Subgroup Of Non-small Cell Lung Cancer Patients Research Articles

Nivolumab plus ipilimumab combination therapy for the first-line treatment NSCLC: evidence to date.

Immune checkpoint inhibitors (ICI) as monotherapy in selected patients as well as in combination with chemotherapy have become the standard of care in the first-line treatment strategy of advanced non-small cell lung cancer (NSCLC) patients. Combination treatment with ICI, such as nivolumab and ipilimumab or durvaluamb and ipilimumab, has also been proposed as potential strategies in this setting in selected advanced NSCLC patients. Characterizing predictive markers of long-term clinical benefit with ICI is a critical objective. Tumor mutational burden has been proposed as a potential predictive biomarker. In this review, we discuss the efficacy of nivolumab and ipilimumab in advanced NSCLC patients as well as the clinical utility of tumor mutational burden in the efficacy of this combination. Ongoing clinical trials with nivolumab and ipilimumab, and the efficacy of this combination in subgroups of NSCLC patients, such as elderly patients and patients with brain metastases, are also discussed.

P3.01-31 Prognostic Factors in Patients with Resected Pathological N2 Non-Small Cell Lung Cancer

Postoperative outcome for non-small cell lung cancer (NSCLC) patients with mediastinal lymph node metastasis is unfavorable even after complete resection. To identify the subgroup of NSCLC patients with mediastinal lymph node metastasis whom we recommend surgical treatment, we sought to investigate prognostic factors in these patients. We retrospectively reviewed NSCLC patients with pathologically identified mediastinal lymph node metastasis who underwent complete resection with systematic nodal dissection between 2000 and 2016. Demographic, clinical, and pathologic factors (sex, age, Brinkman index, performance status [PS], % vital capacity, forced expiratory volume % in 1 second, preoperative carcinoembryonic antigen [CEA], histological subtype, pathological tumor size, p-T factor [7th edition], pleural invasion, pulmonary metastasis, histological grade, number of positive mediastinal nodal stations [single station vs multiple stations], number of positive mediastinal lymph nodes [1-2 vs ≥3], epidermal growth factor receptor [EGFR] mutation status, and adjuvant chemotherapy) were analyzed using the log-rank test as univariate analyses and a Cox proportional hazards regression model for multivariate analyses to identify independent predictors of favorable overall survival (OS). Of the 54 eligible patients, 38 were male and 16 were female. The median age and CEA were 65 years and 5.3 ng/mL, respectively. Lobectomy, bilobectomy, and pneumonectomy were performed in 49/3/2 patients. Histological subtypes were adenocarcinoma in 29 patients, squamous cell carcinoma in 17, and others in 8. EGFR was inspected in 33 patients, and 10 patients were EGFR mutated. Adjuvant chemotherapy was performed in 26 patients. The details of adjuvant chemotherapy were cisplatin-based combination chemotherapy in 18 patients, and carboplatin-based combination chemotherapy in 8. The 3-year and 5-year OS were 64.9% and 44.7%, respectively, with a median follow-up period of 41 months. The preoperative CEA <5.3 ng/mL (HR: 0.2151) and undergoing adjuvant chemotherapy (HR: 0.3580) were identified as significant predictors of favorable OS. The 3-year and 5-year OS in patients with CEA <5.3 and ≥5.3 ng/mL were 88.3/70.8% vs 41.0/17.9%, respectively (p<0.001). The 3-year and 5-year OS in patients who underwent adjuvant chemotherapy or none were 75.3/70.3% vs 55.3/23.1%, respectively (p = 0.009). Even if NSCLC patients have mediastinal lymph node metastasis, favorable postoperative prognosis may be expected in patients with low preoperative serum CEA. Adjuvant chemotherapy should be considered in patients with mediastinal lymph node metastasis on pathological examination.

Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer.

KRAS and TP53 mutations, which are the most common genetic drivers of tumorigenesis, are still considered undruggable targets. Therefore, we analyzed these genetic aberrations in metastatic non-small cell lung cancer (NSCLC) for the development of potential therapeutics. One hundred eighty-five consecutive patients with metastatic NSCLC in a phase 1 trial center were included. Their genomic aberrations, clinical characteristics, survivals, and phase 1 trial therapies were analyzed. About 10%, 18%, 36%, and 36% of the patients had metastatic KRAS+/TP53+, KRAS+/TP53-,KRAS-/TP53+, and KRAS-/TP53- NSCLC, respectively. The most common concurrent genetic aberrations beside KRAS and/or TP53 (>5%) were KIT, epidermal growth factor receptor, PIK3CA, c-MET, BRAF, STK11, ATM, CDKN2A, and APC. KRAS+/TP53+ NSCLC did not respond well to the phase 1 trial therapy and was associated with markedly worse progression-free (PFS) and overall (OS) survivals than the other three groups together. KRAS hotspot mutations at locations other than codon G12 were associated with considerably worse OS than those at this codon. Gene aberration-matched therapy produced prolonged PFS and so was anti-angiogenesis in patients with TP53 mutations. Introduction of the evolutionary action score system of TP53 missense mutations enabled us to identify a subgroup of NSCLC patients with low-risk mutant p53 proteins having a median OS duration of 64.5 months after initial diagnosis of metastasis. These data suggested that patients with metastatic dual KRAS+/TP53+ hotspot-mutant NSCLC had poor clinical outcomes. Further analysis identified remarkably prolonged survival in patients with low-risk mutant p53 proteins, which warrants confirmatory studies.

Osimertinib for the treatment of patients with EGFR mutation-positive non-small cell lung cancer

Epidermal growth factor receptor (EGFR) mutations, mostly seen in exon 19 or exon 21, are present in roughly 50% of patients with advanced non-small cell lung cancer (NSCLC) of Asian ethnicity compared with 12% in Caucasians. EGFR-mutated NSCLC patients have an increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib or afatinib, showing superior response, progression-free survival and overall survival rates with EGFR-TKIs than with platinum doublet chemotherapy, which makes EGFR-TKIs the standard of care in this subgroup of NSCLC patients. This has been the most important step toward molecular-guided precision therapy for NSCLC. Despite the initial rapid and durable clinical responses, acquired resistance to EGFR-TKIs has been found to eventually develop in most cases, with disease progression observed mostly within 9-12 months after treatment. One of the most important mechanisms for resistance to EGFR-TKI therapy is the substitution of threonine to methionine (T790M) on exon 20 of the EGFR gene, which occurs in 49% to 60% of patients. Osimertinib mesylate (formerly AZD-9291) is a potent third-generation TKI which irreversibly inhibits mutated EGFR alleles, including T790M. This review summarizes osimertinib's pharmacology, pharmacokinetics, safety, side effects and clinical utility in the treatment of EGFR-mutated advanced NSCLC.

P1.07-040 Prognosis-Relevant Subgroups in NSCLC According to Granulocytic Myeloid-Derived Suppressor Cell Frequency and Cytokine Levels

The percentage of Polymorphonuclear-MDSCs (PMN-MDSCs) has emerged as an independent prognostic factor for survival in Non-small cell lung cancer (NSCLC) patients. Similarly, cytokine profiles have been used to identify subgroups of NSCLC patients with different clinical outcomes. This prospective study investigated whether the percentage of circulating PMN-MDSC, in conjunction with the levels of plasma cytokines, was more informative of disease progression than the analysis of either factor alone.

MYC expression correlates with PD-L1 expression in non-small cell lung cancer

Objectives Programmed death-ligand 1 (PD-L1) is a widely used biomarker for predicting immune checkpoint inhibitors, but is of limited usefulness in the prediction of drug response. MYC, a transcription factor that is overexpressed in cancers, is involved in preventing immune cells from attacking tumor cells through inducing PD-L1 expression. This study evaluated the relationship between MYC and PD-L1 expression in 84 non-small cell lung cancer (NSCLC) patients who underwent curative surgical resection.Materials and Methods The relationship between MYC and PD-L1 was investigated by introducing pcDNA3-cMYC into A549 and H1299 cells with low PD-L1 expression and siRNA against MYC into H60 and H2009 cells with high PD-L1 expression. Expression of PD-L1 in NSCLC tissues was analyzed by immunostaining using a PD-L1 (22C3) PharmDx protocol using the Dako Automated Link 48 platform and expression of MYC was determined using anti-c-MYC (Y69) (ab320720).Results Of 84 patients, PD-L1 was expressed in 14 (16.7%) and MYC was overexpressed in 30 (35.7%). We investigated the relationship between PD-L1 and MYC expression. There were 49 (58.3%) double-negative patients and 9 (10.7%) double-positive patients. Significant positive correlation was observed between PD-L1 and MYC expression (γ=0.210, P=0.029). Double-negative patients showed better disease free (31.1 vs. 7.1 months, P=0.011) and overall survival (56.1 vs. 14.4 months, P=0.032) than double-positive patients.Conclusion Taken together, MYC expression significantly correlated with PD-L1 expression in NSCLC. The usefulness of MYC expression as a surrogate marker of treatment response assessment is worth evaluating for immune checkpoint inhibitor therapy and special interest are required for the subgroup of NSCLC patients, whose tumor expresses PD-L1 and MYC double positive.

Anti-PD1 treatment to induce M1 polarization of tumor infiltrating macrophages in a 3D ex vivo system of lung cancer patients.

e23090 Background: Nivolumab and pembrolizumab treatment targeting the PD1/PD-L1 axis has demonstrated increased survival benefit in subpopulations of patients with advanced non-small cell lung cancer (NSCLC). The impact of these therapeutics on tumor immune microenvironment is not fully understood. Classical M1 macrophages are critical components involved in the inflammatory response and antitumor immunity. In this study, we evaluated the effect of PD1/PD-L1 blockade on M1 polarization of tumor-associated macrophages (TAMs) and activation of cytotoxic T-cells in a 3D ex vivo system of NSCLC. Methods: Fresh tumor tissues obtained from consented patients with NSCLC at the time of surgical resection were utilized in a 3D ex vivo tumor miscrosphere assay. 3D tumor microspheres were treated with nivolumab or pembrolizumab at 10 mg/ml for 36 hours within an intact tumor microenvironment. Flow cytometry analysis was performed to evaluate treatment-mediated TAM polarization, activation of T-cells and changes in CD4 and CD8 subpopulations. A multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines. Additionally, a NanoString platform containing probes to quantitate 770 immune function genes was used to determine potential positive or negative associations between expression of immune function genes and TIL activation by ex vivo treatment. Results: Both nivolumab and pembrolizumab treatment increased population of M1 macrophages (CD68+, CD80+, CD163-) and simultaneous release of MIP1b, IFN-ɣ, TNF-a, and GM-CSF cytokines as well as expression of genes related to the M1 phenotype that was accompanied by activation of CD8 cells assessed by Ki67 and CD107a expression and increased expression of genes involved in the IFNg pathway. Conclusions: Our studies showed that anti PD1/PD-L1 treatment leads to M1 macrophage polarization and T-cell activation in subgroups of NSCLC patients emphasizing the importance of comprehensive analysis of tumor immune microenvironment for a better understanding of the mechanism of action of immuno-oncology drugs that may help developing rationale combination treatments in NSCLC.

Clinical and prognostic significance of Merkel cell polyomavirus in nonsmall cell lung cancer

Recently, an association between Merkel cell polyomavirus (MCPyV) and epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC) was reported. However, the underlying carcinogenic effects and the prognosis related to MCPyV are still unclear. The aim of this study was to clarify the incidence and prognosis related to MCPyV infections in NSCLC.Tissue samples from 167 NSCLC patients (92 with squamous cell carcinomas [SCCs] and 75 with adenocarcinomas) were analyzed for the presence of MCPyV and EGFR mutations. Clinicopathological characteristics, disease-free survival rate, and overall survival rate were assessed with respect to MCPyV.MCPyV DNA was detected in 30 patients (18.0%) out of 167 patients, and EGFR mutations were found in 31 out of 127 patients (24.4%). EGFR mutations were more frequently detected in MCPyV-positive patients than in MCPyV-negative patients; however, this did not reach statistical significance (P = 0.075). There was no difference in overall survival between patients with and without MCPyV infections. The disease-free survival rate of patients with pN0 stage, SCC, or EGFR mutations was lower for patients with MCPyV than without MCPyV (P = 0.036, 0.042, and 0.050, respectively).Although the prevalence of MCPyV infection was relatively low, the presence of MCPyV DNA was significantly correlated with cancer prognosis in subgroups of NSCLC patients. These results suggest that MCPyV may be partly associated with pathogenesis and prognosis in some cases of NSCLC.

SC05.04 Lung Cancer Vaccines: An Update

SC05.04 Lung Cancer Vaccines: An Update

Detection of epidermal growth factor receptor mutation in plasma as a biomarker in Chinese patients with early-stage non-small cell lung cancer.

PurposeThis preplanned exploratory analysis was conducted to reveal the true status of correlation between tissue and plasma detection for early-stage non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutations, knowing that specific subgroups of NSCLC patients may be potential candidates for EGFR mutation analysis by using plasma samples.Materials and methodsTissue samples were surgically resected from 198 patients with stage I–IV NSCLC, where stage IA to IIIA accounted for 92.4%. EGFR mutations in all these tissues were positive. Paired plasma EGFR mutations were detected by real-time polymerase chain reaction; concentration of cell-free DNA (cfDNA) in plasma was measured by ultraviolet spectrophotometry.ResultsEGFR-activating mutation was detected in 34 plasma samples, and their mutation types were matched with that in tissue. The sensitivity of EGFR mutation for the 198 paired tissue and plasma samples was 17.2%. The sensitivity positively correlated with disease stage and negatively correlated with tumor differentiation. The sensitivity of stage IA, IB, IIA, IIB, and IIIA was 1.6%, 7.9%, 11.1%, 20%, and 33.3%, respectively; the sensitivity of high differentiation was 0% versus 36.8% for poor differentiation. There was no correlation between plasma cfDNA concentration and patient characteristics.ConclusionWe recommend using plasma cfDNA as a biomarker in stage IIIA or poorly differentiated tumors for gene diagnosis, especially in patients whose tissue samples cannot be obtained by surgery. Plasma samples can really reflect the patients’ EGFR mutation types and may contain comprehensive genotypic information that comes from different parts of the tumor than tissue specimens. The concentration of plasma cfDNA does not vary with patient characteristics.

Treatment and prognostic analysis of patients with leptomeningeal metastases from non-small cell lung cancer.

BackgroundLeptomeningeal metastases (LM) from non-small cell lung cancer (NSCLC) are associated with poor prognosis and optimal treatment for this subgroup of NSCLC patients is controversial. The purpose of this study is to evaluate treatment options and prognostic factors of NSCLC patients with LM.MethodsWe retrospectively analyzed data of 108 patients who had been diagnosed with LM from NSCLC between May 2006 and August 2013.ResultsThe median survival time (MST) of the 108 patients was 5.3 months, and the one-year survival rate was 23.7%. Forty-nine patients received whole brain radiotherapy (WBRT) and the MST of patients who received WBRT and those who did not were 6.4 and 4.3 months, respectively. Forty-two patients were treated with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) after being diagnosed with LM. These patients had prolonged survival (11.1 vs. 4.4 months). Patients who received concomitant WBRT and EGFR-TKIs had the longest MST (12.3 months). Eastern Cooperative Oncology Group performance status, whether patients received WBRT, and/or EGFR-TKIs were independent prognostic factors for patients with LM from NSCLC.ConclusionWBRT, EGFR-TKIs or combined therapy, could lead to better clinical outcomes for NSCLC patients with LM. EGFR-TKIs plus WBRT has the potential to be the standard strategy for LM in NSCLC patients.

A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives.

The discovery of Epidermal Growth Factor Receptor (EGFR) mutations in Non Small Cell Lung Cancer (NSCLC) launched the era of personalized medicine in advanced NSCLC, leading to a dramatic shift in the therapeutic landscape of this disease. After ten years from the individuation of activating mutations in the tyrosine kinase domain of the EGFR in NSCLC patients responding to the EGFR tyrosine kinase inhibitor (TKI) Gefitinib, several progresses have been done and first line treatment with EGFR TKIs is a firmly established option in advanced EGFR-mutated NSCLC patients. During the last decade, different EGFR TKIs have been developed and three inhibitors have been approved so far in these selected patients. However, despite great breakthroughs have been made, treatment of these molecularly selected patients poses novel therapeutic challenges, such as emerging of acquired resistance, brain metastases development or the need to translate these treatments in earlier clinical settings, such as adjuvant therapy. The aim of this paper is to provide a comprehensive review of the major progresses reported so far in the EGFR inhibition in this molecularly-selected subgroup of NSCLC patients, from the early successes with first generation EGFR TKIs, Erlotinib and Gefitinib, to the novel irreversible and mutant-selective inhibitors and ultimately the emerging challenges that we, in the next future, are called to deal with.

High expression of trimethylated histone H3 at lysine 27 predicts better prognosis in non-small cell lung cancer

Epigenetic parameters such as DNA methylation and histone modifications play pivotal roles in carcinogenesis. Global histone modification patterns have been implicated as possible predictors of cancer recurrence and prognoses in a great variety of tumor entities. Our study was designed to evaluate the association among trimethylated histone H3 at lysine 27 (H3K27me3), clinicopathological variables and outcome in early-stage non-small cell lung cancer (NSCLC). The expression of H3K27me3 and its methyl-transferase, enhancer of zeste homolog 2 (EZH2) together with proliferating cell nuclear antigen (PCNA) were evaluated by immunohistochemistry in normal lung tissue (n=5) and resected NSCLC patients (n=42). In addition, the specificity of antibody for H3K27me3 was tested by western blot analysis. The optimal cut-off point of H3K27me3 expression for prognosis was determined by the X-tile program. The prognostic significance was determined by means of Kaplan-Meier survival estimates and log-rank tests. As a result, enhanced trimethylation of H3K27me3 was correlated with longer overall survival (OS) and better prognosis (P<0.05). Moreover, both univariate and multivariate analyses indicated that H3K27me3 level was a significant and independent predictor of better survival (hazard ratio, 0.187; 95% confidence interval, 0.066-0.531, P=0.002). Furthermore, H3K27me3 expression was positively correlated with DNA methylation level at CCGG sites while reversely related to EZH2 expression (P<0.05). In conclusion, H3K27me3 level defines unrecognized subgroups of NSCLC patients with distinct epigenetic phenotype and clinical outcome, and can probably be used as a novel predictor for better prognosis in NSCLC patients.

High plasma fibrinogen concentration and platelet count unfavorably impact survival in non-small cell lung cancer patients with brain metastases

High expression of fibrinogen and platelets are often observed in non–small cell lung cancer (NSCLC) patients with local regional or distant metastasis. However, the role of these factors remains unclear. The aims of this study were to evaluate the prognostic significance of plasma fibrinogen concentration and platelet count, as well as to determine the overall survival of NSCLC patients with brain metastases. A total of 275 NSCLC patients with brain metastasis were enrolled into this study. Univariate analysis showed that high plasma fibrinogen concentration was associated with age≥65 years (P = 0.011), smoking status (P = 0.009), intracranial symptoms (P = 0.022), clinical T category (P = 0.010), clinical N category (P = 0.003), increased partial thromboplastin time (P < 0.001), and platelet count (P < 0.001). Patients with low plasma fibrinogen concentration demonstrated longer overall survival compared with those with high plasma fibrinogen concentration (median, 17.3 months versus 11.1 months; P≤0.001). A similar result was observed for platelet counts (median, 16.3 months versus 11.4 months; P = 0.004). Multivariate analysis showed that both plasma fibrinogen concentration and platelet count were independent prognostic factors for NSCLC with brain metastases (R2 = 1.698, P < 0.001 and R2 = 1.699, P < 0.001, respectively). Our results suggest that high plasma fibrinogen concentration and platelet count indicate poor prognosis for NSCLC patients with brain metastases. Thus, these two biomarkers might be independent prognostic predictors for this subgroup of NSCLC patients.

Identification of subgroup patients with stage IIIB/IV non-small cell lung cancer at higher risk for brain metastases

PurposeBrain metastases (BM), a common occurrence in non-small cell lung cancer (NSCLC), usually lead to a poor prognosis. Recently, the selection of treatment modalities for BM has modestly improved patient survival and quality of life. Treatment choice is largely based on the number of BM, the presence of BM-related symptoms, and performance status. Therefore, early BM detection is crucial. In this study, we aimed to elucidate the factors associated with BM and identify subgroups of patients at higher risk for BM. Methods and patientsThe medical records of 596 consecutive patients with stage I–IV NSCLC were reviewed between January 2006 and November 2011. A multivariate logistic regression (MLR) model was used to identify factors associated with BM. ResultsAmong 482 eligible stage IIIB/IV NSCLC patients, 173 (36%) experienced BM during their disease course. On MLR analysis, female gender, age <60 years and adenocarcinoma were associated with BM (OR=1.71, 95% CI=1.06–2.75, P=0.028; OR=2.11, 95% CI=1.38–3.22, P=0.001; and OR=2.39, 95% CI=1.16–4.92, P=0.018, respectively). The actuarial incidence of BM varied widely from 14% to 59% in different subgroups; younger patients with adenocarcinoma tended to experience BM more than older patients with squamous cell carcinoma (OR=6.88, 95% CI=2.97–15.94, P<0.001). Furthermore, the incidence of BM correlated closely with survival after NSCLC diagnosis, and it was 42%, 54% and 64% in patients who survived more than 3, 12 and 24 months, respectively. Notably, the number of BM, the size of the largest BM and the proportion of multiple BM, defined as more than 4 metastatic tumors in brain, were significantly different in NSCLC patients with and without BM-related symptoms or signs (4.0±2.1 vs 2.7±1.9, P<0.001; 2.6±1.5 vs 1.3±1.0 CM, P<0.001, and 50% vs 21%, P<0.001, respectively). ConclusionWe found that subgroups of NSCLC patients characterized by younger age, female gender and adenocarcinoma are at higher risks for BM. These findings might be helpful to detect BM earlier and facilitate the design of clinical trials aiming at their prevention.

Expression of protein tyrosine kinase 6 (PTK6) in nonsmall cell lung cancer and their clinical and prognostic significance

Aim:The aim of the study was to validate the expression of protein tyrosine kinase 6 (PTK6) in nonsmall cell lung cancer (NSCLC), and to evaluate its clinicopathological and prognostic significance.Methods:We first conducted a meta-analysis on the mRNA profiling data sets of NSCLC in the Oncomine database. Then, one of the most significantly upregulated tyrosine kinase targets, PTK6, was further validated by immunohistochemistry in 104 primary NSCLC tumors. Furthermore the association between PTK6 expression, the clinical parameters, and overall survival was further analyzed.Results:Using the Oncomine database, we identified a list of tyrosine kinase genes related to NSCLC, among which PTK6 was the second most overexpressed gene (median rank = 915, P = 2.9 × 10−5). We further confirmed that NSCLC tumors had a higher expression level of PTK6 than normal pulmonary tissues. Moreover, high PTK6 expression correlated positively with shorter overall survival time, but not with other clinicopathological characteristics. In the multivariate Cox regression model, high PTK6 expression was demonstrated to be an independent prognostic factor for NSCLC patients.Conclusion:Our results validated that PTK6 was found to be overexpressed in a proportion of NSCLC samples, and was associated with a poor prognosis, suggesting that this subgroup of NSCLC patients might benefit from PTK6 inhibitors in the future.

HER2 driven non-small cell lung cancer (NSCLC): potential therapeutic approaches.

Oncogenic driver mutations identified in non-small cell lung cancer (NSCLC) have triggered the development of drugs capable of interfering in intracellular signaling pathways involved in tumorigenesis. Tyrosine kinase inhibitors, such as erlotinib or gefitinib, have demonstrated promising results in patients with advanced NSCLC that harbor EGFR mutations. Human epidermal growth factor 2 (HER2/ERBB2/neu) is a member of the ERBB family of tyrosine kinase receptors, and is activated by homodimerization or heterodimerization with other ERBB receptors. Deregulation of HER2 gene, by overexpression and/or gene amplification has been proved important in breast and gastric cancer, in which overexpression of HER2 confers greater response to specific anti-HER2 treatment, including trastuzumab. In lung carcinogenesis, HER2 mutations are thought to be more clinically relevant than overexpression or gene amplification. HER2 mutations in NSCLC, described exclusively in adenocarcinoma histology, are present in approximately 4% of this subset of lung cancer patients, suggesting that thousands of patients per year may possibly benefit from targeted therapy. Therefore, we conclude that systematic genotypic testing in this subgroup of NSCLC patients should include detection of HER2 mutations. In addition, clinical trials with standard antiHER2 agents and new investigational therapies are ongoing, with promising preliminary results, as illustrated in this review, although further research is warranted in this field.

Radical Treatment of Non–Small-Cell Lung Cancer Patients with Synchronous Oligometastases: Long-Term Results of a Prospective Phase II Trial (Nct01282450)

Stage IV non-small-cell lung cancer (NSCLC) patients with oligometastases (< 5 metastatic lesions) may experience long-term survival when all macroscopic tumor sites are treated radically, but no prospective data on NSCLCs with synchronous oligometastases are available. A prospective single-arm phase II trial was conducted. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). The study is listed in clinicaltrials.gov, number NCT01282450. Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44-81). Twenty-nine (74%) had local stage III; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% confidence interval 7.6-19.4); 1-, 2-, and 3-year OS was 56.4%, 23.3%, and 17.5%, respectively. Median progression-free survival (PFS) was 12.1 months (95% confidence interval 9.6-14.3); 1-year PFS was 51.3%, and both 2- and 3-year PFS was 13.6%. Only two patients (5%) had a local recurrence. No patient or tumor parameter, including volume and F-deoxyglucose uptake was significantly correlated with OS or PFS. The treatment was well tolerated. In this phase II study, long-term PFS was found in a subgroup of NSCLC patients with synchronous oligometastases when treated radically. Identification of this favorable subgroup before therapy is needed.

1296P - Radical Treatment of Non-Small Cell Lung Cancer Patients with Synchronous Oligometastases: Long-Term Results of a Prospective Phase II Trial (NCT01282450)

ABSTRACT Background Stage IV non-small cell lung cancer (NSCLC) patients with oligometastases ( Methods Prospective single-arm phase II trial. Main inclusion criteria: pathological proven NSCLC stage IV with less than 5 metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). The study is listed in clinicaltrials.gov number NCT01282450. Results 39 patients (18 males, 21 females) with a mean age of 62.1 ± 9.2 years, range 44-81) were analysed. 29 (74 %) had “local” stage III; 17 (44 %) brain, 7 (18 %) bone and 4 (10 %) adrenal gland metastases. 34 (87 %) had a single metastatic lesion. 37 (95 %) of patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95 % CI 7.6-19.4); 1-, 2- and 3-year OS 56.4 %, 23.3 % and 17.5 %, respectively. Median progression-free survival (PFS) was 12.1 months (95 % CI 9.6-14.3); 1-year PFS was 51.3 %, both 2- and 3 year PFS 13.6 %. Only 2 patients (5 %) had a local recurrence. No patient or tumour parameter, including volume and FDG uptake was significantly correlated with OS or PFS. The treatment was well tolerated. Conclusion In this phase II study, long-term PFS was found in a subgroup of NSCLC patients with synchronous oligometastases when treated radically. Identification of this favourable subgroup before therapy is needed. Disclosure All authors have declared no conflicts of interest.

Comparison of Epidermal Growth Factor Receptor Mutation Statuses in Tissue and Plasma in Stage I–IV Non-Small Cell Lung Cancer Patients

Background: Epidermal growth factor receptor (EGFR) mutations play essential roles in the treatment of non-small cell lung cancer (NSCLC) patients using EGFR tyrosine kinase inhibitors. Detection of EGFR mutations in blood cell-free DNA (cfDNA) seems promising. However, the mutation status in the plasma/serum is not always consistent with that in the tissues. Objectives: The aims of this study were to compare the mutation statuses in plasma to those in tissues and thus to determine the specific subgroups of NSCLC patients who may be the best candidates for EGFR mutation analyses using blood cfDNA. Methods: A total of 111 pairs of tissue and plasma samples were collected. Mutant-enriched PCR and sequencing analyses were performed to detect EGFR exon 19 deletions and exon 21 L858R mutations. Results: Mutations were discovered in 43.2% (48/111) of the patients. The overall rate of consistency of the EGFR mutation statuses for the 111 paired plasma and tissue samples was 71.2% (79/111). The sensitivity and specificity rates of detecting EGFR mutations in the plasma were 35.6% (16/45) and 95.5% (63/66), respectively. The disease stage and tumor differentiation subgroups showed significantly different detection sensitivities; the sensitivity was 10% in early-stage patients and 56% in advanced-stage patients (p = 0.0014). For patients with poorly differentiated tumors, the sensitivity was 77.8%, which was significantly different from those with highly differentiated (20%; p = 0.0230) and moderately differentiated tumors (19%; p = 0.0042). Conclusion: Blood analyses for EGFR mutations may be effectively used in advanced-stage patients or patients with poorly differentiated tumors.