This clinical study synopsis is provided in line with Boehringer Ingelheim s Policy on Transparency and Publication of Clinical Study Data.

Transcription

1 abcd Clinical Study Synopsis 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.

2 1 of 10 Title of trial: Coordinating Investigator: Trial sites: Publication (reference): LUX Lung 2: A Phase II single arm trial of BIBW 2992 in non-small cell lung cancer patients with EGFR activating mutations MD, PhD Taiwan, Multicentre Study, c.f. Appendix (conducted at 7 centers in Taiwan and 23 in the United States that enrolled patients) Yang C, Shih J, Chao T, et al. 44th Ann Mtg of the American Society of Clinical Oncology (ASCO), Chicago, 30 May- 3 Jun 2008 (Poster) (P ). Shih JY, Yang CH, Su WC, et al. 45th Ann Mtg of the American Society of Clinical Oncology (ASCO), Orlando, 29 May - 2 Jun 2009 (Oral Presentation) (P ). Shih JY, Yang CH, Su WC, et al. 45th Ann Mtg of the American Society of Clinical Oncology (ASCO), Orlando, 29 May - 2 Jun 2009 (Poster) (P ). Shih J, Yang C, Su W, et al. 45th Ann Mtg of the American Society of Clinical Oncology (ASCO), Orlando, 29 May - 2 Jun J Clin Oncol 27 (Suppl), 410s, Abstr 8013 (2009) (P ). Yang CH, Shih JY, Su WC, et al. 13th World Conf on Lung Cancer, San Francisco, 31 Jul - 4 Aug 2009 (Oral Presentation) (P ). 13th World Conf on Lung Cancer, San Francisco, 31 Jul - 4 Aug 2009; 45th Ann Mtg of the American Society of Clinical Oncology (ASCO), Orlando, 29 May - 2 Jun 2009 (P ). Yang C, Shih J, Su W, et al. 46th Ann Mtg of the American Society of Clinical Oncology (ASCO), Chicago, 4-8 Jun J Clin Oncol 28 (15S) (Suppl), 543S, Abstr 7521 (2010) (P ). Yang CH, Shih JY, Su WC, et al. 46th Ann Mtg of the American Society of Clinical Oncology (ASCO), Chicago, 4-8 Jun 2010 (Poster) (P ). Yang CH, Shih JY, Su WC, et al. 4th Latin American Conf on Lung Cancer, Buenos Aires, Jun 2010 (Oral Presentation) (P ). Yang C, Shih J, Su W, et al. 35th Ann Cong of the European Society for Medical

3 2 of 10 Oncology (ESMO), Milan, 8-12 Oct Ann Oncol 21 (Suppl 8), VIII123, Abstr 367PD (2010) (P ). Yang CH, Shih JY, Su WC, et al. 35th Ann Cong of the European Society for Medical Oncology (ESMO), Milan, 8-12 Oct 2010 (Poster) (P ). Yang CH, Shih JY, Su WC, et al. APLCC 2010, 4th Asia Pacific Lung Cancer Conf, Seoul, 2-4 Dec 2010 (Oral Presentation) (P ). Yang CH, Shih JY, Su WC, et al. APLCC 2010, 4th Asia Pacific Lung Cancer Conf, Seoul, 2-4 Dec J Thorac Oncol 5 (12) (Suppl 5), S376 - S377, Abstr O-042 (2010) (P ). Yang JCH, Shih JY, Su WC, et al. Lancet Oncol 13 (5), (2012) (P ). Koehler J, Yang JCH, Reguart N, et al. MASCC/ISOO 2013, Int Symp on Supportive Care in Cancer of the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society of Oral Oncology (ISOO), Berlin, Jun 2013 (Oral Presentation) (P ). Schadendorf D, Lacouture ME, Chu CY, et al. MASCC/ISOO 2013, Int Symp on Supportive Care in Cancer of the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society of Oral Oncology (ISOO), Berlin, Jun 2013 (Oral Presentation) (P ). Koehler J, Yang JCH, Reguart N, et al. MASCC/ISOO 2013, Int Symp on Supportive Care in Cancer of the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society of Oral Oncology (ISOO), Berlin, Jun Support Care Cancer 21 (Suppl 1), S248, Abstr MASCC-0708 (2013) (P ). Schadendorf D, Lacouture ME, Chu CY, et al. MASCC/ISOO 2013, Int Symp on Supportive Care in Cancer of the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society of Oral Oncology (ISOO), Berlin, Jun Support Care Cancer 21 (Suppl 1), S248 - S249, Abstr MASCC-0709 (2013) (P ). Yang JCH, Sequist LV, Geater SL, et al. 15th World Conf on Lung Cancer, Sydney, Oct 2013 (Oral Presentation) (P ).

4 3 of 10 Clinical phase: Objectives: Methodology: Yang JC, Sequist LV, Geater SL, et al. 15th World Conf on Lung Cancer, Sydney, Oct J Thorac Oncol 8 (Suppl 2), S141, Abstr O03.05 (2013) (P ). Yang JCH, Sequist LV, Geater SL, et al. Lancet Oncol 16 (7), (2015) (P ). II Primary: Efficacy of afatinib defined by the objective response rate (ORR) (complete response [CR], partial response [PR]) as determined by Response Criteria in Solid Tumors (RECIST 1.0) in patients with advanced non-small cell lung cancer (NSCLC) Stage IIIB or IV whose tumors harbored activating mutations within exon 18 to exon 21 of the epidermal growth factor receptor (EGFR) Secondary: safety, pharmacokinetics of afatinib in patients with EGFR activating mutations who had failed one line of cytotoxic chemotherapy (in Stage 1 or Stage 2 of trial) or who had not received first-line cytotoxic chemotherapy (only in Stage 2 of trial as noted below) This was a non-randomized exploratory trial of afatinib at an initial starting dose of 50 mg daily that followed a two-stage design. In the first stage only patients progressing or relapsing after one prior cytotoxic chemotherapy regimen (including neoadjuvant or adjuvant chemotherapy) were allowed to enter into the trial (second-line patients). An early stopping rule was in place and an end of Stage 1 interim analysis was conducted after 40 second-line patients with NSCLC harboring activating EGFR mutations were treated and completed at least one 4-week course of treatment with afatinib (U , 03 March 2009). The trial passed from Stage 1 to Stage 2 after more than the required 16 second-line patients achieved a complete or partial response ( 40% of patients with CR or PR). After the end of Stage 1 Interim Analysis (U , 03 March 2009) and amendments to the trial protocol, the trial was opened to first-line patients and subsequently the starting dose was lowered to 40 mg, resulting in four trial cohorts defined by line of treatment and afatinib starting dose (40 mg and 50 mg). An assessment of tumor response using RECIST was performed at the end of each course for the first three courses (i.e., every 4 weeks) and from there on

5 4 of 10 No. of subjects: planned: entered: 120 actual: Total screened: 461 Diagnosis and main criteria for inclusion: Test product: dose: every other course (every 8 weeks). Assessment at the investigator site was sufficient for the decision whether the patient would continue therapy. For the primary endpoint, adjudicated independent assessment of tumor response was performed by a central imaging unit. Samples for determination of afatinib plasma concentrations were collected on Days 1 and 15 of Course 1, Day 1 of Course 2 (i.e., Day 28) and Day 1 of Course 3 (i.e., Day 56). Total entered: 129 Total treated: mg afatinib starting dose: entered = 30, treated = 30, analyzed (for primary endpoint and safety) = 30 (including 23 first-line and 7 second-line patients) 50 mg afatinib starting dose: entered = 99, treated = 99, analyzed (for primary endpoint and safety) = 99 (including 38 first-line and 61 second-line patients) Patients with Stage IIIB or Stage IV adenocarcinoma of the lung whose tumor harbored exon 18 to exon 21 EGFR activating mutations and who had failed one line of cytotoxic chemotherapy or who had not received first-line cytotoxic chemotherapy (the latter only in Stage 2 of the trial per Amendment 1). All patients had biopsy samples available and determination of EGFR mutation status prior to start of treatment with afatinib., supplied as 5 mg, 20 mg, 30 mg, 40 mg and 50 mg film-coated tablets (Trial Formulation II) Starting dose of 50 mg daily (per original protocol) or 40 mg daily (per Amendment 2) According to the pre-specified dose reduction scheme based on Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE) grade, for a

6 5 of 10 mode of admin.: patient on a starting dose of 50 mg daily, the dose was to be reduced to 40 mg daily with the first occurrence of an adverse event (AE) requiring dose reduction and to 30 mg daily with the second occurrence of an AE requiring dose reduction. For a patient with a starting dose of 40 mg daily, the dose was to be reduced to 30 mg daily if there was occurrence of a first AE requiring dose reduction and to 20 mg daily of there was occurrence of a second AE requiring dose reduction. If an additional AE requiring dose reduction occurred, or if the patient failed to recover with 14 days from the first/second episode of the AE requiring dose reduction, the patient was to be withdrawn from treatment with afatinib. Oral, once daily continuous batch no.: 5 mg: B , B , B , B Reference therapy: Duration of treatment: 20 mg: B , B , B , B , B , B , B mg: B , B , B , B , B , B , B , B , B , B , B , B mg: B , B , B , B , B , B , B , B mg: B , B , B , B , B , B , B , B , B Not applicable Continuous treatment until disease progression or intolerable adverse effects; each treatment course was 4 weeks (28 days). Treatment courses were defined for administrative purposes only.

7 6 of 10 Criteria for evaluation: Efficacy / clinical pharmacology: Safety: Statistical methods: Efficacy SUMMARY CONCLUSIONS: Efficacy / clinical pharmacology results: Primary: Objective response rate (ORR) based on Response Criteria in Solid Tumors (RECIST 1.0) Secondary: Clinical benefit (complete response [CR], partial response [PR], stable disease [SD]) determined by RECIST, time to objective response, duration of objective response, progression free survival (PFS), and overall survival (OS) Pharmacokinetics Evaluation of afatinib plasma concentrations. Note that pharmacokinetic (PK) results were presented in a previous report and were not repeated in this final report. Incidence of adverse events (AEs), graded according to the Common Terminology Criteria for Adverse Events (CTCAE Version 3.0), AEs of special interest including skin reactions and gastrointestinal events, laboratory evaluation, performance status, cardiac left ventricular ejection fraction (LVEF), electrocardiogram (ECG), vital signs Calculated ORR with exact 95% confidence interval; Kaplan-Meier estimation of PFS and OS; descriptive statistics for all other endpoints The study enrolled a total of 129 patients including 61 first-line patients (23 who received a starting dose of 40 mg and 38 who received a starting dose of 50 mg) and 68 second-line patients (7 who received a starting dose of 40 mg and 61 who received a starting dose of 50 mg). The patients mean age at study entry was 62 years (range 35 to 86), and most patients were Asian (86.8%), female (58.1%), had never smoked (63.6%), and had an ECOG performance score of zero (64.3%). Nearly all patients had clinical Stage IV NSCLC (93.8%) with one (42.6%) or two (27.9%) metastatic sites, mostly located in the lung, bone and brain. The most common EGFR mutations identified were in-frame exon 19 deletions (referred to collectively as Del19; 40.3% [52/129] of patients) and the exon 21 point mutation L858R (41.9% [54/129] of patients). Of the 129 treated patients, 103 (79.8%) patients discontinued treatment due to

8 7 of 10 progressive disease, 17 (13.2%) patients discontinued due to other AE, 3 (2.3%) patients refused to continue medication, and 6 (4.7%) patients discontinued treatment for other reasons. For the primary efficacy endpoint, high confirmed ORRs by RECIST v1.0 criteria were noted by both independent review (62.0%) and by investigator assessment (60.5%) for the 129 treated patients. The disease control rate (DCR), (i.e., clinical benefit) was also high (82.2% by independent review and 86.0% by investigator assessment). Among the 110 patients with target lesions identified per independent review, the confirmed ORR was higher than when all 129 patients were considered (71.8%, 79/110 vs. 62.0%, 80/129, respectively), as was the DCR (86.4% vs. 82.2%, respectively). When considering response regardless of confirmation, similar high rates were observed (66.7% and 67.4% ORR; 89.9% and 93.8% DCR by independent and investigator assessment, respectively). Similar high rates of response were seen regardless of the line of treatment or the starting dose (40 mg or 50 mg) of afatinib. Specifically, ORRs between 57.4% and 75% by independent review were seen across subgroups defined by line of treatment (first and second line), by starting dose (50 and 40 mg), by gender (men and women), by country (Taiwan and USA), by race (Asians and Caucasians), and by the type of the two most common EGFR mutations (Del19 and L858R). Patients with Other mutations (i.e., anything not a single mutation of Del19 or L858R) had a confirmed ORR of 39.1% by independent review. The confirmed ORR for the 11 patients with other uncommon mutations (besides exon 20 insertions and T790M) was similar to that for patients with common mutations: 72.7% ORR and 81.8% DCR by independent review. Most responses to afatinib were observed within the first 8 weeks after start of treatment (66/80 per independent review and 61/78 per investigator assessment). Responses, in general, were durable with a median length of response of 52.3 weeks (range weeks) by independent review and 60.6 weeks (range weeks) by investigator assessment. For first-line patients, median PFS was 15.6 months by investigator assessment and 13.0 months by independent review. For second-line patients, median PFS

9 8 of 10 Safety results: was 10.5 months by investigator assessment and 8.0 months by independent review. Median PFS for patients with Del19 was 13.7 months by independent review, and for patients with L858R, median PFS was 13.0 months by independent review. For the 23 patients with other mutations, the median PFS by independent review was 3.7 months although this estimate was limited by the small sample size. Median OS for afatinib, based on 102 events reported, was estimated to be 26.8 months. The mean total treatment time (including any days of missed treatment) was 17.2 months for the 129 treated patients, with a maximum treatment time of 92.9 months. Of note, the mean total treatment time was shorter for patients who received a starting dose of 40 mg (14.7 months) compared with those who received a starting dose of 50 mg (17.9 months). This difference in duration of exposure was expected due to the timing of the change to a 40 mg starting dose dictated by CTP Amendment 2. Overall, 128 (99.2%) of the 129 treated patients reported at least one AE. At least one study drug related AE was reported for 128 (99.2%) patients. The most common AEs (those reported in 50% of patients overall) were diarrhea (94.6%), rash/acne+ (93.8%), nail effect+ (85.3%), stomatitis+ (79.1%) and pruritus (58.1%); these AEs were reported for similar percentages of patients in both starting dose groups, except stomatitis+ (40 mg: 46.7%; 50 mg: 88.9%). These events were mainly CTCAE Grade 1 or 2, and none was higher than Grade 3. AEs that reached Grade 3 were reported more frequently in the 50 mg starting dose group compared with the 40 mg starting dose group (57.6% vs. 46.7%). The AEs that most frequently reached CTCAE Grade 3 during their course were rash/acne+ (28.6% in the 50 mg starting dose group and 6.7% in the 40 mg starting dose group) and diarrhea (24.5% in the 50 mg starting dose group and 6.7% in the 40 mg starting dose group). These two events accounted for most of the difference in the incidence of all Grade 3 events between the 50 mg and 40 mg starting dose groups. Other AEs that reached Grade 3 less frequently included nail effects+, stomatitis+, fatigue+, hypokalaemia, decreased appetite, nausea and vomiting. Of these events, only hypokalaemia was also reported as a Grade 4 event (40 mg: 1 patient; 50 mg: 2 patients).

10 9 of 10 There were 14 deaths (40 mg: 2 patients; 50 mg: 12 patients) reported due to on-treatment AEs, with none of these AEs considered by the investigator to be related to afatinib treatment. Serious adverse events (SAEs) were reported for 41.1% of patients and were reported more frequently in the 50 mg starting dose group (44.4%) than in the 40 mg starting dose group (30.0%). The most frequently reported SAEs overall were dyspnea (5.4%, 7/129 patients) and rash/acne+ (3.9%, 5/129 patients), which were reported only in the 50 mg starting dose group. All other SAEs occurred in 4 or fewer patients overall. Overall, AEs that led to dose reductions occurred in 61.2% of patients and were more frequent in the 50 mg starting dose group (67.7%) than in the 40 mg starting dose group (40.0%). The five most frequently reported AEs that led to dose reduction overall were rash/acne+ (26.4%, 34/129 patients), diarrhea (25.6%, 33/129 patients), nail effect+ (12.4%, 16/129 patients), stomatitis+ (8.5%, 11/129 patients), and decreased appetite (5.4%, 7/129 patients). In total, 22.5% of patients (29/129) discontinued treatment due to an AE (including 7 patients [5.4%] with an AE in the category of neoplasm [e.g., metastases]); 9.3% of patients (12/129) discontinued treatment due to a related AE. There were no dose discontinuations due to diarrhea, and the rate of discontinuation due to rash/acne+ was low (1.6%, 2/129), suggesting that the trial dose reduction scheme allowed patients to remain on study as long as they continued to benefit from afatinib treatment. Diarrhea, rash/acne+, stomatitis+, and lip, nail, and ocular effects+ represent the mechanistic effects of EGFR inhibition of by afatinib. As such, diarrhea and rash/acne+ were the most frequently reported AEs. Nearly all patients developed diarrhea during the first week of treatment while rash/acne+ manifested during the first 2 weeks of treatment. Most diarrhea and rash/acne+ was adequately managed by a combination of pausing treatment, reducing the dose, and supportive treatment with loperamide for diarrhea and topical antibiotics for rash as recommended per protocol. The effectiveness of the management guidelines is evidenced by the fact that only two patients permanently discontinued treatment due to rash and none due to diarrhea. Stomatitis+, ocular effects+, lip effects+ and nail effects+ were reported frequently. These events all had a CTCAE Grade of 1 or 2; no SAEs or discontinuations due to stomatitis+, ocular

11 10 of 10 Conclusions: effects+, lip effects+ or nail effects+ were reported. AEs were searched for certain predefined AEs of special interest (possible hepatic events, renal, ILD-like events, possible heart failure). Except for ILD-like events, the AEs of special interest were rarely considered by the investigator to be related to afatinib. Renal and possible hepatic events were rarely serious, and there were no significant decreases of LVEF documented. With most reports of AEs of special interest, the patients did not discontinue treatment, except for patients reporting ILD-like symptoms, who were discontinued as required by the protocol. No changes indicative of an adverse effect of afatinib were seen on any laboratory parameters, QTcF, left ventricular ejection fraction or the vital signs and other safety observations assessed (systolic and diastolic blood pressure, or body weight). In conclusion, the results of this trial indicate that the activity of afatinib in patients with EGFR mutations is not limited by line of therapy; both first- and second-line patients evidenced high response rates and prolonged PFS. Specifically, by independent review, first-line patients treated with an afatinib starting dose of either 40 mg or 50 mg had a 67.2% confirmed ORR, a median PFS of 13.0 months, and a median OS of 31.7 months; second-line patients treated with afatinib had a 57.4% confirmed ORR, a median PFS of 8.0 months, and a median OS of 23.6 months. The safety profile of afatinib was consistent with that expected for an EGFR TKI and with the safety profile documented in previous afatinib clinical trials. AEs with the starting dose of 40 mg were of lower intensity compared with the 50 mg starting dose, suggesting that this lower starting dose could provide a better tolerability profile in this population of TKI-naïve patients with tumors that are very sensitive to afatinib.

12 The appended tables on the following pages supplement the trial results presented in the Trial Synopsis. They complement patient disposition results and overall adverse event results for the trial. Results for presented in Patient Disposition Table : 1 Adverse Events Table : 1

13 Table : 1 Summary of patient disposition all enrolled patients 1st line40mg 1st line50mg 2nd line40mg 2nd line50mg Total N(%) N(%) N(%) N(%) N(%) Screened 461 Not treated 332 Treated 23(100.0) 38(100.0) 7(100.0) 61(100.0) 129(100.0) Treatment discontinued 23(100.0) 38(100.0) 7(100.0) 61(100.0) 129(100.0) Reason for treatment discontinuation Progressive disease 18( 78.3) 30( 78.9) 6( 85.7) 49( 80.3) 103( 79.8) Other AE 3( 13.0) 5( 13.2) 1( 14.3) 8( 13.1) 17( 13.2) Non compl with prot. 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) Lost to follow up 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) Refused cont. medicat 0( 0.0) 2( 5.3) 0( 0.0) 1( 1.6) 3( 2.3) Other 2( 8.7) 1( 2.6) 0( 0.0) 3( 4.9) 6( 4.7) Source data: Appendix , Listing 1 ctr15_1\se1disp.sas 22DEC2015

14 Table : 1 Adverse event overall summary treated set Treatment analysis: On treament, by patient cohort 1st line40mg 1st line50mg 2nd line40mg 2nd line50mg Total N (%) N (%) N (%) N (%) N (%) Total treated 23 (100.0) 38 (100.0) 7 (100.0) 61 (100.0) 129 (100.0) Patients with any AE 23 (100.0) 38 (100.0) 7 (100.0) 60 ( 98.4) 128 ( 99.2) Patients with investigator defined drug related 23 (100.0) 38 (100.0) 7 (100.0) 60 ( 98.4) 128 ( 99.2) AEs Patients with any AE leading to dose reduction 10 ( 43.5) 28 ( 73.7) 2 ( 28.6) 39 ( 63.9) 79 ( 61.2) Patients with AEs leading to discontinuation of 7 ( 30.4) 8 ( 21.1) 2 ( 28.6) 12 ( 19.7) 29 ( 22.5) trial drug Patients with serious AEs 8 ( 34.8) 16 ( 42.1) 1 ( 14.3) 28 ( 45.9) 53 ( 41.1) Fatal 2 ( 8.7) 3 ( 7.9) 0 ( 0.0) 9 ( 14.8) 14 ( 10.9) Imm life threatening 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 1.6) 1 ( 0.8) Disability/incap. 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Req.hospitalisation 7 ( 30.4) 15 ( 39.5) 1 ( 14.3) 23 ( 37.7) 46 ( 35.7) Prol.hospitalisation 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 1.6) 1 ( 0.8) Congenital anomaly 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Other 2 ( 8.7) 3 ( 7.9) 0 ( 0.0) 4 ( 6.6) 9 ( 7.0) Patients with CTC grade 3 or higher 16 ( 69.6) 31 ( 81.6) 2 ( 28.6) 41 ( 67.2) 90 ( 69.8) Patients with maximum CTC grade Grade 1 0 ( 0.0) 0 ( 0.0) 1 ( 14.3) 1 ( 1.6) 2 ( 1.6) Grade 2 7 ( 30.4) 7 ( 18.4) 4 ( 57.1) 18 ( 29.5) 36 ( 27.9) Grade 3 13 ( 56.5) 27 ( 71.1) 1 ( 14.3) 30 ( 49.2) 71 ( 55.0) Grade 4 1 ( 4.3) 1 ( 2.6) 1 ( 14.3) 2 ( 3.3) 5 ( 3.9) Grade 5 2 ( 8.7) 3 ( 7.9) 0 ( 0.0) 9 ( 14.8) 14 ( 10.9) A patient may be counted in more than one seriousness criterion. Percentages are calculated using total number of patients per treatment as the denominator. MedDRA version used for reporting: 18.0 Source data: Appendix , Listing 2.3 ctr15_3\ae.sas 22DEC2015