched retrospective study

BackgroundThis retrospective study aimed to evaluate the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with stereotactic body radiation therapy (SBRT) and to elucidate potential mechanisms of acquired resistance.MethodsPatients with advanced NSCLC harboring positive EGFR mutations after initial TKI therapy for at least 8 weeks were eligible for SBRT between August 2016 and August 2019. Eligible patients were treated with thoracic SBRT, and TKI was continued after SBRT until it was considered ineffective. The control group was treated with TKIs monotherapy. Propensity score matching (PSM, ratio of 1:2) was used to account for differences in baseline characteristics. Overall survival (OS), progression-free survival (PFS), treatment safety and resistance mechanisms were evaluated.ResultsThree hundred eight patients were included in the study population. Among them, 262 patients received TKIs alone, and 46 patients received TKIs with SBRT. Baseline characteristics were not significantly different between the two cohorts after PSM. The median PFS was 19.4 months in the TKIs +SBRT group compared to 13.7 months in the TKIs group (p = 0.034). An influence on OS has not yet been shown (p = 0.557). Of the 135 patients evaluated after PSM, 28 and 71 patients in the TKIs and TKIs +SBRT cohorts, respectively, had plasma cell-free DNA (cfDNA) next-generation sequencing (NGS) performed at baseline and disease progression. In the TKIs +SBRT cohort, the NGS results showed that T790M mutations were detected in 64.3% (18/28) of patients. Patients in the TKIs cohort exhibited fewer T790M-positive mutations (40.8%, p = 0.035) compared to patients in the TKIs +SBRT cohort.ConclusionReal world data prove that TKIs plus thoracic SBRT significantly extend PFS with tolerable toxicity. The mutation ratio of T790M was increased in the TKIs +SBRT group compared to the TKIs only group. Further randomized studies are warranted.

Epidermal Growth Factor Receptor Mutation Status and Response to Tyrosine Kinase Inhibitors in Advanced Chinese Female Lung Squamous Cell Carcinoma: A Retrospective Study.

BackgroundThe frequency of epidermal growth factor receptor (EGFR) mutations and the efficacy of tyrosine kinase inhibitor (TKI) in Chinese female patients with lung squamous cell carcinoma (SCC) are unknown. This study was designed to investigate the incidence of EGFR mutations and the role of targeted therapy in advanced Chinese female lung SCC patients.MethodsAdvanced female patients diagnosed with lung SCC at the Shanghai Chest Hospital between January 2013 and December 2018 were retrospectively analyzed.ResultsA total of 4223 advanced lung SCC patients were screened, and there were 154 female lung SCC patients who had underwent EGFR mutation detection. Positive EGFR mutations were found in 29.9% (46/154) of female lung SCC patients, including twenty-three 19del mutation (14.9%), twenty-one 21L858R mutation (13.6%) and other mutations (1.4%, 21861Q and 20ins). For 45 EGFR positive mutation female SCC patients, the median progression-free survival (PFS) of patients who received EGFR-TKI therapy (n=38) was 8.0 months (95% CI, 5.4-10.7 months), which was significantly longer than patients who were treated with chemotherapy (8.0 vs. 3.2 months, p=0.024), and the median overall survival (OS) was also longer (24.9 months vs. 13.9 months, p=0.020). The objective response rate (ORR) was 44.7% (17/38), and the disease control rate (DCR) was 81.6% (31/38). For 105 female SCC patients with EGFR negative mutation, the median OS was 18.6 months (95% CI, 14.2-22.9 months) and it was no different from that of EGFR positive mutation patients (18.6 vs. 22.8 months, p=0.377).ConclusionFor advanced Chinese female lung SCC patients with EGFR positive mutations, targeted therapy could confer longer PFS and OS than chemotherapy, but the survival was similar with patients who were negative EGFR mutations.

Real-world analysis of the effect of gefitinib as a first-line therapy in patients with advanced non-small cell lung cancer with EGFR mutations

Objective: To evaluate the effect of gefitinib as a first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) who were positive for epidermal growth factor receptor (EGFR) mutations. Subject and method: This prospective analysis included 120 patients with advanced NSCLC with EGFR mutations who were administered gefitinib as the first-line therapy. Patient follow-up and evaluation were performed every three months or when there were symptoms of progressive disease. The main criteria for the analysis of response were progression-free survival (PFS) and overall response rate (ORR). The secondary criteria were overall survival (OS) and disease control rate (DCR). Additionally, the relationship of OS with sex, smoking history, and performance status (PS), as well as gefitinib toxicity were analyzed. Result: The ORR and DCR were 59.2% and 95.8%, respectively. The median PFS was 14.5 months and the median OS was 33 months. The longer OS was statistically significant in women and non-smokers, and the patients had a good PS. Adverse events occurred in 59.2% patients, but most of them were grade 1 and 2 events. Conclusion: This study conducted in Vietnam suggests the effectiveness of gefitinib as a first-line treatment option in patients with advanced NSCLC and positive EGFR mutations regardless of whether the patients have a good PS or not. In particular, targeted therapy with gefitinib improved the OS in women and non-smokers.

The Effect of Adding Biological Factors to the Decision-Making Process for Spinal Metastasis of Non-Small Cell Lung Cancer.

Molecular target therapies have markedly improved the survival of non-small cell lung cancer (NSCLC) patients, especially those with epidermal growth factor receptor (EGFR) mutations. A positive EGFR mutation is even more critical when the chronicity of spinal metastasis is considered. However, most prognostic models that estimate the life expectancy of spinal metastasis patients do not include these biological factors. We retrospectively reviewed 85 consecutive NSCLC patients who underwent palliative surgical treatment for spinal metastases to evaluate the following: (1) the prognostic value of positive EGFR mutation and the chronicity of spinal metastasis, and (2) the clinical significance of adding these two factors to an existing prognostic model, namely the New England Spinal Metastasis Score (NESMS). Among 85 patients, 38 (44.7%) were EGFR mutation-positive. Spinal metastasis presented as the initial manifestation of malignancy in 58 (68.2%) patients. The multivariate Cox proportional hazard model showed that the chronicity of spinal metastasis (hazard ratio (HR) = 1.88, p = 0.015) and EGFR mutation positivity (HR = 2.10, p = 0.002) were significantly associated with postoperative survival. The Uno’s C-index and time-dependent AUC 6 months following surgery significantly increased when these factors were added to NESMS (p = 0.004 and p = 0.022, respectively). In conclusion, biological factors provide an additional prognostic value for NSCLC patients with spinal metastasis.

P03.02 Neoadjuvant Osimertinib with/without Chemotherapy vs Chemotherapy for EGFR Mutated Resectable NSCLC: NeoADAURA

Background: Approximately 30% of patients with NSCLC present with resectable disease. Primary treatment for resectable NSCLC is curative surgery; patient prognosis following surgery alone remains poor. Neoadjuvant chemotherapy is recommended in resectable stage-III NSCLC, regardless of EGFR mutation status, and has demonstrated clinical benefit. However, improved treatment options for stage II/III are needed. Recent studies indicate that EGFR-TKI therapy could potentially achieve tumour size reduction and clearance of micrometastases in the neoadjuvant setting; treatment effect can be assessed in resected specimens. Osimertinib is a third-generation, CNS-active EGFR-TKI, with superior efficacy to comparator EGFR-TKI in treatment-naïve EGFR mutation-positive (EGFRm) advanced NSCLC. In the Phase III ADAURA study (NCT02511106), osimertinib showed statistically significant DFS improvement (hazard ratio: 0.20 [99.12% confidence interval 0.14, 0.30; p<0.001) in resected stage IB—IIIA EGFRm NSCLC following adjuvant chemotherapy, when indicated. A recent study (NCT03433469) found neoadjuvant osimertinib was well tolerated in patients with Stage I—IIIA NSCLC. Efficacy and tolerability of osimertinib in advanced and adjuvant settings support its investigation as neoadjuvant treatment in resectable disease. NeoADAURA (NCT04351555) is a Phase III, controlled, randomised study assessing efficacy and safety of osimertinib (with/without chemotherapy) versus chemotherapy plus placebo as neoadjuvant treatment in resectable stage II—IIIB EGFRm NSCLC. Trial Design: Eligible patients: ≥18 years (≥20 years, Japan), ECOG PS 0/1, primary non-squamous stage II—IIIB (IASLC Cancer Staging Manual v8) NSCLC and confirmed EGFRm (Ex19del/L858R), deemed completely resectable. Prior treatment with systemic anti-cancer therapy for NSCLC is not allowed. Approximately 351 patients will be randomised 1:1:1 (Figure) to receive platinum-based chemotherapy (pemetrexed 500 mg/m2 plus carboplatin AUC5 or cisplatin 75 mg/m2) plus placebo (Arm 1; double-blind), platinum-based chemotherapy plus osimertinib 80 mg once-daily (Arm 2; double-blind) or osimertinib 80 mg once-daily alone (Arm 3; open-label). Patients will be stratified by disease stage (II/III), race (non-Asian/Chinese/other Asian) and EGFR mutation (Ex19del/L858R). Following three cycles of chemotherapy (Arms 1 and 2) or nine weeks of osimertinib (Arm 3), patients will undergo complete surgical resection of primary NSCLC. Treatment with osimertinib or placebo may continue until surgery, unless unacceptable toxicity/withdrawn consent/other discontinuation criterion. Post-surgery, patients will receive optimal care (investigator-defined); this may include adjuvant osimertinib treatment for three years (maximum)/until disease recurrence or unmanageable toxicity. The primary endpoint is MPR, (≤10% residual cancer cells in surgical specimen post-surgery) centrally assessed. Secondary endpoints include pCR, EFS, downstaging, DFS, OS and safety. MPR and EFS will be tested using hierarchal testing procedure at MPR primary analysis. osimertinib, Stage II—IIIB NSCLC, Neoadjuvant

The Frequency of Epidermal Growth Factor Receptor (EGFR) mutations in Iraqi patients with Non-Small Cell Lung Cancer (NSCLC).

Objective:Non-Small Cell Lung Cancer (NSCLC) Carcinogenesis could be caused by numerous genetic mutations, one of the most common is the mutation in the Epidermal Growth Factor Receptor (EGFR) which was used in the advanced stages of the disease as a therapeutic goal. This study aims to estimate the frequency of Epidermal Growth Factor Receptor mutations in Iraqi patients with Non-Small Cell Lung Cancer. Methods:One hundred thirty-eight patients confirmed with NSCLC have participated in this study, patients were sent for EGFR testing by different oncology centers in Iraq. Data and samples were collected. The Mutation was detected using COBAS® DNA Sample Preparation Kit that designed to detect the following mutations: Exon 19: deletions and complex mutations; Exon 21: L861Q and L858R; Exon 18 mutation: G719X (G719A, G719C, and G719S); Exon 20: S768I, T790M, and insertions, this kit utilizes the technology of the real time Polymerase Chain Reaction. Results:This study was included 79 males and 59 females, with a mean age of 60.1±12.4 years. A positive EGFR mutations were found in 38 (27.53%) of samples. Exon 19 deletions (25/38, 65.8%) and substitution L858R in exon 21 10/38 (26.3%) were the most common mutations. Multiple mutations (Exon 20 and 19 combined together) were founded in 2/38 (5.3%), and 1/38 (2.6%) ALK mutation. Non-significant differences among age groups and gender in the incidence of mutations were found. Conclusion:The current study represents the first epidemiological study in Iraq to find EGFR mutations frequency among NSCLC patients that reveals the incidence rate of 27.53%, which is between the higher prevalence rate in Asian populations and lower rates in western countries. These results explain the genetic differences of NSCLC in the world due to ethnic differences of the population, more studies are needed in Arab countries to study the EGFR mutations, find the effect of ethnicity and environmental factors for lung cancer, and the subsequent therapy.

Icotinib versus Cisplatin Plus Docetaxel as Adjuvant Chemotherapy in Patients with Stage II (N1+) Non-Small Cell Lung Cancer Harboring Positive EGFR Mutations: A Single-Center Retrospective Study.

PurposeThe superior efficacy of first-line treatment with icotinib over that of standard chemotherapy has been well demonstrated in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation. However, whether icotinib is superior to cisplatin plus docetaxel as adjuvant chemotherapy in patients with stage II (N1+) NSCLC selected by EGFR mutation is controversial.MethodsA total of 43 patients with completely resected stage II (T1-2N1M0) NSCLC and proven sensitive EGFR mutation (19Del or L858R) between January 2010 and December 2019 were included in our study. The disease-free survival (DFS) and overall survival (OS) were analyzed in 22 patients treated with icotinib and 21 patients treated with cisplatin plus docetaxel. Factors affecting DFS and OS were assessed by the Kaplan-Meier (KM) estimator and univariate Cox regression analysis.ResultsOur cohort included 22 icotinib patients and 21 cisplatin plus docetaxel patients with a median follow-up of 35.5 months and 38 months, respectively. Survival time was significantly longer in the icotinib group than in the chemotherapy group, with a median DFS of 47 months (95% CI, not reached) versus 18 months (95% CI, 12.4–23.6; HR 0.16; 95% CI, 0.07–0.35; log-rank p<0.0001). In the icotinib group, the most common adverse effects (AEs) were skin rash (40.9%) and elevated alanine aminotransferase (22.7%), whereas in the cisplatin plus docetaxel group, the most common AEs were nausea or vomiting (90.5%), anorexia (71.4%), and fatigue (71.4%). No deaths were treatment-related.ConclusionIn this study, we demonstrated that in EGFR mutation-positive patients with completely resected stage II (T1-2N1M0) NSCLC, icotinib might provide DFS benefits, and reduced drug toxicity compared to cisplatin plus docetaxel. Thus, icotinib may be a reasonable option for adjuvant chemotherapy in patients with pathological stage II (N1+) NSCLC with EGFR mutation.

Osimertinib Maintenance After Definitive Chemoradiation in Patients With Unresectable EGFR Mutation Positive Stage III Non–small-cell Lung Cancer: LAURA Trial in Progress

The LAURA trial (NCT03521154) will evaluate the efficacy and safety of osimertinib as maintenance therapy in patients with locally advanced, unresectable, epidermal growth factor receptor mutation-positive (EGFRm), stage III non–small-cell lung cancer (NSCLC) without disease progression during/following definitive platinum-based chemoradiation therapy (CRT). Eligible patients include adults aged ≥ 18 years (≥ 20 years in Japan) with locally advanced, unresectable, stage III NSCLC with local/central confirmation of an EGFR exon 19 deletion/L858R mutation. Patients must have received ≥ 2 cycles of concurrent/sequential platinum-based CRT, have no investigator-assessed progression, and have creatinine < 1.5 × upper limit of normal and creatinine clearance ≥ 30 mL/min. In this phase III trial, patients will be randomized 2:1 to once-daily osimertinib 80 mg or placebo, until objective radiological disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, confirmed by blinded independent central review (BICR). The primary objective is to assess the efficacy of osimertinib per BICR-confirmed progression-free survival (PFS). Secondary objectives include central nervous system PFS, overall survival, PFS by mutation status and safety. Patients with BICR-confirmed disease progression (or investigator-confirmed progression if after primary PFS analysis) may be unblinded and receive open-label osimertinib; all will have post-progression follow-up. Serious adverse events and adverse events of special interest will be collected throughout the trial and survival follow-up. The first patient was enrolled in July 2018, with results expected in late 2022.

Treatment patterns, testing practices, and outcomes in the pre-FLAURA era for patients with EGFR mutation-positive advanced NSCLC: a retrospective chart review (REFLECT).

Introduction:For epidermal growth factor receptor mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC), EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the preferred first-line (1 L) treatment in the advanced setting. Osimertinib, a third-generation EGFR-TKI, received full approval in 2017 for second-line (2 L) treatment of EGFR T790M-positive NSCLC. The REFLECT study characterizes real-world treatment/testing patterns, attrition rates, and outcomes in patients with EGFRm advanced NSCLC treated with 1 L first-/second-generation (1G/2G) EGFR-TKIs before 1 L osimertinib approval.Methods:Retrospective chart review (NCT04031898) of European/Israeli adults with EGFRm unresectable locally advanced/metastatic NSCLC, initiating 1 L 1G/2G EGFR-TKIs 01/01/15–30/06/18 (index date).Results:In 896 patients (median follow-up of 21.5 months), the most frequently initiated 1 L EGFR-TKI was afatinib (45%). Disease progression was reported in 81%, including 10% (86/896) who died at 1 L. By the end of study, most patients discontinued 1 L (85%), of whom 33% did not receive 2 L therapy. From index, median 1 L real-world progression-free survival was 13.0 (95% confidence interval (CI): 12.3–14.1) months; median overall survival (OS) was 26.2 (95% CI: 23.6–28.4) months. 71% of patients with 1 L progression were tested for T790M; 58% were positive. Of those with T790M, 95% received osimertinib in 2 L or later. Central nervous system (CNS) metastases were recorded in 22% at index, and 15% developed CNS metastases during treatment (median time from index 13.5 months). Median OS was 19.4 months (95% CI: 17.1–22.1) in patients with CNS metastases at index, 24.8 months (95% CIs not available) with CNS metastases diagnosed during treatment, and 30.3 months (95% CI: 27.1, 33.8) with no CNS metastases recorded.Conclusion:REFLECT is a large real-world study describing treatment patterns prior to 1 L osimertinib availability for EGFRm advanced NSCLC. Given the attrition rates highlighted in the study and the impact of CNS progression on outcomes, offering a 1 L EGFR-TKI with CNS penetration may improve patient outcomes in this treatment setting.

The cost-effectiveness of dacomitinib in first-line treatment of advanced/metastatic epidermal growth factor receptor mutation-positive non-small-cell lung cancer (EGFRm NSCLC) in Sweden

Aims Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) over chemotherapy in EGFR mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC) has been demonstrated in clinical trials, the optimal treatment sequence remains unclear. The objective of our study was to evaluate the cost-effectiveness of dacomitinib in Sweden vs afatinib and osimertinib in first-line treatment of EGFRm NSCLC. Materials and methods A partitioned survival model was developed with three health states: progression-free, post-progression, and death. Progression-free and overall survival curves were used to inform movements between states. Clinical data were taken from randomized trials, compared via a network meta-analysis (NMA). Utility data were taken from published studies and costs from national Swedish sources. The model used a 15-year time horizon and a Swedish healthcare payer perspective. Sensitivity and scenario analyses were performed. Results The base-case analysis showed that dacomitinib accrued a total of 2.10 quality-adjusted life-years (QALYs) at a total cost of Swedish krona (SEK) 874,615. The incremental cost-effectiveness ratio (ICER) for dacomitinib vs afatinib was SEK 461,556 per QALY gained. The ICER of osimertinib vs dacomitinib, where the small QALY gains of the former came at a high additional cost, was SEK 11,444,709. Deterministic and probabilistic sensitivity analyses confirmed the robustness of these results; changes to drug and medical resource use costs and overall survival had the greatest impact on ICER estimates. Limitations This model is subject to uncertainty associated with extrapolating long-term treatment effects from shorter trial follow-up periods, although this would also be a limitation when using direct comparison or time-dependent hazard ratios. The NMA was limited by the use of indirect comparison, although sensitivity analyses supported the robustness of our findings. Conclusions Our model demonstrated that dacomitinib is cost-effective for first-line EGFRm NSCLC treatment in Sweden vs afatinib and osimertinib.