Gilotrif Trials Halted in Head and Neck Cancer Due to Lack of Efficacy

After an independent panel determined that Gilotrif (afatinib) was not likely to demonstrate benefit over placebo for patients with head and neck cancer, two trials examining the pan-HER inhibitor were stopped, according to Boehringer Ingelheim, the manufacturer of the drug.

Both trials—the global LUX-Head & Neck 2 trial (NCT01345669) and its Asian companion trial, LUX-Head & Neck 4 (NCT02131155)—were examining Gilotrif 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 two studies to discontinue treatment and further accrual to the studies has been stopped.

Although the committee observed increased toxicity with Gilotrif 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 Gilotrif 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 Gilotrif or placebo. Patients had to have histologically or cytologically confirmed locoregionally advanced stage 3 to 4b 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 two 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 3 LUX-Head & Neck 1 trial presented at the 2014 ESMO Congress had previously shown a potential benefit with Gilotrif in HNSCC. In the study, the median progression-free survival (PFS) was 2.6 months for patients with relapsed or metastatic disease treated with Gilotrif 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 Gilotrif at 40 mg daily (322 patients) or intravenous methotrexate at 40 mg/m² weekly (161 patients). The primary endpoint was PFS and secondary endpoints included OS, objective response rate, patient-reported outcomes, and safety.

Gilotrif reduced the hazard for progression by 20 percent compared with methotrexate. Patients treated with Gilotrif had a three-month PFS of 42.8 percent versus 30.5 percent for the methotrexate group.

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

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

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

Gilotrif 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.