Metastatic EGFR-mutant NSCLC Research Articles

Advancing evidence-based decisions in the management of EGFR-mutated metastatic NSCLC.

e20663 Background: In patients diagnosed with metastatic NSCLC it is now essential to identify targetable mutations and markers of treatment resistance in order to determine the appropriate therapy. A study was conducted to determine if simulation-based educational interventions to address clinical practice gaps could improve decisions of oncologists in the management of EGFR-mutated metastatic NSCLC. Methods: A cohort of US-oncologists who participated in a virtual patient simulation (VPS)-based education was evaluated. The VPS consisted of 2 cases that allowed oncologists to assess the patient and choose from a database of diagnostic possibilities matching the scope and depth of practice. Clinical decisions were analyzed using a decision engine, and instantaneous clinical guidance (CG) employing current evidence-based and expert faculty recommendations was provided after each decision. Oncologists were allowed a second chance at each decision point and decisions before and after CG were compared using a 2-tailed paired T-test to determine differences from pre- to post CG. P values are shown as a measure of significance; with P < .05 statistically significant. Results: 197 oncologists made clinical decisions within the simulation. As a result of CG, significant improvements were observed in: Ordering EGFR mutational testing (16%, P= 0.008) and making an accurate diagnosis (36%) Selecting an EGFR TKI in the first-line setting (24%, P< 0.001) Ordering a PET scan to assess disease progression (10%) and in diagnosing patients with EGFR T790M disease that is resistant (29% , P< 0.001) Evidence-based treatment selection for individuals whose disease progressed on first-line therapy (19%, P= .003) Number of oncologists who ordered adverse event education and counseling (23%, P< .001) Conclusions: This study showed improvements in evidence-based practices of oncologists in the diagnosis and management of EGFR-mutated NSCLC; demonstrating that VPS-based instruction that immerses and engages oncologists for an authentic, practical and16. consequence-free learning experience can result in an increase in appropriate clinical decisions. Therefore, VPS may have a role in improving the quality of patient care.

Clinical outcome of EGFR-mutant NSCLC patients continuing TKIs beyond progression in combination with local ablative radiotherapy.

e20662 Background: Continuation of EGFR TKIs with or without local ablative treatments in patients with metastatic EGFR-mutant NSCLC experiencing disease progression under TKIs is feasible and may be associated with improved outcomes. Methods: The retrospective analysis includes 130 patients with advanced EGFR-mutant NSCLC experiencing RECIST disease progression under first-line gefitinib or afatinib, treated in 3 Italian centers between 2011 and 2016. In group 1 (n = 99, 76.2%) patients stopped TKI treatment at first RECIST-confirmed progression while in group 2 (n = 31, 23.8%) TKIs were continued and sites of progression were irradiated. The primary endpoint was overall survival (OS). Progression-free survival (PFS) and time to treatment failure (TTF) were calculated from the start of first-line TKIs. Kaplan-Meier method, the log-rank test and multivariate Cox regression models were used to estimate outcome endpoints. Median follow-up time was 40 months. Results: Median OS, PFS and TTF in the whole cohort were 22.4, 11.1 and 13.0 months, respectively. The two groups resulted well balanced in terms of patients’ characteristics and TKI administered. Median OS was significantly longer in group 2 (37.3 vs 15.6 months; HR 0.33; 95%CI 0.22-0.50; p < 0.0001), as well as median PFS (13.8 vs 8.9 months; HR 0.60; 95%CI 0.42-0.86; p = 0.01) and median TTF (29.3 vs 10.4 months; HR 0.30; 95%CI 0.21-0.44; p < 0.0001). Ten out of 31 (32.3%) patients underwent radiotherapy in ≥2 sites of progressive disease; the most frequently irradiated site was bone (n = 16), followed by brain (n = 9), lung (n = 8) and lymph nodes (n = 6). On multivariate analysis including age, sex, smoking history, mutant exon, presence of brain metastases, TKI administered and treatment strategy at progression, only TKI continuation with radiotherapy was independently associated with all outcome endpoints (OS: p = 0.0007, PFS: p = 0.004; TTF: p < 0.0001). Conclusions: In EGFR-mutant NSCLC progressing under first-line TKIs continuation of TKI in association with local ablative radiotherapy is associated with prolonged OS, PFS and TTF. Whether the improved outcome is a result of treatment strategy or more indolent disease remains unclear.

Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib

ObjectivesPatients with metastatic EGFR-mutant (mEGFRmt) NSCLC have favorable survival when treated with erlotinib. We hypothesized that treatment failure in most patients is limited to initial sites of disease, in which case incorporating local therapy such as radiation might further delay progression. We therefore analyzed patterns and predictors of failure in a large cohort of such patients. Materials and methodsWe reviewed 189 patients treated with erlotinib for mEGFRmt NSCLC. We classified first pattern of failure as involving initial sites only (ISF), new sites only (NSF), or the combination (CSF), and used competing-risks regression to identify factors associated with ISF, progression and overall survival (OS). We also separately analyzed intracranial and intrathoracic failure. ResultsOf 171 patients who progressed, 103 (60.2%) had ISF, 30 (17.5%) had NSF, and 38 (22.2%) had CSF. Younger age and lack of initial CNS involvement independently correlated with ISF, with a trend for higher T and N stage. Higher T and N stage was also a significant predictor of progression. Factors predicting shorter OS were female gender, weight loss, initial intracranial involvement, and ≥4 extracranial metastases. Intrathoracic progression was a component of first failure in 61%, and three-year cumulative incidence of brain metastasis was 30%. ConclusionThe main pattern of progression in mEGFRmt NSCLC on erlotinib is in the initial sites of disease. Younger patients and those without brain involvement are particularly likely to develop ISF. This suggests a role for incorporating local therapy into treatment of selected patients with mEGFRmt NSCLC.

Clinical predictors of 5-year survival in patients with EGFR-mutant metastatic NSCLC treated with EGFR-TKIs.

8071 Background: Activating mutations of the epidermal growth factor receptor (EGFR) were discovered over 10 years ago. EGFR mutations predict increased response rates and progression-free survival...

Pattern of Failure in Metastatic EGFR-Mutant NSCLC Treated With Erlotinib: A Role for Upfront Radiation Therapy?: Metastatic Non-Small Cell Lung Cancer

Pattern of Failure in Metastatic EGFR-Mutant NSCLC Treated With Erlotinib: A Role for Upfront Radiation Therapy?: Metastatic Non-Small Cell Lung Cancer

Pattern of Failure in Metastatic EGFR-Mutant NSCLC Treated With Erlotinib: A Role for Upfront Radiation Therapy?

Pattern of Failure in Metastatic EGFR-Mutant NSCLC Treated With Erlotinib: A Role for Upfront Radiation Therapy?

Activity of the EGFR-HER2 Dual Inhibitor Afatinib in EGFR-Mutant Lung Cancer Patients With Acquired Resistance to Reversible EGFR Tyrosine Kinase Inhibitors

BackgroundThe purpose of this study was to evaluate the efficacy of afatinib in EGFR-mutant metastatic NSCLC patients with acquired resistance to erlotinib or gefitinib. Materials and MethodsWe retrospectively analyzed the outcome of patients with EGFR-mutant advanced NSCLC treated with afatinib after failure of chemotherapy and EGFR TKIs. ResultsA total of 96 individuals were included in the study. According to EGFR status, most patients (n = 63; 65.6%) harbored a deletion in exon 19, and de novo T790M mutation was detected in 2 cases (T790M and exon 19). Twenty-four (25%) patients underwent repeated biopsy immediately before starting afatinib and secondary T790M was detected in 8 (33%) samples. Among the 86 patients evaluable for efficacy, response rate was 11.6%, with a median progression free-survival (PFS) and overall survival (OS) of 3.9 and 7.3 months, respectively. No significant difference in PFS and OS was observed according to type of last therapy received before afatinib, type of EGFR mutation or adherence to Jackman criteria, and patients benefiting from afatinib therapy had longer PFS and OS (P < .001). Outcome results for repeated biopsy patients were similar to the whole population, with no evidence of response in T790M-positive patients. All patients were evaluable for toxicity, and 81% experienced an AE of any grade, with grade 3 to 4 AEs, mainly diarrhea and skin toxicity, occurring in 19 (20%) patients. ConclusionOur results showed that afatinib has only modest efficacy in a real life population of EGFR mutant NSCLC patients with acquired resistance to erlotinib or gefitinib.

A phase II trial of induction gefitinib monotherapy followed by cisplatin-docetaxel and concurrent thoracic irradiation in patients with EGFR-mutant locally advanced non-small-cell lung cancer (LA-NSCLC): LOGIK0902/OLCSG0905 intergroup trial.

7045 Background: We previously reported efficacy and safety of cisplatin-docetaxel and concurrent thoracic radiotherapy (TRT) for LA-NSCLC (Segawa Y and Kiura K. JCO 2010). However, its cure rate remains unsatisfied, and further improvement in the treatment outcome is strongly warranted. Recently, systemic chemotherapy has been individualized by intensive anti-cancer researches through the discovery of certain molecular targets in the metastatic NSCLC. Especially, gefitinib, EGFR tyrosine kinase inhibitor, is quite active and now one of the standard chemotherapy for untreated metastatic EGFR-mutant NSCLC (Maemondo M and Inoue A. NEJM 2010). Even in the locally advanced setting, approximately 30% of Japanese NSCLC patients possess EGFR-mutant tumors. Given all of these backgrounds, investigation on the role of adding gefitinib monotherapy to the standard concurrent chemoradiotherapy might cause a new paradigm shift in this setting. Methods: Patients have to meet the following eligibility criteria: LA-NSCLC; active tumor EGFR mutations (exons 19 and 21) but without 790M; measurable lesions; performance status (PS) of 0 or 1; age &lt; 75 years; and V20 ≤ 35%. The primary endpoint is set as 2-year progression-free survival (PFS) rate; assuming that 75% in eligible patients would indicate potential usefulness, whereas 60% would be the lower limit of interest (α = 0.05, ß = 0.20), the estimated accrual number is 46 patients. The secondary endpoint includes toxicity, response rate and overall survival. Patients will receive the induction treatment, specified as gefitinib monotherapy (250 mg/body) for 8 weeks. Patients who have not progressed during the induction therapy will receive cisplatin and docetaxel (40 mg/m2; days 1, 8, 29, 36, each) and concurrent three-dimensional conformal TRT (2-Gy, single, daily fractions for 5 consecutive days each week to provide a total dose of 60 Gy). Enrollment began in 2010, and will complete by 2015. UMIN registration number of 000005086.

Abstract 4901: Preliminary investigation of circulating NSCLC cells using dielectrophoresis-based instrumentation

Abstract Aims: The study of rare cell populations is an extremely important field in cancer research. Our main aim was to carry out a preliminary investigation into a new technological platform capable of identifying and studying rare tumor cells in whole blood samples from patients with advanced cancer. Methods: The study was performed using DEPArray™, a new dielectrophoresis-based instrumentation capable of detecting, examining and sorting circulating tumor cells (CTCs) in a very small quantity (microliters) of enriched whole blood. Analyses were conducted on 3 blood samples from patients with EGFR-mutated metastatic NSCLC and on 15 samples composed of A549 cells spiked into the whole blood of healthy donors. Whole blood starting volume was 7.5 ml. After Ficoll-Paque centrifugation, tumor cells were immunomagnetically enriched via EpCam positive selection or CD45 negative depletion and then fixed and stained with Hoechst and fluorescent conjugated antibodies against CD45 and pan-cytokeratin. Cell recovery was followed by EGFR gene mutation evaluation through sequence analysis. Results: Preliminary data showed that DEPArray™ detected, isolated and sorted enriched CTCs with 100% purity, with no lymphocyte contamination in subsequent analyses. Single or multiple cell sorting was possible, making it simple to perform different downstream molecular assays. In particular, the EGFR gene mutation status of NSCLC was studied to find out whether mutations were present or whether gene status remained that observed in the primary tumor tissue. Although it was decided to work on fixed cells during the investigation of this first set of samples, DEPArray™ is also capable of sorting live cells with high specificity. Conclusions: The study of infrequent tumor or tumor-related cells such as circulating tumor cells, cancer stem cells and/or circulating endothelial cells is an increasingly important area of research from both a preclinical and clinical point of view. A growing number of studies have evaluated different methods and variables involved in the detection of rare cells, in particular CTCs, but there is still no general consensus on the most accurate method to use. DEPArray™ is an innovative dielectrophoresis-based instrument capable of identifying, manipulating and sorting rare live and fixed cells with extremely high purity. Although the most accurate markers to discriminate between normal epithelial cells and tumor cells have yet to be defined, DEPArray™ has already proven to be extremely versatile in the field of rare cell studies, introducing new possibilities such as 100%-pure retrieval of live cells and furthering its potential as a promising new strategy for cancer cell detection and characterization. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4901. doi:10.1158/1538-7445.AM2011-4901