Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial

Abstract

Importance: Locoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC.

Objective: To assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC.

Design, setting, and participants: This multicenter, phase 3, double-blind randomized clinical trial (LUX-Head & Neck 2) studied 617 patients from November 2, 2011, to July 4, 2016. Patients who had complete response after CRT, comprising radiotherapy with cisplatin or carboplatin, with or without resection of residual disease, for locoregionally advanced high- or intermediate-risk HNSCC of the oral cavity, hypopharynx, larynx, or oropharynx were included in the study. Data analysis was of the intention-to-treat population.

Interventions: Patients were randomized (2:1) to treatment with afatinib (40 mg/d) or placebo, stratified by nodal status (N0-2a or N2b-3) and Eastern Cooperative Oncology Group performance status (0 or 1). Treatment continued for 18 months or until disease recurrence, unacceptable adverse events, or patient withdrawal.

Main outcomes and measures: The primary end point was DFS, defined as time from the date of randomization to the date of tumor recurrence or secondary primary tumor or death from any cause. Secondary end points were DFS at 2 years, overall survival (defined as time from the date of randomization to death), and health-related quality of life.

Results: A total of 617 patients were studied (mean [SD] age, 58 [8.4] years; 528 male [85.6%]). Recruitment was stopped after a preplanned interim futility analysis on July 4, 2016, on recommendation from an independent data monitoring committee. Treatment was discontinued. Median DFS was 43.4 months (95% CI, 37.4 months to not estimable) in the afatinib group and not estimable (95% CI, 40.1 months to not estimable) in the placebo group (hazard ratio, 1.13; 95% CI, 0.81-1.57; stratified log-rank test P = .48). The most common grade 3 and 4 drug-related adverse effects were acneiform rash (61 [14.8%] of 411 patients in the afatinib group vs 1 [0.5%] of 206 patients in the placebo group), stomatitis (55 [13.4%] in the afatinib group vs 1 [0.5%] in the placebo group), and diarrhea (32 [7.8%] in the afatinib group vs 1 [0.5%] in the placebo group).

Conclusions and relevance: This study's findings indicate that treatment with afatinib after CRT did not improve DFS and was associated with more adverse events than placebo in patients with primary, unresected, clinically high- to intermediate-risk HNSCC. The use of adjuvant afatinib after CRT is not recommended.

Trial registration: ClinicalTrials.gov identifier: NCT01345669.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Burtness reported receiving grants and personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, and Merck and personal fees from Medimmune. Dr Haddad reported receiving grants and personal fees from Merck, Bristol-Myers Squibb, Pfizer, Genentech, and AstraZeneca; personal fees from Loxo and Celgene; and grants from Boehringer Ingelheim. Dr Yokota reported receiving grants from Boehringer Ingelheim; personal fees from Merck Serono, Bayer, and Eisai; grants from MSD, Novartis, Nanocarrier, and Pfizer; and grants and personal fees from AstraZeneca, Bristol-Myers Squibb, and ONO Pharmaceutical Co Ltd. Dr Vermorken reported a paid advisory role for Merck KGaA. Dr Tahara reported receiving grants from Boehringer Ingelheim; personal fees from MSD, Otsuka, and Bayer; grants and personal fees from Eisai, AstraZeneca, Pfizer, Ono Pharmaceuticals, and Bristol-Myers Squibb; and grants from Novartis and NanoCarrier. Dr Martins Segalla reported receiving honoraria from Roche and Amgen. Dr Nangia reported receiving personal fees from Merck and Novartis. Dr Kiyota reported receiving research funding from Nippon Boehringer Ingelheim Co Ltd, ONO Pharmaceutical Co Ltd, Bristol-Myers Squibb, AstraZeneca, and Pfizer. Dr Asarawala reported receiving research funding from Boehringer Ingelheim. Drs Wang, Gibson, and Ehrnrooth reported employment with Boehringer Ingelheim. Dr Harrington reported receiving travel support from Boehringer Ingelheim and grants, personal fees, and a paid advisory role from AstraZeneca, MSD, Merck Serono, BMS, and Pfizer. Dr Cohen reported a paid consultancy/advisory role with Merck, Pfizer, AstraZeneca, Bristol-Myers Squibb, and Human Longevity Inc. No other disclosures were reported.

Figures

Figure 1.. CONSORT Study Design

DMC indicates data monitoring committee.

Figure 2.. Analysis of Disease-Free Survival (DFS)

A, Kaplan-Meier estimates of DFS for all randomized patients. B, Forest plot of DFS according to predefined subgroups. CRT indicates chemoradiotherapy; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; NE, not estimable; and RT, radiotherapy.

Figure 3.. Disease-Free Survival (DFS) According to p16 Status and PTEN Status by Central Testing

Kaplan-Meier estimates of DFS in patients with p16-negative tumors (A), patients with p16-positive tumors (B), patients with tumors expressing low levels of PTEN (immunohistochemistry [IHC] H score ≤150), and patients with tumors expressing high levels of PTEN (IHC H score >150). HR indicates hazard ratio; NE, not estimable.