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Background In the registrational trials, afatinib (afa) was active against NSCLC tumors harboring common and uncommon EGFR mutations, including G719X, L861Q and S768I,1 and is approved in this setting. Here, we assess 1st-line afa in pts with uncommon EGFR mutations treated in a 'real-world' setting in the largest analysis of its kind to date. Methods Retrospective pooled analysis of three 'real-world' studies: an expanded-access program in Korea (1200.193); an Asian phase IIIB trial (1200.66); a global phase IIIB trial (mainly Europe; 1200.55). Pts had EGFR mutation-positive (EGFRm+) NSCLC, were EGFR TKI-naïve, and received afa 40 mg/day. Dose reduction was permitted (minimum 20 mg/day). Endpoints included time to symptomatic progression (TTSP), investigator-assessed PFS and ORR. Results Overall, 1108 pts were treated with afa: median age, 61 yrs; female, 58%; ECOG PS of 0/1/2, 26%/70%/4%; asymptomatic brain metastases, 19%; 1st-line afatinib, 69%. 198 (18%) had tumors harboring at least one uncommon mutation (exon 20 insertions [Ins20]: n = 70; T790M: n = 20; G719X: n = 41; L861Q: n = 47; S768I: n = 20; other: n = 25. Of note, 35% of pts had Ins20 mutations, a heterogeneous group generally resistant to EGFR TKIs). Median TTSP, PFS and ORR were 8.3 mos (95% CI 7.2–11.0), 7.4 mos (95% CI 6.0–9.0) and 37% respectively. Median duration of response was 10.2 mos (95% CI 8.4–12.9). In those pts with uncommon mutations and brain metastases, median TTSP and PFS were 7.6 mos (95% CI 4.6–10.1) and 7.4 mos (95% CI 4.6–9.1). Clinical activity in pts with uncommon mutations was greatest against tumors harboring G719X, L861Q or S768I. Some pts with Ins20 or T790M mutations appeared to benefit from treatment. Survival data in specific mutation subgroups will be presented. Conclusions In this 'real-world' analysis, nearly 20% of pts with EGFRm+ NSCLC harbored uncommon EGFR mutations. Afa was active in a broad range of these pts, including some with Ins20 mutations. 1. Yang, JC. et al. Lancet Oncol 2015;16:830–8. Table: 503P   EGFR mutation type   Common   Uncommon   Del19  L858R  T790M  Ins20  T790M + Ins 20  G719X, L861Q, S768I and Other  n  531  378  15  65  5  113  Median TTSP, mos (95% CI)  17.2 (15.5, 19.3)  14.5 (13.1, 16.5)  8.2 (2.7, 13.4)  5.9 (3.8, 8.2)  1.5 (0.1, 13.0)  11.0 (9.0, 16.4)  Median PFS, mos (95% CI)  14.5 (13.8, 15.9)  12.6 (11.1, 13.8)  7.1 (2.0, 9.0)  5.6 (3.9, 7.4)  1.5 (0.1, 9.1)  9.2 (7.3, 12.1)  ORR, %  64  52  20  23  20  49  Median DOR, mos (95% CI)  14.1 (12.6, 16.2)  12.5 (11.1, 14.9)  12.5 (1.1, 12.5)  10.1 (3.7, 21.2)  8.3 (NE, NE)  10.2 (8.3, 15.5)    EGFR mutation type   Common   Uncommon   Del19  L858R  T790M  Ins20  T790M + Ins 20  G719X, L861Q, S768I and Other  n  531  378  15  65  5  113  Median TTSP, mos (95% CI)  17.2 (15.5, 19.3)  14.5 (13.1, 16.5)  8.2 (2.7, 13.4)  5.9 (3.8, 8.2)  1.5 (0.1, 13.0)  11.0 (9.0, 16.4)  Median PFS, mos (95% CI)  14.5 (13.8, 15.9)  12.6 (11.1, 13.8)  7.1 (2.0, 9.0)  5.6 (3.9, 7.4)  1.5 (0.1, 9.1)  9.2 (7.3, 12.1)  ORR, %  64  52  20  23  20  49  Median DOR, mos (95% CI)  14.1 (12.6, 16.2)  12.5 (11.1, 14.9)  12.5 (1.1, 12.5)  10.1 (3.7, 21.2)  8.3 (NE, NE)  10.2 (8.3, 15.5)  Table: 503P   EGFR mutation type   Common   Uncommon   Del19  L858R  T790M  Ins20  T790M + Ins 20  G719X, L861Q, S768I and Other  n  531  378  15  65  5  113  Median TTSP, mos (95% CI)  17.2 (15.5, 19.3)  14.5 (13.1, 16.5)  8.2 (2.7, 13.4)  5.9 (3.8, 8.2)  1.5 (0.1, 13.0)  11.0 (9.0, 16.4)  Median PFS, mos (95% CI)  14.5 (13.8, 15.9)  12.6 (11.1, 13.8)  7.1 (2.0, 9.0)  5.6 (3.9, 7.4)  1.5 (0.1, 9.1)  9.2 (7.3, 12.1)  ORR, %  64  52  20  23  20  49  Median DOR, mos (95% CI)  14.1 (12.6, 16.2)  12.5 (11.1, 14.9)  12.5 (1.1, 12.5)  10.1 (3.7, 21.2)  8.3 (NE, NE)  10.2 (8.3, 15.5)    EGFR mutation type   Common   Uncommon   Del19  L858R  T790M  Ins20  T790M + Ins 20  G719X, L861Q, S768I and Other  n  531  378  15  65  5  113  Median TTSP, mos (95% CI)  17.2 (15.5, 19.3)  14.5 (13.1, 16.5)  8.2 (2.7, 13.4)  5.9 (3.8, 8.2)  1.5 (0.1, 13.0)  11.0 (9.0, 16.4)  Median PFS, mos (95% CI)  14.5 (13.8, 15.9)  12.6 (11.1, 13.8)  7.1 (2.0, 9.0)  5.6 (3.9, 7.4)  1.5 (0.1, 9.1)  9.2 (7.3, 12.1)  ORR, %  64  52  20  23  20  49  Median DOR, mos (95% CI)  14.1 (12.6, 16.2)  12.5 (11.1, 14.9)  12.5 (1.1, 12.5)  10.1 (3.7, 21.2)  8.3 (NE, NE)  10.2 (8.3, 15.5)  Clinical trial identification NCT01931306; NCT01953913; NCT01853826. Editorial acknowledgement Lynn Pritchard of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure F. De Marinis: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Boehringer Ingelheim. V. Lee: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self): Eli Lilly; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme. L. Clementi: Full / Part-time employment: Boehringer Ingelheim. W. Tang: Full / Part-time employment: Boehringer Ingelheim. D.C-L. Huang: Full / Part-time employment: Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. K. Park: Advisory / Consultancy: AMGEN; Advisory / Consultancy: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: BluePrint; Advisory / Consultancy: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Hanmi; Advisory / Consultancy: KHK; Advisory / Consultancy: Loxo; Advisory / Consultancy: Merch KGaA; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: ONO; Advisory / Consultancy: Roche. C. Zhou: Honoraria (self): BI; Honoraria (self): Roche; Honoraria (self): Sanofi; Honoraria (self): Hengrui; Honoraria (self): Qilu; Honoraria (self): MSD. Y-L. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly; Honoraria (self): MDS; Honoraria (self): BMS. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background In the LUX-Lung (LL) 3 and 6 trials, first-line afatinib significantly improved PFS vs chemotherapy in pts with EGFRm+ NSCLC and baseline brain mets (HR, 0.50; P = 0.03).1 In LL7, similar PFS improvement with afatinib vs gefitinib was observed in pts with, and without, brain metastases (HR, 0.76 and 0.74; Pint=0.93).2 Competing risk analysis of LL3/6 demonstrated low risk of de novo CNS progression in pts treated with afatinib (6%).3 Here, we assess afatinib in pts with brain metastases treated in a 'real-world' setting. Methods Retrospective pooled analysis of three 'real-world' studies: a multi-center expanded-access program in Korea (1200.193); an Asian phase IIIB trial (1200.66); a global phase IIIB trial (mainly Europe; 1200.55). All three studies recruited EGFR TKI-naïve pts with EGFRm+ NSCLC who received afatinib 40 mg/day, including pts with asymptomatic brain metastases. Dose reduction was permitted (minimum 20 mg/day). Endpoints included investigator-assessed progression-free survival (PFS), time to symptomatic progression (TTSP) and objective response rate (ORR). Results A total of 1108 pts were treated with afatinib. Baseline characteristics were: median age, 61 yrs; female, 58%; ECOG PS of 0/1/2, 26%/70%/4%; uncommon EGFR mutations: 18%; first-line afatinib, 69%. In total, 213 pts had brain metastases. Median PFS and TTSP in these pts were 10.6 months (95% CI 9.1–12.8) and 13.7 months (95% CI 11.0–14.8), respectively. When restricted to pts harboring common EGFR mutations, median PFS and TTSP were 11.7 months (95% CI 10.1–13.8) and 14.4 months (95% CI 12.9–16.4), respectively. ORR was 57% (59% in pts with common EGFR mutations); median duration of response was 11.1 months (95% CI 8.3–12.3). Conclusions Consistent with clinical trial data, afatinib is active in pts with EGFRm+ NSCLC and brain metastases treated in a real-world setting in Asian and Caucasian pts. 1. Schuler, M. et al. J Thorac Oncol 2016;11:380–90 2. Park, K. et al. Lancet Oncol 2016;17:577–89 3. Girard, N. Future Oncol. 2018;14:1117–32. Clinical trial identification NCT01931306; NCT01953913; NCT01853826. Editorial acknowledgement Lynn Pritchard of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure F. de Marinis: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Boehringer Ingelheim. V. Lee: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self): Eli Lilly; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme. L. Clementi: Full / Part-time employment: Boehringer Ingelheim. W. Tang: Full / Part-time employment: Boehringer Ingelheim. D.C-L. Huang: Full / Part-time employment: Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. K. Park: Advisory / Consultancy: AMGEN; Advisory / Consultancy: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: BluePrint; Advisory / Consultancy: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Hanmi; Advisory / Consultancy: KHK; Advisory / Consultancy: Loxo; Advisory / Consultancy: Merch KGaA; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: ONO; Advisory / Consultancy: Roche. C. Zhou: Honoraria (self): BI; Honoraria (self): Roche; Honoraria (self): Sanofi; Honoraria (self): Hengrui; Honoraria (self): Qilu; Honoraria (self): MSD. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AZ; Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: BMS; Full / Part-time employment: Guangdong Provincial People's Hospital, China; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (self): BI. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Afatinib has demonstrated efficacy and safety in pts with EGFRm+ NSCLC. We report a biomarker analysis of EGFR TKI-naïve pts with EGFRm+ NSCLC treated with afatinib in a Phase IIIb study. The analysis explored the effect of tumor mutation status on patient outcomes. Methods Pts with EGFR TKI-naïve locally advanced/metastatic EGFRm+ NSCLC received 40 mg/day afatinib. Primary endpoint was incidence of serious adverse events (SAEs). Secondary endpoints included drug-related AEs (DRAEs). Progression-free survival (PFS) was a further endpoint. For biomarker analysis, DNA was extracted from peripheral blood samples and analyzed using an amplification refractory mutation system. Samples taken at baseline and regular intervals were analyzed for EGFR mutations; specified non-EGFR mutations were identified at baseline. Results This analysis included 64 Chinese pts (female 70%; mean age 57 years; EGFR mutations: L858R 50%; Del19 42%). All pts had ≥1 DRAE, most commonly (all grades/≥3) diarrhea (98/14%) and rash/acne (grouped term; 81/8%). 15 pts (23%) had ≥1 SAE; 6 (9.4%) had drug-related SAEs. 58 pts (90.6%) showed disease control; including 39 (60.9%) with an objective response. At baseline, 19/42 pts analyzed (45%) had additional non-EGFR mutations; 17 progressed, 2 died. Median PFS was 8 months (mo), vs 12 mo for pts with EGFR-only mutations (HR 1.72; 95% CI 0.88, 3.36; p = 0.1054). At Visit 3, EGFR mutation status of 33/40 pts (83%) changed from positive to negative; 28 progressed, 5 died. Median PFS was 11 mo vs 6 mo for pts who remained EGFRm + (HR 1.25; 95% CI 0.47, 3.30; p = 0.6556). Conclusions In this analysis, there were no unexpected safety findings. There was no significant difference in PFS between pts with additional non-EGFR mutations vs those with EGFR-only mutations. Median PFS was almost twice as long in pts who became EGFR-mutation negative compared with those who remained EGFRm + (non-significant). This analysis suggests afatinib has clinical benefit for pts regardless of type of initial EGFR mutation. Clinical trial identification NCT01953913. Editorial acknowledgement Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Beth de Klerk of GeoMed, an Ashfield company, part of UDG Healthcare plc. The authors acknowledge Nick Xue, of Boehringer Ingelheim (China) Investment Co. and Agnieszka Cseh, of Boehringer Ingelheim RCV GmbH & Co. KG, for their support in the development of this abstract. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure S. Meng: Full / Part-time employment: Boehringer Ingelheim. Y. Tian: Full / Part-time employment: Boehringer Ingelheim. D.C-L. Huang: Full / Part-time employment: Boehringer Ingelheim. Y-L. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly; Honoraria (self): MDS; Honoraria (self): BMS. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]