Objectives: Immune checkpoint inhibition after radiochemotherapy (RTCT) has become a new standard of care for locally advanced non-small cell lung cancer with programmed death-ligand 1 (PD-L1) expression. However, little is known about the prognostic role of immune response markers in this setting. We analysed PD-L1 expression and tumour infiltrating lymphocytes (TiLs) in tumour biopsies from the multicenter German Intergroup Lung Trial (GILT), which previously randomised patients with stage III NSCLC to RTCT with or without consolidation chemotherapy. Materials and methods: We retrospectively analyzed tumour biopsies from patients treated in the GILT trial. PD-L1 expression was analysed using the Ventana SP263 assay and TiL score (low, intermediate, high) and pattern (excluded, inflamed, desert) were assessed. The primary endpoint of the biomarker analysis was PFS in patients with PD-L1 > 1% vs. PD-L1 < 1% NSCLC. Secondary endpoints explored the prognostic relevance of additional PD-L1 expression levels and TiL score and pattern. Results: Biopsies were available from 92 patients treated with RTCT. Patients with available tumor tissue did not differ significantly from the whole study population. PD-L1 scores from 78 samples were available for analysis. There was no difference in PFS in the PD-L1 < 1% vs. PD-L1 > 1% subgroups. TiL score was available in 66 patients. Patients with high TiL score showed favourable overall survival compared to the low TiL subgroup. This trend was most pronounced in those patients treated with consolidative chemotherapy. Conclusion: In this analysis, PD-L1 expression did not correlate with PFS following RTCT. However, patients with TiLs > 10% were found to have longer overall survival, especially for those patients treated with consolidation chemotherapy after the end of RTCT. Further analyses to explore the prognostic and predictive relevance of TiLs in the context of consolidative checkpoint inhibition with durvalumab are required.

Micro-abstract: In a Phase I dose-finding study of metronomic daily oral vinorelbine in advanced non-small-cell lung cancer, a recommended dose was established for this therapeutic approach. In addition, this trial revealed promising efficacy data and an acceptable tolerability profile. The observed vinorelbine blood concentrations suggest continuous anti-angiogenic coverage.Introduction: We present a Phase I dose-finding study investigating metronomic daily oral vinorelbine (Navelbine (R) Oral, NVBo) in advanced non-small-cell lung cancer (NSCLC).Patients and methods: Patients with stage III/IV NSCLC received daily NVBo at fixed dose levels of 20-50 mg/d for 21 days of each 4-week cycle. Primary end point was the maximum tolerated dose. Secondary end points included tumor response, time to progression (TTP), overall survival (OS) and tolerability.Results: Twenty-seven patients with advanced NSCLC were enrolled. Most of them were extensively pretreated. Daily NVBo was well tolerated up to 30 mg/d. At 40 mg/d, two of five patients experienced dose-limiting toxicities (DLTs). Three of six patients had DLTs at the 50 mg/d level. The recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2, if tolerated. Pharmacokinetic analyses showed continuous blood exposure over 21 days and only marginal accumulation. The tolerability profile was acceptable (all dose levels - all grades: decreased appetite 33%, diarrhea 33%, leukopenia 33%, nausea 30%, vomiting 26%; >= grade 3: leukopenia 30%, lymphopenia 19%, neutropenia 19%, febrile neutropenia 15%). Disease control rate, OS and TTP signaled a treatment effect.Conclusion: Daily metronomic NVBo therapy in extensively pretreated patients with advanced NSCLC is feasible and safe at the recommended dose of 30 mg/d. Escalation to 40 mg/d in the second cycle is possible. The blood concentrations of vinorelbine after daily metronomic dosing reached lower peaks than intravenous or oral conventional dosing. Blood concentrations were consistent with anti-angiogenic or immune modulating pharmacologic properties of vinorelbine. Further studies are warranted to evaluate the safety and efficacy of this novel approach in specific patient populations.

The treatment of advanced NSCLC has developed significantly over the last decade from an unspecific platinum based chemotherapy approach towards a more individualised molecular or cellular based therapy. In particular, immunotherapy is increasingly important in NSCLC therapy. Passive immunotherapy is administered with agents like monoclonal antibodies or adaptive cell therapy that directly target cancer cells, while active immunotherapy stimulates the immune system of the host to eliminate cancer cells (2). While most studies in lung cancer vaccination did not achieve their primary endpoints, several subgroup analyses revealed that vaccination could be an effective treatment for lung cancer patients. Also, the combination of therapeutic vaccines and immune checkpoint inhibitors is regarded as a promising pharmacotherapeutic approach (2, 8). PET-CT based treatment monitoring is an established method for the evaluation of the efficacy of lung cancer treatment.

Background: Emerging treatment options in advanced non-small cell lung cancer (NSCLC) related to multiple molecular targets brought new hope to lung cancer patients and new technical options for clinicians.

Fortgeschrittene, Chemotherapie-refraktäre nicht-kleinzellige Lungenkarzinome (NSCLC) mit EML4-ALK-Genfusion können gezielt mit dem ALK-Tyrosinkinaseinhibitor Crizotinib behandelt werden. Da ALK-positive NSCLC selten und Biopsie-Proben oft klein sind, ist die Auswahl zur ALK-Testung schwierig. Wir überprüften CT-Merkmale broncho-alveolärer-NSCLCs bei ALK-positiven (Fälle) und ALK-negativen (Kontrollen) Patienten.

Individualised therapy has not yet found its place in the treatment of stage III NSCLC. Although RTCT can be curative, many tumours progress despite multimodal treatment.

Im Stadium III des NSCLC kann die Radiochemotherapie zur Heilung führen. Jedoch erleidet die Mehrheit eine Progression trotz dieser sehr intensiven Therapie. Noch fehlen prädiktive Marker für die Progression nach RTCT.

Background: RTCT can be curative in stage III NSCLC; however, most tumours progress despite intensive treatment. Efforts to understand and predict PR after RTCT are ongoing. The CTRT 99/97 Bronchial Carcinoma Therapy (BROCAT) study (Huber et al., JCO 2006) showed that, after induction CT with paclitaxel and carboplatin, RTCT with paclitaxel leads to longer PFS than RT alone. Here we present site of first PR data for patients in the BROCAT trial. Methods: We analysed site of first PR in the BROCAT study, comparing local, central nervous system (CNS), and systemic PR. Results: The BROCAT trial enrolled 303 patients, and, after induction CT, randomized 214 to RT (n=113) or RTCT (n=101). There was longer progression free survival in the RTCT arm, and a trend to longer overall survival. Site of first PR was available for 102 of 165 patients with progression and differed significantly between the treatment arms (p There was no significant association between histology and PR site (p = 0.328), but there was a trend to more CNS-PR in patients with large cell tumours compared to other histologies. Age and body mass index did not correlate with site of PR. Conclusion: RTCT seems to reduce the rate of systemic PR compared to RT after induction CT in Stage III NSCLC. It is not yet possible to predict which patients will benefit from which type and amount of additional CT.

BACKGROUND:The advent of multiple molecular targets in advanced non-small-cell lung cancer (NSCLC) has brought new treatments, but also new logistic and technical considerations, to the clinician. The small size of endoscopic biopsies and the increasing number of relevant but uncommon markers has increased the need for rational approaches to molecular testing. We present the results of clinical preselection before EML4-ALK testing in a German NSCLC cohort.METHODS:Patients with stage IV NSCLC were included. Clinicians were encouraged to consider screening epidermal growth factor receptor wild-type adenocarcinoma patients with a limited smoking history, relatively young age, or who had benefited from chemotherapy for a relatively long period. Break-apart fluorescence in situ hybridization using archived paraffin tissue was performed in a central facility.RESULTS:From April 2010 to September 2011 we included 61 patients: mean age 56.6 years, 41% women, 90% adenocarcinoma, 5% large-cell, and 5% squamous cell cancers. Only three patients had activating epidermal growth factor receptor mutations; 16.4% of patients were positive for EML4-ALK fusion. The anaplastic lymphoma kinase (ALK)-positive patients included 60% women, tended to be younger, had smoked less, and had received significantly more systemic therapy, on average 3.7 lines of treatment over 3 years, before ALK-testing compared with the ALK-negative patients. Long periods of progression-free survival were experienced by ALK-positive patients treated with pemetrexed, vinorelbine, or cetuximab.CONCLUSIONS:EML4-ALK fusion is uncommon, reported in about 5% of NSCLC patients; however, clinical preselection increased the yield of testing to 16.4%. EML4-ALK positive patients seem to have distinct clinical features and show long responses to a number of systemic therapies.

e19108 Background: Metronomic regimens, in which small, frequent doses of chemotherapy are administered, have been suggested to lower toxicities while maintaining, or even improving, efficacy. The high frequency of administration aims to expose the tumor continuously to the drug, thereby preventing the recovery of malignant cells between cycles. Previous studies have shown that the administration of oral vinorelbine thrice weekly is feasible and well tolerated. We present a phase I dose finding study in which a regimen of daily oral vinorelbine was evaluated in pretreated patients with advanced NSCLC. Methods: Pretreated patients with advanced NSCLC were treated with vinorelbine (Navelbine oral) at fixed daily doses of 20 mg, 30 mg, 40 mg or 50 mg for 21 days of each four-week cycle. The primary end point was the identification of the maximum tolerated dose, which was reached when two out of six patients experienced dose limiting toxicity (DLT) in cycle 1 or 2. Results: 27 patients with advanced NSCLC (78% stage IV, median age 65 y) were enrolled. Most (93%) had received previous systemic therapy (mean: 2.6 lines). Daily administration of oral vinorelbine was well tolerated up to 30 mg/d without any DLT. At 40 mg one of three patients experienced DLT in cycle 1 and another patient in cycle 2. Three out of six patients had DLT at the dose level of 50 mg. Therefore, the recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2 if no DLT had occurred. Eleven patients (2 out of 7 treated with the recommended dose) experienced treatment-related toxicities of grade 3 or higher. The adverse events were primarily hematological (febrile neutropenia: 14.8%, leukopenia: 29.6%, lymphopenia: 18.5%, neutropenia: 18.5%). One patient died as a result of colitis. The frequency of non-hematological toxicities of grade 3 or higher was low with only single cases reported for nausea, fatigue, neutropenic sepsis, pneumonia, increased gamma-glutamyltransferase and anorexia. Conclusions: Daily administration of oral vinorelbine in pretreated patients is feasible and safe. An initial dose of 30mg/d is well tolerated and can be increased to 40mg/d in cycle 2. Further studies are warranted to evaluate the efficacy and safety of this novel approach. Clinical trial information: EudraCT number 2006-001573-25.

Patienten mit nichtkleinzelligem Lungenkarzinom im lokal fortgeschrittenen inoperablen Stadium erreichen durch die Kombination aus Strahlentherapie und Chemotherapie bessere Ansprechraten und besseres Überleben. Die Auswirkungen auf die Lebensqualität sind noch nicht ausreichend untersucht.

7350 Background: Docetaxel-based concurrent chemoradiotherapy (CTRT) regimens have shown promising activity and acceptable toxicity in stage IIIA/B NSCLC. This study was designed to evaluate the optimal therapeutic dose of docetaxel as consolidation therapy (DCT) after docetaxel-cisplatin CTRT. Methods: Patients (pts) with inoperable NSCLC, stage IIIA/B, received chemotherapy with docetaxel (20 mg/m2) and cisplatin (25 mg/m2) on days 1,8,15,22,29,36, with concurrent radiotherapy (5 days per week; 2 Gy per day) starting day 1 for a total dose of 66 Gy. If restaging after CTRT demonstrated disease stabilization or partial/complete response, then DCT with docetaxel (75 mg/m2, day 71 and 92) was added. DCT dose escalation to docetaxel 85 mg/m2 was planned for day 92, and a third docetaxel administration planned for day 113. Results: Of 23 patients enrolled (mean age 58.8±7.0 y), all were evaluable and had NSCLC stage IIIB; 6 and 17 patients had Eastern Cooperative Oncology Group performance status 0 and 1, respectively. Partial response occurred in 10 pts, and 13 pts showed disease stabilization. 1 pt with a partial response had a complete tumor resection and left the study. No pts experienced disease progression. Median survival ± SD was 42.1 ± 24.3 weeks (18 pts are alive and under observation). The DCT dose was reduced to docetaxel 60 mg/m2 in all pts as the first 3 pts had grade 3/4 toxicity. Dose-limiting toxicities included grade 3 esophagitis and pneumonitis, observed in 26% and 13% of pts, respectively. Grade 3/4 hematologic toxicities were seen in 39% of pts. Grade 3 diarrhea and emesis occurred in 2 pts (9%). Conclusions: The optimal dose of docetaxel as consolidation therapy after CTRT is 60mg/m2. This regimen resulted in a high rate of tumor response in pts with good performance status. Schedule modifications are being studied as a result of observed toxicity with CTRT. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Pharma

Die Radiochemotherapie des nicht-kleinzelligen Bronchialkarzinoms (NSCLC) wird derzeit optimiert. Ziel unserer Phase I Studie ist es, die optimale Dosis Docetaxel (DCT) als Konsolidierungstherapie nach SRCHT mit Cisplatin und DCT zu bestimmen.

Introduction: Docetaxel consolidation therapy (DCT) after concurrent cisplatin/docetaxel chemoradiation therapy (CRT) produces high tumor control in non-small-cell lung cancer (NSCLC); toxicity is, however, considerable. We aimed to determine the maximally tolerated dose (MTD) for DCT Patients and Methods: Patients with inoperable stage IIIB NSCLC received docetaxel 20 mg/m(2) and cisplatin 25 mg/m(2) on days 1, 8,15, 22, 29, and 36, with concurrent radiation therapy 5 days per week for a total dose of 66 Gy. Patients achieving stable disease, partial response, or complete response were given DCT on days 71, 92, and 113. DCT was started with 75 mg/m(2) and titrated depending on tolerability. The MTD of docetaxel was defined as the dose preceding that at which 3 or more patients experienced dose-limiting toxicity (DLT). Results: Of 23 patients enrolled (median age, 58.8 years +/- 7.3 years), 19 received complete CRT (4 withdrew because of toxicity). Of the patients receiving complete CRT, 1 patient died and 1 became operable, leaving 17 patients eligible for DCT starting at 75 mg/m(2). After the third patient with DLT, dose was reduced to 60 mg/m(2). Median survival was 27.6 months +/- 23.1 months. Median TTP was 12.4 months +/- 10.7 months. Conclusion: The MTD of DCT after concurrent cisplatin/docetaxel CRT was determined to be 60 mg/m(2), but toxicity was considerable. The benefit-risk ratio of DCT has, however, been questioned by a placebo-controlled phase III trial. Further phase III trials need to consider further stratification factors (pretreatment forced expiratory volume [FEV](1), hemoglobin, performance, and stage) to define a role for DCT in patients with NSCLC.