Background
Approximately 10–12% of patients with EGFRm+ NSCLC have tumours harbouring uncommon EGFR mutations; however, there is a paucity of clinical data on the sensitivity of these tumours to EGFR TKIs. Preclinical data indicate that the irreversible ErbB family blocker, afatinib, has similar activity against certain uncommon mutations (e.g. L858M/S768I) to that against the common L858R mutation.1,2
Methods
Here, we review the key clinical data available for first-line afatinib in EGFRm+ NSCLC harbouring uncommon EGFR mutations.
Results
Post-hoc analysis of the randomised LUX-Lung 2/3/6 trials3 demonstrates that afatinib is clinically active against certain uncommon EGFR mutations. Among 75 afatinib-treated patients with tumours harbouring uncommon mutations in these trials the objective response rate against G719X (n = 18), L861Q (n = 16) and S768I (n = 8) single/compound mutations was 78%, 56% and 100%. Response rate was lower in patients with exon 20 insertions (n = 23; 9%) or de novo T790M (n = 14; 14%). In 38 patients with uncommon mutations/duplications in exons 18–21 PFS was 10.7 months (95% CI 5.6–14.7) and OS was 19.4 months (95% CI 16.4–26.9). The clinical activity of afatinib against uncommon mutations is substantiated by observations outside of the randomised controlled trial setting. In a Phase IIIb single-arm open-label study of afatinib in its registered indication, 67 of 479 TKI-naïve patients had NSCLC with uncommon mutations4 (exon 20 insertions; L861Q; G719S/A/C; T790M; S768I: 5.2; 4.6; 2.3; 1.0; 1.9%, respectively). Median PFS in these patients was 9.1 months (95% CI 5.6–13.6).4 In an analysis of 165 EGFRm+ NSCLC patients treated with first-line afatinib in real-world practice in South Korea median PFS in those with uncommon mutations excluding T790M (n = 10) was not reached vs 4.7 months in those with T790M (n = 4; p = 0.01).5
Conclusions
Afatinib has shown preclinical and clinical activity in patients with NSCLC harbouring uncommon EGFR mutations, including G719X, L861Q and S768I. These data could help inform clinical decisions in this patient population. 1. Saxon. J Thorac Oncol 2017;12:884 2. Banno. Cancer Sci 2016;107:1134 3. Yang. Lancet Oncol 2015;16:830 4. Wu. WCLC 2017 P3.01-036 5. Kim. WCLC 2017 P3.01-023
Clinical trial identification
N/A
Legal entity responsible for the study
Boehringer Ingelheim
Funding
Boehringer Ingelheim
Disclosure
A. Märten: Employment: Boehringer Ingelheim. N. Yamamoto: Membership on an advisory board or board of directors: BI, AZ, Chugai Corporate-sponsored research: BI. C-J. Yu: Membership on an advisory board or board of directors: Roche, ONO, Chugai, Novartis. Y-L. Wu: Honoraria: AstraZeneca, Roche, Eli Lilly, Pfizer, Sanofi. All other authors have declared no conflicts of interest.
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