Advanced Epidermal Growth Factor Receptor Mutation-positive Non-small-cell Lung Cancer Research Articles

Negative-predictive value of SUVmax for Ascertaining the efficacy of osimertinib in EGFR mutation-positive non-small cell lung cancer

BackgroundFluorine-18 2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is routinely used to stage non-small cell lung cancer (NSCLC). However, whether 18F-FDG accumulation in primary tumors affects the efficacy of osimertinib in patients with epidermal growth factor receptor (EGFR) mutation-positive NSCLC remains unclear. MethodsWe retrospectively investigated 74 patients with advanced or postoperative recurrent EGFR mutation-positive NSCLC who underwent 18F-FDG PET/CT and were treated with osimertinib as first-line therapy between September 2018 and March 2023 at Kumamoto University Hospital. The maximum standardized uptake value (SUVmax) of each primary tumor was measured, and the patients were divided into two groups according to the median SUVmax. The effects of SUVmax on progression-free survival (PFS) and overall survival (OS) were assessed using a multivariate Cox proportional hazards model. ResultsThe median SUVmax was 8.2 (interquartile range: 5.5–11.4). The median PFS in the high SUVmax group (≥8.2) was significantly shorter than that in the low SUVmax group (<8.2). The respective median PFSs were 11.2 months (95% confidence interval [CI]: 3.1–19.3 months) vs. 22.9 months (95% CI: 12.4–33.4 months) (P = 0.015), although the OS values did not differ significantly. Multivariate analysis showed that a high SUVmax was an independent negative predictive factor for PFS in patients treated with osimertinib (hazard ratio, 2.25; 95% CI: 1.15–4.39, P = 0.017). ConclusionsHigh primary-lesion SUVmax in patients with EGFR mutation-positive NSCLC correlated with shorter PFS with first-line osimertinib therapy, suggesting that SUVmax is a useful predictive marker for the antitumor efficacy of osimertinib.

Patient-reported outcomes for the phase 3 FURLONG study of furmonertinib versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer

Furmonertinib showed superior efficacy compared with gefitinib as first-line therapy in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in the FURLONG study. Here we present prespecified secondary endpoints of patient-reported outcomes (PRO). In this multicentre, double-blind, double-dummy, randomised phase 3 study, patients were 1:1 randomly assigned to receive furmonertinib 80mg once daily or gefitinib 250mg once daily. PROs assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 and Quality-of-Life Questionnaire Lung Cancer 13 were analysed using a mixed model for repeated measures and time-to-event analyses. A difference in score of 10 points or more was deemed clinically relevant. Three hundred and fifty-seven patients (furmonertinib group, n=178; gefitinib group, n=179) received at least one dose of the study drug, all of whom completed at least one PRO assessment. Statistically significant difference of overall score changes from baseline favoured furmonertinib in physical functioning (between-group difference 2.14 [95% CI 0.25-4.04], p=0.027), nausea/vomiting (-1.56 [95% CI-2.62 to-0.49], p=0.004), appetite loss (-2.24 [95% CI-4.26 to-0.23], p=0.029), diarrhoea (-3.36 [95% CI-5.19 to-1.54], p < 0.001), alopecia (-2.62 [95% CI-4.54 to-0.71], p=0.007), and pain in other parts (-4.55 [95% CI-7.37 to-1.74], p=0.002), but not reached clinical relevance. Time to deterioration in physical functioning (hazard ratio 0.63 [95% CI 0.42-0.94], p=0.021), cognitive functioning (0.73 [95% CI 0.54-0.98], p=0.034), nausea/vomiting (0.64 [95% CI 0.41-0.99], p=0.042), appetite loss (0.63 [95% CI 0.43-0.92], p=0.016), diarrhoea (0.63 [95% CI 0.46-0.85], p=0.002), dyspnoea (0.72 [95% CI 0.53-0.98], p=0.034), cough (0.67 [95% CI 0.44-1.00], p=0.049), dysphagia (0.54 [95% CI 0.35-0.83], p=0.004), and alopecia (0.62 [95% CI 0.42-0.90], p=0.012) was longer with furmonertinib versus gefitinib. In patients with locally advanced or metastatic EGFR mutation-positive NSCLC, furmonertinib showed improved scores and delayed deterioration in several functioning and symptoms compared to gefitinib. Shanghai Allist Pharmaceutical Technology Co., Ltd and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

Efficacy of lazertinib for symptomatic or asymptomatic brain metastases in treatment-naive patients with advanced EGFR mutation-positive non-small cell lung cancer: Protocol of an open-label, single-arm phase II trial.

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation has a higher incidence of brain metastases than wild-type EGFR mutations. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), targets both EGFR-TKI sensitizing and T790M-resistance mutations and has a higher brain penetration rate relative to first- and second-generation EGFR-TKIs. Therefore, osimertinib has become a preferred first-line therapy for advanced EGFR mutation-positive NSCLC. However, lazertinib, an emerging EGFR-TKI, has shown higher selectivity toward EGFR mutations and improved penetration of the blood-brain barrier compared to osimertinib in preclinical studies. This trial will evaluate the efficacy of lazertinib as a first-line therapy in patients with EGFR mutation-positive NSCLC who have brain metastases, with or without additional local therapy. This is a single-center, open-label, single-arm phase II trial. A total of 75 patients with advanced EGFR mutation-positive NSCLC will be recruited. Eligible patients will receive oral lazertinib 240 mg, once daily until disease progression or intolerable toxicity is detected. Patients with moderate to severe symptoms related to brain metastasis will simultaneously receive local therapy for the brain. The primary endpoints are progression-free survival and intracranial progression-free survival. Lazertinib, in combination with local therapy for the brain, if necessary, is expected to improve the clinical benefit in advanced EGFR mutation-positive NSCLC with brain metastases, as a first-line treatment.

Low BMI patients with advanced EGFR mutation-positive NSCLC can get a better outcome from metformin plus EGFR-TKI as first-line therapy: A secondary analysis of a phase 2 randomized clinical trial.

The synergistic association between metformin and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has been confirmed in in vitro studies. It is still controversial which patients can benefit from metformin plus EGFR-TKIs treatment. Body mass index (BMI) was proved to be independently associated with prolonged progression-free survival (PFS) and overall survival (OS). This study aimed to investigate whether BMI is associated with the synergistic effect of metformin and EGFR-TKIs in advanced EGFR mutation (EGFRm)-positive non-small cell lung cancer (NSCLC) among nondiabetic Asian population. We performed a post hoc analysis of a prospective, double-blind phase II randomized clinical trial (COAST, NCT01864681), which enrolled 224 patients without diabetes with treatment-naïve stage IIIB-IV EGFRm NSCLC. We stratified patients into those with a high BMI (≥24kg/m2) and those with a low BMI (<24kg/m2) to allow an analysis of the difference in PFS and OS between the two groups. The PFS and OS were analyzed using Kaplan-Meier curves, and the differences between groups were compared using log-rank test. In the univariate analysis, patients who had a high BMI (n=56) in the gefitinib + metformin group (n=28) did not have a better PFS (8.84 months vs. 11.67 months; P=0.351) or OS (15.58 months vs. 24.36 months; P=0.095) than those in the gefitinib + placebo group (n=28). Similar results were also observed in the low-BMI groups. Strikingly, in the metformin plus gefitinib group, patients who had low BMI (n=69) showed significantly better OS than those with high BMI (24.89 months [95% CI, 20.68 months-not reached] vs. 15.58 months [95% CI, 13.78-31.53 months]; P=0.007), but this difference was not observed in PFS (10.78 months vs. 8.84 months; P=0.285). Our study showed that nondiabetic Asian advanced NSCLC patients with EGFR mutations who have low BMI seem to get better OS from metformin plus EGFR-TKI treatment.

Safety and clinical activity of atezolizumab plus erlotinib in patients with non-small-cell lung cancer

Acquired resistance limits long-term epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) efficacy in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) in whom anti-programmed death-ligand 1 (PD-L1) efficacy is also limited. We hypothesized that combining atezolizumab with erlotinib could enhance antitumor immunity and extend efficacy in these patients. This open-label phase Ib trial was conducted in adults aged ≥18 years who had advanced, unresectable NSCLC. Stage 1 (safety evaluation) enrolled EGFR TKI-naive patients regardless of EGFR status. Stage 2 (expansion) enrolled patients with EGFR-mutant NSCLC treated with ≤1 prior non-EGFR TKI therapy. Patients received 150 mg erlotinib orally once daily. After a 7-day erlotinib run-in, atezolizumab 1200 mg was administered intravenously every 3 weeks. The primary endpoint was the safety and tolerability of the combination in all patients; secondary endpoints included antitumor activity per RECIST 1.1 in stage 2 patients. At the data cut-off on 7 May 2020, 28 patients (8 in stage 1, 20 in stage 2) were assessable for safety. No dose-limiting toxicities or grade 4 or 5 treatment-related adverse events occurred. Grade 3 treatment-related adverse events occurred in 46% of patients; the most common were increased alanine aminotransferase, diarrhea, pyrexia, and rash (each in 7% of patients). Serious adverse events occurred in 50% of patients. Pneumonitis (grade 1) was reported in a single patient (4%). The objective response rate was 75% [95% confidence interval (CI) 50.9% to 91.3%]), median response duration was 18.9 months (95% CI 9.5-40.5 months), median progression-free survival was 15.4 months (95% CI 8.4-39.0 months), and median overall survival was not estimable (NE) (95% CI 34.6-NE). Atezolizumab combined with erlotinib demonstrated a tolerable safety profile and encouraging, durable clinical activity in patients with advanced EGFR mutation-positive NSCLC.

Osimertinib in the Treatment of EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

Background: Non-small cell lung cancer (NSCLC) accounts for about 85% of generally reported lung cancer patients. Objectives: This is a systematic review of the clinical efficacy and safety of osimertinib in treating epidermal growth factor receptor (EGFR) mutation-positive advanced NSCLC. Methods: A network search was completed for clinical research literature (from inception of each database to May 30, 2020) on osimertinib for EGFR mutation-positive advanced NSCLC. Strict inclusion and exclusion criteria were formulated to screen the literature. After data extraction, RevMan 5.3 software was utilized for quality evaluation and meta-analysis. The primary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events of grades 3 and 4. Results: Finally, 6 eligible articles and a total of 1,848 patients containing 1,123 in experimental groups and 725 in control groups were included. Meta-analysis indicated that ORR (odds ratio [OR] = 3.40, 95% CI 1.64∼7.01, p = 0.0009), DCR (OR = 4.36, 95% CI 3.09∼6.15, p < 0.00001), PFS (HR = 0.36, 95% CI 0.27∼0.47, p < 0.00001), and OS (OR = 0.58, 95% CI 0.46∼0.72, p < 0.00001) of the experimental group were prominently better than the control group. Adverse events of grades 3 and 4 mainly incorporated decreased nausea, rash, stomatitis, and vomiting, which were dramatically relieved compared with the control group. Conclusion: Osimertinib is currently an appreciably effective and well-tolerated therapeutic avenue for EGFR mutation-positive advanced NSCLC.

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.

Observational study of rebiopsy in EGFR-TKI-resistant patients with EGFR mutation-positive advanced NSCLC

The identification of acquired resistance mutations has been essential in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) active mutations. Rebiopsy plays a pivotal role in selecting the optimal treatment for patients who develop resistance to initial EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This multicenter, observational study was conducted to investigate the details of rebiopsy in Japanese clinical practice. The primary endpoints were the implementation rate of rebiopsy and the concordance rate for T790M mutation detection between histological and cytological specimens using the cobas EGFR Mutation Test, version 2. One hundred ninety-four patients with EGFR-mutant NSCLC were enrolled, and 120 patients developed acquired resistance to EGFR-TKIs. The median age was 68 years (range 20–87), and 52.5% of the patients were women. Rebiopsy was performed in 109 patients, and the implementation rate of rebiopsy was 90.8%. The success rates of rebiopsy in the total, histology, cytology and liquid biopsy populations were 67.9%, 81.3%, 66.7% and 43.8%, respectively. The positive percent agreement and the negative percent agreement in the detection of the T790M mutation between the histological and cytological specimens were both 90.9%. Obtaining histological or cytological tissue samples at rebiopsy may contribute to improving the detection rate of the T790M mutation (trial registration number: UMIN000026019).

Chinese Herbal Medicine (Yiqi-Yangyin-Jiedu Decoction) Combined With Osimertinib as First-Line Treatment in EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer (CATLA-2): A Study Protocol for a Double-Blind Randomized Controlled Trial.

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) significantly improve the prognosis of non-small cell lung cancer (NSCLC) with EGFR mutation-positive. Although third-generation EGFR-TKI osimertinib is demonstrated with superior efficacy compared with first-generation EGFR-TKIs, acquired resistance to EGFR-TKIs remains the bottleneck. The Chinese herbal medicine (CHM) Yiqi-Yangyin-Jiedu decoction (YYJD) has been shown to delay acquired resistance to first-generation EGFR-TKIs in the CATLA study, but there is no high-level evidence for its effect when combined with osimertinib. This trial aims to evaluate the efficacy and safety of YYJD combined with osimertinib as first-line treatment in EGFR mutation-positive advanced NSCLC. Methods: This is a double-blind, multi-center, randomized controlled trial conducted in eight hospitals in China. A total of 314 participants will be randomly assigned to the osimertinib plus YYJD group (O+YYJD) or the osimertinib plus placebo group (O+placebo). Treatment will last until disease progression or death. Patients diagnosed with advanced NSCLC harboring EGFR Ex19del or L858R will be enrolled if they are ready to take osimertinib as first-line treatment, aged 18–74 years old, and provide signed informed consent. The primary outcome is progression-free survival (PFS). The secondary outcomes include a comparison of overall survival (OS), objective response rate (ORR), disease control rate (DCR), and quality of life (QoL). The analysis will be based on intention-to-treat and per-protocol subject analysis principles. Discussion: The goal of this trial is to evaluate the efficacy and safety of YYJD when added to osimertinib as first-line treatment in EGFR mutation-positive advanced NSCLC.

Aumolertinib: A Review in Non-Small Cell Lung Cancer.

Aumolertinib (formerly almonertinib; Ameile®) is an oral, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) that is selective for mutant EGFR over wild-type EGFR. It has been developed for the treatment of advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). In the phase3 AENEAS trial conducted in Chinese patients, aumolertinib as first-line treatment significantly prolonged progression-free survival (PFS) and duration of response (DoR) compared with gefitinib in patients with advanced EGFR mutation-positive NSCLC; overall survival (OS) data from this study are immature. In the phase1/2 APOLLO trial, aumolertinib showed good clinical activity (based on objective response rate, PFS, DoR and OS) in Chinese patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who had progressed on or after prior EGFR-TKI therapy. Aumolertinib has a generally manageable tolerability profile; adverse events associated with wild-type EGFR inhibition (e.g. rash and diarrhoea) were less frequent with aumolertinib than gefitinib in AENEAS. Thus, aumolertinib is a promising new option for both first-line and second-line treatment in patients with advanced EGFR mutation-positive NSCLC.

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).

A prospective, phase II trial of monotherapy with low-dose afatinib for patients with EGFR, mutation-positive, non-small cell lung cancer: Thoracic oncology research group 1632

ObjectivesAfatinib is an effective treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, the toxicity associated with this agent often leads to dose modifications. The aim of this study was to assess the efficacy, safety and plasma concentrations of low dose afatinib monotherapy in patients with EGFR mutation-positive NSCLC. Patients and MethodsThis was a multicenter, single-arm, open-label, phase II trial involving treatment-naïve patients with advanced EGFR mutation-positive NSCLC. From March 2017 to September 2018, 53 patients were enrolled from 21 institutions in Japan.Patients initially received afatinib 20 mg/day orally. For patients in whom the tumor progressed within stable disease, the investigators were able to increase the afatinib dose (10 mg increments). The primary endpoint was progression-free survival (PFS). The threshold and expected median PFS was 9.2 and 13.8 months, respectively. Additionally, the correlation of the plasma concentration of low-dose afatinib with clinical outcome and adverse events were evaluated. ResultsThe median age of patients was 70 years (range: 37–85 years); 28 patients (52.8%) were females. The median duration of the follow-up was 20.8 months. The median PFS, and overall survival were 12.6 months (90% confidence interval [CI]: 9.7–14.3 months), and not reached, respectively. The primary endpoint was met. The objective response rate and disease control rate were 66.0% (95% CI: 51.7–78.5) and 92.5% (95% CI: 81.8–97.9), respectively. Grade ≥ 3 adverse events occurred in 12 patients (22.6%), including diarrhea in four patients (7.5%). The rate of adverse events was lower than that observed in previous phase III studies of 40 mg afatinib. ConclusionBased on its promising clinical efficacy and tolerability profile, monotherapy with low-dose afatinib should become one of the standard therapies for EGFR mutation-positive NSCLC.

An Observational Study to Assess the Molecular Epidemiology and Direct Medical Costs of Epidermal Growth Factor Receptor (EGFR) Mutations in Patients with Advanced EGFR Mutation-Positive Non-Small Cell Lung Cancer Treated with Afatinib in Real-World Clinical Settings in Greece.

PurposeEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line option for patients with advanced, EGFR-mutant non-small cell lung cancer (NSCLC). Afatinib, a second-generation irreversible EGFR-TKI, has been extensively used in Greece in this setting; however, real-world data regarding molecular epidemiology and financial implications of afatinib use are lacking.Materials and MethodsThis was an observational, non-interventional, multicenter, retrospective cohort study, based on real-world data collected from the medical charts/records of patients treated with afatinib between 15/03/2015 and 25/06/2020 and were recorded on a web-based data capture system. Cox models were used to assess the prognostic significance of clinicopathological parameters with respect to clinical outcomes of interest. Cost analysis was conducted from a public third-payer perspective, and only direct medical costs reimbursed by the payer were considered.ResultsA total of 59 patients were treated with afatinib for their EGFR mutation-positive advanced NSCLC; the median age was 61 years (range: 37–91). Performance status was zero in 61%, and brain metastases were present in 13.6%. Forty-four patients (74.6%) had a deletion in exon 19 only, while nine (15.3%) had a mutation in exon 21, 8 of them in L858R and one in L861Q. At a median follow-up of 41.8 months (95% CI 35.9–51.4), the median PFS was 14.3 months (95% CI 12.2–16.4), and the median OS was 29 months (95% CI 25.6–33.4). Corresponding values for patients with deletion 19 only were 14.3 months (95% CI 11.5–18.5) and 28.1 months (95% CI 21.1–32.6), respectively. The mean expenditure for the treatment of each patient equals €25,333.68; with €21,865.06 being attributed to drug acquisition costs, €3325.35 to monitoring costs and €143.27 to adverse event treatment-related costs.ConclusionLong-term data in the real-world setting in Greece confirm activity, tolerability and cost-effectiveness of afatinib as first-line treatment of patients with advanced EGFR-mutant NSCLC.Clinical Trial RegistrationClinicaltrials.gov NCT04640870.

Cost-effectiveness analysis of dacomitinib versus gefitinib for the first-line therapy of patients with EGFR mutation-positive non-small-cell lung cancer in the United States and China.

BackgroundThis study aimed to investigate the cost-effectiveness of dacomitinib and gefitinib for the first-line treatment of advanced non-small-cell lung cancer (NSCLC) in epidermal growth factor receptor (EGFR) mutation-positive patients from the perspective of healthcare systems in the United States and China.MethodsA Markov model, which included 3 health states over 10 years, was established in this study. The state transition probabilities and clinical data were extracted from the ARCHER 1050 trial (dacomitinib versus gefitinib in patients with EGFR mutation-positive advanced NSCLC). Health utilities were derived from published literature. Based on the healthcare system payer’s perspective in the United States and China, the cost data were estimated from local pricing or the relevant literature. The health outcomes are expressed by quality-adjusted life years (QALYs). All costs and incremental cost-effectiveness ratios (ICERs) are presented in US dollars. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to test the robustness of the results.ResultsIn the United States, compared with gefitinib, dacomitinib yielded an additional 0.55 QALYs, while the ICERs were $600.69 per QALY. The cost of dacomitinib was the most influential parameter. The willingness payment curve showed that dacomitinib was cost-effective at the $100,000/QALY willingness-to-pay (WTP) threshold. Meanwhile, when the WTP threshold was higher than $200,000/QALY, the probability of dacomitinib being the best treatment plan was more than 80%. In China, compared with gefitinib, dacomitinib was associated with a mean healthcare savings of $160,173.27 and 0.41 additional QALYs per patient, which was a dominant intervention over a 10-year time horizon. The cost of progressive disease was shown to have the strongest impact on the results. Dacomitinib had more than a 90% probability of being chosen as the preferred therapy when the Chinese WTP threshold was $27,000/QALY.ConclusionsAs the first-line treatment for EGFR mutation-positive NSCLC, dacomitinib is likely to be more cost-effective than gefitinib from the healthcare system’s perspective in the United States and China.

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.

A prospective phase II study of multimodal prophylactic treatment for afatinib-induced adverse events in advanced non-small cell lung cancer (Niigata Lung Cancer Treatment Group 1401).

BackgroundAfatinib has shown clinical benefits in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Many patients treated with afatinib experience skin or gastrointestinal toxicity. However, an effective management strategy has not been established. This prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity.MethodsThis single-arm prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity in patients with EGFR mutation positive advanced NSCLC who planned to receive a 40 mg dose of afatinib. Eligible patients were treated with oral loperamide (2 mg twice per day), prophylactic minocycline (100 mg once per day), topical medium-class steroids, and gargling with sodium azulene. The primary endpoint was the ability of prophylactic loperamide to prevent severe or intolerable diarrhea during the 4 weeks after the initial administration of afatinib. The incidence, severity and time to occurrence of diarrhea, rash, oral mucositis and paronychia were evaluated based on a daily patient questionnaire.ResultsForty-six patients were enrolled. The primary endpoint analysis was performed in 35 patients as the per-protocol (PP) population. The 4-week successful prophylaxis rate for severe or intolerable diarrhea was 82.9% (90% confidence interval: 70.1–91.9%). In the total population, the incidences of grade 3 or higher rash, oral mucositis and paronychia within 4 weeks were 4%, 2% and 4%, respectively.ConclusionsProphylactic loperamide administration was not effective in preventing severe or intolerable diarrhea during afatinib treatment. Adequate dose reduction will be a better approach to manage afatinib-induced diarrhea. Multimodal prevention using minocycline, topical steroids and gargling with sodium azulene may be helpful to maintain compliance with afatinib treatment (UMIN000016167).

Effect of Dose Adjustments on the Safety and Efficacy of Afatinib in Chinese Patients with EGFR-Mutated Non-Small Cell Lung Cancer Who Participated in the LUX-Lung Clinical Trial Program.

BackgroundPost hoc analysis of the LUX-Lung 3 and 6 (LL3/6) Phase III trials showed that tolerability-guided dose-adjustments of afatinib reduced treatment-related adverse events (TRAEs) without affecting progression-free survival (PFS) in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). The current post hoc analysis evaluated outcomes of tolerability-guided dose adjustments of afatinib in patients enrolled in the LL3/6/7 trials in Chinese centers.Patients and MethodsPatients enrolled in LL3/6/7 had advanced EGFR mutation-positive NSCLC. LL3 and LL7 recruited patients globally (including China) and LL6 enrolled Asian patients from China, Thailand, and South Korea. In LL3 and LL6, patients were randomized to afatinib 40 mg/day or cisplatin-based chemotherapy. In the Phase IIb LL7 trial, patients were randomized to afatinib 40 mg/day or gefitinib. Tolerability-guided dose adjustments were permitted for TRAEs, and PFS was the primary endpoint. This post hoc analysis pooled data from patients enrolled in Chinese centers in LL3/6/7 and analyzed the frequency and severity of TRAEs before and after afatinib dose reductions during the first 6 months. PFS and overall survival (OS) were compared for patients who had a dose reduction in the first 6 months and those who did not.ResultsOverall, 299 patients were enrolled in Chinese centers; 68 (23%) had afatinib dose reductions to <40 mg/day in the first 6 months. Prior to dose reduction, 55/68 patients (81%) experienced grade ≥3 TRAE versus 13/68 (19%) after dose reduction. Grade ≥3 TRAEs were much more common in patients with than in those without dose reduction. Median PFS was 11.0 months in both groups, and median OS did not differ significantly: 23.1 months in patients with a dose reduction and 26.9 months in those without a dose reduction.ConclusionTolerability-guided afatinib dose adjustment is an effective strategy to reduce TRAEs without affecting efficacy in Chinese patients.

Abstract CT024: Utility of longitudinal circulating tumor DNA (ctDNA) modeling to predict RECIST-defined progression in first-line patients with epidermal growth factor receptor mutation-positive (EGFRm) advanced non-small cell lung cancer (NSCLC)

Abstract Circulating tumor DNA is released into the bloodstream from tumors and can reflect both intra-tumor heterogeneity and clonal evolution.1 As ctDNA levels are thought to reflect tumor burden, a decrease in ctDNA while on therapy may suggest treatment efficacy.2 We assessed whether longitudinal changes in ctDNA could supplement or improve RECIST-based measures for decision making during drug development. Plasma samples collected at regular intervals were analyzed to predict the risk of disease progression in patients with EGFRm (Ex19del or L858R) advanced NSCLC following initiation of first-line EGFR tyrosine kinase inhibitor (TKI) treatment in the FLAURA study (NCT02296125). Of 556 patients who received treatment (osimertinib 80 mg daily [QD] or comparator EGFR-TKI [gefitinib 250 mg QD or erlotinib 150 mg QD]), 353 (63%) had an available sample with detectable levels of ctDNA at baseline. Patients with both imaging and ctDNA samples at baseline and 3 additional timepoints (n=320, the analysis set) were divided (as implemented in caret R package)3 into training (n=259) and validation (n=61) cohorts. Clinical data from these patients (data cut-off: June 12 2017) were used to fit joint models of either ctDNA dynamics or sum of the longest tumor diameters (SLD) and progression-free survival (PFS). Longitudinal ctDNA levels were measured using droplet digital PCR (ddPCR; Biodesix®) for EGFR-TKI sensitizing mutations (Ex19del or L858R) in all available samples. Model covariates were selected based on their statistical significance for the longitudinal and hazard sub-models and were analyzed using JMbayes package as implemented in R software (3.5.1). Our analysis indicates that the joint model can independently characterize changes in ctDNA and SLD and can predict PFS in the validation cohort, using only ctDNA changes occurring within 6 weeks from the initiation of therapy. Similarly, in the training cohort, joint modelling indicates that the relationship between SLD and PFS using RECIST is consistent with the longitudinal ctDNA analysis. In the analysis set, our model estimated a PFS of 16.6 months (95% confidence interval [CI] 12.1, NC) for osimertinib (n=153) and 9.4 months (95% CI 8.0, 13.5) for comparator EGFR-TKI (n=167). Model-predicted PFS probability using either ctDNA or SLD data was similar, suggesting ctDNA dynamics may provide similar information to RECIST for clinical decision making. Based on this analysis, ctDNA dynamics could be utilized to predict RECIST-defined progression for decision making during drug development of treatments for patients with NSCLC.

P1.16-36 Treatment Patterns Among Patients with EGFRm NSCLC Treated in the US Community Oncology Setting

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is associated with improved outcomes in patients with EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Despite initial responses, most patients develop resistance. Little is known about treatment following first-line (1L) TKIs. This study aimed to understand real world treatment patterns, T790M testing rates, and disposition of EGFRm patients following availability of newer TKIs. Adult patients with EGFRm stage IV NSCLC treated between Dec 1, 2015 and Aug 31, 2017, were retrospectively identified from the US Oncology Network’s iKnowMedSM (iKM) electronic health record. Patient characteristics, treatment patterns, and T790M testing data were obtained via programmatic database abstraction and supplemented with chart review. 308 patients were identified during the study period. Median age at diagnosis was 69 years, 67% were female, 63% Caucasian, 49% never smokers and 59% with ECOG performance status 0–1. Nearly all patients (n=302; 98%) received treatment with a TKI, 80% (n=246) with a TKI as 1L therapy. The most frequently used TKIs as 1L monotherapy were erlotinib (n=204; 66%), afatinib (n=27; 9%), and gefitinib (n=3; 1%). Combination chemotherapy with or without a TKI was used in 24% of patients. Among all patients treated with a 1L TKI, 19% (n=47) were tested for the T790M mutation after 1L TKI, and 34% (n=16) were positive. The most common 2L therapies in patients who received a 1L TKI (n=44 patients) were pemetrexed-based chemotherapy (n=20; 45%), afatinib (n=7; 16%), and osimertinib (n=7; 16%). Among all patients who received a 1L TKI, 15% (n=41) had died, 18% (n=51) were still alive and on TKI therapy, 12% (n=29) went on to receive subsequent therapy, and 53% (n=149) stopped their TKI and received no subsequent therapy at the end of the follow-up period. The majority of patients with EGFRm advanced NSCLC received 1L TKI therapy, most often with erlotinib. Following 1L TKI, less than 20% of patients were tested for T790M, and most did not receive any subsequent therapy following TKI. As understanding of resistance mechanisms in mutation-driven lung cancer is rapidly evolving, and as ongoing studies evaluate optimal treatments, it is imperative to integrate this information into clinical practice.

Cost-effectiveness of tyrosine kinase inhibition in first-line treatment of patients with EGFR-mutated advanced non-small cell lung cancer.

e20504 Background: Patients with advanced non-small cell lung cancer (NSCLC) harbouring an epidermal growth factor receptor (EGFR) mutation have improved survival with tyrosine kinase inhibitor (TKI) treatments, but the economic efficiency of this application is unclear, especially in limited health resource settings. To inform policy makers about the value of these medications, we developed a Markov model to compare the cost-effectiveness of these strategies. Methods: A Markov model was developed to compare the cost-effectiveness of chemotherapy, gefitinib, erlotinib, afatinib and osimertinib treatments from a public payers’ perspective in the U.S and China. Health states consisted of progression-free survival, progressive disease, and death. Model transition, adverse event probabilities, disease progression, and death were obtained from randomized clinical trials and network meta-analysis. Costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) over a 10-year lifetime horizon were calculated. One-way and probabilistic sensitivity analyses were performed by multiple potentially modifiable parameters. Results: The tyrosine kinase inhibitors were more cost-effective than chemotherapy treatment in both the U.S and China. In the U.S, compared with erlotinib, afatinib had an ICER of $241,420/QALY while osimertinib had an ICER of $351,315/QALY. In China, the incremental utility for osimertinib versus gefitinib was 0.68QALYs, and the ICER was $25,622/QALY. The probability sensitivity analyses also illustrated that the erlotinib was the optimal treatment at a willingness-to-pay (WTP) threshold of $150,000/QALY in the U.S and osimertinib was the most cost-effective treatment at a WTP of $26,508/QALY in China. Conclusions: Based on our current analysis, erlotinib appears to be the preferred first-line treatment for advanced EGFR mutation-positive NSCLC patients in the US at a WTP of $150,000/QALY. However, because of the price reduction and more health benefits, osimertinib was considered to be most cost-effective at a WTP of $26,508/QALY in China.