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Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial

Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung... Annals of Oncology 28: 270–277, 2017 doi:10.1093/annonc/mdw611 Published online 7 February 2017 ORIGINAL ARTICLE Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial 1* 2 3 4 5 6 7 8 9 L. Paz-Ares , E.-H. Tan , K. O’Byrne , L. Zhang , V. Hirsh , M. Boyer , J. C.-H. Yang ,T.Mok , K. H. Lee , 10 11 12 13 14 15 16 17 18 S. Lu , Y. Shi , D. H. Lee , J. Laskin , D.-W. Kim , S. A. Laurie ,K. Ko¨lbeck , J. Fan , N. Dodd , 19 20 A. Marten & K. Park 1 2 Medical Oncology Department, Hospital Universitario Doce de Octubre, Universidad Complutense and CNIO, Madrid, Spain; Division of Medical Oncology, 3 4 National Cancer Centre, Singapore; Cancer Section, Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Australia; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China; 5 6 7 Department of Oncology, McGill University, Montreal, Canada; Department of Medical Oncology, Chris O’Brien Lifehouse, Camperdown, Australia; Department of Oncology, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan; Department of Clinical Oncology, State Key Laboratory of South China, The Chinese University of Hong Kong, Hong Kong; Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Chungbuk, South 10 11 Korea; Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai; Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 12 13 China; Department of Oncology, Asan Medical Center, Seoul, South Korea; Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada; 14 15 Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Division of Medical Oncology, The Ottawa Hospital Cancer Centre, 16 17 Ottawa, Ontario, Canada; Pulmonary Diseases, Karolinska University Hospital, Solna, Stockholm, Sweden; Clinical Program Leader, Boehringer Ingelheim 18 19 Pharmaceuticals, Inc, Ridgefield, USA; Biostatistics, Boehringer Ingelheim Ltd UK, Bracknell, UK; TA Oncology, Boehringer Ingelheim GmbH, Ingelheim, Germany; Division of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea *Correspondence to: Prof Luis Paz-Ares, Medical Oncology Department, Hospital Universitario Doce de Octubre, Av. de Cordoba, s/n, 28041, Madrid, Spain. Tel: þ 34-913908349; E-mail: lpazaresr@seom.org Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth fac- tor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data. Patients and methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naı¨ve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after 213 OS events and32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases. Results: Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) ¼ 0.86, 95% confidence inter- val (CI) 0.66–1.12, P¼ 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58–1.17, P¼ 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62–1.36, P¼ 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent sys- temic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third- generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Conclusion: In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Clinicaltrials.gov identifier: NCT01466660. V C The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Annals of Oncology Original article Key words: afatinib, gefitinib, NSCLC, overall survival endpoint. AEs were assessed according to National Cancer Institute Introduction Common Terminology Criteria for Adverse Events, version 3.0 (NCI Non-small-cell lung cancers (NSCLCs) with activating epidermal CTCAE 3.0). Post-study treatments were provided at the physician’s dis- cretion and assessed retrospectively. growth factor receptor (EGFR) mutations are extremely sensitive The study was conducted in accordance with the principles of the to the EGFR-targeting tyrosine kinase inhibitors (TKIs) gefitinib, Declaration of Helsinki and Good Clinical Practice guidelines as defined erlotinib and afatinib [1–8]. These three agents are established by the International Conference on Harmonization. All patients pro- first-line treatment options in this setting; however, until re- vided written informed consent. cently, there was an absence of prospective randomised head-to- head comparisons to help guide treatment decisions. To our knowledge, the recent randomised phase IIb LUX-Lung Statistical plan 7 trial was the first study to compare the irreversible ErbB family Three analysis timepoints were planned. The primary PFS/TTF analysis blocker, afatinib, with a reversible EGFR TKI, gefitinib, in treat- was planned after 250 PFS events and was previously published [9]. The ment-naı¨ve patients with advanced NSCLC harbouring a com- primary OS analysis (reported herein) was planned after approximately mon EGFR mutation (exon 19 deletion/L858R) [9]. In this trial, 213 OS events and a follow-up period of at least 32 months for patients still alive. The final analysis will be undertaken at study completion afatinib significantly improved progression-free survival [PFS; (when all patients have completed treatment, or 5 years since the last pa- hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.57–0.95, tient was entered, whichever occurs first). P¼ 0.0165], time-to-treatment failure (TTF; HR 0.73, 95% CI All randomised patients were included in the primary assessment of 0.58–0.92, P¼ 0.0073) and objective response rate (ORR; 70% OS, and updated analysis of PFS and TTF (intention-to-treat popula- versus 56%; odds ratio 1.873, 95% CI 1.176–2.985, P¼ 0.0083) tion). Safety analysis included all patients who received at least one dose compared with gefitinib. Overall, afatinib was well tolerated, with of study drug. OS and PFS/TTF were analysed by a log-rank test stratified a predictable and manageable adverse event (AE) profile. by EGFR mutation type and the presence of baseline brain metastases. A Cox proportional hazards model was used to calculate HRs and 95% CIs. Treatment-related AEs were experienced in 97.5% and 96.2% of Prespecified subgroups included EGFR mutation type (exon 19 deletion/ patients in the afatinib and gefitinib arms, respectively. The most L858R), baseline brain metastases (presence versus absence), ECOG PS frequent grade3 treatment-related AEs were diarrhoea (0 versus 1), sex, age (<65 versus65 years), ethnic origin (Asian versus (12.5%), rash/acne (9.4%) and fatigue (5.6%) with afatinib and non-Asian) and smoking history. ORR and disease control rate (DCR) elevated liver enzymes (8.8%), rash/acne (3.1%) and interstitial were compared with a logistic regression model. All statistical testing was lung disease (ILD) (1.9%) with gefitinib. There was one drug- two sided at the nominal 5% significance level, with no adjustment for related fatal AE; a case of hepatic and renal failure with gefitinib multiplicity. Data were analysed with SAS version 9.4. treatment. There was no difference in the drug discontinuation rate due to treatment-related AEs between afatinib and gefitinib. Along with PFS and TTF, overall survival (OS) was a co- Results primary endpoint of LUX-Lung 7; however, OS data were imma- ture at the time of the primary analysis. Here, we report the ma- Patients ture OS results, including prespecified subgroup analysis and post-hoc analysis of the impact of post-study treatment on OS. A total of 319 patients were randomised and treated with afatinib (n¼ 160) or gefitinib (n¼ 159). Baseline characteristics have been published and were similar between treatment groups [9]. Two-hundred and twenty-six OS events had occurred at the data Methods cut-off of 8 April 2016; 109 (68.1%) and 117 (73.6%) patients treated with afatinib and gefitinib, respectively, had died by this Study design and treatment time. At the time of analysis, the median duration of treatment Full details on the trial design of LUX-Lung 7 have been published [9]. was 13.7 months (range: 0–46.4) with afatinib and 11.5 months LUX-Lung 7 was a multicentre, international, randomised, open-label (range: 0.5–48.7) with gefitinib. Forty (25.0%) and 21 (13.2%) phase IIb trial (64 sites; 13 countries). Eligible patients were aged18 years patients were treated for>24 months with afatinib and gefitinib, with treatment-na¨ıve pathologically confirmed stage IIIB/IV adenocarcin- respectively. At data cut-off, 14 (8.8%) and 8 (5.0%) patients re- oma and a documented common activating EGFR mutation (exon 19 dele- mained on treatment with afatinib and gefitinib. tion/L858R). Patients had an Eastern Cooperative Oncology Group Following discontinuation of study treatment, the majority of performance status (ECOG PS) of 0 or 1, at least one measurable lesion patients received at least one systematic anti-cancer therapy [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] and adequate organ function. Patients were randomised 1:1 to once-daily oral (72.6% and 76.8% in the afatinib and gefitinib arms, respectively; afatinib 40 mg or gefitinib 250 mg and were treated until disease progres- Table 1). Many patients also received third-line (43.8% and sion, intolerable AEs or other reasons necessitating withdrawal. Treatment 55.0%), fourth-line (24.0% and 31.1%) and fifth-line therapies beyond radiological progression was allowed for patients deemed to be (13.0% and 19.2%, respectively). Fewer patients in the afatinib receiving continued clinical benefit by the treating physician. arm received a subsequent EGFR TKI than in the gefitinib arm The co-primary endpoints were PFS by independent central review, (45.9% versus 55.6%); this imbalance was observed in both the TTF (time from randomisation to the time of treatment discontinuation EGFR exon 19 deletion (51.8% versus 59.8%) and L858R (38.1% for any reason including disease progression, treatment toxicity, and death) and OS. ORR by independent central review was a secondary versus 50.0%) subgroups. Twenty (13.7%) and 23 (15.2%) Volume 28 | Issue 2 | 2017 doi:10.1093/annonc/mdw611 | 271 Annals of Oncology Original article Table 1. Subsequent therapies in patients who discontinued study treatment, in the overall population and in EGFR mutation subgroups Treatment, n (%) Overall population Exon 19 deletion L858R mutation Afatinib Gefitinib Afatinib Gefitinib Afatinib Gefitinib (n 5 146) (n 5 151) (n 5 83) (n 5 87) (n 5 63) (n 5 64) None 38 (26.0) 28 (18.5) 20 (24.1) 14 (16.1) 18 (28.6) 14 (21.9) Systemic anti-cancer therapy 106 (72.6) 116 (76.8) 61 (73.5) 69 (79.3) 45 (71.4) 47 (73.4) Chemotherapy 84 (57.5) 91 (60.3) 48 (57.8) 55 (63.2) 36 (57.1) 36 (56.3) Platinum based 70 (47.9) 71 (47.0) 40 (48.2) 44 (50.6) 30 (47.6) 27 (42.2) EGFR TKI 67 (45.9) 84 (55.6) 43 (51.8) 52 (59.8) 24 (38.1) 32 (50.0) EGFR TKI monotherapy 63 (43.2) 74 (49.0) 39 (47.0) 47 (54.0) 24 (38.1) 27 (42.2) First-generation Gefitinib 22 (15.1) 27 (17.9) 11 (13.3) 21 (24.1) 11 (17.5) 6 (9.4) Erlotinib 23 (15.8) 30 (19.9) 16 (19.3) 21 (24.1) 7 (11.1) 9 (14.1) Second-generation Afatinib 6 (4.1) 12 (7.9) 4 (4.8) 8 (9.2) 2 (3.2) 4 (6.3) Poziotinib 0 (0.0) 4 (2.6) 0 (0.0) 1 (1.1) 0 (0.0) 3 (4.7) Third-generation Osimertinib 15 (10.3) 17 (11.3) 9 (10.8) 11 (12.6) 6 (9.5) 6 (9.4) Olmutinib 5 (3.4) 5 (3.3) 5 (6.0) 3 (3.4) 0 (0.0) 2 (3.1) EGFR TKI-containing combination 7 (4.8) 15 (9.9) 5 (6.0) 8 (9.2) 2 (3.2) 7 (10.9) Immune checkpoint inhibitor 3 (2.1) 4 (2.6) 2 (2.4) 4 (4.6) 1 (1.6) 0 (0.0) Radiotherapy 26 (17.8) 34 (22.5) 16 (19.3) 15 (17.2) 10 (15.9) 19 (29.7) Chemotherapy or chemotherapy-based combination. Including gefitinib (afatinib arm, n¼ 7; gefitinib arm, n¼ 11), erlotinib (n¼ 0; n¼ 5) and osimertinib (n¼ 0; n¼ 1). EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor. patients who discontinued study treatment in the afatinib and discontinuation of study treatment was ‘not evaluable’ versus 46.0 gefitinib arms received a third-generation EGFR TKI. months (HR 0.51, 95% CI 0.17–1.52, P¼ 0.22; Figure 3). Overall survival Other efficacy endpoints After a median follow-up of 42.6 months, median OS with afati- Updated analysis of the co-primary endpoints showed similar nib versus gefitinib was 27.9 versus 24.5 months (HR, 0.86; 95% findings to the primary analysis [9]. PFS by independent review CI 0.66–1.12; P¼ 0.2580; Figure 1A). (median 11.0 versus 10.9 months; HR 0.74, 95% CI 0.57–0.95, OS with afatinib versus gefitinib was similar across prespeci- P¼ 0.0178; supplementary Figure S2, available at Annals of fied subgroups of interest (Figure 1B). There was no significant Oncology online) and TTF (median 13.7 versus 11.5 months; HR OS difference between afatinib and gefitinib in pre-planned 0.75, 95% CI 0.60–0.94, P¼ 0.0136; supplementary Figure S3, subgroupsthatwereusedasstratification factors, i.e. baseline available at Annals of Oncology online) were significantly im- brain metastases (presence versus absence) and EGFR mutation proved with afatinib versus gefitinib. type (exon 19 deletion versus L858R). Median OS with afatinib Updated ORR was also significantly higher with afatinib than versus gefitinib in patients with exon 19 deletions (30.7 versus with gefitinib [72.5% versus 56.0%; odds ratio 2.121 (95% CI 26.4 months; HR 0.83, 95% CI 0.58–1.17, P¼ 0.2841; Figure 1.32–3.40); P¼ 0.0018; supplementary Table S1, available at 2A) and patients with the L858R mutation (25.0 versus 21.2 Annals of Oncology online]. The DCR was 91.3% versus 87.4% months; HR 0.91, 95% CI 0.62–1.36, P¼ 0.6585; Figure 2B) was (afatinib versus gefitinib; odds ratio 1.552, 95% CI 0.75–3.22, generally consistent with the overall EGFR mutation-positive P¼ 0.2372). study population. There was no interaction between OS and pa- tient subgroups, except for age based on the cut-offs of<65 Safety and65 years (Figure 1B). However, further post-hoc analysis demonstrated a consistent trend for OS benefit with afatinib inde- The safety profiles of afatinib and gefitinib were virtually un- pendent of age group (no interaction observed at cut-offs of 60, 70 changed since the primary analysis [9]. The frequency of all- or 75 years). Similar median OS with afatinib was seen at cut-offs cause grade3 AEs was 56.9% and 53.5%, and of treatment- of 60, 65, 70 and 75 years (supplementary Figure S1,available at related grade3 AEs was 31.3% and 19.5%, with afatinib and Annals of Oncology online). Of note, subgroup sample sizes gefitinib, respectively (supplementary Table S2, available at decreased with increasing age cut-off. Annals of Oncology online). The most frequent treatment- In a post-hoc analysis, median OS with afatinib versus gefitinib related grade3 AEs with afatinib were diarrhoea (13.1% ver- in patients who received a third-generation EGFR TKI following sus 1.3%), rash/acne (9.4% versus 3.1%) and fatigue (5.6% 272 | Paz-Ares et al. Volume 28 | Issue 2 | 2017 Annals of Oncology Original article A 1.0 Afatinib (n = 160) Gefitinib (n = 159) HR 0.86 (95% CI 0.66–1.12) 0.8 Log-rank P = 0.2580 0.6 0.4 0.2 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Number at risk Afatinib 160 156 153 148 139 125 111 104 94 81 74 61 50 36 30 12 2 0 Gefitinib 159 153 148 142 133 119 105 90 80 71 62 56 48 44 27 7 0 0 B P Events/patients HR (95% CI) interaction Total 226/319 0.86 (0.66–1.12) EGFR mutation L858R 99/133 0.91 (0.62–1.36) 0.7086 Exon 19 deletion 127/186 0.83 (0.58–1.17) Brain metastases Absent 189/268 0.81 (0.61–1.07) 0.2133 Present 37/51 1.16 (0.61–2.21) Baseline ECOG score 0 63/98 1.32 (0.80–2.18) 0.0949 1 163/221 0.75 (0.55–1.02) Gender Male 91/122 0.80 (0.53–1.21) 0.7252 Female 135/197 0.88 (0.63–1.24) Age group <65 years 126/177 0.66 (0.46–0.94) 0.0228 ≥65 years 100/142 1.22 (0.82–1.81) Race group Non-Asian 93/137 0.78 (0.52–1.17) 0.4419 Asian 133/182 0.95 (0.67–1.33) Smoking history Never smoked 146/212 0.92 (0.67–1.28) 0.3900 <15 pack years + stopped >1 year before 32/40 1.12 (0.55–2.28) Other current or ex-smokers 48/67 0.63 (0.36–1.11) 1/16 1/4 1 4 16 Favours afatinib Favours gefitinib Figure 1 Overall survival. Kaplan–Meier curve (A) and forest plot of pre-specified subgroup analyses (B). CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; HR, hazard ratio. versus 0%). The most frequent treatment-related grade3 Discussion AEs with gefitinib were elevated alanine transaminase (8.2% In this updated analysis of LUX-Lung 7, a 14% reduction in risk versus 0%), rash/acne, elevated aspartate aminotransferase (2.5% of death was observed in patients with EGFR mutation-positive versus 0%) and interstitial lung disease (1.9% versus 0%; NSCLC treated with first-line afatinib versus gefitinib, that cor- supplementary Table S2, available at Annals of Oncology responded to a numerical difference of 3.4 months in median OS, online). There was one drug-related fatal AE; a case of hepatic without reaching statistical significance. These findings were gen- and renal failure with gefitinib treatment. Rates of treatment erally consistent across key patient subgroups, including those discontinuations due to drug-related AEs remained equally based on gender, ethnicity (Asian versus non-Asian), and EGFR low (6.3% each). Volume 28 | Issue 2 | 2017 doi:10.1093/annonc/mdw611 | 273 Estimated overall survival probability Annals of Oncology Original article A 1.0 Patients with exon 19 deletion Afatinib (n = 93) Gefitinib (n = 93) 0.8 HR 0.83 (95% CI 0.58–1.17) Log-rank P = 0.2841 0.6 0.4 0.2 03 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Number at risk Afatinib 93 91 88 88 82 74 68 63 61 54 50 41 35 24 20 91 0 Gefitinib 93 88 86 82 79 72 66 57 52 46 39 36 29 28 17 5 0 0 1.0 Patients with L858R mutation Afatinib (n = 67) Gefitinib (n = 66) 0.8 HR 0.91 (95% CI 0.62–1.36) Log-rank P = 0.6585 0.6 0.4 0.2 0369 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Number at risk Afatinib 67 65 65 60 57 51 43 41 33 27 24 20 15 12 10 3 1 0 Gefitinib 66 65 62 60 54 47 39 33 28 25 23 20 19 16 10 2 0 0 Figure 2 Overall survival in patients with common EGFR mutations. Patients with exon 19 deletion (A) and patients with L858R mutation (B). CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio. mutation type (exon 19 deletion versus L858R). Although initial afatinib significantly improved PFS, TTF and ORR versus gefiti- analyses suggested a potential interaction between OS and patient nib. No unexpected AEs were observed and discontinuation rates age, subsequent post-hoc analysis demonstrated no clear pattern due to treatment-related AEs remained equally low in both arms. of association, and similar median OS with afatinib was observed Despite being recognised as the first-line standard-of-care in for patients aged</60,</65,</70 and</75 years. patients with EGFR mutation-positive NSCLC, an enduring fea- Afatinib conferred long-term survival in a high proportion of pa- ture of randomised controlled trials of EGFR TKIs in this setting tients, with 24-month and 30-month survival rates of 60.9% and has been a lack of clear OS benefit, even against platinum-doublet 48.0%, respectively. These frequencies were consistent with a pre- chemotherapy. Across multiple phase III trials, neither erlotinib vious global, phase III trial, which assessed afatinib versus cis- [4, 7, 11] nor gefitinib [12–14] has demonstrated statistically sig- platin/pemetrexed in patients with NSCLC harbouring common nificant OS improvement against chemotherapy. Although afati- EGFR mutations (LUX-Lung 3). In this study, 59.6% and 49.8% nib did not significantly improve OS versus chemotherapy in the of afatinib-treated patients survived for at least 24 and 30 months, overall populations of the LUX-Lung 3 and LUX-Lung 6 trials, a respectively [10]. In the present study, as in the primary analysis, significant improvement in OS was observed with afatinib in a 274 | Paz-Ares et al. Volume 28 | Issue 2 | 2017 Estimated overall survival probability Estimated overall survival probability Annals of Oncology Original article 1.0 0.8 0.6 0.4 Patients subsequently treated with a third-generation EGFR TKI Afatinib (n = 20) Gefitinib (n = 23) 0.2 HR 0.51 (95% CI 0.17–1.52) Log-rank P = 0.22 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Number at risk Afatinib 20 20 20 20 20 20 20 19 19 19 19 16 13 10 8 2 0 0 Gefitinib 23 23 23 22 22 22 21 20 20 20 19 19 19 15 7 4 00 Figure 3 Overall survival in patients subsequently treated with a third-generation EGFR TKI following discontinuation of study treatment. CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; TKIs, tyrosine kinase inhibitors. prespecified sub-analysis of each trial, in patients with NSCLC Furthermore, the limited sample size may have impaired the harbouring exon 19 deletion mutations [10]. In the current power of the trial to address the differences in OS benefit between study, there was no significant difference in OS between afatinib afatinib and gefitinib in clinical practice. and gefitinib in patients with NSCLC harbouring an exon 19 de- The primary OS analysis described herein fulfilled the protocol letion. Emerging evidence suggests that first-generation and se- requirement in terms of the planned number of events and min- cond-generation EGFR TKIs may be particularly active in imum follow-up time. However, at the time of writing, 29% of NSCLC with exon 19 deletions compared with the L858R muta- patients in LUX-Lung 7 were still alive and a final OS analysis is tion [15], but this is based on trials that used chemotherapy as a planned on study completion to assess the impact of a reduction comparator rather than TKI versus TKI comparisons. Therefore, in censored patients. It should be noted that LUX-Lung 7 was not as any efficacy benefit with afatinib over gefitinib in LUX-Lung 7 powered for OS. As an exploratory phase IIb trial, no formal hy- would not necessarily be restricted to patients harbouring exon pothesis was defined and sample size was based on controlling 19 deletions only, we claim that the choice of a TKI for an individ- the width of the CI for the HR of PFS [9]. Given the influence of ual patient might not be based on EGFR mutational profile. non-NSCLC-related deaths and post-study treatments, OS re- The rates of post-progression therapy observed in this trial quires larger sample sizes than PFS [20]. were noticeably high. Around 75% of patients in both arms Given the recent development of third-generation EGFR TKIs received at least one systemic anti-cancer therapy, and multiple such as osimertinib and olmutinib, which are highly effective lines of therapy were common (25% received at least four against T790M mutation-positive tumours [21, 22], improved lines). This rate of post-progression therapy is somewhat higher understanding of, and screening for, mechanisms of acquired re- than reported in most previous trials including EGFR mutation- sistance to first-line EGFR-targeted agents will allow for the most positive patients treated with EGFR TKIs (66%–68% in appropriate and effective sequence of treatments for EGFR erlotinib trials [4, 7, 11], 64%–90% in gefitinib trials [12, 14, 16] mutation-positive NSCLC patients. It is known that 50%–60% of and 58%–70% in afatinib trials [5, 6]. In LUX-Lung 7, there were patients treated with erlotinib or gefitinib develop T790M- slight imbalances in the number of patients who received a subse- positive tumours following disease progression [23, 24]. Recent quent first- (30.8% and 37.7%) or second-generation (4.1% and data indicate a similar frequency of T790M-mediated resistance 10.6%) EGFR TKI monotherapy in the afatinib and gefitinib in patients treated with first-line afatinib [25]. Therefore, regard- arms, respectively, although the uptake of third-generation EGFR less of the choice of the first-line TKI in patients with EGFR TKIs was similar (13.7% and 15.2%). Although there is a general mutation-positive NSCLC, similar numbers of patients are likely paucity of prospective data assessing the effectiveness of sequenc- to benefit from a subsequent third-generation EGFR TKI. ing of first- and second-generation EGFR TKIs, it is conceivable Although patient numbers are small, this assertion is supported that these imbalances might have influenced OS. Previous stud- by the current study. In both treatment arms, survival rates were ies, for example, indicate that afatinib therapy administered post- striking in patients who received a subsequent third-generation gefitinib/erlotinib [17, 18], or gefitinib rechallenge [19] offer EGFR TKI, with 3-year OS rates of up to 90%. These findings modest efficacy benefits. bode well for the strategy of sequential treatment with EGFR Volume 28 | Issue 2 | 2017 doi:10.1093/annonc/mdw611 | 275 Estimated overall survival probability Annals of Oncology Original article TKIs, which could potentially make EGFR mutation-positive Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, NSCLC a chronic disease, at least in a subset of patients. Novartis, Clovis Oncology, Merrimack, BMS and Ono pharma- ceutical. TM is employed by The Chinese University of Hong Other than the recent CTONG 0901 trial which compared gefi- tinib with erlotinib and found no difference in efficacy and safety Kong and reports stock ownership/options in Sanomics Ltd. He has received honoraria and participated in advisory boards for [26], LUX-Lung 7 is the only published trial to compare the first- line EGFR-targeted TKIs in patients with EGFR mutation-positive AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer NSCLC [although another head-to-head trial is currently compar- Ingelheim, Merck Serono, MSD, Janssen, Clovis Oncology, ing the second-generation TKI, dacomitinib, versus gefitinib BioMarin, GlaxoSmithKline, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, Celgene, AVEO (ARCHER-1050)]. In summary, although LUX-Lung 7 was an ex- ploratory phase IIb trial, we believe that the size of the trial (with and Biodesix. He has also received honoraria from Prime Oncology and Amgen and participated in advisory boards for 319 randomised patients it was as large as many phase III trials in the same setting) and the totality of the data being largely positive geneDecode Co., Ltd. He has conducted corporate-sponsored re- across multiple clinically relevant, independently assessed end- search for AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, points, suggests that afatinib may be a more effective treatment SFJ Pharmaceutical, Roche, MSD, Clovis Oncology and BMS. He is a member of the Board of Directors for IASLC, Chinese Lung option than gefitinib in the first-line setting. Treatment-related AEs with afatinib were predictable, did not negatively impact Cancer Research Foundation Ltd, Chinese Society of Oncology and the Hong Kong Cancer Therapy Society. DHL has received health-related quality of life, and were largely manageable with tolerability-guided dose reductions such that the treatment dis- honoraria from AstraZeneca Korea, BMS Korea, Boehringer Ingelheim Korea, MSD Korea, Mundi Korea, Ono Korea, Roche continuation rate was the same as with gefitinib. We hypothesise that the efficacy benefits with afatinib reflect a broader mechanism Korea and Samyang Biopharmaceuticals. JL has received honora- of action compared with gefitinib. ria for academic talks from Boehringer Ingelheim, Eli Lilly, AstraZeneca and Roche. SAL has participated in an advisory board for Boehringer Ingelheim. JF, ND and AM are employees Acknowledgements of Boehringer Ingelheim. KP has participated in an advisory board for Boehringer Ingelheim and has conducted corporate- We thank the patients, their families, the investigators and staff sponsored research for AstraZeneca. All remaining authors have who participated in the study. The authors were fully responsible declared no conflicts of interest. for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. References 1. Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy Funding for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362: 2380–2388. This work was supported by Boehringer Ingelheim. Medical 2. Mitsudomi T, Morita S, Yatabe Y et al. Gefitinib versus cisplatin plus writing assistance, supported financially by Boehringer docetaxel in patients with non-small-cell lung cancer harbouring muta- Ingelheim, was provided by Lynn Pritchard of GeoMed, an tions of the epidermal growth factor receptor (WJTOG3405): an open Ashfield company, part of UDG Healthcare plc, during the label, randomised phase 3 trial. Lancet Oncol 2010; 11: 121–128. preparation of this article. There is no applicable grant number. 3. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–957. 4. Rosell R, Carcereny E, Gervais R et al. Erlotinib versus standard chemo- therapy as first-line treatment for European patients with advanced Disclosure EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multi- centre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: LP-A has received honoraria from Roche, MSD, BMS, Novartis, 239–246. Lilly, Pfizer, Boehringer Ingelheim, AstraZeneca, Clovis and 5. Sequist LV, Yang JC, Yamamoto N et al. Phase III study of afatinib or cis- Bayer. KO’B has received honoraria for participating in advisory platin plus pemetrexed in patients with metastatic lung adenocarcinoma boards and/or speaker bureaus and has received travel grants with EGFR mutations. J Clin Oncol 2013; 31: 3327–3334. 6. Wu YL, Zhou C, Hu CP et al. Afatinib versus cisplatin plus gemcitabine from Boehringer Ingelheim, AstraZeneca, Roche, Pfizer, Lilly for first-line treatment of Asian patients with advanced non-small-cell Oncology, MSD, BMS and Novartis. LZ has participated in advis- lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, ory boards for AstraZeneca and BMS and has conducted randomised phase 3 trial. Lancet Oncol 2014; 15: 213–222. corporate-sponsored research for BMS, Pfizer and Lilly. He has 7. Wu YL, Zhou C, Liam CK et al. First-line erlotinib versus gemcitabine/ also received honoraria from AstraZeneca, Roche and Lilly. VH cisplatin in patients with advanced EGFR mutation-positive non-small- has participated in advisory boards for AstraZeneca, Roche, cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015; 26: 1883–1889. Pfizer, Merck, Boehringer Ingelheim, Amgen and Lilly. MB has 8. Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line participated in advisory boards for Merck Sharpe & Dohme, treatment for patients with advanced EGFR mutation-positive non- Pfizer, AstraZeneca and BMS, and has conducted corporate- small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open- sponsored research for Merck Sharpe & Dohme, Pfizer, label, randomised, phase 3 study. Lancet Oncol 2011; 12: 735–742. AstraZeneca, BMS, Amgen, Eli Lilly, Clovis, Novartis, Boehringer 9. Park K, Tan EH, O’Byrne K et al. Afatinib versus gefitinib as first-line Ingelheim and Genentech. He is a member of the Board of treatment of patients with EGFR mutation-positive non-small-cell lung Directors for IASLC. JC-HY has participated in advisory boards cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016; 17: 577–589. and received honoraria from Boehringer Ingelheim, Eli Lilly, 276 | Paz-Ares et al. Volume 28 | Issue 2 | 2017 Annals of Oncology Original article 10. Yang JC, Wu YL, Schuler M et al. Afatinib versus cisplatin-based chemo- erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX- therapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012; 13: 528–538. and LUX-Lung 6): analysis of overall survival data from two randomised, 18. Schuler M, Yang JC, Park K et al. Afatinib beyond progression in patients phase 3 trials. Lancet Oncol 2015; 16: 141–151. with non-small-cell lung cancer following chemotherapy, erlotinib/gefiti- 11. Zhou C, Wu YL, Chen G et al. Final overall survival results from a rando- nib and afatinib: phase III randomized LUX-Lung 5 trial. Ann Oncol mised, Phase III study of erlotinib versus chemotherapy as first-line treat- 2016; 27: 417–423. ment of EGFR mutation-positive advanced non-small-cell lung cancer 19. Cappuzzo F, Morabito A, Normanno N et al. Efficacy and safety of (OPTIMAL, CTONG-0802). Ann Oncol 2015; 26: 1877–1883. rechallenge treatment with gefitinib in patients with advanced non-small 12. Fukuoka M, Wu YL, Thongprasert S et al. Biomarker analyses and cell lung cancer. Lung Cancer 2016; 99: 31–37. final overall survival results from a phase III, randomized, open- 20. Pilz LR, Manegold C, Schmid-Bindert G. Statistical considerations and label, first-line study of gefitinib versus carboplatin/paclitaxel in clin- endpoints for clinical lung cancer studies: Can progression free survival ically selected patients with advanced non-small-cell lung cancer in (PFS) substitute overall survival (OS) as a valid endpoint in clinical trials Asia (IPASS). J Clin Oncol 2011; 29: 2866–2874. for advanced non-small-cell lung cancer? Transl Lung Cancer Res 2012; 13. Inoue A, Kobayashi K, Maemondo M et al. Updated overall survival re- 1: 26–35. sults from a randomized phase III trial comparing gefitinib with 21. Janne PA, Yang JC, Kim DW et al. AZD9291 in EGFR inhibitor-resistant carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with non-small-cell lung cancer. N Engl J Med 2015; 372: 1689–1699. sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013; 24: 54–59. 22. Park K, Lee JS, Lee KH et al. Updated safety and efficacy results from 14. Yoshioka H, Mitsudomi T, Morita S et al. Final overall survival results of phase I/II study of HM61713 in patients (pts) with EGFR mutation posi- WJTOG 3405, a randomized phase 3 trial comparing gefitinib (G) with tive non-small cell lung cancer (NSCLC) who failed previous EGFR- cisplatin plus docetaxel (CD) as the first-line treatment for patients with tyrosine kinase inhibitor (TKI). J Clin Oncol 2015; 33 (Suppl. 15): ab- non-small cell lung cancer (NSCLC) harboring mutations of the epider- stract 8084. mal growth factor receptor (EGFR). J Clin Oncol 2014; 32 (Suppl. 15): 23. Kobayashi S, Boggon TJ, Dayaram T et al. EGFR mutation and resistance abstract 8117. of non-small-cell lung cancer to gefitinib. N Engl J Med 2005; 352: 15. Lee CK, Wu YL, Ding PN et al. Impact of Specific Epidermal Growth 786–792. Factor Receptor (EGFR) Mutations and Clinical Characteristics on 24. Pao W, Miller VA, Politi KA et al. Acquired resistance of lung adenocar- Outcomes After Treatment With EGFR Tyrosine Kinase Inhibitors cinomas to gefitinib or erlotinib is associated with a second mutation in Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis. J the EGFR kinase domain. PLoS Med 2005; 2: e73. Clin Oncol 2015; 33: 1958–1965. 25. Wu SG, Liu YN, Tsai MF et al. The mechanism of acquired resistance to 16. Inoue A, Kobayashi K, Maemondo M et al. Final overall survival results irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcin- of NEJ002, a phase III trial comparing gefitinib to carboplatin (CBDCA) oma patients. Oncotarget 2016; 7: 12404–12413. plus paclitaxel (TXL) as the first-line treatment for advanced non-small 26. Yang J-J, Zhou Q, Yan H-H et al. A Randomized Controlled Trial of cell lung cancer (NSCLC) with EGFR mutations. J Clin Oncol 2011; 29 Erlotinib versus Gefitinib in Advanced Non-Small-Cell Lung Cancer (Suppl. 15): abstract 7519. Harboring EGFR Mutations (CTONG0901). J Thorac Oncol 2015; 10 17. Miller VA, Hirsh V, Cadranel J et al. Afatinib versus placebo for patients (Suppl 2): S321. with advanced, metastatic non-small-cell lung cancer after failure of Volume 28 | Issue 2 | 2017 doi:10.1093/annonc/mdw611 | 277 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Pubmed Central

Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial

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Annals of Oncology 28: 270–277, 2017 doi:10.1093/annonc/mdw611 Published online 7 February 2017 ORIGINAL ARTICLE Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial 1* 2 3 4 5 6 7 8 9 L. Paz-Ares , E.-H. Tan , K. O’Byrne , L. Zhang , V. Hirsh , M. Boyer , J. C.-H. Yang ,T.Mok , K. H. Lee , 10 11 12 13 14 15 16 17 18 S. Lu , Y. Shi , D. H. Lee , J. Laskin , D.-W. Kim , S. A. Laurie ,K. Ko¨lbeck , J. Fan , N. Dodd , 19 20 A. Marten & K. Park 1 2 Medical Oncology Department, Hospital Universitario Doce de Octubre, Universidad Complutense and CNIO, Madrid, Spain; Division of Medical Oncology, 3 4 National Cancer Centre, Singapore; Cancer Section, Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Australia; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China; 5 6 7 Department of Oncology, McGill University, Montreal, Canada; Department of Medical Oncology, Chris O’Brien Lifehouse, Camperdown, Australia; Department of Oncology, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan; Department of Clinical Oncology, State Key Laboratory of South China, The Chinese University of Hong Kong, Hong Kong; Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Chungbuk, South 10 11 Korea; Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai; Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 12 13 China; Department of Oncology, Asan Medical Center, Seoul, South Korea; Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada; 14 15 Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Division of Medical Oncology, The Ottawa Hospital Cancer Centre, 16 17 Ottawa, Ontario, Canada; Pulmonary Diseases, Karolinska University Hospital, Solna, Stockholm, Sweden; Clinical Program Leader, Boehringer Ingelheim 18 19 Pharmaceuticals, Inc, Ridgefield, USA; Biostatistics, Boehringer Ingelheim Ltd UK, Bracknell, UK; TA Oncology, Boehringer Ingelheim GmbH, Ingelheim, Germany; Division of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea *Correspondence to: Prof Luis Paz-Ares, Medical Oncology Department, Hospital Universitario Doce de Octubre, Av. de Cordoba, s/n, 28041, Madrid, Spain. Tel: þ 34-913908349; E-mail: lpazaresr@seom.org Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth fac- tor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data. Patients and methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naı¨ve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after 213 OS events and32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases. Results: Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) ¼ 0.86, 95% confidence inter- val (CI) 0.66–1.12, P¼ 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58–1.17, P¼ 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62–1.36, P¼ 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent sys- temic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third- generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Conclusion: In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Clinicaltrials.gov identifier: NCT01466660. V C The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Annals of Oncology Original article Key words: afatinib, gefitinib, NSCLC, overall survival endpoint. AEs were assessed according to National Cancer Institute Introduction Common Terminology Criteria for Adverse Events, version 3.0 (NCI Non-small-cell lung cancers (NSCLCs) with activating epidermal CTCAE 3.0). Post-study treatments were provided at the physician’s dis- cretion and assessed retrospectively. growth factor receptor (EGFR) mutations are extremely sensitive The study was conducted in accordance with the principles of the to the EGFR-targeting tyrosine kinase inhibitors (TKIs) gefitinib, Declaration of Helsinki and Good Clinical Practice guidelines as defined erlotinib and afatinib [1–8]. These three agents are established by the International Conference on Harmonization. All patients pro- first-line treatment options in this setting; however, until re- vided written informed consent. cently, there was an absence of prospective randomised head-to- head comparisons to help guide treatment decisions. To our knowledge, the recent randomised phase IIb LUX-Lung Statistical plan 7 trial was the first study to compare the irreversible ErbB family Three analysis timepoints were planned. The primary PFS/TTF analysis blocker, afatinib, with a reversible EGFR TKI, gefitinib, in treat- was planned after 250 PFS events and was previously published [9]. The ment-naı¨ve patients with advanced NSCLC harbouring a com- primary OS analysis (reported herein) was planned after approximately mon EGFR mutation (exon 19 deletion/L858R) [9]. In this trial, 213 OS events and a follow-up period of at least 32 months for patients still alive. The final analysis will be undertaken at study completion afatinib significantly improved progression-free survival [PFS; (when all patients have completed treatment, or 5 years since the last pa- hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.57–0.95, tient was entered, whichever occurs first). P¼ 0.0165], time-to-treatment failure (TTF; HR 0.73, 95% CI All randomised patients were included in the primary assessment of 0.58–0.92, P¼ 0.0073) and objective response rate (ORR; 70% OS, and updated analysis of PFS and TTF (intention-to-treat popula- versus 56%; odds ratio 1.873, 95% CI 1.176–2.985, P¼ 0.0083) tion). Safety analysis included all patients who received at least one dose compared with gefitinib. Overall, afatinib was well tolerated, with of study drug. OS and PFS/TTF were analysed by a log-rank test stratified a predictable and manageable adverse event (AE) profile. by EGFR mutation type and the presence of baseline brain metastases. A Cox proportional hazards model was used to calculate HRs and 95% CIs. Treatment-related AEs were experienced in 97.5% and 96.2% of Prespecified subgroups included EGFR mutation type (exon 19 deletion/ patients in the afatinib and gefitinib arms, respectively. The most L858R), baseline brain metastases (presence versus absence), ECOG PS frequent grade3 treatment-related AEs were diarrhoea (0 versus 1), sex, age (<65 versus65 years), ethnic origin (Asian versus (12.5%), rash/acne (9.4%) and fatigue (5.6%) with afatinib and non-Asian) and smoking history. ORR and disease control rate (DCR) elevated liver enzymes (8.8%), rash/acne (3.1%) and interstitial were compared with a logistic regression model. All statistical testing was lung disease (ILD) (1.9%) with gefitinib. There was one drug- two sided at the nominal 5% significance level, with no adjustment for related fatal AE; a case of hepatic and renal failure with gefitinib multiplicity. Data were analysed with SAS version 9.4. treatment. There was no difference in the drug discontinuation rate due to treatment-related AEs between afatinib and gefitinib. Along with PFS and TTF, overall survival (OS) was a co- Results primary endpoint of LUX-Lung 7; however, OS data were imma- ture at the time of the primary analysis. Here, we report the ma- Patients ture OS results, including prespecified subgroup analysis and post-hoc analysis of the impact of post-study treatment on OS. A total of 319 patients were randomised and treated with afatinib (n¼ 160) or gefitinib (n¼ 159). Baseline characteristics have been published and were similar between treatment groups [9]. Two-hundred and twenty-six OS events had occurred at the data Methods cut-off of 8 April 2016; 109 (68.1%) and 117 (73.6%) patients treated with afatinib and gefitinib, respectively, had died by this Study design and treatment time. At the time of analysis, the median duration of treatment Full details on the trial design of LUX-Lung 7 have been published [9]. was 13.7 months (range: 0–46.4) with afatinib and 11.5 months LUX-Lung 7 was a multicentre, international, randomised, open-label (range: 0.5–48.7) with gefitinib. Forty (25.0%) and 21 (13.2%) phase IIb trial (64 sites; 13 countries). Eligible patients were aged18 years patients were treated for>24 months with afatinib and gefitinib, with treatment-na¨ıve pathologically confirmed stage IIIB/IV adenocarcin- respectively. At data cut-off, 14 (8.8%) and 8 (5.0%) patients re- oma and a documented common activating EGFR mutation (exon 19 dele- mained on treatment with afatinib and gefitinib. tion/L858R). Patients had an Eastern Cooperative Oncology Group Following discontinuation of study treatment, the majority of performance status (ECOG PS) of 0 or 1, at least one measurable lesion patients received at least one systematic anti-cancer therapy [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] and adequate organ function. Patients were randomised 1:1 to once-daily oral (72.6% and 76.8% in the afatinib and gefitinib arms, respectively; afatinib 40 mg or gefitinib 250 mg and were treated until disease progres- Table 1). Many patients also received third-line (43.8% and sion, intolerable AEs or other reasons necessitating withdrawal. Treatment 55.0%), fourth-line (24.0% and 31.1%) and fifth-line therapies beyond radiological progression was allowed for patients deemed to be (13.0% and 19.2%, respectively). Fewer patients in the afatinib receiving continued clinical benefit by the treating physician. arm received a subsequent EGFR TKI than in the gefitinib arm The co-primary endpoints were PFS by independent central review, (45.9% versus 55.6%); this imbalance was observed in both the TTF (time from randomisation to the time of treatment discontinuation EGFR exon 19 deletion (51.8% versus 59.8%) and L858R (38.1% for any reason including disease progression, treatment toxicity, and death) and OS. ORR by independent central review was a secondary versus 50.0%) subgroups. Twenty (13.7%) and 23 (15.2%) Volume 28 | Issue 2 | 2017 doi:10.1093/annonc/mdw611 | 271 Annals of Oncology Original article Table 1. Subsequent therapies in patients who discontinued study treatment, in the overall population and in EGFR mutation subgroups Treatment, n (%) Overall population Exon 19 deletion L858R mutation Afatinib Gefitinib Afatinib Gefitinib Afatinib Gefitinib (n 5 146) (n 5 151) (n 5 83) (n 5 87) (n 5 63) (n 5 64) None 38 (26.0) 28 (18.5) 20 (24.1) 14 (16.1) 18 (28.6) 14 (21.9) Systemic anti-cancer therapy 106 (72.6) 116 (76.8) 61 (73.5) 69 (79.3) 45 (71.4) 47 (73.4) Chemotherapy 84 (57.5) 91 (60.3) 48 (57.8) 55 (63.2) 36 (57.1) 36 (56.3) Platinum based 70 (47.9) 71 (47.0) 40 (48.2) 44 (50.6) 30 (47.6) 27 (42.2) EGFR TKI 67 (45.9) 84 (55.6) 43 (51.8) 52 (59.8) 24 (38.1) 32 (50.0) EGFR TKI monotherapy 63 (43.2) 74 (49.0) 39 (47.0) 47 (54.0) 24 (38.1) 27 (42.2) First-generation Gefitinib 22 (15.1) 27 (17.9) 11 (13.3) 21 (24.1) 11 (17.5) 6 (9.4) Erlotinib 23 (15.8) 30 (19.9) 16 (19.3) 21 (24.1) 7 (11.1) 9 (14.1) Second-generation Afatinib 6 (4.1) 12 (7.9) 4 (4.8) 8 (9.2) 2 (3.2) 4 (6.3) Poziotinib 0 (0.0) 4 (2.6) 0 (0.0) 1 (1.1) 0 (0.0) 3 (4.7) Third-generation Osimertinib 15 (10.3) 17 (11.3) 9 (10.8) 11 (12.6) 6 (9.5) 6 (9.4) Olmutinib 5 (3.4) 5 (3.3) 5 (6.0) 3 (3.4) 0 (0.0) 2 (3.1) EGFR TKI-containing combination 7 (4.8) 15 (9.9) 5 (6.0) 8 (9.2) 2 (3.2) 7 (10.9) Immune checkpoint inhibitor 3 (2.1) 4 (2.6) 2 (2.4) 4 (4.6) 1 (1.6) 0 (0.0) Radiotherapy 26 (17.8) 34 (22.5) 16 (19.3) 15 (17.2) 10 (15.9) 19 (29.7) Chemotherapy or chemotherapy-based combination. Including gefitinib (afatinib arm, n¼ 7; gefitinib arm, n¼ 11), erlotinib (n¼ 0; n¼ 5) and osimertinib (n¼ 0; n¼ 1). EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor. patients who discontinued study treatment in the afatinib and discontinuation of study treatment was ‘not evaluable’ versus 46.0 gefitinib arms received a third-generation EGFR TKI. months (HR 0.51, 95% CI 0.17–1.52, P¼ 0.22; Figure 3). Overall survival Other efficacy endpoints After a median follow-up of 42.6 months, median OS with afati- Updated analysis of the co-primary endpoints showed similar nib versus gefitinib was 27.9 versus 24.5 months (HR, 0.86; 95% findings to the primary analysis [9]. PFS by independent review CI 0.66–1.12; P¼ 0.2580; Figure 1A). (median 11.0 versus 10.9 months; HR 0.74, 95% CI 0.57–0.95, OS with afatinib versus gefitinib was similar across prespeci- P¼ 0.0178; supplementary Figure S2, available at Annals of fied subgroups of interest (Figure 1B). There was no significant Oncology online) and TTF (median 13.7 versus 11.5 months; HR OS difference between afatinib and gefitinib in pre-planned 0.75, 95% CI 0.60–0.94, P¼ 0.0136; supplementary Figure S3, subgroupsthatwereusedasstratification factors, i.e. baseline available at Annals of Oncology online) were significantly im- brain metastases (presence versus absence) and EGFR mutation proved with afatinib versus gefitinib. type (exon 19 deletion versus L858R). Median OS with afatinib Updated ORR was also significantly higher with afatinib than versus gefitinib in patients with exon 19 deletions (30.7 versus with gefitinib [72.5% versus 56.0%; odds ratio 2.121 (95% CI 26.4 months; HR 0.83, 95% CI 0.58–1.17, P¼ 0.2841; Figure 1.32–3.40); P¼ 0.0018; supplementary Table S1, available at 2A) and patients with the L858R mutation (25.0 versus 21.2 Annals of Oncology online]. The DCR was 91.3% versus 87.4% months; HR 0.91, 95% CI 0.62–1.36, P¼ 0.6585; Figure 2B) was (afatinib versus gefitinib; odds ratio 1.552, 95% CI 0.75–3.22, generally consistent with the overall EGFR mutation-positive P¼ 0.2372). study population. There was no interaction between OS and pa- tient subgroups, except for age based on the cut-offs of<65 Safety and65 years (Figure 1B). However, further post-hoc analysis demonstrated a consistent trend for OS benefit with afatinib inde- The safety profiles of afatinib and gefitinib were virtually un- pendent of age group (no interaction observed at cut-offs of 60, 70 changed since the primary analysis [9]. The frequency of all- or 75 years). Similar median OS with afatinib was seen at cut-offs cause grade3 AEs was 56.9% and 53.5%, and of treatment- of 60, 65, 70 and 75 years (supplementary Figure S1,available at related grade3 AEs was 31.3% and 19.5%, with afatinib and Annals of Oncology online). Of note, subgroup sample sizes gefitinib, respectively (supplementary Table S2, available at decreased with increasing age cut-off. Annals of Oncology online). The most frequent treatment- In a post-hoc analysis, median OS with afatinib versus gefitinib related grade3 AEs with afatinib were diarrhoea (13.1% ver- in patients who received a third-generation EGFR TKI following sus 1.3%), rash/acne (9.4% versus 3.1%) and fatigue (5.6% 272 | Paz-Ares et al. Volume 28 | Issue 2 | 2017 Annals of Oncology Original article A 1.0 Afatinib (n = 160) Gefitinib (n = 159) HR 0.86 (95% CI 0.66–1.12) 0.8 Log-rank P = 0.2580 0.6 0.4 0.2 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Number at risk Afatinib 160 156 153 148 139 125 111 104 94 81 74 61 50 36 30 12 2 0 Gefitinib 159 153 148 142 133 119 105 90 80 71 62 56 48 44 27 7 0 0 B P Events/patients HR (95% CI) interaction Total 226/319 0.86 (0.66–1.12) EGFR mutation L858R 99/133 0.91 (0.62–1.36) 0.7086 Exon 19 deletion 127/186 0.83 (0.58–1.17) Brain metastases Absent 189/268 0.81 (0.61–1.07) 0.2133 Present 37/51 1.16 (0.61–2.21) Baseline ECOG score 0 63/98 1.32 (0.80–2.18) 0.0949 1 163/221 0.75 (0.55–1.02) Gender Male 91/122 0.80 (0.53–1.21) 0.7252 Female 135/197 0.88 (0.63–1.24) Age group <65 years 126/177 0.66 (0.46–0.94) 0.0228 ≥65 years 100/142 1.22 (0.82–1.81) Race group Non-Asian 93/137 0.78 (0.52–1.17) 0.4419 Asian 133/182 0.95 (0.67–1.33) Smoking history Never smoked 146/212 0.92 (0.67–1.28) 0.3900 <15 pack years + stopped >1 year before 32/40 1.12 (0.55–2.28) Other current or ex-smokers 48/67 0.63 (0.36–1.11) 1/16 1/4 1 4 16 Favours afatinib Favours gefitinib Figure 1 Overall survival. Kaplan–Meier curve (A) and forest plot of pre-specified subgroup analyses (B). CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; HR, hazard ratio. versus 0%). The most frequent treatment-related grade3 Discussion AEs with gefitinib were elevated alanine transaminase (8.2% In this updated analysis of LUX-Lung 7, a 14% reduction in risk versus 0%), rash/acne, elevated aspartate aminotransferase (2.5% of death was observed in patients with EGFR mutation-positive versus 0%) and interstitial lung disease (1.9% versus 0%; NSCLC treated with first-line afatinib versus gefitinib, that cor- supplementary Table S2, available at Annals of Oncology responded to a numerical difference of 3.4 months in median OS, online). There was one drug-related fatal AE; a case of hepatic without reaching statistical significance. These findings were gen- and renal failure with gefitinib treatment. Rates of treatment erally consistent across key patient subgroups, including those discontinuations due to drug-related AEs remained equally based on gender, ethnicity (Asian versus non-Asian), and EGFR low (6.3% each). Volume 28 | Issue 2 | 2017 doi:10.1093/annonc/mdw611 | 273 Estimated overall survival probability Annals of Oncology Original article A 1.0 Patients with exon 19 deletion Afatinib (n = 93) Gefitinib (n = 93) 0.8 HR 0.83 (95% CI 0.58–1.17) Log-rank P = 0.2841 0.6 0.4 0.2 03 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Number at risk Afatinib 93 91 88 88 82 74 68 63 61 54 50 41 35 24 20 91 0 Gefitinib 93 88 86 82 79 72 66 57 52 46 39 36 29 28 17 5 0 0 1.0 Patients with L858R mutation Afatinib (n = 67) Gefitinib (n = 66) 0.8 HR 0.91 (95% CI 0.62–1.36) Log-rank P = 0.6585 0.6 0.4 0.2 0369 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Number at risk Afatinib 67 65 65 60 57 51 43 41 33 27 24 20 15 12 10 3 1 0 Gefitinib 66 65 62 60 54 47 39 33 28 25 23 20 19 16 10 2 0 0 Figure 2 Overall survival in patients with common EGFR mutations. Patients with exon 19 deletion (A) and patients with L858R mutation (B). CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio. mutation type (exon 19 deletion versus L858R). Although initial afatinib significantly improved PFS, TTF and ORR versus gefiti- analyses suggested a potential interaction between OS and patient nib. No unexpected AEs were observed and discontinuation rates age, subsequent post-hoc analysis demonstrated no clear pattern due to treatment-related AEs remained equally low in both arms. of association, and similar median OS with afatinib was observed Despite being recognised as the first-line standard-of-care in for patients aged</60,</65,</70 and</75 years. patients with EGFR mutation-positive NSCLC, an enduring fea- Afatinib conferred long-term survival in a high proportion of pa- ture of randomised controlled trials of EGFR TKIs in this setting tients, with 24-month and 30-month survival rates of 60.9% and has been a lack of clear OS benefit, even against platinum-doublet 48.0%, respectively. These frequencies were consistent with a pre- chemotherapy. Across multiple phase III trials, neither erlotinib vious global, phase III trial, which assessed afatinib versus cis- [4, 7, 11] nor gefitinib [12–14] has demonstrated statistically sig- platin/pemetrexed in patients with NSCLC harbouring common nificant OS improvement against chemotherapy. Although afati- EGFR mutations (LUX-Lung 3). In this study, 59.6% and 49.8% nib did not significantly improve OS versus chemotherapy in the of afatinib-treated patients survived for at least 24 and 30 months, overall populations of the LUX-Lung 3 and LUX-Lung 6 trials, a respectively [10]. In the present study, as in the primary analysis, significant improvement in OS was observed with afatinib in a 274 | Paz-Ares et al. Volume 28 | Issue 2 | 2017 Estimated overall survival probability Estimated overall survival probability Annals of Oncology Original article 1.0 0.8 0.6 0.4 Patients subsequently treated with a third-generation EGFR TKI Afatinib (n = 20) Gefitinib (n = 23) 0.2 HR 0.51 (95% CI 0.17–1.52) Log-rank P = 0.22 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Number at risk Afatinib 20 20 20 20 20 20 20 19 19 19 19 16 13 10 8 2 0 0 Gefitinib 23 23 23 22 22 22 21 20 20 20 19 19 19 15 7 4 00 Figure 3 Overall survival in patients subsequently treated with a third-generation EGFR TKI following discontinuation of study treatment. CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; TKIs, tyrosine kinase inhibitors. prespecified sub-analysis of each trial, in patients with NSCLC Furthermore, the limited sample size may have impaired the harbouring exon 19 deletion mutations [10]. In the current power of the trial to address the differences in OS benefit between study, there was no significant difference in OS between afatinib afatinib and gefitinib in clinical practice. and gefitinib in patients with NSCLC harbouring an exon 19 de- The primary OS analysis described herein fulfilled the protocol letion. Emerging evidence suggests that first-generation and se- requirement in terms of the planned number of events and min- cond-generation EGFR TKIs may be particularly active in imum follow-up time. However, at the time of writing, 29% of NSCLC with exon 19 deletions compared with the L858R muta- patients in LUX-Lung 7 were still alive and a final OS analysis is tion [15], but this is based on trials that used chemotherapy as a planned on study completion to assess the impact of a reduction comparator rather than TKI versus TKI comparisons. Therefore, in censored patients. It should be noted that LUX-Lung 7 was not as any efficacy benefit with afatinib over gefitinib in LUX-Lung 7 powered for OS. As an exploratory phase IIb trial, no formal hy- would not necessarily be restricted to patients harbouring exon pothesis was defined and sample size was based on controlling 19 deletions only, we claim that the choice of a TKI for an individ- the width of the CI for the HR of PFS [9]. Given the influence of ual patient might not be based on EGFR mutational profile. non-NSCLC-related deaths and post-study treatments, OS re- The rates of post-progression therapy observed in this trial quires larger sample sizes than PFS [20]. were noticeably high. Around 75% of patients in both arms Given the recent development of third-generation EGFR TKIs received at least one systemic anti-cancer therapy, and multiple such as osimertinib and olmutinib, which are highly effective lines of therapy were common (25% received at least four against T790M mutation-positive tumours [21, 22], improved lines). This rate of post-progression therapy is somewhat higher understanding of, and screening for, mechanisms of acquired re- than reported in most previous trials including EGFR mutation- sistance to first-line EGFR-targeted agents will allow for the most positive patients treated with EGFR TKIs (66%–68% in appropriate and effective sequence of treatments for EGFR erlotinib trials [4, 7, 11], 64%–90% in gefitinib trials [12, 14, 16] mutation-positive NSCLC patients. It is known that 50%–60% of and 58%–70% in afatinib trials [5, 6]. In LUX-Lung 7, there were patients treated with erlotinib or gefitinib develop T790M- slight imbalances in the number of patients who received a subse- positive tumours following disease progression [23, 24]. Recent quent first- (30.8% and 37.7%) or second-generation (4.1% and data indicate a similar frequency of T790M-mediated resistance 10.6%) EGFR TKI monotherapy in the afatinib and gefitinib in patients treated with first-line afatinib [25]. Therefore, regard- arms, respectively, although the uptake of third-generation EGFR less of the choice of the first-line TKI in patients with EGFR TKIs was similar (13.7% and 15.2%). Although there is a general mutation-positive NSCLC, similar numbers of patients are likely paucity of prospective data assessing the effectiveness of sequenc- to benefit from a subsequent third-generation EGFR TKI. ing of first- and second-generation EGFR TKIs, it is conceivable Although patient numbers are small, this assertion is supported that these imbalances might have influenced OS. Previous stud- by the current study. In both treatment arms, survival rates were ies, for example, indicate that afatinib therapy administered post- striking in patients who received a subsequent third-generation gefitinib/erlotinib [17, 18], or gefitinib rechallenge [19] offer EGFR TKI, with 3-year OS rates of up to 90%. These findings modest efficacy benefits. bode well for the strategy of sequential treatment with EGFR Volume 28 | Issue 2 | 2017 doi:10.1093/annonc/mdw611 | 275 Estimated overall survival probability Annals of Oncology Original article TKIs, which could potentially make EGFR mutation-positive Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, NSCLC a chronic disease, at least in a subset of patients. Novartis, Clovis Oncology, Merrimack, BMS and Ono pharma- ceutical. TM is employed by The Chinese University of Hong Other than the recent CTONG 0901 trial which compared gefi- tinib with erlotinib and found no difference in efficacy and safety Kong and reports stock ownership/options in Sanomics Ltd. He has received honoraria and participated in advisory boards for [26], LUX-Lung 7 is the only published trial to compare the first- line EGFR-targeted TKIs in patients with EGFR mutation-positive AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer NSCLC [although another head-to-head trial is currently compar- Ingelheim, Merck Serono, MSD, Janssen, Clovis Oncology, ing the second-generation TKI, dacomitinib, versus gefitinib BioMarin, GlaxoSmithKline, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, Celgene, AVEO (ARCHER-1050)]. In summary, although LUX-Lung 7 was an ex- ploratory phase IIb trial, we believe that the size of the trial (with and Biodesix. He has also received honoraria from Prime Oncology and Amgen and participated in advisory boards for 319 randomised patients it was as large as many phase III trials in the same setting) and the totality of the data being largely positive geneDecode Co., Ltd. He has conducted corporate-sponsored re- across multiple clinically relevant, independently assessed end- search for AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, points, suggests that afatinib may be a more effective treatment SFJ Pharmaceutical, Roche, MSD, Clovis Oncology and BMS. He is a member of the Board of Directors for IASLC, Chinese Lung option than gefitinib in the first-line setting. Treatment-related AEs with afatinib were predictable, did not negatively impact Cancer Research Foundation Ltd, Chinese Society of Oncology and the Hong Kong Cancer Therapy Society. DHL has received health-related quality of life, and were largely manageable with tolerability-guided dose reductions such that the treatment dis- honoraria from AstraZeneca Korea, BMS Korea, Boehringer Ingelheim Korea, MSD Korea, Mundi Korea, Ono Korea, Roche continuation rate was the same as with gefitinib. We hypothesise that the efficacy benefits with afatinib reflect a broader mechanism Korea and Samyang Biopharmaceuticals. JL has received honora- of action compared with gefitinib. ria for academic talks from Boehringer Ingelheim, Eli Lilly, AstraZeneca and Roche. SAL has participated in an advisory board for Boehringer Ingelheim. JF, ND and AM are employees Acknowledgements of Boehringer Ingelheim. KP has participated in an advisory board for Boehringer Ingelheim and has conducted corporate- We thank the patients, their families, the investigators and staff sponsored research for AstraZeneca. All remaining authors have who participated in the study. The authors were fully responsible declared no conflicts of interest. for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. References 1. Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy Funding for non-small-cell lung cancer with mutated EGFR. 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Oncotarget 2016; 7: 12404–12413. plus paclitaxel (TXL) as the first-line treatment for advanced non-small 26. Yang J-J, Zhou Q, Yan H-H et al. A Randomized Controlled Trial of cell lung cancer (NSCLC) with EGFR mutations. J Clin Oncol 2011; 29 Erlotinib versus Gefitinib in Advanced Non-Small-Cell Lung Cancer (Suppl. 15): abstract 7519. Harboring EGFR Mutations (CTONG0901). J Thorac Oncol 2015; 10 17. Miller VA, Hirsh V, Cadranel J et al. Afatinib versus placebo for patients (Suppl 2): S321. with advanced, metastatic non-small-cell lung cancer after failure of Volume 28 | Issue 2 | 2017 doi:10.1093/annonc/mdw611 | 277

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Published: Feb 7, 2017

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