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Clinical Trial
. 2017 Oct 1;28(10):2526-2532.
doi: 10.1093/annonc/mdx344.

Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer

E E W Cohen  1 , L F Licitra  2 , B Burtness  3 , J Fayette  4 , T Gauler  5 , P M Clement  6 , J J Grau  7 , J M Del Campo  8 , A Mailliez  9 , R I Haddad  10 , J B Vermorken  11 , M Tahara  12 , J Guigay  13 , L Geoffrois  14 , M C Merlano  15 , N Dupuis  16 , N Krämer  17 , X J Cong  18 , N Gibson  19 , F Solca  20 , E Ehrnrooth  21 , J-P H Machiels  22
Affiliations
Clinical Trial

Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer

E E W Cohen et al. Ann Oncol. .

Abstract

Background: In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1.

Patients and methods: Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes.

Results: Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35).

Conclusions: Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings.

Clinical trial registration: NCT01345682.

Keywords: EGFR; HNSCC; afatinib; biomarker; methotrexate; phase III.

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Figures

Figure 1.
Figure 1.
PFS (A) and OS (B) according to biomarker-defined subgroups. *Based on central test results; includes tumors from all subsites (oropharyngeal and non-oropharyngeal). CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.
Figure 1.
Figure 1.
PFS (A) and OS (B) according to biomarker-defined subgroups. *Based on central test results; includes tumors from all subsites (oropharyngeal and non-oropharyngeal). CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.
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