First-line afatinib vs gefitinib for patients with EGFR mutation-positive NSCLC (LUX-Lung 7): impact of afatinib dose adjustment and analysis of mode of initial progression for patients who continued treatment beyond progression

Abstract

Purpose: In the randomized phase IIb LUX-Lung 7 trial, afatinib significantly improved progression-free survival (PFS) and time-to-treatment failure vs gefitinib in patients with treatment-naïve epidermal growth factor receptor mutation-positive non-small cell lung cancer. We report post hoc analyses of tolerability-guided dose adjustment for afatinib and summarize the clinical characteristics of patients who continued afatinib/gefitinib beyond initial radiological progression in LUX-Lung 7.

Methods: Patients received afatinib 40 mg/day or gefitinib 250 mg/day until investigator-assessed progression or beyond if beneficial. In case of selected treatment-related adverse events (TRAEs), the afatinib dose could be reduced by 10-mg decrements to minimum 20 mg (only dose interruptions were permitted with gefitinib).

Results: All randomized patients were treated (afatinib, n = 160; gefitinib, n = 159). Sixty-three patients had afatinib dose reduction (< 40 mg/day; 47 within first 6 months). Dose reduction decreased TRAE incidence/severity (before vs after; all grade/grade 3: 100.0%/63.5% vs 90.5%/23.8%). There was no evidence of significant difference in PFS for patients who received < 40 mg/day vs ≥ 40 mg/day for the first 6 months [median: 12.8 vs 11.0 months; hazard ratio 1.34 (95% confidence interval 0.90-2.00)]. Twenty-four and 26 patients continued afatinib and gefitinib, respectively, beyond progression in target lesions; median time from nadir of target lesion diameters to initial progression was 6.7 months and 5.6 months. Of these patients, ~ 70% had objective response or non-complete response/non-progressive disease in non-target lesions at initial progression.

Conclusions: Protocol-defined dose adjustment of afatinib may allow patients to remain on treatment longer, maximizing clinical benefit even in the presence of radiological progression.

Keywords: Afatinib; Dose adjustment; EGFR; NSCLC; Time-to-treatment failure.

Conflict of interest statement

Dr. O’Byrne has received advisory board fees, speaker bureau fees and travel grants from BMS, MSD, Lilly Oncology, Boehringer Ingelheim, Pfizer, Novartis, Roche-Genentech, Teva and AstraZeneca. Dr. Boyer reports grants from Boehringer Ingelheim, during the conduct of the study, grants from Pfizer, grants and non-financial support from Roche and AstraZeneca, outside the submitted work. Dr. Hirsh is a member of the Boehringer Ingelheim advisory board. Dr. Kim D-W reports travel support for advisory meeting from Novartis, outside the submitted work. Dr Märten reports employment from Boehringer Ingelheim, outside the submitted work. Dr. Massey reports employment from Boehringer Ingelheim, outside the submitted work. Dr. Mok reports grants and personal fees from AstraZeneca, Roche/Genentech, BMS, Boehringer Ingelheim, Novartis, MSD, Pfizer, Clovis Oncology, SFJ Pharmaceuticals, Takeda and Taiho, personal fees from Eli Lilly, Merck Serono, Janssen, Vertex, Celgene, ACEA Biosciences, Oncogenex, Ignyta Inc, OrigiMed, Fishawack Facilitate Ltd, Hengrui Therapeutics, Sanofi-Aventis R&D and Yuhan Corporation, non-financial support from geneDecode, grants from Eisai, personal fees and other from Hutchison ChiMed, grants from XCovery and other from Sanomics, outside the submitted work. Dr. Park reports personal fees from Boehringer Ingelheim for an advisory and consultancy role. Dr. Paz-Ares reports personal fees from Novartis, MSD, BMS, Boehringer Ingelheim, AstraZeneca, Pfizer, Roche, Lilly, Amgen and Clovis, outside the submitted work. Dr. Schuler reports grants and personal fees from Boehringer Ingelheim, during the conduct of the study, grants and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb and Novartis and personal fees from Roche, Abbvie, Alexion, Celgene, Lilly, MSD and Pierre Fabre, outside the submitted work. Dr. Yang reports personal fees from Boehringer Ingelheim, Eli Lilly, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi Sankyo, AstraZeneca, Hansoh Pharmaceuticals and Takeda Pharmaceuticals, outside the submitted work. Dr. Zhang reports grants from Pfizer, BMS and AstraZeneca, outside the submitted work. The remaining authors declare no conflict of interest.

Figures

Fig. 1

Key treatment-related adverse events (AEs) before and after afatinib dose reduction from 40 mg (n = 63). aGrouped terms of AEs

Fig. 2

Median progression-free survival (PFS) in afatinib-treated patients who received a dose reduction to

Fig. 3

EuroQol 5 dimensions questionnaire (EQ-5D) and EuroQol Visual Analog Scale (EQ-VAS) scores in afatinib-treated patients who received a dose reduction to

Fig. 4

Percentage change from baselinea in the sum of target lesion (TL) diameters for patients who continued afatinib (a) or gefitinib (b) beyond progressive disease (PD) in TLs. aUntil the point of initial disease progression