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Background Recent phase II–III trials of immuno(chemo)therapy before resection in locally advanced resectable non-small cell lung cancer (NSCLC) report high rates of pathological response and promising survival. However, primarily, patients who did not undergo resection were excluded from these studies. Moreover, there are no data on chemoradiotherapy (CRT) after immuno(chemo)therapy in patients who are primarily not amenable to CRT. We hypothesised that induction immuno(chemo)therapy may enable patients with NSCLC with a potentially curative stage (III–IVA), for whom primary curative treatment (either resection or CRT) is not possible for anatomical or functional reasons, to receive curative treatment. Patients and methods We enrolled 35 patients with NSCLC with aforementioned characteristics into a prospective real-world trial of induction immuno(chemo)therapy followed by morphologic and metabolic reassessment and multidisciplinary board-guided curative treatment (resection [preferred] or CRT) or palliative therapy. The primary end-point was the proportion of patients receiving curative treatment. Results Thirty-two patients (91%) received curative treatment (11 resections and 21 CRT). 73% and 64% of patients who underwent resection had a major or complete pathological response, respectively. There were 14 recurrences: 2 (18%) in patients who underwent resection, 9 (43%) in patients who received CRT and 3 (100%) in patients who received palliative therapy (median follow-up 17 months). Eight tumour-related deaths occurred: 5 (24%) in patients who received CRT; and 3 (100%) in patients who received palliative therapy. There were no treatment-related deaths. Conclusions In locally advanced or oligometastatic NSCLC without a primary curative option, induction immuno(chemo)therapy results in a high rate of curative treatment with promising early survival data. patients who underwent resection achieved a high rate of prognostically favourable pathological response.

Objectives Implementation of tyrosine kinase inhibitors (TKI) and other targeted therapies was a main advance in thoracic oncology with survival gains ranging from several months to years for non-small-cell lung cancer (NSCLC) patients. High-throughput comprehensive molecular profiling is of key importance to identify patients that can potentially benefit from these novel treatments. Material and Methods Next-generation sequencing (NGS) was performed on 4500 consecutive formalin-fixed, paraffin-embedded specimens of advanced NSCLC (n = 4172 patients) after automated extraction of DNA and RNA for parallel detection of mutations and gene fusions, respectively. Results and Conclusion Besides the 24.9 % (n = 1040) of cases eligible for approved targeted therapies based on the presence of canonical alterations in EGFR exons 18–21, BRAF, ROS1, ALK, NTRK, and RET, an additional n = 1260 patients (30.2 %) displayed rare or non-canonical mutations in EGFR (n = 748), BRAF (n = 135), ERBB2 (n = 30), KIT (n = 32), PIK3CA (n = 221), and CTNNB1 (n = 94), for which targeted therapies could also be potentially effective. A systematic literature search in conjunction with in silico evaluation identified n = 232 (5.5 %) patients, for which a trial of targeted treatment would be warranted according to available evidence (NCT level 1, i.e. published data showing efficacy in the same tumor entity). In conclusion, a sizeable fraction of NSCLC patients harbors rare or non-canonical alterations that may be associated with clinical benefit from currently available targeted drugs. Systematic identification and individualized management of these cases can expand applicability of precision oncology in NSCLC and extend clinical gain from established molecular targets. These results can also inform clinical trials.

Background Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. Methods Data from 56 centres were analysed for adverse events (AE), progression-free survival (PFS), overall survival (OS). Results 126 patients actually received at least 1 cycle durvalumab. Compared to the PACIFIC trial, the EAP population had more advanced stage and included “oligometastatic” stage IV patients and patients with autoimmune disease. PFS (20.1 months) and OS (not reached) were similar in the EAP and the PACIFIC trial. 42.9 % completed 12 months of durvalumab without deaths during FU. Stage IV patients (n = 7) had encouraging OS (not reached at 27 months). Autoimmune disease did not affect survival. PFS and OS were similar in PD-L1-negative patients (n = 32) and PD-L1-positive patients (n = 79). Conclusions Survival in the EAP was comparable to the PACIFIC trial. Selected stage IV patients and patients with autoimmune disease may benefit from durvalumab consolidation and should be included in future immuno-oncological trials. PD-L1 did not predict survival challenging the exclusion of PD-L1-negative patients from durvalumab consolidation. In summary, durvalumab consolidation is safe and effective in a European real-world setting.

Objective Panel-based next-generation sequencing (NGS) is increasingly used for the diagnosis of EGFR-mutated non-small-cell lung cancer (NSCLC) and could improve risk assessment in combination with clinical parameters. Materials and methods To this end, we retrospectively analyzed the outcome of 400 tyrosine kinase inhibitor (TKI)-treated EGFR+ NSCLC patients with validation of results in an independent cohort (n = 130). Results EGFR alterations other than exon 19 deletions (non-del19), TP53 co-mutations, and brain metastases at baseline showed independent associations of similar strengths with progression-free (PFS hazard ratios [HR] 2.1–2.3) and overall survival (OS HR 1.7–2.2), in combination defining patient subgroups with distinct outcome ( E GFR+ N SCLC risk S core, "ENS", p Conclusions EGFR variant, TP53 status and brain metastases predict TKI efficacy and survival in EGFR+ NSCLC irrespective of other currently available parameters ("ENS"). Together, they constitute a practical and reproducible approach for risk stratification of newly diagnosed metastatic EGFR+ NSCLC.

BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. PATIENTS AND METHODS: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. RESULTS: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR)= 1.02 (0.66-1.58), two-sided P= 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR= 0.95 (0.59-1.52), P= 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade =3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. CONCLUSIONS: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

Tyrosine kinase inhibitors currently confer the greatest survival gain for nonsmall cell lung cancer (NSCLC) patients with actionable genetic alterations. Simultaneously, the increasing number of targets and compounds poses the challenge of reliable, broad and timely molecular assays for the identification of patients likely to benefit from novel treatments. Here, we demonstrate the feasibility and clinical utility of comprehensive, NGS-based genetic profiling for routine workup of advanced NSCLC based on the first 3,000 patients analyzed in our department. Following automated extraction of DNA and RNA from formalin-fixed, paraffin-embedded tissue samples, parallel sequencing of DNA and RNA for detection of mutations and gene fusions, respectively, was performed using PCR-based enrichment with an ion semiconductor sequencing platform. Overall, 807 patients (27%) were eligible for currently approved, EGFR-/BRAF-/ALK- and ROS1-directed therapies, while 218 additional cases (7%) with MET, ERBB2 (HER2) and RET alterations could potentially benefit from experimental targeted compounds. In addition, routine capturing of comutations, e.g. TP53 (55%), KEAP1 (11%) and STK11 (11%), as well as the precise typing of fusion partners and involved exons in case of actionable translocations including ALK and ROS1, are prognostic and predictive tools currently gaining importance for further refinement of therapeutic and surveillance strategies. The reliability, low dropout rates (

Background: Epidermal growth factor receptor-mutated (EGFR+) non-small-cell lung cancer (NSCLC) patients failing tyrosine kinase inhibitors (TKI) can benefit from next-line targeted therapies, but implementation is challenging. Methods: EGFR+ NSCLC patients treated with first/second-generation (1G/2G) TKI at our institution with a last follow-up after osimertinib approval (February 2016), were analyzed retrospectively, and the results compared with published data under osimertinib. Results: A total of 207 patients received erlotinib (37%), gefitinib (16%) or afatinib (47%). The median age was 66 years, with a predominance of female (70%), never/light-smokers (69%). T790M testing was performed in 174/202 progressive cases (86%), positive in 93/174 (53%), and followed by osimertinib in 87/93 (94%). Among the 135 deceased patients, 94 (70%) received subsequent systemic treatment (43% chemotherapy, 39% osimertinib), while 30% died without, either before (4%) or after progression, due to rapid clinical deterioration (22%), patient refusal of further therapy (2%), or severe competing illness (2%). Lack of subsequent treatment was significantly (4.5x, p Conclusion: Osimertinib after 1G/2G TKI failure prolongs survival, but approximately 15% and 30% of patients forego molecular retesting and subsequent treatment, respectively, mainly due to rapid clinical deterioration. This is an important remediable obstacle to sequential TKI treatment for EGFR+ NSCLC. It pertains also to other actionable resistance mechanisms emerging under 1G/2G inhibitors or osimertinib, whose rate for lack of next-line therapy is similar (approximately 35% in the FLAURA/AURA3 trials), and highlights the need for closer monitoring alongside broader profiling of TKI-treated EGFR+ NSCLC in the future.

Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. 211 patients were registered by 90 German centres. Data were collected retrospectively by questionnaire and queries. 56 centres reported data on 126 patients who actually received at least one cycle of durvalumab. In contrast to the PACIFIC-trial population, some patients with oligometastatic disease and a history of autoimmune disease are included in the EAP population. Information on PD-L1 status was obtained for 111 patients. Baseline data include age, gender, ECOG, stage (IASLC 8th ed.), and smoking history. Treatment data include mode of chemoradiotherapy, used chemotherapy agent, and duration of durvalumab therapy. Adverse evants were documented according to CTAEC 5.0. Data were analysed for progression-free survival (PFS), overall survival (OS), and adverse events (AE). The results were published in Lung Cancer [1].

Panel-based next-generation sequencing (NGS) is increasingly used for the diagnosis of EGFR-mutated non-small-cell lung cancer (NSCLC) and could improve risk assessment in combination with clinical parameters.To this end, we retrospectively analyzed the outcome of 400 tyrosine kinase inhibitor (TKI)-treated EGFREGFR alterations other than exon 19 deletions (non-del19), TP53 co-mutations, and brain metastases at baseline showed independent associations of similar strengths with progression-free (PFS hazard ratios [HR] 2.1-2.3) and overall survival (OS HR 1.7-2.2), in combination defining patient subgroups with distinct outcome (EGFREGFR variant, TP53 status and brain metastases predict TKI efficacy and survival in EGFR

Patients with non-small cell lung cancer (NSCLC) and a prior or synchronous second malignancy are generally excluded from clinical trials. Therefore, little is known on prevalence and prognosis of these patients. 1252 patients diagnosed with NSCLC in our center from 2006 to 2017 were studied. Overall survival (OS) of patients with a prior or synchronous malignancy was compared to controls including case–control analysis. 158 patients (12.6%) had a prior malignancy. The most common sites were prostate (17%), breast (16%), gastrointestinal tract (12%), head and neck (11%), bladder (10%), and lung (8%). Compared to controls, patients with prior malignancy were older (71.3 vs. 67.5 years), but had otherwise better prognostic characteristics (stage I–III 63 vs. 53%). Survival was identical compared to controls [hazard ratio (HR) 1.017, CI 0.776–1.333]. A further 3.5% of patients had a synchronous malignancy including 34% prior lung cancer. Patients with a synchronous malignancy had an earlier stage (I–III 84%), and had longer median OS in unselected patients (38.6 vs. 16.2 months, p = 0.021). However, the case–control analysis showed similar OS [hazard ratio (HR) 0.899, CI 0.497–1.621]. Prior or synchronous second malignancies are common at diagnosis of NSCLC. The sites reflect the high proportion of smokers in the population. The earlier stage of NSCLC with a second malignancy might be attributed to chance finding of NSCLC during follow-up. The second malignancy does not affect OS of NSCLC. Therefore, the exclusion of patients with second malignancies from NSCLC trials should be reconsidered.

// Martin Faehling 1 , Birgit Schwenk 1 , Sebastian Kramberg 1 , Robert Eckert 2 , Anna-Lena Volckmar 3 , Albrecht Stenzinger 3, * and Jorn Strater 4, * 1 Department of Cardiology and Pneumology, Hospital Esslingen, Esslingen, Germany 2 Outpatient Cancer Treatment Clinic Esslingen, Esslingen, Germany 3 Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany 4 Institute of Pathology Esslingen, Esslingen, Germany * These authors have contributed equally to this work Correspondence to: Martin Faehling, email: m.faehling@klinikum-esslingen.de Keywords: NSCLC, EGFR, ALK, BRAF, overall survival Received: April 18, 2017 Accepted: July 06, 2017 Published: September 13, 2017 ABSTRACT Introduction : Oncogenic driver mutations activating EGFR , ALK , or BRAF in NSCLC predict sensitivity to specific tyrosine-kinase inhibitors (TKIs). We provide data on prevalence, treatment and survival of driver-mutation positive NSCLC in a predominantly Caucasian population in routine clinical practice. Patients and Methods : NSCLC patients diagnosed from 2006-2015 with an EGFR-test result were included (n=265). Testing for EGFR , ALK , or BRAF was performed if specific TKI therapy was considered. Case-control analyses of overall survival (OS) comparing driver-mutation positive and negative patients were performed. Results : 44 sensitizing EGFR mutations (17%), 8 ALK translocations (7%, n=111) and 3 BRAF mutations (8%, n=39) were detected in adenocarcinoma or adenosquamous carcinoma. We did not find mutations in tumors without an adenocarcinoma-component. More than 90% of inoperable driver-mutation positive patients received TKI-therapy. Case-control analysis revealed improved OS of driver-mutation positive patients (39.6 vs. 19.4 months, HR 0.51). OS was improved in stage IV patients but not in stage I-III patients. OS of EGFR-TKI treated patients was similar for 1 st and 2 nd -line EGFR-TKI treatment. Patients not treated with EGFR-TKI had no benefit in OS. Re-biopsies obtained at progression revealed an EGFR -T790M mutation in 73% (n=11). These patients responded to the 3 rd -generation EGFR-TKI osimertinib. Discussion : Testing guided by predictive clinical parameters resulted in twice as high rates of mutation-positive patients than expected, and TKI treatment resulted in a strong long-term OS advantage. Conclusion: Testing for driver mutations is feasible in routine clinical practice, and identifies patients who benefit from TKI-therapy. OS compares favorably with OS in clinical studies.

Background: Immuno-oncological (IO) therapies such as PD-1 and PD-L1 antibodies have been introduced in the treatment of advanced non-small cell lung cancer (NSCLC) since 2015 based on randomized trials showing unprecedented advantages in overall survival (OS) with hazard ratios (HRs) between 0.5 and 0.7. The impact of these treatments on OS in routine clinical practice and the role of tumor mass have not been studied. Methods: 557 consecutive patients with inoperable stage III or stage IV NSCLC diagnosed in our certified lung cancer center from 2006 to 2018 were included if they had received at least one line of systemic treatment. OS of immuno-oncologically treated patients (IO patients, n = 144) who received treatment with a PD-1 antibody (nivolumab [n = 77] or pembrolizumab [n = 51]) or a PD-L1 antibody (atezolizumab [n = 4] or durvalumab [n = 12]) was compared to historic controls treated before availability of IO treatment (n = 413) using case-control analysis. IO patients and historic controls were individually matched for stage, performance state, histology, smoking status, gender, age, and initial treatment mode (palliative vs. definitive radio-chemotherapy). Results: Case-control analysis of 91 matched pairs showed significantly longer OS in IO patients compared to historic controls (21.2 vs. 10.9 months, HR 0.526, CI 0.373–0.723). The benefit was more pronounced in patients with lower tumor stage (HR 0.48 [stage III], 0.40 [IVA], 0.63 [IVB]) or smaller tumor size (HR 0.38 [RECIST ≤57 mm], 0.40 [RECIST 58–94 mm], 0.59 [RECIST 95–141 mm], 0.75 [RECIST ≥142 mm]). Conclusions: IO patients showed significant benefit in OS with HRs comparable to those reported in phase III trials. The benefit tended to be greater in patients with lower tumor mass.

9050 Background: Recently reported, extended follow-up data from KEYNOTE-024 or -010 indicates that non-small-cell lung cancer (NSCLC) patients can experience long-term benefit from immunotherapy irrespective of discontinuation (per protocol: 35 cycles ∼24 months) or type of response in computed tomography (CT). Similar results were observed in the pooled analysis of 5-year follow-up data from CheckMate-017 and -057. This raises the question, whether patients may safely discontinue immunotherapy after achieving durable response. However, recently published results from CheckMate-153 demonstrated inferior survival rates in patients ceasing immunotherapy after one year, therefore optimal treatment duration of immunotherapy in advanced NSCLC remains unknown. Protocols from published Phase-III trials implemented treatment for a period of approximately 24 months or until evidence of disease progression or unbearable toxicity. Therefore, the ideal duration of immunotherapy remains unclear, and finding markers of beneficial outcome is of great importance. Here, we determine the proportion of complete metabolic responses (CMR) in patients that have not progressed after 24 months of immunotherapy. Methods: This is a retrospective analysis of forty-five patients with positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) imaging for assessment of residual metabolic activity after at least 24 months of immunotherapy. Lesion-uptake in FDG PET on or below background level (using mediastinum as reference) was considered as CMR. Time until best objective morphological response including disease stabilization was measured from start of immunotherapy until first stable CT-scan (i.e. no progression or further response compared to previous scan) using RECIST 1.1. Results: Out of 45 patients, 29 patients had a CMR (64%). CMR was observed more frequently in non-first line patients. Patients with CMR were younger (median 65.7 vs. 75.5, P = 0.03). Fourteen patients with CMR have discontinued therapy and have not progressed until time of analysis; however median follow-up was only 5.6 (range 0.8-17.0) months. Conclusions: After a minimum of 24 months of palliative immunotherapy for NSCLC, CMR occurred in almost two thirds of patients. Potentially, achievement of CMR might identify patients, for whom palliative immunotherapy may be safely discontinued.

The controlled phase III trial SATURN demonstrated that maintenance therapy with erlotinib after the first-line platinum-based chemotherapy prolonged progression-free survival (PFS) and overall survival (OS) of non-small cell lung cancer (NSCLC) patients with advanced, non-progressive disease. We conducted the non-interventional study SATURN NIS to investigate the effectiveness and tolerability of erlotinib maintenance in daily clinical practice. This single-arm NIS screened 290 patients with locally advanced or metastatic NSCLC (stage IIIB or IV) and stable disease after standard platinum-based first-line chemotherapy in 95 institutions across Germany. Erlotinib was dosed and administered corresponding to the terms of the marketing authorization at the time of recruitment. The main effectiveness endpoint was subjects’ OS at 1 year. Subgroup analyses of survival estimates of OS and PFS were performed. 272 patients were eligible for analysis (median age 66 years, 37.1% females, 99.6% Caucasian, median ECOG performance status 1, 61.8% adenocarcinoma, 96.3% of patients with stable disease). Maintenance therapy with erlotinib resulted in median OS comparable to that of the SATURN phase III trial 10.4 months [95% CI: (8.8; 12.5) vs. 11.9 months]. The 1-year survival rate was 45.6% [95% CI: (37.5%; 53.6%)]. No new safety signals were observed. As expected, patients with epidermal growth factor receptor (EGFR) mutations derived a greater benefit concerning OS and PFS than EGFR–wild-type patients. Moreover, a significant association of OS and PFS and the smoking status was observed. The results of this non-interventional study support the current clinical practice of erlotinib switch maintenance in EGFR-mutation-positive patients.

Background Osimertinib is the preferable therapeutic option for many epidermal growth factor receptor (EGFR)+ non-small cell lung cancer (NSCLC) patients failing other tyrosine kinase inhibitors (TKI), but implementation of EGFR TKI sequencing is often problematic. Methods We retrospectively studied the clinical course of EGFR+ NSCLC patients that received first-/second-generation TKI at our institutions and had their last follow-up after osimertinib approval (02/2016). Results A total of n = 283 EGFR+ NSCLC patients received erlotinib (45%), gefitinib (19%) and/or afatinib (36%) in the 1st-4th treatment lines with a median age of 66 years, a median ECOG performance status of 0 (137/266 patients with available data) and a predominance of female (183/283=65%) never-/light-smokers (177/283=63%). Median overall survival (OS) from treatment start was 32.7 months (95% confidence interval [CI] 28.1 – 37.3) with 2.2 treatment lines on average (standard deviation 1.4). EGFR T790M testing was performed for 139/203 (68%) patients after TKI failure, with a positive result in 77/139 (55%) and subsequent treatment with osimertinib in 50/77 (65%). Overall, 50/203 (25%) of patients received osimertinib, with a median OS of 44.9 (27.9 – 62.1) months, significantly longer than the 30.4 (20.6 – 40.3) months for patients with alternative or no subsequent therapies (logrank p = 0.053, Breslow p = 0.002). Among the 134 deceased patients with complete follow-up, 84 (63%) received additional systemic treatment (37% chemotherapy, 16% osimertinib, 8% only alternative EGFR inhibitors, 2% only immunotherapy), while 50/134 (37%) died without next-line therapy. For patients that subsequently received chemotherapy, median time to start of chemotherapy was 11.6 (8.9 – 14.3) months. Conclusions Sequential treatment with osimertinib after first- or second-generation EGFR inhibitors significantly prolongs OS, but in the real-world setting a considerable fraction of patients will not be able to benefit from that. Main obstacles in our cohort were lack of EGFR T790M testing (32% of total cases), T790M-negative progression (45% of tested cases), and rapid clinical deterioration without the chance of next-line therapy (about one-third of patients). Legal entity responsible for the study Thoraxklinik at Heidelberg University Hospital. Funding Thoraxklinik at Heidelberg University Hospital AstraZeneca. Disclosure P. Christopoulos: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Chugai; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Boehringer; Research grant / Funding (institution): Takeda. F. Bozorgmehr: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self): MSD. J.B. Kuon: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Cellgene. V. Endris: Honoraria (self), Advisory / Consultancy: ThermoFisher; Honoraria (self), Advisory / Consultancy: AstraZeneca. T. Bochtler: Honoraria (institution), Research grant / Funding (institution): Roche. F.J.F. Herth: Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Boehringer; Honoraria (self), Research grant / Funding (institution): Chiesi; Honoraria (self), Research grant / Funding (institution): Teva; Honoraria (self): Pulmonx BTG; Honoraria (self): Olympus. C. Heussel: Honoraria (self), Honoraria (institution): Novartis, Basilea, Bayer, Grifols, Boehringer, Pierre Fabre, Covidien, Siemens, Chiesi, Intermune, MEDA Pharma, Bracco, Pfizer, MSD, Roche, Lilly, AstraZeneca, Schering-Plough, Essex, Gilead, MeVis, Fresenius, Astellas; Shareholder / Stockholder / Stock options: GSK. T. Muley: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Roche. J.R. Fischer: Advisory / Consultancy: Boehringer, Roche, Celgene and AstraZeneca. A. Stenzinger: Honoraria (self), Advisory / Consultancy: Novartis, AstraZeneca, ThermoFisher, BMS; Honoraria (self): BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, MSD, Roche; Research grant / Funding (institution): Chugai; Honoraria (self): Illumina, AstraZeneca, Novartis, ThermoFisher . M. Thomas: Honoraria (self), Advisory / Consultancy: Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer, Lilly, MSD, Takeda; Research grant / Funding (institution): AstraZeneca, BMS, Celgene, Novartis, Roche, Takeda. All other authors have declared no conflicts of interest.

Background: Erlotinib is a standard of treatment for metastatic non-small-cell lung cancer after failure of initial therapy. Patient selection based on clinical factors is under discussion. Methods: We analyzed the outcome in relation to clinical factors of 121 consecutive Caucasian patients treated with erlotinib in a routine clinical setting in a comprehensive cancer center and 2 regional oncology centers. Results: For patients with erlotinib treatment at the 1st/2nd/3rd/≧4th line, progression-free survival (PFS) was 4.5/3.5/2.5/3.0 months, and overall survival (OS) was 8.0/8.5/7.8/6.5 months. Patients with adenocarcinoma had an improved PFS, but a similar OS. Never-smokers had longer PFS (7 months) and OS (13 months) than smokers and ex-smokers. Male patients had a slightly longer survival than female patients (PFS 3.0 vs. 2.5 months, OS 8.5 vs. 7.0 months). After adjustment for smoking and histology, the gender difference in OS was significant (adjusted hazard ratio 0.57). Patients with clinically relevant skin toxicity (grade 2, 3) had a significantly prolonged PFS and OS. Patients with partial response on 1st radiological evaluation had a significantly prolonged PFS and OS. Conclusion: Among clinical factors, never-smoking status and male gender predicted a prolonged survival. During treatment, skin toxicity and radiological response were related to better survival.

Haufig ergibt sich der klinische Verdacht einer pulmonalen Hypertonie bei einer ungeklarten Belastungsdyspnoe oder aufgrund zufallig angefertigter Untersuchungen mit Zeichen der Rechtsherzinsuffizienz. Die Kenntnis der Venedig-Klassifikation ist fur das systematische diagnostische Vorgehen zur exakten Klassenzuordnung entscheidend. Zu den Basisuntersuchungen zahlen EKG, Rontgenthoraxaufnahme, Lungenfunktionsuntersuchung und die Echokardiographie, die die wichtigste nicht-invasive Untersuchung zur atiologischen Abklarung und Verlaufsbeurteilung darstellt, aber auch zur Screeningdiagnostik dient. Echokardiographische Kriterien einer pulmonalen Hypertonie sind ein hypertrophierter und dilatierter rechter Ventrikel, eine paradoxe Septumbewegung, ein dilatierter rechter Vorhof und eine erweitere untere Hohlvene. Mittels Dopplerechokardiographie kann bei Trikuspidalinsuffizienz der systolische rechtsventrikulare und pulmonal-arterielle Druck bestimmt werden. Eine CT des Thorax dient zum Ausschluss von Lungenembolien und interstitiellen Lungenerkrankungen. Die kardiale MRT gewinnt zunehmende Bedeutung in der Beurteilung der rechtsventrikularen Morphologie, Funktion und Hamodynamik. Zur Beurteilung des Schweregrads, aber auch als Verlaufsparameter, dient der 6-Minuten-Gehtest. Die Spiroergometrie objektiviert den Schweregrad, die Prognoseeinschatzung und dient zur Verlaufsbeurteilung. Zur definitiven Diagnosestellung wird die Rechtsherzkatheteruntersuchung einschlieslich einer pharmakologischen Testung einer „Teilreversibilitat“ der pulmonal-vaskularen Druckerhohung eingesetzt.

Patients with ischaemic heart disease commonly have an impaired glucose tolerance. On the 2004 congress of the ESC, the 75-75-rule was announced, indicating that 75% of all diabetics die of cardiovascular complications, and that 75% of all patients with myocardial infarction have diabetes or an (often undiagnosed) impaired glucose tolerance. Data of our "Esslinger Koronarregister" confirm that diabetics and in particular women with diabetes have a higher mortality both after STEMI and NSTEMI. During acute myocardial infarction, a higher blood glucose level strongly correlates with increased mortality. This increased blood glucose level on the one hand is due to preexisting diabetes mellitus or metabolic syndrome, but on the other hand may be a marker of larger myocardial damage with excess katecholamine release. Recent data indicate that intensive glucose control results in a reduction of cardiovascular risk, e. g. the risk of sudden cardiac death. The data presented show that an early intervention in preclinical diabetics aiming at normalization of blood glucose control is necessary in order to reduce cardiovascular mortality.

Introduction Some patients with advanced NSCLC show prolonged disease stabilization on treatment with an EGFR-tyrosine kinase inhibitor (TKI) such as erlotinib. It is not clear how to treat patients who progress after prolonged response to erlotinib. We hypothesized that TKI therapy beyond progression with added chemotherapy, radiotherapy or best supportive care may improve survival. Patients and methods We retrospectively analyzed all NSCLC patients treated with erlotinib at our institutions since 2004who progressed after at least stable disease on erlotinib for at least 6 months. The first 16 patients did not receive further TKI treatment after progression (controls). The following 25 patients were treated with TKI beyond progression (TKI patients). Overall survival (OS) was analyzed for the whole population, a case–control analysis of pairs matched for gender, smoking status, and histology ( n = 28), and for patients with known EGFR mutation status ( n = 23). Results Treatment with TKI and chemotherapy was well tolerated. TKI-patients had a significantly longer OS from progression on TKI (case–control: median 14.5 vs. 2.0 months, HR 0.154) and longer OS from diagnosis of lung cancer (case–control: median 54.5 vs. 28.3 months, HR 0.474). An activating EGFR mutation was detected in 13 of the 23 patient tested (57%). Both among patients with and without detection of an activating EGFR mutation, those treated with erlotinib beyond progression had a longer survival. Conclusions In our case–control analysis in long-term erlotinib responders, treatment with TKI beyond progression in addition to chemotherapy or radiotherapy was feasible and lead to prolonged overall survival.

We report a successful pregnancy in a patient with longstanding LAM on treatment with sirolimus. During temporary discontinuation fo sirolimus in early pregnancy, lung function declined but recovered after resumption of sirolimus. Pregnancy was complicated by a persistent pneumothorax which was treated surgically postnatally. The child has had a normal development despite exposure to low dose sirolimus intermittently during early embryonal and mid-fetal life.

Commonly, pulmonary hypertension is clinically suspected because of unexplained exertional dyspnoea or as a chance finding in clinical examination revealing signs of right heart failure. The systematic diagnostic approach and exact classification is based on the Venice classification. Basic investigations include ECG, chest radiograph, lung function studies and echocardiography. Echocardiography is the most important investigation for the diagnosis of pulmonary hypertension. It also serves as non invasive control during treatment and as the main screening test for pulmonary hypertension. Echocardiographic criteria of pulmonary hypertension are a dilated and hypertrophied right ventricle, paradoxic septum movement, a dilated right atrium, and a distended inferior Vena cava. Using Doppler echocardiography, the right ventricular and thus pulmonary arterial systolic pressure can be determined from the tricuspid regurgitant jet velocity. CT of the chest serves to exclude pulmonary embolism and interstitial lung disorders. Cardiac MRI is increasingly being used for analysis of right ventricular morphology, function and haemdynamics. The 6 minute walk test and cardiopulmonary exercise test are used to assess severity and response to treatment and give prognostic information. For the definite diagnosis of pulmonary hypertension, right heart catheterisation is required for the determination of the pulmonary vascular resistance and pharmacological testing of "reversibility".