Afatinib versus placebo as adjuvant therapy after chemoradiation in a double-blind, phase III study (LUX-Head & Neck 2) in patients with primary unresected, clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized controlled trial

Abstract

BackgroundOver 50% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced disease. Those at intermediate-to-high risk of recurrence after definitive therapy exhibit advanced disease based on tumour size or lymph node involvement, non-oropharynx primary sites, human papillomavirus (HPV)-negative oropharyngeal cancer, or HPV-positive oropharynx cancer with smoking history (>10-pack-years). Non-surgical approaches include concurrent chemoradiotherapy, induction chemotherapy followed by definitive radiotherapy or chemoradiotherapy, or radiotherapy alone. Following locoregional therapies (including surgical salvage of residual cervical nodes), no standard intervention exists. Overexpression of epidermal growth factor receptor (EGFR), an ErbB family member, is associated with poor prognosis in HNSCC. EGFR-targeted cetuximab is the only targeted therapy that impacts overall survival and is approved for HNSCC in the USA or Europe. However, resistance often occurs, and new approaches, such as targeting multiple ErbB family members, may be required. Afatinib, an irreversible ErbB family blocker, demonstrated antiproliferative activity in preclinical models and comparable clinical efficacy with cetuximab in a randomized phase II trial in recurrent or metastatic HNSCC. LUX-Head & Neck 2, a phase III study, will assess adjuvant afatinib versus placebo following chemoradiotherapy in primary unresected locoregionally advanced intermediate-to-high-risk HNSCC.Methods/designPatients with primary unresected locoregionally advanced HNSCC, in good clinical condition with unfavourable risk of recurrence, and no evidence of disease after chemoradiotherapy will be randomized 2:1 to oral once-daily afatinib (40 mg starting dose) or placebo. As HPV status will not be determined for eligibility, unfavourable risk is defined as non-oropharynx primary site or oropharynx cancer in patients with a smoking history (>10 pack-years). Treatment will continue for 18 months or until recurrence or unacceptable adverse events occur. The primary endpoint measure is duration of disease-free survival; secondary endpoint measures are disease-free survival rate at 2 years, overall survival, health-related quality of life and safety.DiscussionGiven the unmet need in the adjuvant treatment of intermediate-to-high-risk HNSCC patients, it is expected that LUX-Head & Neck 2 will provide new insights into treatment in this setting and might demonstrate the ability of afatinib to significantly improve disease-free survival, compared with placebo.Trial registrationClinicalTrials.gov NCT01345669.Electronic supplementary materialThe online version of this article (doi:10.1186/1745-6215-15-469) contains supplementary material, which is available to authorized users.

Effect of TLR4 on the growth of SiHa human cervical cancer cells via the MyD88‑TRAF6-TAK1 and NF-κB-cyclin D1-STAT3 signaling pathways

“…The 5-year survival rate of cervical cancer is ~20-30% (2). The major cause of the low survival rates may be due to high recurrence rates of 80%, poor progression and tolerance to chemotherapy (3). As a first-line agent, paclitaxel serves an important role in the treatment of cervical cancer.…”

miR-124 Regulates the Epithelial-Restricted with Serine Box/Epidermal Growth Factor Receptor Signaling Axis in Head and Neck Squamous Cell Carcinoma

“…Progression-free survival was 2.6 months for the afatinib arm and 1.7 months for the methotrexate arm (p=0.030; hazard ratio 0.80) (35). Separate phase III trials in HNSCC are ongoing to assess the efficacy of single-agent afatinib or lapatinb in the adjuvant setting to reduce the risk of disease recurrence and progression (36). Even though there is evidence that afatinib has activity in the recurrent/metastatic HNSCC setting, the clinical benefit with this molecularly-targeted agent is quite modest suggesting that the kinase-independent actions of EGFR may be able to compensate for kinase activity blockade and thus, a select population of HNSCC cells may utilize a non-canonical EGFR pathway to maintain survival.…”

Application of molecular targeted therapies in the treatment of head and neck squamous cell carcinoma (Review)

“…The phase II trial indicated a comparable clinical efficacy of afatynib to cetuximab in recurrent HNSCC treated previously with chemotherapy based on platinum (47). It is evaluated in the phase III trial as an adjuvant following chemoradiotherapy in the treatment of unresectable advanced (stages III to IVa) HNSCC (48). One of the phase II trials determined that dacomitynib, another EGFR inhibitor, indicated clinical activity in the first-line treatment of recurrent or metastatic HNSCC (49).…”