Uncommon EGFR mutations show heterogeneity in their EGFR TKI sensitivities.1 Afatinib has shown broad inhibitory activity against uncommon mutations in vitro,1 and clinical activity against major uncommon mutations (G719X/L861Q/S768I).2 However, clinical data regarding the efficacy of afatinib against other uncommon EGFR mutations are lacking, particularly between ethnicities.
This pooled analysis assessed afatinib activity in Asian/non-Asian, EGFR TKI-naïve pts with NSCLC and uncommon EGFR mutations, treated in RCTs and real-world studies. Uncommon mutations were classed as: de novo T790M; exon 20 insertions (Ins20); major uncommon mutations (G719X/L861Q/S768I); compound mutations (≥2 uncommon mutations); and other uncommon mutations. Key endpoints were overall response rate (ORR), duration of response (DoR), and time to treatment failure (TTF).
Of the 178/120 Asian/non-Asian pts with uncommon EGFR mutations, 62/35% had a major uncommon mutation (G719X only: 20/20%; L861Q only: 26/8%; S768I only: 3/4%), 16/39% had an Ins20 mutation. Clinical activity (Asian/non-Asian) was observed against major uncommon mutations (ORR: 66/59%; median DoR: 14.7/15.9 mos; G719X: 62/65%; L861Q: 60/50%; S768I: 80/25%), compound mutations (ORR: 81/100%; median DoR: 11.5/18.6 mos) and other uncommon mutations (ORR: 79/60%; median DoR: 9.0/10.7 mos). Some pts with Ins20 responded (21/23%). TTF was longest in pts with compound mutations, particularly non-Asian pts (median 18.5 mos).
Afatinib is effective in pts with NSCLC with major uncommon and compound EGFR mutations, with broad activity against other uncommon EGFR mutations and some Ins20 mutations, unaffected by ethnicity. Asian pts appeared to have a high proportion of major uncommon mutations, known to be highly sensitive to afatinib.2 1. Kohsaka S, et al. Sci Transl Med 2017;9:eaan6566 2. Yang JC, et al. Lancet Oncol 2015;16:830‒8 *Patients may be included in >1 group; †Includes patients with MU + Del19/L858R compound mutations.
Patients*, n (%) ORR, % TTF, mos (95% CI) Asian (N=178) Non-Asian (N=120) Asian Non-Asian Asian Non-Asian Major uncommon (MU)† 110 (61.8) 42 (35.0) 66 59 11.5 (11.5, 13.8) 9.0 (4.6, 15.4) G719X 36 (20.2) 24 (20.0) 62 65 11.5 (9.6, 17.1) 9.0 (3.2, 18.7) L861Q 46 (25.8) 9 (7.5) 60 50 11.5 (11.1, 11.5) 5.7 (1.4, 10.7) S768I 5 (2.8) 5 (4.2) 80 25 NR (2.6, NR) 15.6 (3.0, 20.7) Compound 26 (14.6) 8 (6.7) 81 100 11.5 (8.2, 16.6) 18.5 (1.6, NR) Ins20 29 (16.3) 47 (39.2) 21 23 4.5 (2.6, 5.4) 3.9 (2.8, 5.4) Any de novo T790M 19 (10.7) 14 (11.7) 38 17 4.7 (1.2, 5.5) 2.9 (0.9, 6.7) Other 17 (9.6) 13 (10.8) 79 60 7.2 (1.8, 11.9) 10.7 (2.0, 24.0)
Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Nadia Fowler, of GeoMed, an Ashfield company, part of UDG Healthcare plc.
Boehringer Ingelheim.
Boehringer Ingelheim.
J.C-H. Yang: Honoraria (institution), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (institution), Advisory/Consultancy: Novartis; Honoraria (institution), Advisory/Consultancy: AstraZeneca; Honoraria (institution), Advisory/Consultancy: Roche/Genentech; Honoraria (institution), Advisory/Consultancy: Lilly; Honoraria (institution), Advisory/Consultancy: MSD Oncology; Honoraria (institution), Advisory/Consultancy: Merck Serono; Honoraria (institution), Advisory/Consultancy: Celgene; Honoraria (institution), Advisory/Consultancy: Bayer; Honoraria (institution), Advisory/Consultancy: Pfizer; Honoraria (institution), Advisory/Consultancy: Ono Pharmaceutical; Honoraria (institution), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (institution), Advisory/Consultancy: Yuhan; Honoraria (institution), Advisory/Consultancy: Hansoh; Honoraria (institution), Advisory/Consultancy: Brueprint Medicines; Honoraria (institution), Advisory/Consultancy: Daiichi Snakyo; Honoraria (institution), Advisory/Consultancy: Amgen; Honoraria (institution), Advisory/Consultancy: Takeda Oncology; Honoraria (institution), Advisory/Consultancy: Incyte; Honoraria (institution), Advisory/Consultancy: H: Boehringer Ingelheim; Roche; MSD; AstraZeneca; Novartis; Bristol-Myers Squibb; Ono Pharmaceutical; Takeda Oncology; Eli Lilly; Pfizer. M. Schuler: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Janssen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Takeda; Honoraria (self): Amgen; Honoraria (self): MSD; Honoraria (self): Pierre Fabre. S. Popat: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Takeda; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AZ; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Guardant Health; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Lilly; Honoraria (self), Advisory/Consultancy: EMD Serono; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Incyte; Honoraria (self), Advisory/Consultancy: Paradox; Research grant/Funding (institution): Ariad. S. Miura: Advisory/Consultancy, Speaker Bureau/Expert testimony: Chugai Pharma; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Speaker Bureau/Expert testimony: Boehringer Ingelheim; Speaker Bureau/Expert testimony: Taiho Pharma; Speaker Bureau/Expert testimony: Ono Pharma; Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: AbbVie; Speaker Bureau/Expert testimony: Kyowa Hakko Kirin. S. Heeke: Honoraria (self): Boehringer Ingelheim; Honoraria (self): Qiagen; Travel/Accommodation/Expenses: Roche. A. Passaro: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Dako. K. Park: Advisory/Consultancy: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): AZ; Advisory/Consultancy, Speaker Bureau/Expert testimony: BI; Advisory/Consultancy: BMS; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: JNJ; Advisory/Consultancy: Merck KGaA; Advisory/Consultancy: MSD; Advisory/Consultancy: Roche; Research grant/Funding (self): MSD Research. E.S. Kim: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Takeda; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer. All other authors have declared no conflicts of interest.