In the Phase III LUX-H&N1 trial, afatinib, an irreversible ErbB family blocker, significantly improved progression-free survival (PFS) vs MTX (median 2.6 vs 1.7 mos; HR 0.80; p = 0.03) in pts with second-line R/M HNSCC (Machiels, Lancet Oncol 2015). Here we report PFS and response rates (RR) in the pre-defined subgroups and biomarker-defined populations.
R/M HNSCC pts progressing on/after platinum therapy were randomized 2:1 to 40 mg/d oral afatinib (n = 322) or 40 mg/m2/wk IV MTX (n = 161), stratified by ECOG PS (0/1) and prior use of anti-EGFR monoclonal antibody (mAb) therapy (Yes/No) in the R/M setting. The primary endpoint was PFS by independent review. Optional tumor biomarker assessments, including human papillomavirus status assessed by p16, EGFR amplification, HER3 and PTEN, were conducted in a central laboratory.
Improvements in PFS and RR with afatinib vs MTX in subgroups based on geographical region (Asia, Europe, or North/Latin America) and age (<65 or ≥65 yrs) were consistent with the overall study population (Table). Afatinib demonstrated a more pronounced effect in pts not previously treated with anti-EGFR mAb therapy. In the biomarker subgroups, improvements in PFS were observed with afatinib vs MTX in pts with p16-negative, HER3-low, and PTEN-high disease; a trend towards prolonged PFS was observed in pts with EGFR-amplified tumors (Table). Higher RRs with afatinib vs MTX were observed in all biomarker subgroups, with the exception of p16-positive disease.
Efficacy outcomes according to subgroups/biomarkers (all comparisons are afatinib vs MTX)
|Subgroup/biomarker||Median PFS, mos||PFS HR (95% CI)||RR, %||RR odds ratio (95% CI)*|
|Prior anti-EGFR mAb|
|Yes (n = 287)||1.6 vs 1.6||0.91 (0.70–1.19)||3.7 vs 4.1||0.90 (0.26–3.17)|
|No (n = 196)||2.8 vs 2.0||0.63 (0.45–0.88)||19.6 vs 7.9||2.82 (1.03–7.73)|
|Asia (n = 43)||2.7 vs 1.5||0.62 (0.32–1.20)||23.1 vs 11.8||2.25 (0.40–12.75)|
|Europe (n = 369)||2.6 vs 1.9||0.82 (0.64–1.04)||8.4 vs 5.8||1.49 (0.61–3.60)|
|North/Latin America (n = 60)||2.9 vs 1.6||0.41 (0.21–0.79)||12.8 vs 0||NE|
|<65 (n = 355)||2.6 vs 1.6||0.79 (0.62–1.01)||10.0 vs 5.2||2.05 (0.81–5.15)|
|≥65 (n = 128)||2.8 vs 2.3||0.68 (0.45–1.03)||10.8 vs 6.7||1.70 (0.44–6.64)|
|p16-negâ (H-score <210; n = 199)||2.7 vs 1.6||0.70 (0.50–0.97)||14.1 vs 1.6||10.32 (1.35–78.90)|
|p16-pos (H-score ≥210; n = 35)||2.0 vs 2.3||0.81 (0.39–1.69)||0 vs 8.3||NE|
|EGFR-amplifiedâ¡ (n = 66)||2.8 vs 1.6||0.66 (0.35–1.24)||14.0 vs 0||NE|
|EGFR not amplified (n = 80)||1.7 vs 2.4||1.13 (0.68–1.86)||3.8 vs 0||NE|
|HER3-low (H-score ≤50; n = 66)||2.9 vs 2.0||0.47 (0.25–0.86)||12.2 vs 0||NE|
|HER3-high (H-score >50; n = 90)||1.7 vs 2.4||1.33 (0.79–2.24)||9.4 vs 0||NE|
|PTEN-high (H-score >150; n = 42)||2.9 vs 1.4||0.36 (0.16–0.81)||6.7 vs 0||NE|
|PTEN-low (H-score ≤150; n = 115)||2.6 vs 2.7||1.01 (0.65–1.58)||12.2 vs 0||NE|
*Odds ratios are not available for comparisons of subgroups with no responders;
â p16 staining was analyzed in tumors from all subsites;
â¡ ≥50% of cells with ≥4 copies, or ≥1 cell with ≥8 copies.
CI, confidence interval; HR, hazard ratio; H-score, histology score; NE, not estimable
More pronounced anti-tumor effects were observed with afatinib vs MTX in subgroups of R/M HNSCC pts with p16-negative, EGFR-amplified, HER3-low, and PTEN-high disease. Future prospective studies based on these subgroups and biomarkers are needed to provide a more robust readout of clinical outcomes.
Clinical trial identification
M. Tahara: advisory board participation for Merck Sharp & Dohme; honoraria from Merck Serono, Bristol-Myers Squibb, Eisai, Otsuka and Bayer; and research funding from Eisai, Merck Sharp & Dohme, Boehringer Ingelheim and AstraZeneca. E.E.W. Cohen: advisory board participation for Merck and Pfizer; and honoraria from Eisai and Bayer. R.I. Haddad: advisory board participation for BMS, Merck and Bayer; and corporate-sponsored research from Merck, BMS, Celgene and Boehringer Ingelheim. L.F. Licitra: advisory board participation for EISAI, BMS, GlaxoSmithKline, Lilly, Merk – Serono, Amgen, Boehringer Ingelheim, DEBIOPHARM, VentiRX, SOBI, Novartis, AstraZeneca, Bayer, MSD, Celgene, and Roche; corporate-sponsored research for EISAI, Exelixis, Lilly, Merk – Serono, Amgen, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Roche, and MSD; and travel coverage for medical meetings from Merk – Serono. J.B. Vermorken: advisory board participation for Boehringer Ingelheim and being on the steering committee of the LUX H&N trials. T. Gauler: stock ownership or options from Bayer AG since 1984; advisory board participation for Boehringer Ingelheim, Merck Serono, Novartis and MSD; honoraria from Novartis, Merck Serono, Boehringer Ingelheim and Roche. J. Guigay: advisory board participation from BMS and Merck Serono; and research grants from BMS, Boehringer Ingelheim, Chugai, GSK, MSD, Merck Serono and Sanofi. K. Okami: honoraria from Merck Serono and Bristol-Myers Squibb. S. Takahashi: corporate-sponsored research from Boehringer Ingelheim. B. Burtness: advisory board participation for VentiRX, Medimmune, Amgen, Bayer and Boehringer Ingelheim; corporate-sponsored research for Merck; and expert testimony for Johnson & Johnson. X.J. Cong, N. Gibson, F. Solca, E. Ehrnrooth: employment by Boehringer Ingelheim. J.-P.H. Machiels: advisory board participation for Boehringer Ingelheim (without compensation). All other authors have declared no conflicts of interest.