Late-Stage Afatinib Trials Halted in Head and Neck Cancer

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Two phase III trials examining afatinib (Gilotrif) in head and neck cancer have been stopped after an independent panel determined the pan-HER inhibitor was unlikely to demonstrate an efficacy benefit over placebo.

Two phase III trials examining afatinib (Gilotrif) in head and neck cancer have been stopped after an independent panel determined the pan-HER inhibitor was unlikely to demonstrate an efficacy benefit over placebo, according to the manufacturer of the drug, Boehringer Ingelheim.

Both trials—the global LUX-Head & Neck 2 trial (NCT01345669) and its Asian companion trial, LUX-Head & Neck 4 (NCT02131155)—were examining afatinib as adjuvant therapy in patients with locally advanced head and neck cancer who had no evidence of disease following chemotherapy and radiotherapy. In a statement, Boehringer reported that investigators are advising patients enrolled in the 2 studies to discontinue treatment and further accrual to the studies has been stopped.

Although the committee observed increased toxicity with afatinib versus placebo, there were no major safety issues with the drug. As recommended by the independent committee during the same analysis, a third trial, LUX-Head & Neck 3, which is assessing afatinib in an Asian population with recurrent and/or metastatic head and neck cancer, will continue.

The double-blind LUX-Head & Neck 2 trial randomized patients to a once daily dose of afatinib or placebo. Patients had to have histologically or cytologically confirmed locoregionally advanced stage III to IVb head and neck squamous cell carcinoma (HNSCC) and an ECOG performance status of 0 or 1. Prior treatment with EGFR-targeted therapies or investigational therapies for HNSCC was not allowed.

The trial was being conducted at 171 locations across the globe. The primary endpoint was disease-free survival (DFS), with secondary outcome measures including DFS at 2 years, overall survival (OS), and health-related quality of life.

The design of the LUX-Head & Neck 4 trial was identical to the LUX-Head & Neck 2 trial. The only difference between the trials was that LUX-Head & Neck 4 was conducted exclusively in Asian patients in China, Korea, Singapore, and Taiwan. Boehringer intends to present the full data from both studies at an upcoming medical meeting.

Data from the phase III LUX-Head & Neck 1 trial presented at the 2014 ESMO Congress had previously shown a potential benefit with afatinib in HNSCC.1 In the study, the median progression-free survival (PFS) was 2.6 months for patients with relapsed or metastatic disease treated with afatinib versus 1.7 months for those receiving methotrexate.


The study randomized 483 patients with HNSCC who had progressed on platinum-based chemotherapy in a 2:1 ratio to oral afatinib at 40 mg daily (n = 322) or intravenous methotrexate at 40 mg/m2 weekly (n = 161). The primary endpoint was PFS and secondary endpoints included OS, objective response rate, patient-reported outcomes, and safety.

Afatinib reduced the hazard for progression by 20% compared with methotrexate (P = .030). Patients treated with afatinib had a 3-month PFS of 42.8% versus 30.5% for the methotrexate group.

Median OS did not differ significantly between treatment groups: 6.8 months with afatinib and 6.2 months with methotrexate. The disease control rate (response plus stable disease) was significantly higher in the afatinib arm (49.1% vs 38.5%; P = .04).

Other secondary endpoints did not differ significantly between treatment groups. Overall response rate was 10.2% with afatinib and 5.6% with methotrexate. The proportion of patients who had tumor shrinkage with treatment was 34.8% in afatinib-treated patients and 22.4% in the methotrexate group.

Afatinib and methotrexate were associated with different adverse event profiles. The most common grade 3/4 adverse events with afatinib were rash/acne (9.7%) and diarrhea (9.4%), whereas leukopenia (15.6%) and stomatitis (8.1%) occurred most often among the patients randomized to methotrexate.

Afatinib is an irreversible ErbB family blocker that specifically inhibits EGFR (ErbB1), HER2 (ErbB2), and ErbB4. The drug is approved by the FDA for the first-line treatment of EGFR-positive patients with advanced NSCLC and for the second-line treatment of patients with advanced squamous cell NSCLC.

1. Machiels J-P, Haddad RI, Fayette J, et al. Afatinib versus methotrexate (MTX) as second-line treatment for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who progressed after platinum-based therapy: primary efficacy results of LUX-Head & Neck 1. Paper presented at: ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. Abstract LBA29.