J. Barrueco

Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial

BACKGROUND The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). METHODS Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m(2) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2-21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194. FINDINGS Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8-11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months [95% CI 2·9-3·9] vs 2·7 months [2·6-2·8]; hazard ratio [HR] 0·79 [95% CI 0·68-0·92], p=0·0019). After a median follow-up of 31·7 months (IQR 27·8-36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months [95% CI 8·5-12·6] vs 7·9 months [6·7-9·1]; HR 0·75 [95% CI 0·60-0·92], p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months [95% CI 10·6-15·1] vs 10·3 months [95% CI 8·6-12·2]; HR 0·83 [95% CI 0·70-0·99], p=0·0359), but not in the total study population (median 10·1 months [95% CI 8·8-11·2] vs 9·1 months [8·4-10·4]; HR 0·94, 95% CI 0·83-1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6·6%] of 652 vs 17 [2·6%] of 655), reversible increases in alanine aminotransferase (51 [7·8%] vs six [0·9%]), and reversible increases in aspartate aminotransferase (22 [3·4%] vs three [0·5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). INTERPRETATION Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. FUNDING Boehringer Ingelheim.

Analysis of patient-reported outcomes from the LUME-Lung 1 trial: A randomised, double-blind, placebo-controlled, Phase III study of second-line nintedanib in patients with advanced non-small cell lung cancer

INTRODUCTION The LUME-Lung 1 trial (NCT00805194; Study 1199.13) demonstrated a significant overall survival (OS) advantage for nintedanib plus docetaxel compared with placebo plus docetaxel as second-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and adenocarcinoma histology. Patient-reported outcomes (PROs) for symptoms and health-related quality of life (QoL) are reported here. METHODS PROs were assessed at screening, on Day 1 of each 21-day treatment cycle, at the end of active treatment, and at the first follow-up visit. PRO instruments were the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 supplement, and the EuroQol disease-generic questionnaire (EQ-5D and EQ-VAS). Analyses of PRO items for lung cancer-specific symptoms of cough, dyspnoea and pain were prespecified. RESULTS Rates of questionnaire completion were high. There was no significant difference in time to deterioration of global health status/QoL, or symptoms of cough, dyspnoea or pain, between the treatment groups for both the overall study population and the adenocarcinoma population. Time to deterioration of some gastrointestinal events was shorter with nintedanib versus placebo. Longitudinal analysis for the adenocarcinoma population showed comparable changes between the groups in symptom scores over time, with numerical differences in favour of nintedanib for cough and pain scales, and significant reductions in some pain items with nintedanib versus placebo. There was no statistically significant difference in EQ-5D or EQ-VAS between the groups. CONCLUSION The significant OS benefit observed with the addition of nintedanib to docetaxel therapy was achieved with no detrimental effect on patient self-reported QoL.

Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial

OBJECTIVES LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC). MATERIALS AND METHODS Patients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500mg/m2 on Day 1 plus nintedanib 200mg orally twice daily or matching placebo on Days 2-21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint. RESULTS Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n=353 nintedanib/pemetrexed; n=360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR]=0.83, 95% confidence interval [CI] 0.70-0.99, p=0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR=1.01, 95% CI 0.85-1.21, p=0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis. CONCLUSION Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile.

Anti-angiogenic-specific adverse events in patients with non-small cell lung cancer treated with nintedanib and docetaxel

OBJECTIVES LUME-Lung 1 was a randomized, placebo-controlled, Phase III trial investigating nintedanib+docetaxel versus placebo+docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy. Progression-free survival was significantly improved with nintedanib+docetaxel in the overall population and overall survival was significantly improved in the pre-specified analysis of patients with adenocarcinoma. We evaluated the frequency of characteristic adverse events (AEs) commonly seen with existing anti-angiogenic agents. MATERIALS AND METHODS The incidence and intensity of AEs were evaluated in all patients who received at least one dose of study medication (N=1307) and for the two main histologies: adenocarcinoma (n=653) and squamous cell carcinoma (SCC; n=553). AEs of special interest were analyzed by category, preferred term, and worst CTCAE grade and included perforation, hypertension, bleeding, thromboembolic events, and skin disorders. RESULTS AND CONCLUSION The incidence of patients with all-grade gastrointestinal (GI) perforations was low and balanced between arms (0.5% in both) and across histologies; the incidence of non-GI perforations was 1.2% with nintedanib+docetaxel versus 0.2% with placebo+docetaxel. The incidence of some events was higher with nintedanib+docetaxel versus placebo+docetaxel; hypertension (3.5% vs 0.9%), rash (11.0% vs 8.1%), and cutaneous adverse reactions (13.0% vs 10.7%). Rash and cutaneous adverse reactions were predominantly Grade 1-2 with both treatments. The incidence of all-grade bleeding was also slightly higher in nintedanib+docetaxel-treated patients (14.1% vs 11.6%) driven by between-treatment differences in the SCC subpopulation; most events were Grade 1-2. The proportion of patients with a thromboembolic event was low and comparable between arms for all grades (5.1% vs 4.6%) and Grade ≥3 (2.1% vs 3.1%). Safety evaluation of the LUME-Lung 1 study showed that the frequency of AEs commonly associated with other anti-angiogenic agents was lower with nintedanib+docetaxel. Survival benefits from addition of nintedanib to docetaxel in patients with adenocarcinoma after first-line therapy can be achieved alongside a manageable safety profile.

Time since start of first-line therapy as a predictive clinical marker for nintedanib in patients with previously treated non-small cell lung cancer

Introduction No predictive clinical or genetic markers have been identified or validated for antiangiogenic agents in lung cancer. We aimed to identify a predictive clinical marker of benefit for nintedanib, an angiokinase inhibitor, using data from two large second-line non-small cell lung cancer Phase III trials (LUME-Lung 1 ([LL1] and LUME-Lung 2). Methods Predictive marker identification was conducted in a multi-step process using data from both trials; a hypothesis was generated, confirmed and validated. Statistical analyses included a stepwise selection approach, a recursive partitioning method and the evaluation of HRs, including treatment-by-covariate interactions. The marker was finally validated using a prospectively defined hierarchical testing procedure and treatment-by-covariate interaction for overall survival (OS) based on LL1. Results Time since start of first-line therapy (TSFLT) was identified as the only predictive clinical marker. A cut-off of 9 months was chosen for further analysis, based on HRs and recursive partitioning. The prospectively defined final validation using OS data from LL1 established the strong relationship between TSFLT and treatment with nintedanib. Patients with adenocarcinoma with TSFLT <9 months showed a greater survival benefit (median OS 10.9 vs 7.9 months, HR 0.75 [95% CI 0.60–0.92]; p=0.0073) compared with patients in the TSFLT >9 months group (median OS 17.0 vs 15.1 months, HR 0.89 [95% CI 0.66–1.19]). Conclusions Patients with shorter TSFLT derive a greater progression-free survival and OS benefit from nintedanib. This clinical marker could be used for patient selection and further investigation is warranted regarding pathways promoting aggressive tumour growth and antiangiogenic tyrosine kinase inhibitor benefit.

471PEFFECT OF NINTEDANIB (BIBF 1120) COMBINED WITH STANDARD 2ND-LINE DOCETAXEL IN NSCLC PATIENTS WHO RECEIVED PRIOR PEMETREXED IN LUME-LUNG 1: A RANDOMISED, PLACEBO-CONTROLLED PHASE III TRIAL

ABSTRACT Aim: Nintedanib (N) is an oral, triple angiokinase inhibitor of VEGF, PDGF and FGF signalling. Primary analysis of the LUME-Lung 1 trial (NCT00805194; 1199.13) showed a significant improvement in PFS with N + docetaxel (D) in NSCLC patients (pts) regardless of histology; OS was also significantly improved in adenocarcinoma (adeno) pts. Pemetrexed (PEM) is a standard 1st-line and maintenance treatment for nonsquamous NSCLC pts. To determine whether prior PEM would influence outcomes of pts in LUME-Lung 1, we evaluated the efficacy and safety of N + D in pts who received 1st-line and maintenance PEM. Methods: 1314 pts with Stage IIIB/IV recurrent NSCLC were randomised to receive either N 200 mg bid + D 75 mg/m2 q21d (n = 655) or placebo (Pl) + D (n = 659) in LUME-Lung 1. Retrospective subgroup analyses according to prior PEM treatment (1st line or maintenance) were performed to determine OS and safety. Results: The percentage of pts with adeno tumour histology who were treated 1st line with PEM along with platinum was approximately 19% (N arm, n = 61; Pl arm, n = 65). Pt characteristics were balanced across groups. OS results according to receipt of any PEM 1st-line and maintenance therapy for adeno pts are shown in the table. For all pts and those with adeno histology in particular, no significant difference in OS was noted between those who did or did not receive PEM; no significant interaction between treatment groups and any PEM treatment was observed. Further, slightly more pts in the N arms across all subgroups experienced grade ≥3 adverse events; diarrhoea and reversible increases in liver enzymes occurred more frequently in pts in both N arms. OS results in NSCLC pts with adeno histology who received 1st-line and/or maintenance PEM No PEM 1st-line PEM 1st-line No maintenance PEM 1st-line Maintenance PEM 1st-line N n = 261 Pl n = 271 N n = 61 Pl n = 65 N n = 309 Pl n = 322 N n = 13 Pl n = 14 Median OS, months 13.4 10.8 12.0 8.0 12.6 10.0 18.9 12.8 HR (95% CI); p-value 0.83 (0.68–1.00); p = 0.05 0.79 (0.53–1.18); p = 0.25 0.84 (0.70–1.00); p = 0.05 0.78 (0.30–2.07); p = 0.62 Interaction between treatment & subgroup variable, p-value p = 0.9026 p = 0.7162 Conclusions: On-study treatment with N + D resulted in a comparably favourable improvement in OS regardless of whether pts with adeno tumours were treated 1st line with a PEM- or non-PEM-containing platinum doublet. Disclosure: A. Mellemgaard: Advisory Board: Boehringer Ingelheim; J. von Pawel: Advisory Board/Consultant: AbbVie, Clovis, Daiichi Sankyo, Novartis, Pfizer, Vertex Pharmaceuticals; J. Barrueco: Employee: Boehringer Ingelheim Pharmaceuticals Inc., USA; H. Buchner, J. Hocke and R. Kaiser: Employee: Boehringer Ingelheim Pharma GmbH KG, Germany;S. Novello: Advisory Board/Honoraria/Invited Speaker: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Roche; J. Douillard: Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck Serono, Roche; Educational Symposia: Amgen, AstraZeneca, Bayer; Research Grants: Merck Serono; M. Reck: Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Hoffmann-la Roche, Lilly, Novartis, Pfizer. All other authors have declared no conflicts of interest.

BIBF1120 (Vargatef) Inhibits Preretinal Neovascularization and Enhances Normal Vascularization in a Model of Vasoproliferative Retinopathy.

PURPOSE This study evaluated the effects of BIBF1120, a novel triple angiokinase inhibitor against pathological retinal neovascularization. METHODS BIBF1120 effect on development of the normal retinal vasculature was evaluated in Sprague-Dawley rat pups. Two models of ischemic oxygen-induced retinopathy (OIR) and the aortic ring assay were used to assess the antiangiogenic effects of BIBF1120. In the vaso-obliteration model (VO), rat pups were exposed to 80% O2 from postnatal day (P) 5 to P10. In the preretinal neovascularization (NV) model, rat pups were exposed to cycling O2 (50% and 10%) from P1 to P14, followed by room air until P18. Animals were intravitreally or orally treated with BIBF1120. Retinal vasculature, VO, and NV were evaluated in retinal flat mounts. Retinal expression of VEGF, Delta-like ligand 4 (Dll4), Netrin-1, Ephrin-B2, and EphB4 was analyzed by quantitative PCR and Western blot analysis. RESULTS BIBF1120 interfered with normal retinal vascular development and microvessel branching in the aortic assay. However, in VO model BIBF1120 did not accrue VO. On the contrary, in the NV model BIBF1120 accelerated normal retinal vascularization and robustly diminished preretinal neovascularization compared to vehicle (by ~80%). The expression levels of VEGF negative regulator Dll4 and repulsive cues EphrinB2 and EphB4 mRNA in the retina of vehicle-treated OIR animals were markedly increased compared to normoxia, but were normalized by BIBF1120. CONCLUSIONS Data reveal efficacy of BIBF1120 on preretinal neovascularization and, of greater interest, on acceleration of normal vascularization, consistent with interference of major repulsive cues expressed in the retina during OIR. Accordingly, BIBF1120 appears to exhibit preferable properties compared to anti-VEGF therapies for the treatment of ischemic retinopathies.

473PPRIOR TAXANE USE IN THE LUME-LUNG 1 PHASE III TRIAL AND THE EFFECT ON OUTCOME FOLLOWING 2ND-LINE TREATMENT WITH NINTEDANIB (BIBF 1120) AND DOCETAXEL IN PATIENTS WITH ADVANCED NSCLC

ABSTRACT Aim: Several Phase III studies confirm the efficacy of standard 2nd-line docetaxel (D) in advanced non-small cell lung cancer (NSCLC) patients (pts) previously treated with 1st-line paclitaxel-based therapy irrespective of tumour histology. In LUME-Lung 1, nintedanib (N)—an oral, triple angiokinase inhibitor of VEGF, PDGF and FGF signalling—has demonstrated clinically meaningful efficacy along with 2nd-line chemotherapy (NCT00805194; 1199.13). Here we report the efficacy and safety of N + D in pts previously treated with taxanes as part of a preplanned analysis. Methods: Stage IIIB/IV recurrent NSCLC pts (N = 1314) progressing after 1st-line chemotherapy were randomised 1:1 to receive either N 200 mg bid + D 75 mg/m2 q21d (n = 655) or placebo (Pl) + D (n = 659). Endpoints evaluated included progression-free survival (PFS) by central independent review, overall survival (OS) and safety. Chemotherapy with 1st-line D was an exclusion criterion; subgroup analyses according to the pts use of 1st-line taxane therapy and NSCLC histology were also performed. Results: Pt characteristics were balanced across all groups. For all pts and those with adenocarcinoma (Ad) in particular, no significant difference in survival benefit was noted regardless of the use of 1st-line taxane therapy (Table). Comparison of N + D and Pl + D showed that the percentage of all pts with grade ≥3 adverse events (AEs) was slightly higher for pts in the N arm (no 1st-line taxane = 71.6% vs 65.5%; prior 1st-line taxane = 70.3% vs 59.4%). Consistent with overall findings in LUME-Lung 1, reversible increases in alanine and aspartate aminotransferases as well as diarrhoea were the AEs that were more common among all pts in the N arm. OS results for LUME-Lung 1 in NSCLC pts who received 1st-line taxane therapy All pts Pts with Ad No taxane 1st-line Taxane 1st-line No taxane 1st-line Taxane 1st-line N, n = 510 Pl, n = 519 N, n = 145 Pl, n = 140 N, n = 245 Pl, n = 271 N, n = 77 Pl, n = 65 Median OS, months 10.0 9.1 11.5 9.0 12.2 10.3 15.1 11.6 HR (95% CI); p-value 0.97 (0.85–1.11); p = 0.67 0.81 (0.62–1.06); p = 0.13 0.86 (0.71–1.05); p = 0.13 0.75 (0.51–1.11); p = 0.15 Interaction between treatment & subgroup variable, p-value p = 0.2562 p = 0.6135 Conclusions: On-study treatment with N + D resulted in a comparably favourable OS improvement regardless of whether pts with tumours of Ad histology were treated 1st line with a taxane- or non-taxane-containing platinum doublet. Disclosure: A. Mellemgaard: Advisory Board: Boehringer Ingelheim; J. von Pawel: Advisory Board/Consultant: AbbVie, Clovis, Daiichi Sankyo, Novartis, Pfizer, Vertex Pharmaceuticals; J. Barrueco: Employee: Boehringer Ingelheim Pharmaceuticals Inc., USA; B. Gaschler-Markefski and R. Kaiser: Employee: Boehringer Ingelheim Pharma GmbH KG, Germany S. Novello: Advisory Board/Honoraria/Invited Speaker: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Roche; J. Douillard: Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck Serono, Roche; Educational Symposia: Amgen, AstraZeneca, Bayer; Research Grants: Merck Serono; M. Reck: Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Hoffmann-la Roche, Lilly, Novartis, Pfizer. All other authors have declared no conflicts of interest.

30 Nintedanib (BIBF 1120) + docetaxel as second-line therapy in patients with stage IIIB/IV or recurrent NSCLC: results of the phase III, randomised, double-blind LUME-Lung 1 trial

• The current randomised, Phase III study (LUME-Lung 1; NCT00805194) was designed to investigate the efficacy and safety of nintedanib 200 mg twice daily (bid) in combination with docetaxel versus placebo and docetaxel for the treatment of patients with advanced or recurrent NSCLC who had previously failed first-line chemotherapy – during this study, patient-reported quality of life (QoL) was recorded at regular intervals using standard QoL questionnaires and so the effect of treatment on prespecified symptoms of interest in patients with NSCLC is also examined RESULTS