Epidermal Growth Factor Receptor Wild-type Tumors Research Articles

A rare case of Exon 19 deletion transforming to Exon 20 insertion in a case of adenocarcinoma of lung

Epidermal growth factor receptor (EGFR) gene mutations play an important role in the presentation, prognosis, and management of non-small cell lung cancer (NSCLC) patients. Several clinical studies claimed the incidence of EGFR Exon 20 insertion mutations in NSCLC and have similar clinical characteristics to those with common EGFR mutations but poorer prognosis. Insertion mutations within the Exon 20 of the EGFR gene are typically located after the C-helix of the tyrosine kinase to result in the domain of EGFR and have been reported to increase the kinase activity of the protein. This eventually leads to the ligand-independent activation of several downstream pathways such as mitogen activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (Pi3K)-(mTOR) mammalian target of rapamycin pathways, which are involved in several cellular processes such as cell proliferation, metastasis, and migration while preventing apoptosis. Thus, EGFR exon insertion mutations are gain of function mutations. Specific EGFR and frame-in insertions occur in 3–7% of NSCLC and are known to predict primary resistance to treatment with all clinically available EGFR-tyrosine kinase inhibitors (TKIs). Many clinical and preclinical studies have reported significant antitumor activity with various first and second-generation EGFR TKIs such as Erlotinib, Gefitinib, and Afatinib and have led to prolonged survival in EGFR mutated patients, as compared to wild-type EGFR tumors with chemotherapy. In addition, third-generation EGFR TKIs, such as Osimertinib, have shown encouraging results in metastatic NSCLC patients harboring EGFR mutations including EGFR, p. Thr790Met-mutations, that have shown to confer resistance to first and second-generation EGFR TKIs and who have progressed on prior TKI therapy. Drugs such as Afatinib, Dacomitinib, Erlotinib, Gefitinib, and Osimertinib have already gained FDA approval for use in EGFR-mutated metastatic NSCLC patients. Here, we report the case of a 47-year-old man who is a non-smoker with an EGFR Exon 19 positive NSCLC treated with Gefitinib developed an EGFR Exon 20 insertion positive brain metastasis initiated on Afatinib as the targeted therapy and responded well to the treatment.

Lazertinib: on the Way to Its Throne.

Lazertinib is an oral, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that forms an irreversible covalent bond to the Cys797 residue in the ATP-binding site of the EGFR kinase domain and exhibits a high selectivity for sensitizing and T790M EGFR mutations. In January 2021, it was first approved for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) patients with EGFR T790M who had previously received EGFR TKI therapy based on LASER201, a phase I/II trial. At a recommended dose of 240 mg, lazertinib achieved an encouraging anti-tumor activity in both extra- and intracranial lesions. With a high half-maximal inhibitory concentration for EGFR wildtype tumors, it is anticipated to pose a lower risk of skin and cardiac adverse events compared to osimertinib. Lazertinib is currently being investigated as a monotherapy in first-line treatment and in combination with amivantamab under various settings. In this review, we systematically summarize the preclinical and clinical data of lazertinib and discuss future perspectives on the treatment of EGFR-mutant NSCLC.

Dysregulation of TFH-B-TRM lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer

Patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations exhibit an unfavorable response to PD-1 inhibitor through unclear mechanisms. Hypothesizing that EGFR mutations alter tumor-immune interactions, we compare tumor-infiltrating lymphocytes between EGFR mutant (EGFR-MT) and wild type (EGFR-WT) tumors through single-cell transcriptomic analysis. We find that B cells, CXCL13-producing follicular helper CD4+ T (TFH)-like cells, and tissue-resident memory CD8+ T (TRM)-like cells decreased in EGFR-MT tumors. The NOTCH-RBPJ regulatory network, which is vital for persistence of TRM state, is perturbed, and the interactions between TFH and B cells through the CXCL13-CXCR5 axis disappear in EGFR-MT tumors. Notably, the proportion of TRM-like cells is predictive for anti-PD-1 response in NSCLC. Our findings suggest that the impairment of TFH-B-TRM cooperation in tertiary lymphoid structure formation, accompanied by the dysregulation of TRM homeostasis and the loss of TFH-B crosstalk, underlies unfavorable anti-PD-1 response in EGFR-MT lung tumors.

Phase I/II Study of Capmatinib Plus Erlotinib in Patients With MET-Positive Non-Small-Cell Lung Cancer.

PURPOSEMET dysregulation is an oncogenic driver in non–small-cell lung cancer (NSCLC), as well as a mechanism of TKI (tyrosine kinase inhibitor) resistance in patients with epidermal growth factor receptor (EGFR)–mutated disease. This study was conducted to determine safety and preliminary efficacy of the combination EGFR and MET inhibitors as a strategy to overcome and/or delay EGFR-TKI resistance.METHODSA standard 3 + 3 dose-escalation trial of capmatinib in combination with erlotinib in patients with MET-positive NSCLC was used. Eighteen patients in the dose-escalation cohort received 100-600 mg twice daily of capmatinib with 100-150 mg daily of erlotinib. There were two dose-expansion cohorts. Cohort A included 12 patients with EGFR-mutant tumors resistant to TKIs. Cohort B included five patients with EGFR wild-type tumors. The primary outcome was to assess safety and determine the recommended phase II dose (RP2D) of the combination.RESULTSThe most common adverse events of any grade were rash (62.9%), fatigue (51%), and nausea (45.7%). Capmatinib exhibited nonlinear pharmacokinetics combined with erlotinib, while showing no significant drug interactions. The RP2D was 400 mg twice daily capmatinib tablets with 150 mg daily erlotinib. The overall response rate (ORR) and DCR in dose-expansion cohort A was 50% and 50%, respectively. In cohort B, the ORR and disease control rate were 75% and 75%.CONCLUSIONCapmatinib in combination with erlotinib demonstrated safety profiles consistent with prior studies. We observed efficacy in specific patient populations. Continued evaluation of capmatinib plus EGFR-TKIs is warranted in patients with EGFR activating mutations.

Diagnostic and Predictive Values of 18F-FDG PET/CT Metabolic Parameters in EGFR-Mutated Advanced Lung Adenocarcinoma.

PurposeThe clinical implications of the metabolic parameters of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) in epidermal growth factor receptor (EGFR)-mutated lung cancer are not fully understood. The aim of this study was to evaluate the diagnostic and prognostic utility of the parameters in EGFR-mutated lung cancer patients.Patients and MethodsWe retrospectively enrolled 134 patients with advanced lung adenocarcinoma (72 EGFR-negative and 62 EGFR-positive). We evaluated the correlation between EGFR mutational status and the maximum standardized uptake value (SUVmax), as well as the associations between treatment outcomes in EGFR-mutated patients and various metabolic parameters of primary tumors. For the best predictive parameters, we calculated the metabolic tumor volume (MTV) and total lesion glycolysis (TLG) using two SUV cutoffs: 1.5 (MTV1.5, TLG1.5) and 2.5 (MTV2.5, TLG2.5).ResultsMean SUVmax was lower for EGFR-mutated tumors compared with EGFR wild-type (6.11 vs 10.41, p < 0.001) tumors. Low SUVmax was significantly associated with positive EGFR mutation (odds ratio = 1.74). Multivariate analysis for survival demonstrated that high MTV1.5, TLG1.5, MTV2.5, and TLG2.5 were independently associated with shorter progression-free survival (PFS) and overall survival (OS), and the highest hazard ratios were found in TLG1.5 (3.26 for PFS and 4.62 for OS).ConclusionSUVmax may be predictive for EGFR mutational status, and MTV and TLG of primary tumors may be promising prognostic parameters; 18F-FDG PET/CT has potential utility for the risk stratification of EGFR-mutated patients treated with targeted therapy.

P1.16-60 A High Risk of Recurrence After the Resection of Lower Lobe Adenocarcinoma

According to previous reports, non-small cell lung cancers arising in the lower lobe are associated with a worse prognosis than those arising in the upper lobe; however, the reason remains to be elucidated. Thus, we attempted to identify high-risk population in patients with lower lobe disease, that may substantially cause poor prognosis of lower lobe disease. We retrospectively reviewed a consecutive series of 400 patients with completely resected lung adenocarcinoma who were treated between January 2006 and December 2015. All patients underwent major lung resection and lymph node dissection. The clinicopathological factors that were investigated included the solid component size, the pathological subtype (pre-invasive, minimally invasive/invasive), the epidermal growth factor receptor (EGFR) mutation status, and some other characteristics (TNM 8th edition). The proportion of never-smokers among patients with lower lobe disease was significantly higher than that among those with upper lobe disease. According to a multivariate proportional hazards analysis, primary site (upper/lower) was an independent predictor of early recurrence, along with the solid component size, pleural lavage cytology results, pathological pleural invasion, and pathological lymph node metastasis. However, although lower lobe disease was associated with early recurrence in never smokers (Fig 1A), it was not in smokers (Fig 1B). Furthermore, although lower lobe disease was associated with early recurrence in never smokers with EGFR wild-type tumors (Fig 1C), it was not in never smokers with EGFR mutant tumors (Fig 1D). EGFR wild-type tumors were more frequently detected in patients with lower lobe disease than in those with upper lobe disease when the analysis was restricted to never smokers. Patients with lower lobe cancer, particularly those without a smoking history or those with EGFR wild-type tumors, showed a higher risk of recurrence than their counterparts with upper lobe disease. Further studies that include the molecular profiling of such aggressive lesions, are warranted.

Frequency of actionable alterations in epidermal growth factor receptor (EGFR) wild type non-small cell lung cancer: experience of the Wide Catchment Area of Romagna (AVR).

Molecular diagnostics for non-small cell lung cancer (NSCLC) has become the standard of care for personalized treatment. Epidermal growth factor receptor (EGFR) mutation and EML4-ALK translocation represent the two most important alterations in first-line treatment decision-making. However, other potentially targetable alterations are also present. One thousand consecutive NSCLC patients with EGFR wild type (wt) tumors diagnosed by routine molecular analysis were considered. KRAS, BRAF, ERBB2, PIK3CA, NRAS, ALK, MAP2K1, RET and DDR2 gene mutations were analyzed using the multiparametric Sequenom MassARRAY® platform. EML4-ALK and ROS1 rearrangements were also assessed by fluorescent in situ hybridization. HER4 status was determined by direct sequencing. Three hundred and forty-eight (34.8%), 31 (3.1%), 39 (4.4%), 14 (1.8%), 6 (0.7%), 16 (1.8%), 5 (0.6%) and 9 (0.9%) patients showed an alteration in KRAS, BRAF, ALK, ROS1, NRAS, PIK3CA, MAPK1/2 and HER2 genes, respectively. Of the 657 patients for whom all markers were determined, 318 (48%) patients had at least one alteration. Eight patients showed overlapping mutations, 4 KRAS mutation/EML4-ALK translocation, one KRAS mutation/ROS1 rearrangement, 2 KRAS/PIK3CA mutations, and one BRAF/PIK3CA mutations. About 50% of our patients had a potentially targetable alteration, confirming the usefulness of a multiparametric approach for routine molecular diagnostics aimed at identifying potential therapeutic targets.

Computed tomography characteristics of lung adenocarcinomas with epidermal growth factor receptor mutation: A propensity score matching study

ObjectivesWe investigated the relationship between computed tomography (CT) characteristics and epidermal growth factor receptor (EGFR) mutations in a large Asian cohort who received surgical resection of invasive lung adenocarcinoma. Materials and MethodsWe retrospectively included 864 patients (524 with EGFR mutation and 340 with EGFR wild-type) who received surgical resections for invasive lung adenocarcinomas. After applying propensity score matching, 312 patients with mutated EGFR were matched with 312 patients with wild-type EGFR. CT characteristics, predominant histologic subtype, and CT measurement parameters (volume and estimated diameter of the total tumor and inner solid portion and ground-glass opacity [GGO] proportion) were compared within matched pairs. ResultsTumors in the EGFR mutation group showed higher proportions of pure ground-glass nodules (4.1% vs 1.3%), GGO-predominant (23.7% vs 14.7%), and solid-predominant part-solid nodules (37.2% vs 31.7%) CT characteristics, whereas EGFR wild-type tumors predominantly presented as pure solid nodules (34.6% vs 52.2%, P < 0.0001). EGFR mutation tumors more frequently had a lepidic-predominant subtype than did EGFR wild-type tumors (20.2% and 11.9%; P < 0.0001), and showed a smaller whole tumor size and solid portion (P < 0.0001) with a higher GGO proportion (P < 0.0001). Tumors with exon 21 missense mutations showed the highest GGO proportion and the smallest inner solid portion size, followed by tumors harboring an exon 19 deletion, compared with EGFR wild-type tumors (posthoc P < 0.01). ConclusionAdenocarcinomas with EGFR mutations had a higher GGO proportion than those with wild-type EGFR after matching of clinical variables. Lesions with an exon 21 mutation had a higher GGO proportion than lesions with other mutations.

Relation of EGFR Mutation Status to Metabolic Activity in Localized Lung Adenocarcinoma and Its Influence on the Use of FDG PET/CT Parameters in Prognosis.

The purposes of this study were to assess the relation between epidermal growth factor receptor (EGFR) mutation status and FDG PET/CT findings and to evaluate the influence of this relation on the use of FDG PET/CT parameters to establish a prognosis in cases of localized lung adenocarcinoma. Patients with stage I and II lung adenocarcinomas were retrospectively enrolled. At the initial FDG PET/CT examination, maximum and peak standardized uptake, tumor-to-background ratio, and volumetric parameters of metabolic tumor volume and total lesion glycolysis were measured. The values of all the metabolic and volumetric FDG PET/CT parameters were significantly lower in EGFR mutant than in EGFR wild-type lung adenocarcinomas. All parameters were statistically significant for predicting recurrence-free survival. In multivariate analyses, peak standardized uptake and total lesion glycolysis were more significant prognostic factors than was TNM stage (p < 0.001). Optimal cutoff values of parameters for predicting recurrence-free survival were slightly different between the two groups. EGFR mutation is related to low metabolic activity of localized lung adenocarcinoma at FDG PET/CT. Because of differences in the metabolic activity of EGFR mutant and wild-type tumors, EGFR mutation status must be considered when FDG PET/CT parameters are used for prognosis.

Family with sequence similarity 83, member B is a predictor of poor prognosis and a potential therapeutic target for lung adenocarcinoma expressing wild-type epidermal growth factor receptor.

Lung adenocarcinoma (ADC) patients with tumors that harbor no targetable driver gene mutation, such as epidermal growth factor receptor (EGFR) gene mutations, have unfavorable prognosis, and thus, novel therapeutic targets are required. Family with sequence similarity 83, member B (FAM83B) is a biomarker for squamous cell lung cancer. FAM83B has also recently been shown to serve an important role in the EGFR signaling pathway. In the present study, the molecular and clinical impact of FAM83B in lung ADC was investigated. Matched tumor and adjacent normal tissue samples were obtained from 216 patients who underwent complete lung resection for primary lung ADC and were examined for FAM83B expression using cDNA microarray analysis. The associations between FAM83B expression and clinicopathological parameters, including patient survival, were examined. FAM83B was highly expressed in tumors from males, smokers and in tumors with wild-type EGFR. Multivariate analyses further confirmed that wild-type EGFR tumors were significantly positively associated with FAM83B expression. In survival analysis, FAM83B expression was associated with poor outcomes in disease-free survival and overall survival, particularly when stratified against tumors with wild-type EGFR. Furthermore, FAM83B knockdown was performed to investigate its phenotypic effect on lung ADC cell lines. Gene silencing by FAM83B RNA interference induced growth suppression in the HLC-1 and H1975 lung ADC cell lines. FAM83B may be involved in lung ADC tumor proliferation and can be a predictor of poor survival. FAM83B is also a potential novel therapeutic target for ADC with wild-type EGFR.

Which treatment is preferred for advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor in second-line therapy? A meta-analysis comparing immune checkpoint inhibitor, tyrosine kinase inhibitor and chemotherapy.

BackgroundThe recommendations regarding the optimum treatment for advanced non-small-cell lung cancer (NSCLC) patients with wild-type (WT) epidermal growth factor receptor (EGFR) tumors remain unclear. This meta-analysis was conducted to assess the efficacy among programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) antibody, EGFR-tyrosine kinase inhibitors (TKI) and chemotherapy in second-and third-line therapy.Patients and methodsRandomized trials investigating two of the three treatments were searched and included. Multiple treatments comparison and pairwise comparison were performed to assess overall survival (OS) and progression-free survival (PFS), expressed as hazard ratios (HRs). The effect of prespecified study-level characteristics was assessed by subgroup analysis and meta-regression.Results12 randomized trials accruing 3341 advanced patients with WT EGFR tumors were analyzed. PD-1/PD-L1 antibody was associated with significantly longer OS and PFS than chemotherapy (OS: HR 0.67, 95% CrI 0.60–0.75; PFS: HR 0.83, 95% CrI 0.73–0.95) and TKI (OS: HR 0.59, 95% CrI 0.50–0.70; PFS: HR 0.75, 95% CrI 0.66–0.84) , while chemotherapy was associated with significantly longer OS (HR 0.88, 95% CrI 0.77–0.99) and PFS (HR 0.75, 95% CrI 0.66–0.84) than TKI.ConclusionsFor advanced NSCLC patients with WT-EGFR tumors in second- or third-line therapy, PD-1/PD-L1 antibody appeared to be the most efficacious treatment, which was followed by chemotherapy. EGFR-TKI was worse than chemotherapy.

P3.02b-019 TTF-1 Expression as a Predictor of Response to EGFR-TKIs in Patients with Lung Adenocarcinoma: Topic: EGFR Biomarkers

Several studies have shown that overexpression of thyroid transcription factor (TTF-1) may be associated with the presence of epidermal growth factor receptor (EGFR) gene mutations and predict survival in patients with non-small cell lung cancer (NSCLC). Nevertheless, the potential significance of TTF-1 immunostaining as a predictor of response to EGFR tyrosine kinase inhibitors (TKIs) has received limited research attention thus far. The aim of this study was to further explore the potential association between TTF-1 immunohistochemical expression and response to EGFR TKIs in patients with lung adenocarcinoma. The medical records of 129 patients with stage IV lung adenocarcinoma, treated at the Oncology Unit of “Sotiria” Athens General Hospital between January 2011 and December 2014, were retrospectively reviewed. All patients had received treatment with EGFR TKIs (erlotinib or gefitinib) and had a known TTF-1 immunohistochemical expression status in formalin-fixed, paraffin-embedded tumor tissue. Demographic and clinicopathological features (age, gender, smoking status and performance status), TTF-1 immunohistochemistry and EGFR mutation status results were correlated to each other as well as with the response rate (RR) to EGFR TKIs, using univariate and multivariate regression analysis. Median age of our study population was 68 years (range 26-88 years), while the majority were male (79/129 cases, 61.2%). Patients with EGFR mutant tumors had significantly higher response rates to EGFR TKIs compared to patients with wild-type EGFR tumors (p=0.001). TTF-1 positive staining was weakly associated with the presence of EGFR mutations, without reaching the level of statistical significance (p=0.053). Most importantly, TTF-1 positive staining was not significantly correlated with RR to EGFR TKIs, when gender, age, smoking status, EGFR mutation status and PS were included in the multivariate model. The present results failed to demonstrate any independent association between TTF-1 overexpression and the RR to EGFR TKIs in patients with advanced-stage lung adenocarcinoma. Prospective data from larger cohorts of patients are needed to clarify the exact predictive value of TTF-1 immunostaining in this setting.

Impact of active smoking on survival of patients with metastatic lung adenocarcinoma harboring an epidermal growth factor receptor (EGFR) mutation

Lung cancer in smokers and non-smokers demonstrates distinct genetic profiles, and cigarette smoking affects epidermal growth factor receptor (EGFR) function and causes secondary EGFR tyrosine kinase resistance. We evaluated the effect of active smoking in patients with metastatic lung adenocarcinoma. A total of 132 metastatic lung adenocarcinoma patients, diagnosed between 2008 and 2013, with known EGFR mutation status, were evaluated retrospectively. Among these patients, 40 had an activating EGFR mutation. Patients who continued smoking during the treatment were defined as active smokers. Former smokers and never smokers were together defined as non-smokers. The outcomes of the treatment in relation to the EGFR mutation and smoking status were evaluated. The median follow-up time was 10.5 months. The overall response rate for the first-line therapy was significantly higher among the EGFR-mutant patients (p = 0.01), however, smoking status had no impact on the response rate (p = 0.1). The EGFR-mutant active smokers progressed earlier than the non-smokers (p < 0.01). The overall survival (OS) of the non-smokers and patients treated with erlotinib was significantly longer (p = 0.02 and p = 0.01, respectively). Smoking status did not affect the OS in EGFR wild type tumors (p = 0.49) but EGFR-mutant non-smokers had a longer OS than the active smokers (p = 0.01).The active smokers treated with erlotinib had poorer survival than the non-smokers (p = 0.03). Multivariate analysis of EGFR-mutant patients showed that erlotinib treatment at any line and non-smoking were independent prognostic factors for the OS (p = 0.04 and p = 0.01, respectively). Smoking during treatment is a negative prognostic factor in metastatic lung adenocarcinoma with an EGFR mutation.

Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non–small-cell Lung Cancer

BackgroundPharmacodynamic separation of pemetrexed and erlotinib avoids negative cellular interactions and results in antitumor synergy in erlotinib-resistant non–small-cell lung cancer (NSCLC) cells, independent of EGFR (epidermal growth factor receptor) genotype. Patients and MethodsPatients with platinum-treated metastatic nonsquamous NSCLC were randomly assigned 1:2 to pemetrexed alone (500 mg/m2 provided intravenously on day 1) or pemetrexed followed by erlotinib (150 mg provided orally once daily on days 2-17) every 21 days. EGFR genotype was centrally confirmed by Sequenom multiplex oncogenotyping assay. The primary end point was progression-free survival (PFS), which would be considered promising for future study if median PFS was ≥ 4.5 months. ResultsOf 83 patients enrolled, 79 were randomized to either pemetrexed alone (n = 27) or in combination (n = 52). Fifty-nine (79%) of 75 eligible patients had tumors with confirmed EGFR genotype: 7 with activating mutations and 52 wild type. Median PFS was 4.7 and 2.9 months in the combination and pemetrexed-alone groups, respectively. In patients with EGFR wild-type tumors, median PFS was 5.3 and 3.5 months in the combination and pemetrexed-alone groups, respectively. Objective response rate (29% vs. 10%, P = .17), 6-month PFS (45% vs. 29%, P = .26), and 12-month PFS (23% vs. 10%, P = .28) were all higher in the combination arm. Rash (67% vs. 26%, P = .0007) and diarrhea (44% vs. 11%, P = .003) were significantly more common in the combination arm. ConclusionIn patients with unselected or EGFR wild-type advanced nonsquamous NSCLC, pharmacodynamic separation of pemetrexed and intercalated erlotinib had promising antitumor activity without new safety concerns. The combination merits further evaluation as maintenance or second-line therapy against new standards in patients with EGFR wild-type advanced NSCLC.

A Potent Derivative of Indolizino[6,7-b]Indole for Treatment of Human Non–Small Cell Lung Cancer Cells

The therapeutic effect in non–small cell lung cancer (NSCLC) patients is limited because of intrinsic and acquired resistance. Thus, an unmet need exists for the development of new drugs to improve the therapeutic efficacy in NSCLC patients. In this study, the novel small molecule indolizino[6,7-b]indole derivative BO-1978 was selected to evaluate its therapeutic effects on NSCLC and its preclinical toxicity in animal models. An in vitro cytotoxicity assay revealed that BO-1978 significantly suppressed the growth of various NSCLC cell lines with or without mutations in epidermal growth factor receptor (EGFR). Mechanistically, we demonstrated that BO-1978 exhibited multiple modes of action, including inhibition of topoisomerase I/II and induction of DNA cross-linking. Treatment of NSCLC cells with BO-1978 caused DNA damage, disturbed cell cycle progression, and triggered apoptotic cell death. Furthermore, BO-1978 significantly suppressed the growth of EGFR wild-type and mutant NSCLC tumors in xenograft tumor and orthotopic lung tumor models with negligible body weight loss. The combination of BO-1978 with gefitinib further suppressed EGFR mutant NSCLC cell growth in xenograft tumor and orthotopic lung tumor models. Preclinical toxicity studies showed that BO-1978 administration did not cause apparent toxicity in mice. Based on its significant therapeutic efficacy and low drug toxicity, BO-1978 is a potential therapeutic agent for treatment of NSCLC.

The Efficacy of Single-Agent Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Biologically Selected Patients with Non-Small-Cell Lung Cancer: A Meta-Analysis of 19 Randomized Controlled Trials

Objective: To determine the efficacy of first-generation single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in advanced non-small-cell lung cancer patients with known EGFR mutation status, we undertook this pooled analysis. Method: We searched for randomized controlled trials (RCTs) in Medline, Embase, the Cochrane Controlled Trials Register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. Results: Out of 2,129 retrieved articles, 19 RCTs enrolling 2,016 patients with wild-type EGFR tumors and 1,034 patients with mutant EGFR tumors were identified. For these EGFR mutant patients, single-agent EGFR-TKI therapy improved progression-free survival (PFS) over chemotherapy: the summary hazard ratios (HRs) were 0.41 (p < 0.001) for the first-line setting and 0.46 (p = 0.02) for the second-/third-line setting. For those EGFR wild-type patients, single-agent EGFR-TKI therapy did not do as well as chemotherapy in the first-line setting (HR = 1.65, p = 0.03) and in the second-/third-line setting (HR = 1.27, p = 0.006). No statistically significant difference was observed in terms of overall survival (OS). Using platinum-based doublet chemotherapy as a common comparator, indirect comparison showed the superior efficacy of single-agent EGFR-TKI therapy over EGFR-TKIs added to chemotherapy in PFS [HR = 1.35 (1.03, 1.77), p = 0.03]. Additionally, a marginal trend towards the same direction was found in the OS analysis [HR = 1.16 (0.99, 1.35), p = 0.06]. Interestingly, for those EGFR wild-type tumors, single-agent EGFR-TKI therapy was inferior to EGFR-TKIs added to chemotherapy in PFS [HR = 0.38 (0.33, 0.44), p < 0.001] and OS [HR = 0.83 (0.71, 0.97), p = 0.02]. Conclusions: For these EGFR mutant patients, single-agent EGFR-TKI therapy prolonged PFS over chemotherapy. However, single-agent EGFR-TKI therapy was inferior to chemotherapy in PFS for those EGFR wild-type patients. Single-agent EGFR-TKI therapy could improve PFS over the combination of EGFR-TKIs and chemotherapy in these EGFR mutant patients. However, EGFR-TKIs combined with chemotherapy could provide additive PFS and OS benefit over single-agent EGFR-TKI therapy in those EGFR wild-type patients.

Impact of an Interactive On-line Tool on Therapeutic Decision-Making for Patients with Advanced Non-Small-Cell Lung Cancer

Treatment guidelines provide recommendations but cannot account for the wide variability in patient-tumor characteristics in individual patients. We developed an on-line interactive decision tool to provide expert recommendations for specific patient scenarios in the first-line and maintenance settings for advanced non-small-cell lung cancer. We sought to determine how providing expert feedback would influence clinical decision-making. Five lung cancer experts selected treatment for 96 different patient cases based on patient and/or tumor-specific features. These data were used to develop an on-line decision tool. Participant physicians entered variables for their patient scenario with treatment choices, and then received expert treatment recommendations for that scenario. To determine the impact on decision-making, users were asked whether the expert feedback impacted their original plan. A total of 442 individual physicians, of which 88% were from outside the United States, entered 653 cases, with report on impact in 389 cases. Expert feedback affected treatment choice in 73% of cases (23% changed and 50% confirmed decisions). For cases with epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) fusion, all experts selected targeted therapy whereas 51% and 58% of participants did not. Greater variability was seen between experts and participants for cases involving EGFR or ALK wild-type tumors. Participants were 2.5-fold more likely to change to expert recommended therapy for ALK fusions than for EGFR mutations (p = 0.017). This online tool for treatment decision-making resulted in a positive influence on clinician's decisions. This approach offers opportunities for improving quality of care and meets an educational need in application of new therapeutic paradigms.

Erlotinib as Second-Line Therapy for Patients with Advanced Non-Small-Cell Lung Cancer and Wild-Type EGFR Tumors

Aim: The objective of the study was to determine the efficacy and safety of erlotinib in second-line therapy for patients with advanced non-small-cell lung carcinoma (NSCLC) and wild-type tumors, measuring progression-free survival (PFS), the response rate, and overall survival (OS). Material and Methods: This retrospective, observational, and multicenter study involved 47 patients diagnosed with NSCLC and wild-type epidermal growth factor receptor(EGFR) who received erlotinib as second-line therapy in four Spanish hospitals. Primary and secondary endpoints included the determination of the efficacy (by measuring progression-free survival, PFS, the response rate, and overall survival, OS) and safety profile of erlotinib. Results: The median PFS was 2.33 months (95% CI, 0.4-10.9). No differences in PFS were found regarding sex, age, smoking habits, ECOG performance status, and tumor histology. The median OS was 4.00 months (95% CI, 1.18-6.82). Four patients developed grade 3-4 non-hematological toxicities, including asthenia, cutaneous toxicity, and renal failure. One patient developed grade 3-4 thrombocytopenia. Conclusion: Our study corroborates the modest but clear benefit of second-line agents, including erlotinib, for the treatment of advanced NSCLC, and supports their administration in patients with wild-type EGFR. Further prospective studies involving large number of patients are required to corroborate such results.

Impact of epidermal growth factor receptor (EGFR) activating mutations and their targeted treatment in the prognosis of stage IV non-small cell lung cancer (NSCLC) patients harboring liver metastasis.

ObjectivesLiver metastases appear in 20–30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between EGFR mutations, liver infiltration and clinical outcomes.MethodsA total of 236 consecutive stage IV NSCLC patients treated at the Clínica Universidad de Navarra were analyzed.ResultsAt onset, liver metastases were present in 16.9% of patients conferring them a shorter overall survival (OS) compared to those with different metastatic locations excluding liver infiltration (10 vs. 21 months; p = 0.001). Patients with EGFR wild-type tumors receiving standard chemotherapy and showing no liver involvement presented a superior median OS compared to those with liver metastases (23 vs. 13 months; p = 0.001). Conversely, patients with EGFR-mutated tumors treated with EGFR tyrosin-kinase inhibitors (TKI’s) presented no significant differences in OS regardless of liver involvement (median OS not reached vs. 25 months; p = 0.81).ConclusionOverall, liver metastases at onset negatively impact OS of NSCLC patients. EGFR TKIs however, may reverse the effects of an initial negative prognosis of liver metastasis in first-line treatment of EGFR mutated NSCLC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0622-x) contains supplementary material, which is available to authorized users.

Retrospective efficacy and safety analyses of erlotinib, pemetrexed, and docetaxel in EGFR-mutation-negative patients with previously treated advanced non-squamous non-small-cell lung cancer.

Several guidelines recommend erlotinib, pemetrexed, or docetaxel for second-line chemotherapy in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The aim of this study was to retrospectively evaluate the efficacy of erlotinib, pemetrexed, and docetaxel in epidermal growth factor receptor (EGFR) mutation-negative patients with previously treated advanced non-squamous NSCLC. We analyzed the efficacy of these agents in patients with previously treated advanced non-squamous NSCLC who had EGFR wild-type tumors, performance status (PS) of 0, 1, or 2 and received erlotinib, pemetrexed, or docetaxel between December 2007 and September 2011. Variability among patient backgrounds was evaluated using propensity scores to assess comparability. The efficacy of these agents was evaluated in patient subgroups with low variability. The propensity scores showed that the backgrounds of the groups that received second-line therapy with each agent had low variability and were adequate for comparison. Patients were divided into the PS0/1 and PS2 groups for analysis. The median progression-free survival (PFS) in patients treated with erlotinib was 2.8 months in the PS0/1 group, as compared with 1.0 month in the PS0/1/2 group and 0.90 months in the PS2 group. PFS in PS0/1 patients who received erlotinib was comparable to that in PS0/1 patients who received pemetrexed (2.5 months) or docetaxel (1.9 months). Overall survival (OS) in erlotinib-, pemetrexed-, and docetaxel-treated PS0/1 patients was 16.1, 7.4 and 10.0 months, respectively. The study had limited power to detect differences in PFS and OS because of the small sample size. Erlotinib appears to be a useful second-line option in PS0/1 patients with EGFR mutation-negative advanced non-squamous NSCLC given its mild adverse effects. The results should be carefully interpreted because of the small sample size, limited power, and retrospective nature of the study.