abcd Clinical Study for Public Disclosure This clinical study synopsis is provided in line with s Policy on Transparency and Publication of Clinical Study Data. The synopsis which is part of the clinical study report had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of.
Page 1 of 9 BI Trial No.: 1199.14 Follow-up Report 2016 International GmbH or one or more of its affiliated companies 1 of 9 Title of trial: Multicentre, randomized, double-blind, Phase III trial to investigate the efficacy and safety of oral BIBF 1120 plus standard pemetrexed therapy compared to placebo plus standard pemetrexed therapy in patients with stage IIIB/IV or recurrent non-small cell lung cancer after failure of first-line chemotherapy (LUME Lung 2) Coordinating Investigator: USA Trial sites: Publication (reference): Clinical phase: Objectives: Methodology: No. of subjects: Multicentre trial (patients randomised in 202 centres in 32 countries) Data from this trial have not been published III To investigate the efficacy and safety of nintedanib as compared to matching placebo in patients with stage IIIB/IV or recurrent non-small cell lung cancer (NSCLC) treated with standard therapy of pemetrexed after failure of first-line chemotherapy Two-arm, randomised, double-blind, placebo-controlled, parallel-group comparison of nintedanib versus matching placebo planned: entered: 1300 patients (650 patients in each treatment arm) actual: enrolled: 1116 patients randomised: 713 patients Placebo (in addition to standard second-line chemotherapy with pemetrexed): randomised: 360 patients treated: 357 patients Nintedanib (in addition to standard second-line chemotherapy with pemetrexed): randomised: 353 patients treated: 347 patients Recruitment into this trial was prematurely terminated by the Data Monitoring Committee, and therefore the numbers of patients randomised and treated was lower than planned.
Page 2 of 9 BI Trial No.: 1199.14 Follow-up Report 2016 International GmbH or one or more of its affiliated companies 2 of 9 Diagnosis and main criteria for inclusion: Test product: dose: mode of admin.: Patients with histologically or cytologically confirmed, locally advanced, or metastatic NSCLC of stage IIIB or IV (according to the American Joint Committee on Cancer), or recurrent NSCLC (non-squamous histologies) after relapse or failure of 1 prior first-line chemotherapy, with Eastern Cooperative Oncology Group performance score (ECOG PS) of 0 or 1 Nintedanib (in addition to standard second-line chemotherapy with pemetrexed) on days 2-21 of each 21-day treatment course 200 mg twice daily (b.i.d.) with dose reduction to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme) if required. No dose increase was allowed after a dose reduction. Oral batch no.: See Appendix 16.1.6 Reference therapy: dose: mode of admin.: Placebo (in addition to standard second-line chemotherapy with pemetrexed) (intake schedule as for the test product nintedanib) Oral batch no.: See Appendix 16.1.6 Concomitant therapy: dose: mode of admin.: Pemetrexed 500 mg/m² on Day 1 of each 21-day treatment course, with 2 dose reductions (according to the protocol-defined dose-reduction scheme) if required Intravenous infusion batch no.: See Appendix 16.1.6 Duration of treatment: Each treatment course was planned to be 21 days, with repeated treatment courses as long as the patient did not develop progression, tolerated the therapy, did not meet one of the withdrawal criteria, and neither patient nor investigator requested discontinuation of the therapy.
Page 3 of 9 BI Trial No.: 1199.14 Follow-up Report 2016 International GmbH or one or more of its affiliated companies 3 of 9 Criteria for evaluation: Efficacy / clinical pharmacology: Safety: Statistical methods: Primary endpoint: The primary endpoint was progression-free survival (PFS) as assessed by central independent review according to modified Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0. Secondary endpoints: Overall survival (OS), analysed as the key secondary endpoint. PFS according to modified RECIST version 1.0, based on investigator assessment. Tumour response according to modified RECIST version 1.0: confirmed objective tumour response, duration of confirmed objective response, time to confirmed objective response, disease control, duration of disease control, change in tumour size. Clinical improvement (time to deterioration in body weight or ECOG performance score) Health-related quality of life (HRQoL) measured by European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaires Core 30 (QLQ-C30) and lung cancer module (QLQ-LC13), with the prespecified endpoints cough, dyspnoea, and pain. Pharmacokinetics of nintedanib and of clinically relevant metabolites (described in the CTR reporting the primary PFS analysis) Safety was assessed based on the incidence of patients and severity of adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and changes in safety laboratory parameters. The aim of this trial was to demonstrate that nintedanib in combination with standard pemetrexed therapy is more effective than placebo in combination with standard pemetrexed therapy in patients with stage IIIB or IV or recurrent NSCLC (non-squamous histologies) after failure of first-line chemotherapy. The primary analysis was planned after 713 patients had progressed (according to central independent review) or died. Based on the results of a pre-planned futility analysis conducted using investigator-assessed PFS, the Data
Page 4 of 9 BI Trial No.: 1199.14 Follow-up Report 2016 International GmbH or one or more of its affiliated companies 4 of 9 Statistical methods (continued): SUMMARY CONCLUSIONS: Monitoring Committee (DMC) concluded that the study was unlikely to reach the pre-defined efficacy criteria according to the protocol. Accordingly, the sponsor decided to stop recruitment from 18 June 2011 and to unblind all patients who were still on treatment at that time. personnel involved in the management and analysis of the trial remained blinded. Patients who were still on study treatment on 18 June 2011 could continue in the trial; however, all placebo treatment was stopped. Patients could continue with nintedanib alone, pemetrexed alone, or a combination of nintedanib plus pemetrexed. Patients were not permitted to switch treatment. Despite the hold of recruitment, the patients treated in the study were followed for safety and efficacy, as described in the original protocol. The data were analysed based on a revised trial statistical analysis plan (TSAP, signed 5 July 2012). The stratified log-rank test (stratification factors at randomisation: tumour histology [adeno- vs non-adenocarcinoma], ECOG PS at baseline, presence of brain metastases at study entry, prior bevacizumab therapy) was used for PFS to test for the effect of nintedanib at the 2-sided alpha-level of 0.05. Efficacy results: The primary analysis of PFS was performed at an earlier time point (9 July 2012; after 498 PFS events in all patients), after the study was prematurely stopped, and is reported in the primary PFS report. The analysis showed a statistically significant prolongation of independently assessed PFS for patients treated with nintedanib plus pemetrexed compared with placebo plus pemetrexed (hazard ratio 0.83; 95% CI 0.70, 0.99; p=0.0435). Median PFS was 3.6 months in the placebo arm and 4.4 months in the nintedanib arm. All planned efficacy analyses were repeated for this follow-up report (15 Feb 2013; after 504 PFS events), using all entered patients (713 patients). As the overall number of patients and the number of PFS events changed only slightly between the 2 analyses, results are consistent with the previously reported results.
Page 5 of 9 BI Trial No.: 1199.14 Follow-up Report 2016 International GmbH or one or more of its affiliated companies 5 of 9 Efficacy results (cont.): Demographics and baseline characteristics Overall, the patient population in this study was representative of what would be expected for patients with NSCLC in the second-line setting who have progressed after previous first-line chemotherapy, and was balanced between the 2 treatment arms. The majority of patients were white (63.8%), male (56.5%); mean age was 59.0 years. About a third of patients (29.3%) were Asian. Most patients had metastases present at screening (91.1% in the placebo arm and 87.0% in the nintedanib arm). Most patients (94.0%) had a tumour histology of adenocarcinoma. At the cut-off date of the original follow-up report, 9 patients were still on study treatment (placebo: 2 patients, nintedanib: 7 patients), while 695 patients had permanently discontinued treatment. Efficacy The follow up analysis confirmed the primary PFS analysis, whereas the OS analysis showed no difference. The addition of nintedanib to pemetrexed showed a prolongation of PFS (based on central independent review) compared with placebo plus pemetrexed (hazard ratio 0.84; 95% CI 0.70, 1.00). Median PFS was 3.4 months in the placebo arm and 4.4 months in the nintedanib arm. Median PFS as assessed by the investigator was 4.3 months in the placebo arm and 5.3 months in the nintedanib arm with a HR of 0.86 (95% CI 0.73, 1.02). There was no difference in OS between the treatment groups (hazard ratio for nintedanib vs. placebo: 1.01, 95% CI 0.85, 1.21). The confirmed objective response rate based on central independent review was similar in both treatment groups (placebo: 8.3%; nintedanib: 9.1%; odds ratio: 1.10; 95% CI 0.65, 1.85). The median duration of confirmed objective response was 4.4 months (P25, P75: 3.3, 8.9) in the placebo arm and 6.9 months (P25, P75: 5.1, 11.3) in the nintedanib arm. The median time to confirmed objective response was 2.7 months (P25, P75: 1.4, 4.2) in the placebo arm and 2.6 months (P25, P75: 1.4, 4.0) in the nintedanib arm. There was a trend for a better treatment effect of nintedanib compared with placebo in disease control (placebo: 53.3%; nintedanib: 60.9%; odds ratio: 1.37; 95% CI 1.02, 1.85). The median duration of disease control was 6.8 months (P25, P75: 4.2, 12.5) in the placebo arm and 7.4 months (P25, P75: 4.3, 11.2) in the nintedanib arm. The adjusted mean of best percentage change in the size of target lesions from baseline based on central independent review was -7.53% (95% CI -10.03, -5.04) in the placebo arm and -10.10% (95% CI -12.63, -7.58) in the nintedanib arm.
Page 6 of 9 BI Trial No.: 1199.14 Follow-up Report 2016 International GmbH or one or more of its affiliated companies 6 of 9 Efficacy results (cont.): Confirmed objective response rate based on investigator assessment was 13.3% in the placebo arm and 15.0% in the nintedanib arm (odds ratio: 1.15; 95% CI 0.75, 1.76). The median duration of confirmed objective response was 7.2 months (P25, P75: 4.2, 16.2) in the placebo arm and 6.5 months (P25, P75: 4.4, 12.7) in the nintedanib arm. Median time to confirmed objective response was 2.8 months (P25, P75: 1.4, 3.1) in the placebo arm and 2.6 months (P25, P75: 1.4, 3.0) in the nintedanib arm. There was a trend for a better treatment effect of nintedanib compared with placebo in disease control based on investigator assessment (placebo: 60.3%; nintedanib: 66.0%; odds ratio: 1.29; 95% CI 0.95, 1.75). The median duration of disease control was 6.8 months (P25, P75: 4.4, 11.1) in the placebo arm and 6.9 months (P25, P75: 4.4, 12.5) in the nintedanib arm. The adjusted mean of best percentage change in the size of target lesions from baseline was -11.28% (95% CI -14.42, -8.15) in the placebo arm and -15.60% (95% CI -18.75, -12.46) in the nintedanib arm. The proportion of patients with clinical deterioration (time to body weight loss of >10% or ECOG worsening) was comparable between treatment groups. (placebo: 43.3%, nintedanib: 42.5%). Median time to deterioration was 7.5 months in the placebo arm and 7.2 months in the nintedanib arm (hazard ratio: 0.93; 95% CI 0.74, 1.16). For the overall patient population, no differences between the 2 treatment groups for the time to deterioration of cough (HR 0.83; 95% CI 0.66, 1.05), dyspnoea (HR 0.93; 95% CI 0.77, 1.12), and pain (HR 1.01; 95% CI 0.84, 1.23) were observed.
Page 7 of 9 BI Trial No.: 1199.14 Follow-up Report 2016 International GmbH or one or more of its affiliated companies 7 of 9 Efficacy results (cont.): Patients with tumours of adenocarcinoma histology As in the primary PFS analysis, the addition of nintedanib to pemetrexed showed a prolongation of PFS compared with placebo plus pemetrexed with a hazard ratio of 0.84 (95% CI 0.70, 1.01, median PFS: placebo: 3.9 months; nintedanib: 4.5 months) for patients with adenocarcinoma histology. There was no difference in OS (hazard ratio: 1.00, 95% CI 0.84, 1.20). There was an improved PFS for adenocarcinoma patients and <9 months since start of first-line therapy treated with nintedanib plus pemetrexed compared to placebo plus pemetrexed with a hazard ratio of 0.79 (95% CI 0.63, 1.00, median PFS: placebo: 2.8 months; nintedanib: 4.1 months) and a trend with respect to OS with a hazard ratio of 0.87 (95% CI 0.69, 1.10, median OS: placebo: 9.3 months; nintedanib: 10.6 months). The addition of nintedanib to pemetrexed resulted in an improved disease control rate based on central independent review for adenocarcinoma patients (placebo: 54.6%; nintedanib: 61.8%; odds ratio: 1.36; 95% CI: 1.00, 1.86), as well as for patients with adenocarcinoma and <9 months since start of first-line therapy (placebo: 43.3%; nintedanib: 58.5%; odds ratio: 1.88; 95% CI 1.26, 2.81). Pharmacokinetics Pharmacokinetics of nintedanib and of clinically relevant metabolites for the overall patient population were described in the CTR reporting the primary PFS analysis. Nintedanib exposure as determined by trough plasma concentrations was in the same range as observed in other studies of nintedanib mono- and/or combination therapy with pemetrexed. There was no correlation between exposure and severity of AEs or laboratory values of special interest for the overall patient population. The gmean C pre,ss,norm values of the 200 mg b.i.d. plus pemetrexed group were for nintedanib 0.0883 ng/ml/mg (n = 188 patients; gcv 66.4%), for BIBF 1202 0.131 ng/ml/mg (n = 188 patients; gcv 123%), and for BIBF 1202 glucuronide 1.40 ng/ml/mg (n = 184 patients; gcv 169%).
Page 8 of 9 BI Trial No.: 1199.14 Follow-up Report 2016 International GmbH or one or more of its affiliated companies 8 of 9 Safety results: Exposure The mean overall exposure to study medication (nintedanib, placebo, and pemetrexed) was slightly higher in the nintedanib arm (6.0 months) than in the placebo arm (5.5 months). This can be attributed to the halting of placebo treatment after 18 June 2011. Exposure to pemetrexed was comparable between the 2 treatment arms. The mean numbers of pemetrexed courses were 7.3 in the placebo arm and 7.8 in the nintedanib arm. Adverse events Overall, the percentage of patients with at least 1 AE was comparable between the treatment arms (placebo: 94.1%; nintedanib: 95.4%), as was the percentage of patients with SAEs (placebo: 32.8%; nintedanib: 30.0%). By PT, the most commonly reported AEs overall were ALT increased, nausea, and fatigue. Percentages of patients with AEs were markedly higher in the nintedanib arm for diarrhoea, ALKP increased, and hypokalaemia. The number of patients with a drug-related AE (as assessed by the investigator) was higher in the nintedanib arm than in the placebo arm (placebo: 68.3%; nintedanib: 83.3%). This was also the case for the number of patients with CTCAE grade 3 to 5 events (placebo: 54.3%; nintedanib: 68.3%). The frequency of patients with AEs leading to permanent discontinuation of the last study medication was similar for both treatment arms (placebo: 17.9%; nintedanib: 16.1%). Overall, 43 patients (12.0%) in the placebo arm and 34 patients (9.8%) in the nintedanib arm had an AE leading to death during the on-treatment period. The most commonly reported causes of death were respiratory failure, dyspnoea, and pneumonia. Adverse events of special interest Adverse events were also categorised into adverse events of special interest (AESIs) by pooling MedDRA terms and by using Standardized MedDRA Queries (SMQs). The following AESIs occurred with higher incidences of patients in the nintedanib arm than in the placebo arm: AEs within the SMQ liver-related investigations (placebo: 30.3%; nintedanib: 49.6%), within the SSC diarrhoea (placebo: 15.4%; nintedanib: 34.9%), within the SSC nausea (placebo: 33.3%; nintedanib: 36.9%), within the SSC vomiting (placebo: 20.2%;
Page 9 of 9 BI Trial No.: 1199.14 Follow-up Report 2016 International GmbH or one or more of its affiliated companies 9 of 9 Safety results (continued): Conclusions: nintedanib: 24.8%), and within the SSC dehydration (placebo: 2.2%; nintedanib: 4.0%). With respect to haematological AEs, neutropenia (based on SSC; placebo: 19.3%; nintedanib: 29.1%) and thrombocytopenia (based on SSC; placebo: 6.7%; nintedanib: 8.9%) were reported for a greater percentage of patients in the nintedanib arm. The frequency of patients with febrile neutropenia (SSC) was higher in the nintedanib arm than in the placebo arm. The frequency of patients with pneumonia (SSC) was higher in the placebo arm; and the frequencies of patients with infection (SSC) and of patients with sepsis (SSC) were similar between treatment groups. There were no notable differences between the treatment arms in the incidence of patients with the following AESIs analysed based on SSCs or SMQs: abdominal pain, fatigue, perforation, hypertension, bleeding, thromboembolism, renal or hepatic failure, peripheral neuropathy, mucositis, skin disorders, pulmonary hypertension, osteonecrosis, ovarian failure, hypothyroidism, cardiac events, interstitial lung disease, and photosensitivity. Patients with tumours of adenocarcinoma histology Results of safety analyses in the adenocarcinoma population were similar to the results of the overall population. The results of this follow-up efficacy analysis of the 1199.14 trial were consistent with the results of the primary analysis of the study, confirming an improvement in PFS by central independent review for patients treated with nintedanib in combination with pemetrexed, although the study was stopped prematurely. The analysis of OS was also consistent with the primary analysis of the 1199.14 study. On balance, while not conclusive, when attempts are made to exclude potential external influences, the data suggest that a treatment effect on overall survival may have been discernable for patients treated with nintedanib in combination with pemetrexed had the study been allowed to complete, as originally planned. The safety of nintedanib in combination with pemetrexed was in line with the known safety profile of the individual compounds. Overall, adverse events were manageable in the majority of patients, using dose reductions and symptomatic therapy.