Afatinib dose adjustment: Effect on safety, efficacy and patient-reported outcomes in the LUX-Lung 3/6 trials in EGFRm+ NSCLC

Transcription

1 Afatinib dose adjustment: Effect on safety, efficacy and patient-reported outcomes in the LUX-Lung 3/6 trials in EGFRm+ NSCLC Vera Hirsh, 1 Eng-Huat Tan, 2 Yi-Long Wu, 3 Lecia V. Sequist, 4 Caicun Zhou, 5 Martin Schuler, 6 Sarayut L. Geater, 7 Tony Mok, 8 Cheng-Ping Hu, 9 Nobuyuki Yamamoto, 10 Jifeng Feng, 11 Kenneth O Byrne, 12 Shun Lu, 13 Yunchao Huang, 14 Martin Sebastian, 15 Isamu Okamoto, 16 Nicolas Dickgreber, 17 Riyaz Shah, 18 Michael Palmer, 19 Angela Märten, 20 Dan Massey, 21 Carl Samuelsen, 20 James Chih-Hsin Yang, 22 1 McGill University, Montreal, Canada; 2 Division of Medical Oncology, National Cancer Centre Singapore, Singapore; 3 Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; 4 Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 5 Shanghai Pulmonary Hospital, Tongji University, Shanghai, China; 6 West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany; 7 Prince of Songkla University, Songkhla, Thailand; 8 State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, China; 9 Xiangya Hospital, Central South University, Changsha, China; 10 Wakayama Medical University, Wakayama, Japan; 11 Jiangsu Province Cancer Hospital, Nanjing, Jiangsu, China; 12 Princess Alexandra Hospital, Woolloongabba, and Queensland University of Technology, Brisbane, Queensland, Australia; 13 Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; 14 Yunnan Tumor Hospital (The Third Affiliated Hospital of Kunming Medical University), Kunming, Yunnan Province, China; 15 Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany; 16 Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 17 Thoracic Oncology and Respiratory Care Medicine, Mathias Spital Rheine, Rheine, Germany; 18 Kent Oncology Centre, Maidstone Hospital, Kent, UK; 19 School of Healthcare Science, Manchester Metropolitan University, Manchester, UK; 20 Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 21 Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, UK; 22 National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan Presented at the IASLC 18 th World Conference on Lung Cancer (WCLC), Yokohama, Japan, October 15 18, 2017

2 Introduction Afatinib improved PFS versus chemotherapy in treatment-naïve patients with EGFR mutations in two large, Phase III trials: LL3 and LL6 (Figure 1) 1,2 Figure 1. LL3 and LL6 study design Stage IIIB/IV adenocarcinoma of the lung Presence of EGFR mutation in the tumor tissue* Treatment-naïve ECOG PS 0/1 Randomization (2:1) Stratification by EGFR mutation type: Del19/L858R/other and by race (LL3 only): Asian/non-Asian LL3: cisplatin/pemetrexed up to 6 cycles Afatinib 40 mg orally once daily LL6: cisplatin/gemcitabine up to 6 cycles Primary endpoint: PFS (independent review) Secondary endpoints: OS, objective response, disease control, PRO, safety *EGFR29: 19 deletions in exon 19, three insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I

3 Introduction (cont d) Afatinib-related AEs are generally managed with dose modifications 3 Here, we present post-hoc analyses of LL3 and LL6 that assessed the impact of afatinib dose reduction on safety, PKs, PFS, and PROs AE, adverse event; ECOG PS, Eastern Cooperative Oncology Group performance status; LL, LUX-Lung; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; PRO, patient-reported outcome

4 Methods Dose reduction in LL3 and LL6 studies 1 3 Afatinib dose reduction was permitted (Figure 2) Figure 2. Dose reduction scheme in LL3 and LL6 Starting dose 40 mg 30 mg 20 mg Patients with any treatment-related grade 3 AE, prolonged grade 2 diarrhea, prolonged grade 2 nausea or vomiting,* or grade 2 worsening renal function Afatinib interrupted for up to 14 days until severity reduced to grade 1 or baseline Afatinib resumed at a lower dose (10 mg decrements to a minimum of 20 mg) *For 7 days despite supportive care

5 Methods (cont d) The frequency and severity of the most common AEs, PK data collected on Days 22 and 43, and PFS pre- and post-dose reduction from 40 mg were analyzed in each trial PROs were measured using the EORTC Quality of Life Questionnaire and the EQ- 5D health status self-assessment questionnaire: these included scores on: EORTC Global Health/Quality of Life scale (GH; 0 100) EORTC Physical Functioning scale (PF; 0 100) EQ Visual Analogue Scale (VAS; 0 100) EQ-5D UK utility scale (EQ UK utility; 0 1) PK data from LL3 and LL6 were combined to increase sample size EORTC, European Organization for Research and Treatment of Cancer

6 Results Dose reduction frequency and treatment exposure in LL3 and LL6 are shown in Figure 3 Baseline demographics of patients who had dose reductions in the first 6 months and those who did not are shown in Table 1 In both LL3 and LL6, dose reductions were more frequent in female patients In LL3, dose reduction was also more frequent in older patients ( 65 years) and patients from Japanese sites

7 Results (cont d) Figure 3. Dose reduction and treatment exposure in LL3 and LL6 LL3; n=229 LL6; n=239 Dose reductions Yes No 47% (n=107) 53% (n=122) 72% (n=172) 28% (n=67) Median total treatment time, days (range): patients who had dose reductions Median total treatment time, days (range): patients who had no dose reductions Proportion (n) of dose-reduced patients with a reduction in the first 6 months (28 827) (42 832) (7 827) (3 871) 86% (105) 82% (55)

8 Results (cont d) Table 1. Patient characteristics at baseline Data are n (%) Dose reduced to <40 mg in first 6 months (n=105) LL3 Dose at 40 mg in first 6 months (n=124) Dose reduced to <40 mg in first 6 months (n=55) LL6 Dose at 40 mg in first 6 months (n=184) Characteristic Gender Male 25 (23.8) 57 (46.0) 16 (29.1) 71 (38.6) Female 80 (76.2) 67 (54.0) 39 (70.9) 113 (61.4) Age <65 years 55 (52.4) 84 (67.7) 39 (70.9) 136 (73.9) 65 years 50 (47.6) 40 (32.3) 16 (29.1) 48 (26.1) Race Caucasian 21 (20.0) 40 (32.3) 0 0 Asian Japanese sites 33 (31.4) 21 (16.9) 0 0 Asian non-japanese sites 50 (47.6) 61 (49.2) 55 (100.0) 184 (100.0) Other 1 (1.0) 2 (1.6) 0 0 Smoking status Never smoker 74 (70.5) 80 (64.5) 40 (72.7) 138 (75.0) Ex-smoker 30 (28.6) 40 (32.3) 13 (23.6) 31 (16.8) Current smoker 1 (1.0) 4 (3.2) 2 (3.6) 15 (8.2) Weight category <50 kg 29 (27.6) 16 (12.9) 12 (21.8) 20 (10.9) 50 kg 76 (72.4) 108 (87.1) 43 (78.2) 164 (89.1) ECOG PS 0 40 (38.1) 52 (41.9) 13 (23.6) 35 (19.0) 1 65 (61.9) 72 (58.1) 42 (76.4) 149 (81.0)

9 Results (cont d) Adverse events Despite longer treatment exposure at lower doses, tolerability-guided dose reduction led to decreases in the incidence and severity of treatment-related AEs (Figure 4)

10 Results (cont d) Figure 4. Key treatment-related AEs in patients pre- and post-dose reductions in LL3 (A) and LL6 (B) (A) LL3 (n=122) Patients (%) Grade 1 2 Grade Pre Post Pre Post Pre Post Pre Post Pre Post Any Diarrhea Rash/acne Stomatitis Nail effect

11 Results (cont d)

12 Results (cont d) Pharmacokinetic analyses Afatinib trough plasma concentrations with the 40 mg dose were higher at Day 22 among patients who subsequently dose reduced to 30 mg compared with those who remained on the 40 mg dose (Figure 5) On Day 43, afatinib trough plasma concentrations for those who dose reduced to 30 mg were similar to those who remained on the 40 mg dose Although PK data from LL3 and LL6 were combined to increase sample size, the described effects were also observed in both individual trials (data not shown)

13 Results (cont d) Figure 5. Afatinib plasma levels in patients who dose reduced to 30 mg or who remained on 40 mg: combined analyses of LL3 and LL6 Afatinib trough plasma concentration (ng/ml) mg (n=282) 40 mg (n=22) 40 mg (n=284) Day 22 Day 43 Afatinib dose Patients who remained on afatinib 40 mg until Day 43 Patients who dose reduced to afatinib 30 mg before Day mg (n=59) Boxes represent the median and interquartile range; the whiskers represent the 10th and 90th percentiles and the dots show data points outside percentiles

14 Efficacy Median PFS was similar in patients who dose reduced and those who did not in both LL3 and LL6 (Figure 6) Figure 6. PFS in patients with or without dose reduction of afatinib in the first 6 months of treatment in LL3 (A) and LL6 (B) (A) LL3 Estimated PFS probability No. at risk: <40 mg in first 6 mo mg for first 6 mo <40 mg in first 6 mo (n=105) 40 mg for first 6 mo (n=124) Median PFS (mo) HR (95% Cl) 1.25 ( ) p value Time (mo)

15 Efficacy (cont d) (B) LL6 Estimated PFS probability No. at risk: <40 mg in first 6 mo 40 mg for first 6 mo Time (mo) <40 mg in first 6 mo (n=55) mg for first 6 mo (n=184) Median PFS (mo) HR (95% Cl) 1.00 ( ) p value CI, confidence interval; HR, hazard ratio; mo, months

16 Efficacy (cont d) Patient-reported outcomes PRO data from LL3 and LL6 were pooled in this analysis There were no clinically meaningful changes in PROs following afatinib dose reduction (Table 2) Table 2. Summary of PRO measures in patients with first dose change from 40 mg to 30 mg PRO measure* Statistic Last PRO value on 40 mg First PRO value on 30 mg Change in PRO measure GH (n=136) Mean (SD) 59.1 (20.8) 66.9 (17.7) 7.7 (18.4) PF (n=136) Mean (SD) 79.4 (19.0) 83.0 (17.5) 3.6 (14.2) EQ-VAS (n=135) Mean (SD) 70.1 (17.7) 75.1 (15.1) 5.0 (11.5) EQ UK Utility (n=135) Mean (SD) 0.70 (0.28) 0.78 (0.23) 0.08 (0.25) *Increasing values represent improving PRO outcomes SD, standard deviation

17 Key Findings and Conclusions Post-hoc analyses from LL3 and LL6 suggest that tolerability-guided dose adjustment of afatinib is an effective measure to reduce treatment-related AEs without affecting therapeutic efficacy The incidence and severity of treatment-related AEs were lower following dose reduction Tolerability-guided dose modification reduced the interpatient variability of afatinib exposure, while maintaining efficacious plasma levels Efficacy outcomes were similar in patients who dose reduced due to AEs versus those who did not There were no clinically meaningful changes in PROs following afatinib dose reduction

18 References 1. Sequist LV, et al. J Clin Oncol 2013;31: Wu Y-L, et al. Lancet Oncol 2014;15: Yang JC-H, et al. Ann Oncol 2016;27: Acknowledgments This study was funded by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of poster development and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Hashem Dbouk of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this poster. Corresponding author address: vera.hirsh@much.mcgill.ca These materials are for personal use only and may not be reproduced without written permission of the authors and the appropriate copyright permissions