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

Abstract

BackgroundIn 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 methodsRandomized 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.ResultsOf 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).ConclusionsSubgroups 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 registrationNCT01345682.

Review of emerging biomarkers in head and neck squamous cell carcinoma in the era of immunotherapy and targeted therapy

“…In the phase III LUX‐Head&Neck 1 (LUX‐H&N1) trial, 2nd line afatinib significantly improved PFS vs methotrexate in patients with recurrent/metastatic HNSCC. In subgroup analysis, patients who have benefited from afatinib were identified in those with p16 neg , EGFR amplified , HER3 low , PTEN high status . That indicates that p16, HER3, and PTEN might serve as predictive markers in afatinib treatment.…”

“…Some biomarkers have shown predictive value for outcomes with standard anticancer therapies, including platinum agents, cetuximab‐based chemotherapy, panitumumab‐based chemotherapy, afatinib, radiotherapy, concurrent chemoradiotherapy (CCRT), and immunotherapy . Such biomarkers are particularly important for clinical trial design, as they can aid in patient selection or stratification at randomization, serve as treatment‐monitoring tools, and help predict which specific patient groups are likely to derive the greatest benefit from a particular treatment.…”

“…Patients positive for p16 have shown a greater response to, and improved overall outcomes with radiotherapy, as well as improved outcomes from CTC count during treatment (CCRT), vs those with p16 nonexpression. In addition, some studies indicate a predictive role for p16 status in patients receiving EGFR‐targeted therapy for HNSCC, including cetuximab plus chemotherapy, panitumumab plus chemotherapy (vs chemotherapy alone), and afatinib …”

“…For example, as briefly described above, p16 status appears to influence response to EGFR‐targeted therapies. Patients with p16‐positive tumors responded well to cetuximab‐based therapy, those with p16‐negative tumors responded better to panitumumab‐based therapy and afatinib . In the phase III LUX‐Head&Neck 1 (LUX‐H&N1) trial, 2nd line afatinib significantly improved PFS vs methotrexate in patients with recurrent/metastatic HNSCC.…”

A pilot study of the pan‐class I PI3K inhibitor buparlisib in combination with cetuximab in patients with recurrent or metastatic head and neck cancer

“…Given the high frequency of PI3K aberrations (downstream of membrane bound EGFR), activating aberrations in the PI3K pathway are likely unaffected by EGFR blockade for example, with cetuximab or EGFR tyrosine kinase inhibitors. Recent clinical data support the rationale of PI3K pathway activation for example, via PTEN in a large trial of EGFR inhibitor afatinib in HNC making the combination of cetuximab with buparlisib of high interest …”