A phase IIIb, open-label study of afatinib in EGFR TKI-naïve patients with EGFR mutation-positive NSCLC: A biomarker analysis

Abstract Background Treatment with an EGFR TKI is the standard of care for patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC, based on findings from randomized controlled trials, but acquired resistance is inevitable. A phase IIIb study (NCT01853826) was conducted to assess outcomes with afatinib in a broad EGFRm+ NSCLC patient population, similar to real-world practice. Here we report results from a sub-study of the trial, to assess the relationship between afatinib efficacy and the presence of biomarkers associated with resistance to EGFR TKIs. Methods EGFR TKI-naive pts with locally advanced/metastatic EGFRm+ NSCLC and ECOG PS 0–2 received afatinib starting at 40 mg/day. Tumor biopsies were performed prior to study entry; baseline T790M status (presence vs absence), and total BIM, BIMEL and mTOR mRNA expression (high vs low, according to median values) were analyzed for patients who consented to sub-study participation. Exploratory efficacy analyses were conducted. Time to symptomatic progression (TTSP) and progression-free survival (PFS) were calculated using the Kaplan–Meier method. Results A total of 113 pts were included in this sub-study (data cut-off 21 June 2018). Baseline characteristics, n (%): white race, 112 (99); female, 70 (62); 1st/2nd/≥3rd-line therapy, 94/16/3 (83/14/3); ECOG PS 0/1, 106 (94); brain metastases, 16 (14); common/uncommon mutations, 105/8 (93/7). Median time on treatment was 581 days. Objective response/disease control rates were 58%/95%. Median (95% CI) TTSP was 20.6 months (18.9–24.9) and PFS was 19.8 months (16.1–23.5). TTSP and PFS by biomarker status at baseline are reported in the table. Table . 483P TTSP PFS Median (95% CI) HR (95% CI) Median (95% CI) HR (95% CI) T790M* Present (n = 51) Absent (n = 60) 19.5 (14.9–25.1) 21.4 (17.7–26.3) 1.0 (0.67–1.60) 18.8 (14.1–24.0) 21.4 (15.9–26.1) 1.1 (0.7–1.7) BIM total mRNA expression† High (n = 35) Low (n = 35) 23.7 (14.7–37.1) 25.7 (19.3–35.8) 1.2 (0.7–2.1) 21.8 (14.1–28.5) 26.0 (18.9–35.5) 1.2 (0.7–2.1) BIMEL mRNA expression‡ High (n = 22) Low (n = 21) 19.1 (11.9–24.8) 24.9 (14.8–42.2) 1.3 (0.6–2.7) 18.8 (11.6–23.5) 25.2 (16.1–38.6) 1.4 (0.7–2.9) mTOR mRNA expression§ High (n = 39) Low (n = 37) 22.3 (14.8–29.5) 26.1 (19.1–35.8) 1.0 (0.6–1.7) 21.8 (14.3–29.5) 23.1 (14.5–35.5) 1.0 (0.6–1.8) Non-evaluable or missing: *n=2; †n = 43; ‡n = 36; §n = 37. Conclusions In this broad population of EGFR TKI-naive pts with EGFRm+ NSCLC who were treated with afatinib, biomarker analysis indicated no notable differences in efficacy outcomes by baseline T790M status (presence vs absence), or baseline mRNA expression of BIM, BIMEL or mTOR (high vs low). Clinical trial identification NCT01853826. Editorial acknowledgement Laura Winton of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure M. Hochmair: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme, ; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: Takeda; Speaker Bureau / Expert testimony: Pfizer. R. Ramlau: Advisory / Consultancy: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. J. Skrickova: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche. P. Bidoli: Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: BMS ; Advisory / Consultancy: Boehringer Ingelheim. L. Clementi: Full / Part-time employment: Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. F. De Marinis: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Boehringer Ingelheim. All other authors have declared no conflicts of interest.