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EPI-14-1149 . EGFR mutation type by tissue source tested

Supplemental Table S3. Tissue source and testing method used for EGFR mutation analysis

Purpose: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non–small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC.Experimental Design: Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed.Results: KEAP1 mutations occurred with a frequency of 11.3% (n = 157) and NFE2L2 mutations with a frequency of 3.5% (n = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD; 72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC; 59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with KEAP1 mutation had a response on systemic treatment in first-, second-, or third-line setting. Of NFE2L2-mutated patients, none responded to second- or third-line therapy.Conclusions: KEAP1- and NFE2L2-mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. Clin Cancer Res; 24(13); 3087–96. ©2018 AACR.

Introduction: EGFR mutations confer sensitivity to EGFR tyrosine kinase inhibitors (TKI) in advanced non–small cell lung cancer (NSCLC). We investigated the clinicopathologic characteristics associated with EGFR mutations and their impact on real-world treatment decisions and outcomes in Caucasian patients with advanced NSCLC.Methods: REASON (NCT00997230) was a noninterventional multicenter study in patients (≥18 years) with stage IIIb/IV NSCLC, who were candidates for EGFR mutation testing and first-line systemic treatment, but not eligible for surgery or radiotherapy. Patients were followed up according to normal clinical practice and assessed for primary (correlation of mutation status with baseline characteristics) and secondary endpoints (first-line treatment decision).Results: Baseline data were obtained for 4,200 patients; 4,196 fulfilled the inclusion criteria; EGFR mutations were detected in 431 patients; no EGFR mutations were detected in 3,590 patients; mutation status was not evaluable in 175 patients. In multivariate analysis, the odds of EGFR mutations were significantly higher (P < 0.0001) in females versus males (odds ratio: 1.85; 95% confidence interval, 1.48–2.32), never-smokers versus smokers (3.64; 2.91–4.56), and patients with adenocarcinoma versus other histologic subtypes (2.94; 2.17–4.08). The most commonly prescribed first-line systemic treatments were: EGFR-TKIs in EGFR mutation–positive NSCLC (56.6%) and combination chemotherapy in EGFR mutation–negative NSCLC (78.5%).Conclusions: This represents the largest dataset for EGFR mutations in Caucasian patients and shows EGFR mutations to be most prevalent in females with adenocarcinoma who had never smoked.Impact: These findings add to our understanding of the prognostic and predictive factors of NSCLC, supporting future improved treatment selection. Cancer Epidemiol Biomarkers Prev; 24(8); 1254–61. ©2015 AACR.

Supplemental Table 1-7 Supplemental Table 1: Diagnostic panels used for Next-generation sequencing (NGS) Supplemental Table 2: KEAP1 mutations Supplemental Table 3: NFE2L2 mutations Supplemental Table 4: Co-aberrations of KEAP1 Supplemental Table 5: Co-aberrations of NFE2L2 Supplemental Table 6: Distribution on FISH finding depending on histology Supplemental Table 7: Therapeutic outcome of patients receiving systemic therapy.

Main characteristics of the control group.

Background Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor. Patients and methods Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator’s choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS). Results Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T. Conclusion In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.

Das kleinzellige Lungenkarzinom (SCLC) ist mit 13–15 % der Lungentumoren eher selten vertreten, die Mehrheit wird als nichtkleinzellige Lungenkarzinome (NSCLC) klassifiziert. Nur bei einem Drittel der SCLC-Erkrankten wird ein potenziell kurativ behandelbares lokalisiertes Stadium diagnostiziert; die meisten SCLC werden allerdings erst im Stadium IV entdeckt.

Robust data on the outcome of MET-aberrant NSCLC with nontargeted therapies are limited, especially in consideration of the heterogeneity of MET-amplified tumors (METamp).A total of 337 tumor specimens of patients with MET-altered Union for International Cancer Control stage IIIB/IV NSCLC were analyzed using next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry. The evaluation focused on the type of MET aberration, co-occurring mutations, programmed death-ligand 1 expression, and overall survival (OS).METamp tumors (n = 278) had a high frequency of co-occurring mutations (80% for all amplification levels), whereas 57.6% of the 59 patients with MET gene and exon 14 (METex14) tumors had no additional mutations. In the METamp tumors, with increasing gene copy number (GCN), the frequency of inactivating TP53 mutations increased (GCN4: 58.2%; GCN ≥ 10: 76.5%), whereas the frequency of KRAS mutations decreased (GCN4: 43.2%; GCN ≥ 10: 11.8%). A total of 10.1% of all the METamp tumors with a GCN ≥ 10 had a significant worse OS (4.0 mo; 95% CI: 1.9-6.0) compared with the tumors with GCN10 (12.0 mo; 95% confidence interval [CI]: 9.4-14.6). In the METamp NSCLC, OS with immune checkpoint inhibitor (ICI) therapy was significantly better compared with chemotherapy with 19.0 months (95% CI: 15.8-22.2) versus 8.0 months (95% CI: 5.8-10.2, p0.0001). No significant difference in median OS was found between ICI therapy and chemotherapy in the patients with METex14 (p = 0.147).METex14, METamp GCN ≥ 10, and METamp GCN10 represent the subgroups of MET-dysregulated NSCLC with distinct molecular and clinical features. The patients with METex14 do not seem to benefit from immunotherapy in contrast to the patients with METamp, which is of particular relevance for the prognostically poor METamp GCN ≥ 10 subgroup.

Background: Large cell neuroendocrine carcinomas (LCNEC) are rare pulmonary malignancies. Reported survival rates are heterogeneous and the optimal therapeutic strategy is still debated. The prognosis of LCNEC is generally inferior compared to other non-small lung cancers. In early stages, surgery is recommended but might not be sufficient alone. Methods: We retrospectively analyzed all consecutive LCNEC patients operated at three institutions with curative intent between May 2005 and January 2017. Data retrieved from individual clinical databases were analyzed with the aim to identify prognostic parameters. Results: A total of 251 patients with LCNEC underwent curative intent surgery during the observation period. The median age was 64 years, 156 patients (62.2%) were male and 88.4% were smokers. The pathologic AJCC stage was I in 136 patients, II in 77, III in 33, and IV in 5 patients. Median followup was 26 months. Lymphatic vessel invasion (P=0.031) was identified as significant prognostic factor by multivariable analysis. There was a trend towards decreased survival in patients with blood vessel invasion (P=0.067). Even in earlier tumor stages, adjuvant chemotherapy had a positive effect on survival. The overall 1-, 3- and 5-year survival rates were 79.2%, 48.6% and 38.8% respectively. Conclusions: Lymphatic invasion (L1) is an independent prognostic factor. Surgery in LCNEC is beneficial in early tumor stages and platinum-based adjuvant chemotherapy may help in achieving better long-term outcomes resulting in most obvious survival differences in stage Ib. CA extern

Purpose: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non–small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC. Experimental Design: Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed. Results: KEAP1 mutations occurred with a frequency of 11.3% (n = 157) and NFE2L2 mutations with a frequency of 3.5% (n = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD; 72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC; 59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with KEAP1 mutation had a response on systemic treatment in first-, second-, or third-line setting. Of NFE2L2-mutated patients, none responded to second- or third-line therapy. Conclusions: KEAP1- and NFE2L2-mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. Clin Cancer Res; 24(13); 3087–96. ©2018 AACR.

Background Large-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC. Patients and methods In this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment. Results Forty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval [CI] 31%-60%), the disease control rate 74% (CI 59%-85%), the median progression-free survival 4.4 (CI 3.2-6) months and the median overall survival 9.9 (CI 6.9-11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%-88%) according to Kaplan-Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (

The aim of the present study was to assess the expression of epithelial-mesenchymal transition biomarkers (E-cadherin and vimentin) and their potential significance as prognostic markers in patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC) enrolled in the INNOVATIONS trial, receiving treatment with either erlotinib/bevacizumab (EB) or cisplatin/gemcitabine/bevacizumab (PGB). The tumor tissues of 104 patients were retrospectively analyzed using immunohistochemistry to assess the expression of E-cadherin and vimentin. The distribution between the treatment arms was 46 patients in the EB-arm and 58 in the PGB-arm. Comparing the treatment arms according to E-cadherin and vimentin expression, the analysis revealed that progression-free survival (PFS) was increased in the PGB treatment group when compared with EB treatment in patients with low expression of E-cadherin [hazard ratio (HR)=0.353; 95% confidence interval (CI) 0.189- 0.658; log-rank P=0.0007] and in those with high expression of vimentin [HR=0.276 (95% CI, 0.115- 0.659), log-rank P=0.0021]. In patients that exhibited high E-cadherin and were negative for vimentin, there was no difference in the PFS between the PGB and EB treatment groups. In conclusion, in non-squamous NSCLC with downregulated E-cadherin and upregulated vimentin, the efficacy of chemotherapy with PGB was superior compared with EB; but the same effect was not observed in patients with high E-cadherin and low vimentin. Although increased PFS was observed in patients with PGB treatment compared with EB treatment in the whole analysis populations, in the subgroup of patients with the mesenchymal phenotype, no prognostic or predictive value of either biomarker could be identified. The potential role of bevacizumab in overcoming chemotherapy resistance in the population with the mesenchymal phenotype has to be further explored.

Background The immune surveillance reactivator lefitolimod (MGN1703), a DNA-based TLR9 agonist, might foster innate and adaptive immune response and thus improve immune-mediated control of residual cancer disease. The IMPULSE phase II study evaluated the efficacy and safety of lefitolimod as maintenance treatment in extensive-stage small-cell lung cancer (ES-SCLC) after objective response to first-line chemotherapy, an indication with a high unmet medical need and stagnant treatment improvement in the last decades. Patients and methods 103 patients with ES-SCLC and objective tumor response (as per RECIST 1.1) following four cycles of platinum-based first-line induction therapy were randomized to receive either lefitolimod maintenance therapy or local standard of care at a ratio of 3 : 2 until progression or unacceptable toxicity. Results From 103 patients enrolled, 62 were randomized to lefitolimod, 41 to the control arm. Patient demographics and response patterns to first-line therapy were balanced. Lefitolimod exhibited a favorable safety profile and pharmacodynamic assessment confirmed the mode-of-action showing a clear activation of monocytes and production of interferon-gamma-induced protein 10 (IP-10). While in the intent-to-treat (ITT) population no relevant effect of lefitolimod on progression-free and overall survival (OS) could be observed, two predefined patient subgroups indicated promising results, favoring lefitolimod with respect to OS: in patients with a low frequency of activated CD86+ B cells (hazard ratio, HR 0.53, 95% CI: 0.26–1.08; n = 38 of 88 analyzed) and in patients with reported chronic obstructive pulmonary disease (COPD) (HR 0.48, 95% CI: 0.20–1.17, n = 25 of 103). Conclusions The IMPULSE study showed no relevant effect of lefitolimod on the main efficacy end point OS in the ITT, but (1) the expected pharmacodynamic response to lefitolimod, (2) positive OS efficacy signals in two predefined subgroups and (3) a favorable safety profile. These data support further exploration of lefitolimod in SCLC.

Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.

Introduction Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes. Methods Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients. Results We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds. Conclusion KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design.

Prior studies have demonstrated an association between excision repair cross-complementation group 1 (ERCC1) expression level and outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy. The aim of this study was to assess the impact of ERCC1 on survival for patients with stage IIIB/IV non-squamous NSCLC (NS-NSCLC) enrolled in the INNOVATIONS trial, thus receiving as treatment either erlotinib/bevacizumab (EB) or cisplatin/gemcitabine/bevacizumab (PGB). We retrospectively analyzed tumor tissue of 72 patients using immunohistochemistry to assess the expression of ERCC1. The distribution between treatment arms was equal (36 patients each). Two different H scores were calculated and correlated with survival. In ERCC1-positive patients, no significant difference in terms of progression-free survival (PFS) between treatment arms has been detected. ERCC1-negative patients benefited from PGB compared to EB arm (H score: HR = 0.377, 95% CI [0.167–0.849], p = 0.0151; modified H score: HR = 0.484, 95% CI [0.234–1.004], p = 0.0468). With respect to the scoring system, in the EB-arm, a significant superior PFS turned out in ERCC1-positive patients when employing the H-score (HR = 0.430, 95% CI [0.188–0.981], p = 0.0397; median 4.9 vs. 3.9 months), but not with the modified H-score. Our findings support the hypothesis that NS-NSCLC displaying a low ERCC1 expression might benefit from cisplatin-based chemotherapy. High expression indicated better PFS in the EB arm supporting the prognostic impact. However, as impact of ERCC1-assessment even might depend on scoring systems differences, the need in standardization of assessment methodology is emphasized.

This study was performed to evaluate for a potentially important role of T cells in the pathophysiology and treatment sensitivity of large cell neuroendocrine lung carcinoma (LCNEC), an orphan disease with poor prognosis and scarce data to guide novel therapeutic strategies.We performed T-cell receptor (TCR) β-chain spectratyping on blood samples of patients treated within the CRAD001KDE37 trial (n = 35) using age-matched current or former (n = 11) and never smokers (n = 10) as controls. The data were analyzed in conjunction with the complete blood counts of the probands as well as the data about response to treatment and overall survival in the clinical trial.Untreated stage IV LCNEC patients had significant T-cell repertoire alterations (p 0.001) compared to age-matched smokers. These changes correlated positively with blood lymphocyte counts (r = 0.49, p 0.01), suggesting antigen-induced T-cell proliferation as the causative mechanism. At the same time, LCNEC patients showed mild lymphopenia (1.54 vs. 2.51/nl in median, p 0.01), which reveals a second, antigen-independent mechanism of systemic immune dysregulation. More pronounced T-cell repertoire alterations and higher blood lymphocyte counts at diagnosis were associated with a better treatment response by RECIST and with a longer overall survival (441 vs. 157 days in median, p = 0.019). A higher degree of T-cell repertoire normalization after 3 months of therapy also distinguished a patient group with more favourable prognosis (median overall survival 617 vs. 316 days, p = 0.036) independent of radiological response. Thus, LCNEC induces clinically relevant changes of the T-cell repertoire, which are measurable in the blood and could be exploited for prognostic, predictive and therapeutic purposes. Their pathogenesis appears to involve antigen-induced oligoclonal T-cell expansions superimposed on TCR-independent lymphopenia.

Wolfgang Schuette,1 Claus-Peter Schneider,2,3 Walburga Engel-Riedel,4 Christian Schumann,5,6 Martin Kohlhaeufl,7 Monika Heidi Ursel Serke,8 Gert Hoeffken,9 Cornelius Kortsik,10 Martin Reck11 1Department of Internal MedicineII, Hospital Martha-Maria Halle-Doelau, Halle, 2Department of Pneumonology, Central Hospital, Bad Berka, 3Department of Internal Medicine, DRK Manniske Hospital, Bad Frankenhausen, 4Cologne Clinics, Merheim Lung Hospital, Cologne, 5Pneumonology, Department of Internal MedicineII, University Hospital Ulm, 6Clinic for Pneumology, Thoracic Oncology, Sleep, and Respiratory Critical Care, Kempten-Oberallgäu, 7Center of Pneumonology and Chest Surgery, Hospital Schillerhoehe, Gerlingen, 8Pneumonology, Lung Clinics, Hemer, 9Center of Pneumonology, Chest and Vascular Surgery, Specialty Hospital Coswig, Coswig, 10Department of Pneumonology, Catholic Hospital, Mainz, 11Department of Thoracic Oncology, Lung Clinic, Grosshansdorf, Germany Background: The aim of the study was to investigate in terms of noninferiority the efficacy and safety of a monochemotherapy regimen of pemetrexed plus bevacizumab (BevPem) versus carboplatin/pemetrexed plus bevacizumab (BevCPem) in elderly patients as first-line treatment for advanced metastatic or recurrent nonsquamous non-small-cell lung cancer (NSCLC).Materials and methods: 65Plus was a Phase III, randomized, open-label study. In total, 253 patients received BevPem (n=119) or BevCPem (n=134). The primary outcome measure was progression-free survival. Secondary end points were overall survival, tumor response, and safety outcomes. Evaluations were performed for the whole study population and stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS).Results: Noninferiority of BevPem in comparison to BevCPem could not be demonstrated for the overall population (P=0.7864). Significant superiority of the combined treatment BevCPem was seen in patients of ECOG PS 0–1 (median PFS 5.1 vs 6.9 months, HR 1.353, 95% CI 1.03–1.777), while the opposite tendency was observed in patients with ECOG PS 2 (median PFS 2.9 vs 1.5 months, HR 0.628, 95% CI 0.195–2.025). Overall, better tolerability was found for the BevPem group, irrespective of ECOG PS.Conclusion: Results from the 65plus study give evidence that BevPem and BevCPem treatments may exert differential effects on PFS, depending on the patients ECOG PS. It appears that patients with better ECOG PS (0–1) benefited more from the combined treatment with carboplatin, while the group comprising more severely impaired patients (ECOG PS 2) benefited more from the monochemotherapy. Keywords: bevacizumab, pemetrexed, carboplatin, NSCLC, elderly patients

Introduction: EGFR mutations confer sensitivity to EGFR tyrosine kinase inhibitors (TKI) in advanced non–small cell lung cancer (NSCLC). We investigated the clinicopathologic characteristics associated with EGFR mutations and their impact on real-world treatment decisions and outcomes in Caucasian patients with advanced NSCLC. Methods: REASON (NCT00997230) was a noninterventional multicenter study in patients (≥18 years) with stage IIIb/IV NSCLC, who were candidates for EGFR mutation testing and first-line systemic treatment, but not eligible for surgery or radiotherapy. Patients were followed up according to normal clinical practice and assessed for primary (correlation of mutation status with baseline characteristics) and secondary endpoints (first-line treatment decision). Results: Baseline data were obtained for 4,200 patients; 4,196 fulfilled the inclusion criteria; EGFR mutations were detected in 431 patients; no EGFR mutations were detected in 3,590 patients; mutation status was not evaluable in 175 patients. In multivariate analysis, the odds of EGFR mutations were significantly higher (P < 0.0001) in females versus males (odds ratio: 1.85; 95% confidence interval, 1.48–2.32), never-smokers versus smokers (3.64; 2.91–4.56), and patients with adenocarcinoma versus other histologic subtypes (2.94; 2.17–4.08). The most commonly prescribed first-line systemic treatments were: EGFR-TKIs in EGFR mutation–positive NSCLC (56.6%) and combination chemotherapy in EGFR mutation–negative NSCLC (78.5%). Conclusions: This represents the largest dataset for EGFR mutations in Caucasian patients and shows EGFR mutations to be most prevalent in females with adenocarcinoma who had never smoked. Impact: These findings add to our understanding of the prognostic and predictive factors of NSCLC, supporting future improved treatment selection. Cancer Epidemiol Biomarkers Prev; 24(8); 1254–61. ©2015 AACR.

Erlotinib with bevacizumab showed promising activity in recurrent nonsquamous (NS) nonsmall cell lung cancer (NSCLC). The INNOVATIONS study was designed to assess in first-line treatment of unselected cisplatin-eligible patients this combination compared to cisplatin, gemcitabine and bevacizumab.Stage IIIB/IV patients with NS-NSCLC were randomised on erlotinib (150 mg daily) and bevacizumab (15 mg·kg−1 on day 1, every 3 weeks) (EB) until progression, or cisplatin (80 mg·m−2 on day 1, every 3 weeks) and gemcitabine (1250 mg·m−2 on days 1 and 8, every 3 weeks) up to six cycles and bevacizumab (15 mg·kg−1 on day 1, every 3 weeks) (PGB) until progression.224 patients were randomised (EB n=111, PGB n=113). The response rate (12% versus 36%; pversus 6.9 months; hazard ratio (HR) 1.85, 95% CI 1.39–2.45; pversus 17.8 months; HR 1.41, 95% CI 1.01–1.97; p=0.04) clearly favoured PGB. In patients with epidermal growth factor receptor mutations (n=32), response rate, progression-free survival and overall survival were not superior with EB.Platinum-based combination chemotherapy remains the standard of care in first-line treatment of unselected NS-NSCLC. Molecular targeted approaches strongly mandate appropriate testing and patient selection.

Purpose: MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adeno- and squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer. Experimental Design: We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-naïve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC. Results: Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio ≥2.0 or average gene copy number per nucleus ≥6.0 or ≥10% of tumor cells containing ≥15 MET copies). The remaining cases can be subdivided into intermediate- (6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations. Conclusion: MET amplification is not a mutually exclusive genetic event in therapy-naïve non–small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors. Clin Cancer Res; 21(4); 907–15. ©2014 AACR.

Oncotarget 6(2), 1315-1326 (2015). doi:10.18632/oncotarget.2834, Published by Impact Journals LLC, [S.l.]

Concurrent chemoradiotherapy (CT+RT) is a standard of care for good-performance patients with unresectable stage IIIA/IIIB non-small cell lung cancer (NSCLC).1 2 In a phase II study, treatment with two cycles of pemetrexed-cisplatin (Pem-Cis) induction, followed by full-dose Pem-Cis plus concurrent RT was well tolerated and effective in 90 patients with stage IIIA/IIIB unresectable, non-squamous NSCLC.3 Here, we report by-age subgroup data for 17 elderly (aged >70 years) and 73 non-elderly patients (aged ≤70 years). The Eastern Cooperative Oncology Group performance status 0–1, no prior systemic therapy, adequate pulmonary function (FEV1 >50% and carbon monoxide diffusing capacity (DLCO) >40% of predicted normal value) and a total lung volume to receive at least 20 Gy (V20) of ≤35% were required (patient characteristics: see online supplementary material). Patients received two 3-week cycles of Pem 500 mg/m2 and Cis 75 mg/m2 as per PEM label (vitamin supplementation). Patients with complete response (CR), partial response or stable disease were then eligible for concurrent CT+RT, which included two additional cycles of …

Background The combination of oral vinorelbine plus cisplatin has been studied in numerous trials as first-line treatment of patients with non–small cell lung cancer (NSCLC) regardless of histologic subtype. NAVoTrial 01 is the first study that explores this combination specifically in nonsquamous (NS) NSCLC by assessing the feasibility of this doublet (ratio 1:2) in an investigational approach. A reference arm with pemetrexed plus cisplatin was included. Maintenance therapy with single-agent therapy after 4 cycles of combination therapy was included in the study schedules because it reflected a trend in first-line treatment of NSCLC. Patients and Methods Stage IIIB/IV untreated/relapsed patients with NS NSCLC received a 3-week cycle of pemetrexed 500 mg/m² and cisplatin 75 mg/m² on day 1 (arm A) or oral vinorelbine 80 mg/m² on days 1 and 8 (first cycle 60 mg/m²) and cisplatin 80 mg/m² on day 1 (arm B). After 4 cycles, patients without disease progression received single-agent maintenance treatment with pemetrexed or oral vinorelbine. Results Overall, 153 patients were randomized (arm A/arm B: 51/102). Disease control rate (%) for arm A was 76.5 (95% confidence interval [CI], 62.5-87.2) and for arm B it was 75.0 (95% CI, 65.3-83.1), Response rates for arm A were 31.4% (95% CI, 19.1-45.9) and for arm B were 24.0% (95% CI, 16.0-33.6). Median progression-free survival for arm A was 4.3 months (95% CI, 3.8-5.6) and for arm B it was 4.2 months (95% CI, 3.6-4.7). Median survival for arm A was 10.8 months (95% CI, 7.0-16.4) and for arm B it was 10.2 months (95% CI, 7.8-11.9). Main grade 3/4 hematologic toxicities were neutropenia 18.3% (arm A) and 44.0% (arm B), whereas febrile neutropenia was reported in 2% of patients in each arm. Conclusion Oral vinorelbine and cisplatin had an efficacy in line with that achieved with a standard treatment such as pemetrexed and cisplatin, coupled with an acceptable safety profile.

Neuroendocrine tumors (NETs; syn. carcinoid tumors) are highly or moderately differentiated neoplasms. They comprise a large variety of rare and heterogeneous tumors with an estimated incidence of 3-5/100,000/year. They can arise in virtually every internal organ, but mainly occur in the gastroenteropancreatic and bronchopulmonary systems. Around 25% of the NETs are localized in the bronchopulmonary system. Approximately 2% of all lung tumors are NETs. According to the World Health Organization (WHO) classification of lung tumors, bronchopulmonary NETs are subdivided into typical carcinoids (TCs) and atypical carcinoids (ACs). The parameter with the highest impact on NET behavior and prognosis is the histological classification and staging according to the tumor/node/metastasis (TNM) system. The diagnosis of NETs is established by histological examination and the immunohistochemical detection of general neuroendocrine markers, such as chromogranin A (CgA) and synaptophysin. Serum markers and the use of functional imaging techniques are important additive tools to establish the diagnosis of a NET. The only curative option for lung NETs is complete surgical resection. Beyond that, the currently available interdisciplinary therapeutic options are local ablation, biotherapy (somatostatin analogues), or chemotherapy. New therapeutic options such as peptide receptor radionuclide therapy (PRRT) and molecularly targeted therapies achieve promising results and are under further evaluation. This report is a consensus summary of the interdisciplinary symposium ‘Neuroendocrine Tumors of the Lung and of the Gastroenteropancreatic System (GEP NET) - Expert Dialogue' held on February 25-26, 2011 in Weimar, Germany. At this conference, a panel of 23 German experts shared their knowledge and exchanged their thoughts about research, diagnosis, and clinical management of NETs, whereby special attention was paid to NETs of the respiratory tract.

In diesem Artikel prasentieren wir einen Uberblick uber die aktuellen Entwicklungen im Bereich der EGFR-TKI beim Lungenkarzinom. Neben den etablierten Substanzen Erlotinib und Gefitinib liegt der Fokus auf klinischen Daten zu den irreversiblen TKI der zweiten Generation wie Afatinib, Dacomitinib, Neratinib, Pelitinib und Canertinib, die nicht nur den EGF-Rezeptor blockieren, sondern sich durch ein breiteres Wirkspektrum auszeichnen. Auch Anwendungen von aus anderen Indikationen bekannten und dort zugelassenen TKI wie Lapatinib und Vandetanib bei NSCLC werden beleuchtet. Ein wichtiger Aspekt in der Behandlung mit TKI ist neben den reinen Uberlebensdaten der Erhalt der Lebensqualitat der Patienten, der bei der Wahl der Therapie mit berucksichtigt werden sollte.

Zusammenfassung Das maligne Pleuramesotheliom (MPM) ist ein aggressiver thorakaler Tumor mit ungunstiger Prognose. Haufig findet sich bei Patienten mit MPM eine anamnestische Asbestexposition und wir erwarten eine zunehmende Inzidenz. In den letzten Jahren konnten wesentliche Fortschritte in der systemischen Therapie des MPM erzielt werden. Die Ergebnisse zweier groser Studien zeigten eine Uberlebensverlangerung gegenuber einer Platin-Monotherapie, so dass die Pemetrexed-Platin-Zweifachkombination zum Standard wurde. Diese verspricht Patienten in gutem Allgemeinzustand Symptomlinderung und Uberlebensverlangerung. Bei Tumorprogress empfiehlt sich in zweiter Linie eine Wiederaufnahme der Therapie (“rechallenge”), alternativ kommen Monotherapien mit Vinorelbine oder Gemcitabine infrage. Pleuraergusse sollten mittels Talkumpleurodese, in Einzelfallen auch mit palliativer Dekortikation behandelt werden. Zudem sollten alle Patienten sollten eine optimale supportive Therapie erhalten.

Many different approaches for improving the prognosis of patients with advanced non-small-cell lung cancer (NSCLC) are currently being investigated. This article discusses the significance of maintenance therapy after primary chemotherapy and reviews study data on second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), inhibitors of insulin-like growth factor receptors (IGFR), vascular-disrupting agents (VDAs) and multi-TKIs of vascular endothelial growth factor receptors (VEGFR). The article also looks at the future prospects of using genetic markers in the field of NSCLC.

Non-tuberculous mycobacterioses differ substantially from infections with M. tuberculosis complex in regard to both clinical presentation and treatment. In persons infected with HIV the pathogenic organism is almost always M. avium complex, which leads to various pulmonary diseases with specific characteristics and disseminated courses. In patients not infected with HIV, a number of factors that reduce local resistance and certain systemic conditions increase the risk of the infection's reaching a degree of severity requiring treatment. Since these factors are associated with a wide variety of clinical presentations and treatment is species-specific, assessment needs to be individualised for almost all patients. In contrast to the treatment of tuberculosis, in non-tuberculous mycobacterioses the extent to which the treatment can be based on in vitro resistance tests is limited. Clinicians therefore have to draw on their previous clinical experience and the few existing controlled studies, at least initially. In view of the high rate of recurrence compared to tuberculosis, surgical removal of local risk factors (bronchiectasis, bullae, post-specific changes) and thus the mycobacterial infection itself should be considered in all cases.

Introduction Rearrangements of RET are rare oncogenic events in patients with non–small cell lung cancer (NSCLC). While the characterization of Asian patients suggests a predominance of nonsmokers of young age in this genetically defined lung cancer subgroup, little is known about the characteristics of non-Asian patients. We present the results of an analysis of a European cohort of patients with RET rearranged NSCLC. Methods Nine hundred ninety-seven patients with KRAS/EGFR/ALK wildtype lung adenocarcinomas were analyzed using fluorescence in situ hybridization for RET fusions. Tumor specimens were molecularly profiled and clinicopathological characteristics of the patients were collected. Results Rearrangements of RET were identified in 22 patients, with a prevalence of 2.2% in the KRAS/EGFR/ALK wildtype subgroup. Co-occurring genetic aberrations were detected in 10 patients, and the majority had mutations in TP53 . The median age at diagnosis was 62 years (range, 39–80 years; mean ± SD, 61 ± 11.7 years) with a higher proportion of men (59% versus 41%). There was only a slight predominance of nonsmokers (54.5%) compared to current or former smokers (45.5%). Conclusions Patients with RET rearranged adenocarcinomas represent a rare and heterogeneous NSCLC subgroup. In some contrast to published data, we see a high prevalence of current and former smokers in our white RET cohort. The significance of co-occurring aberrations, so far, is unclear.

We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

Targeted therapies are discussed as an approach to improve outcome in neuroendocrine tumors of the lung. With current treatment options like platinum derivates and etoposide, large cell neuroendocrine carcinoma of the lung (LCNEC) patients have a poor prognosis. Everolimus (RAD001) is an inhibitor of mTOR, a component of the PI3K/AKT/mTOR pathway known to be dysregulated in neuroendocrine tumors (NETs). In the presented trial for advanced LCNEC patients, daily RAD001 is combined in first-line with carboplatin and paclitaxel, a standard chemotherapy for this population. Enrolled patients receive 4 cycles of combined treatment followed by RAD001 maintenance therapy. The primary endpoint is the proportion of progression-free patients after 3 months. Main inclusion criteria are histologically confirmed stage IV LCNEC and at least one positive neuroendocrine marker. Main exclusion criteria are symptomatic CNS metastases and prior treatment for advanced LCNEC. Here a case report of a 56-year old patient with stage IV LCNEC enrolled in this trial is presented. The tumor histologically revealed NSCLC morphology of the large-cell type and a considerable CD56 and synaptophysin staining as well as a proliferation rate of more than 60% in Ki67 staining. The patient received in first-line 4 cycles of carboplatin and paclitaxel combined with RAD001 and subsequently RAD001 monotherapy for further 9 months. The tumor response revealed as per RECIST a partial remission during the first 3 months and an ongoing stabilization of the tumor for further 9 months before a disease progression was detected 12 months after initial diagnosis. At the fifth cycle of a second-line treatment with carboplatin and etoposide, the patient has still a stable disease 16 months after initial diagnosis of LCNEC. These data show that a combined therapy of carboplatin and paclitaxel with mTOR-inhibitor RAD001 in first-line might be a promising approach for more efficient treatment of LCNEC patients.

Seit der 1995 publizierten Meta-Analyse der NSCLC Cooperative Group gelten platinhaltige Regime bei Patienten mit inoperablem, lokal fortgeschrittenem oder metastasiertem NSCLC in der Erstlinientherapie als Standard [1]. Die platinbasierte Chemotherapie besitzt dieser Analyse zufolge einen 1-Jahres-Uberlebensbenefit von absolut 10% gegenuber einer alleinigen Supportivtherapie. Gleichzeitig wird eine effektivere Symptomkontrolle erreicht, die sich in einer verbesserten Lebensqualitat ausert. Dieses Ergebnis schlug sich in den Empfehlungen der American Society of Clinical Oncology (ASCO) nieder, die sich 1997 bei NSCLC-Patienten im Stadium IV und gutem Performance-Status (PS) fur die platinhaltige Chemotherapie aussprach [2]. Allerdings wird die Verlangerung des Uberlebens um wenige Monate mit einer gewissen Toxizitat erkauft. Als problematisch gilt vor allem die Neurotoxizitat, wahrend die Nephrotoxizitat heute beherrschbar ist. Auch Ubelkeit und Erbrechen lassen sich mittlerweile dank effektiver Antiemetika gut kontrollieren. Erschwert wird die Cisplatin-basierte Therapie jedoch durch die fur den Patienten belastende Hydrierung. Platinfreie Regime auf dem Vormarsch

Purpose A phase III study to determine whether a weekly docetaxel schedule improves the therapeutic index compared with the classic 3-weekly schedule. Patients and Methods Patients with stage IIIB-IV non–small-cell lung cancer (NSCLC) were randomly assigned to docetaxel 75 mg/m2 on day 1 every 3 weeks (3-weekly) and 35 mg/m2 on days 1, 8, and 15 (weekly) for ≤ eight cycles. End points included survival (primary), toxicity, and response. Results Of 215 patients enrolled, 208 (103 in the 3-weekly arm and 105 in the weekly arm) were assessable for response. At baseline, 24.5% of patients (51 out of 208) had received prior paclitaxel therapy and 43.3% of patients (90 out of 208) had been progression-free for more than 3 months after first-line therapy. After 12 months' follow-up, median survival was 6.3 months (95% CI, 4.68 to 7.84 months) with 3-weekly docetaxel and 9.2 months (95% CI, 5.83 to 12.59 months) with weekly docetaxel (P = .07) after a median of four (range, one to eight) and two (range, one to eight) treatment cycles, respectively. Overall, response rates were 12.6% v 10.5% with 3-weekly versus weekly docetaxel. Significantly fewer patients reported grade 3 to 4 toxicities with weekly docetaxel versus 3-weekly docetaxel (P ≤ .05). There were significantly lower rates of grade 3 to 4 anemia (P ≤ .05), leucopenia (P < .0001), and neutropenia (P ≤ .001) with weekly versus 3-weekly treatment. No grade 3 to 4 thrombocytopenia or mucositis was reported. Conclusion Weekly docetaxel 35 mg/m2 demonstrated similar efficacy and better tolerability than standard 3-weekly docetaxel 75 mg/m2 and can be recommended as a feasible alternative second-line treatment option for patients with advanced NSCLC.

Eine Kombinationschemotherpie mit Cisplatin plus Pemetrexed ist die Standardbehandlung fur Patienten mit Pleuramesotheliom. Fur Betroffene, bei denen der Tumor nicht reseziert werden kann, hat eine gezielte Antiangiogenese zusatzliche Vorteile.

e20664 Background: Fibroblast growth factor receptor 1 ( FGFR1) amplification in squamous cell non-small cell lung cancer (sqNSCLC) has been described as potential oncogenic and targetable driver in cell lines and murine models. However, a phase I study evaluating FGFR 1-3 inhibitor BGJ398 showed moderate response rate of 11% in FGFR1amplified sgNSCLC treated with dose ≥ 100mg. To identify underlying mechanisms of resistance, we analyzed tumor tissues of selected patients. Methods: Within the phase I BGJ398 study, patients (pts) with FGFR1amplified sqNSCLC were treated orally with escalating dose (5 to 150mg) of BGJ398 once daily (QD) or 50mg twice a day. In the expansion phase, pts received BGJ398 either continuously QD or on a 3-weeks on/1-week off schedule. CT scans for response were performed every 8 weeks. Available tumor tissue of pts treated with BGJ398 at our center was analyzed using hybrid capture–based massively parallel sequencing (CAGE). Results: Twenty-one pts with FGFR1 amplified sqNSCLC were treated with ≥ 100mg BGJ398 at our site. As best response, 3 pts showed partial response (PR), 7 pts stable disease (SD) and 7 pts progressive disease (PD). Two pts withdrew their consents and 2 pts died ahead of first CT scan: one due to infection and one due to sudden death. We performed CAGE covering 256 genes on 9 patients: on 3 pts with PR, 2 pts with SD, 2 pts with PD and 2 pts who died before first CT scan. All analyzed patients harbored mutations in TP53. Additionally, we detected two CDKN2A (one patient with PR and one patient who died before first CT) and three MLL2 stop codon and frame shift mutations (two patients with SD and one patient with PD). Of interest, we identified three patients with two canonical (one patient with SD and one patient who died before first CT) and one non-canonical mutations in PIK3CA(one patient with SD). Conclusions: In our analysis, MLL2 and PIK3CA mutations seem to have a negative impact on response in FGFR1 amplified pts treated with BGJ398. Further analysis with higher patient number is needed to identify the role of MLL2 and PIK3CA mutations in FGFR1 amplified sqNSCLC. Clinical trial information: NCT01004224.