Afatinib in EGFR TKI-naïve patients (pts) with locally advanced/metastatic NSCLC harbouring EGFR mutations: An interim analysis of a phase IIIB trial
Authors: A. Passaro, K.K. Laktionov, A. Poltoratskiy, I. Egorova, M. Hochmair, M.R. Migliorino, G. Metro, M. Gottfried, D. Tsoi, G. Ostoros, S. Rizzato, G.Z. Mukhametshina, M. Schumacher, S. Novello, R. Dziadziuszko, W. Tang, L. Clementi, A. Cseh, D. Kowalski, F. De Marinis
Journal: Annals of Oncology (2019)

Background: First-line afatinib significantly improved progression-free survival (PFS) in pts with EGFR mutation-positive (EGFRm+) NSCLC (including uncommon mutations) vs chemotherapy (CT) in the LUX-Lung (LL) 3/6 trials (median 11.1 vs 6.9 mos; HR 0.58/11.0 vs 5.6 mos; HR 0.28) and vs gefitinib in LL7 (median 11.0 vs 10.9 mos; HR 0.73). However, in real-world (RW) practice CT remains a first-line choice. Here, we report an interim analysis of a Phase IIIb study of afatinib in treatment-naïve or CT pre-treated pts with EGFRm+ NSCLC, similar to RW practice. Methods: EGFR TKI-naïve pts with locally advanced/metastatic EGFRm+ NSCLC and ECOG PS 0–2 received 40 mg/day afatinib (starting dose). Dose reduction was permitted (to minimum 20 mg/day). Primary endpoint: adverse events (AEs) in a descriptive fashion. Efficacy was also assessed. Results: At data cut-off (30 April 2018), 479 pts were enrolled and treated with afatinib (Caucasian/Asian/other: 97%/2%/<1%; male/female: 34%/66%; 1st/2nd/≥3rd-line therapy: 78%/17%/5%; ECOG PS 0/1/2: 36%/57%/8%; brain metastases: 17%; common/uncommon mutations: 87%/13%). Median time on afatinib was 359 days. The most common grade ≥3 afatinib-related AEs were diarrhoea (16%) and rash (11%). AEs led to dose reduction in 258 (54%) pts (most frequently diarrhoea 25%; rash 11%) and to afatinib discontinuation in 105 (22%) pts (most frequently diarrhoea 3% [rash 0.8%]). Afatinib-related serious AEs occurred in 39 (8%) pts. Time to symptomatic progression (TTSP) and PFS are shown in the table. Objective response rate and disease control rate were 46% and 86%, respectively.Table115OMedian TTSP, months (95% CI)Median PFS, months (95% CI)All pts (n = 479)14.9 (13.8–17.6)13.4 (11.8–14.5)Line of therapy1st (n = 374)15.6 (14.1–18.5)13.8 (12.6–15.1)2nd (n = 81)14.7 (11.3–20.6)13.2 (8.3–17.7)≥3rd (n = 24)8.1 (3.7–14.4)6.6 (3.2–12.6)Baseline ECOG PS*Missing (n = 1);0 (n = 171)17.2 (14.8–19.8)15.4 (13.4–18.8)1 (n = 271)14.7 (13.0–18.7)12.9 (10.3–14.4)2 (n = 36)8.9 (5.7–13.2)6.2 (2.5–11.6)Baseline brain metastasesNo (n = 395)15.8 (14.1–18.8)13.9 (12.7–15.5)Yes (n = 83)13.7 (9.7–17.2)10.1 (8.2–13.9)Baseline mutation type*Missing (n = 1);Common†Del 19 and/or L858R with or without uncommon mutation; (n = 416)15.9 (14.5–19.1)14.1 (13.0–15.7)Uncommon‡Includes ex 20 ins, T790M, S768I, G719S/A/C, L861Q (n = 62)7.4 (5.7–9.0)6.0 (4.2–8.1)* Missing (n = 1);† Del 19 and/or L858R with or without uncommon mutation;‡ Includes ex 20 ins, T790M, S768I, G719S/A/C, L861Q Open table in a new tab Conclusions: Interim analysis of this study, which included pts treated with afatinib in later lines, and pts with ECOG PS 2, brain metastases and/or uncommon mutations, indicates a predictable and manageable safety profile for afatinib, consistent with the pivotal LL trials. Interim efficacy findings are encouraging, with a median TTSP of 14.9 months. Clinical trial identification: NCT01853826. Editorial acknowledgement: Robert Lorence of Boehringer Ingelheim assisted in the study concept, design and data analysis. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Jessica Sturgess of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this abstract. Legal entity responsible for the study: Boehringer Ingelheim. Funding: Boehringer Ingelheim. Disclosure: M. Hochmair: Honoraria for speakers' bureau, advisory role: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Novartis, Pfizer, Roche. M.R. Migliorino: Board of directors, consulting fees: Boehringer Ingelheim, Roche, MSD, Bristol-Myers Squibb, AstraZeneca, Pfizer; Honoraria: Boehringer Ingelheim, Roche, MSD, Bristol-Myers Squibb, AstraZeneca, Pfizer, Gentili. S. Rizzato: Honoraria for Advisory board: AbbVie. G.Z. Mukhametshina: Employment: Republic Clinical Oncology Dispensary. S. Novello: Honoraria for speaker bureau/advisory roles: Eli Lilly, Celgene, AstraZeneca, Boehringer Ingelheim, MSD, Roche, Bristol-Myers Squibb. R. Dziadziuszko: Honoraria: Roche, Pfizer, Boehringer Ingelheim, AstraZeneca, Foundation Medicine, Novartis. W. Tang, L. Clementi, A. Cseh: Employment: Boehringer Ingelheim. F. De Marinis: Advisory council/committee membership: Roche, Pfizer Honoraria: Roche, Bristol-Myers Squibb, AstraZeneca; Grants/funds: Boehringer Ingelheim. All other authors have declared no conflicts of interest.