Clinical Trials

Date: 2016-07-25

Type of information: Halting of the trial

phase: 3

Announcement: halting of the trial

Company: Boehringer Ingelheim (Germany)

Product: afatinib

Action mechanism:

• kinase inhibitor/tyrosine kinase inhibitor. Afatinib is an irreversible ErbB Family Blocker which inhibits signal transduction of all kinase receptors from the ErbB Family, and is known to play a critical role in the growth and spread of the most pervasive cancers and cancers associated with high mortality (lung, breast, and head & neck cancers). Over-expression of the Epidermal Growth Factor Receptor (EGFR, also referred to as ErbB1) 1 is found in at least 90% of head and neck cancers and strongly correlates with poor prognosis and overall survival.

Disease: metastatic and recurrent head and neck cancer

Therapeutic area: Cancer - Oncology

Country: Australia, Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Italy, Japan, Netherlands, Russian Federation, South Africa, Spain, Sweden, UK

Trial details:

• The LUX-Head & Neck clinical trial programme is evaluating patients in the second line R/M setting after first-line platinum based therapy and as adjuvant therapy in the loco-regionally advanced setting. These trials include:
• - LUX-Head & Neck 1 and 3 (NCT01345682 and NCT01856478), Phase III trials that investigate afatinib in patients with R/M HNSCC who have progressed on/after platinum-based chemotherapy. Estimated study completion dates are July 2015 and April 2016 respectively.
• - LUX-Head & Neck 2 and 4 (NCT01345669 and NCT02131155), Phase III trials that evaluate afatinib in patients with locally advanced head and neck cancer after chemo-radiotherapy. Estimated study completion dates are May 2019 and August 2020 respectively.

Latest news:

• • On July 25, 2016, Boehringer Ingelheim has decided to stop the global LUX-Head & Neck 2 trial (NCT01345669) as well as its Asian companion trial, LUX-Head & Neck 4 (NCT02131155). Both Phase III trials investigate afatinib in patients with locally advanced head and neck cancer who have no evidence of disease after treatment with chemotherapy and radiotherapy. Trial participants were randomly assigned to receive either afatinib or placebo (inactive drug) for up to 1½ years. It was hoped that afatinib, when given after chemo-radiotherapy, would prolong the disease-free/remission-free period of the head and neck cancer. Patients in LUX-Head & Neck 2 and 4 are being instructed by investigators to discontinue treatment, and further recruitment and/or randomization of patients has been halted. Health authorities and investigators have been informed.
• During a pre-planned analysis, an independent Data Monitoring Committee (DMC) made the assessment that it would be highly unlikely that LUX-Head & Neck 2 will demonstrate a significant advantage in efficacy for patients treated with afatinib. The DMC therefore recommended to halt the trial and Boehringer Ingelheim has decided to discontinue it accordingly, as well as its companion trial LUX-Head & Neck 4. The DMC did not identify any major safety concern in its assessment of the data, however noted that there were more side effects on afatinib compared to placebo.
• The LUX-Head & Neck 3 trial investigating afatinib in Asian patients with recurrent and/or metastatic head and neck cancer will continue as planned, as recommended by the DMC during the same analysis. The positive results of its global pivotal trial LUX-Head & Neck 1 were presented in 2014. Results of LUX-Head & Neck 2 and 4 will be presented in the future.
• The discontinuation of LUX-Head & Neck 2 and 4 in patients with locally advanced head and neck cancer does not affect afatinib as an approved treatment for patients with distinct types of EGFR mutation-positive non-small cell lung cancer (NSCLC) and advanced squamous cell carcinoma of the lung. Continued development of afatinib in other solid tumours is therefore not affected.
• • On September 27, 2014, Boehringer Ingelheim announced Phase III data from the LUX-Head & Neck 1 study evaluating the efficacy and safety of afatinib in patients with recurrent and/or metastatic head and neck squamous cell cancer (HNSCC) versus methotrexate. The results of this global trial, with 483 patients from 19 countries, showed that afatinib, a once-daily, irreversible ErbB blocker, is the first tyrosine kinase inhibitor (TKI) to significantly delay tumour growth versus chemotherapy in patients with head and neck squamous cell cancer after failure of previous therapy.1 Results of this late-breaking abstract (abstract #LBA29) have been presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid, Spain (September 26-30). LUX-Head & Neck 1 met its primary endpoint of progression-free survival by showing that patients taking afatinib, after failure of previous platinum-based chemotherapy, experienced a significant delay in tumour growth of 2.6 months versus 1.7 months with chemotherapy. This translated into a 20% reduction in risk of disease progression.1 With regard to secondary endpoints, afatinib significantly improved the disease control rate (DCR: the percentage of patients whose tumour size was stable or reduced, 49.1% vs. 38.5%), and the objective response rate (ORR: percentage of patients who achieved a partial or complete response to therapy) was numerically higher with afatinib compared to chemotherapy (10.2% vs. 5.6%). No significant difference between afatinib and chemotherapy was observed regarding overall survival (median 6.8 vs. 6.0 months). In quality-of-life questionnaires, patients taking afatinib reported significantly less pain and a delay in time to worsening of symptoms including pain, swallowing and global health status (overall health and quality of life), when compared to chemotherapy. The most frequent drug-related severe adverse events (> grade 3) were rash/acne (9.7%) and diarrhoea (9.4%) with afatinib, and leukopenia (15.6%) and stomatitis (8.1%) with chemotherapy. The most common side effects in patients treated with afatinib compared to chemotherapy were rash/acne (74.4% vs. 8.1%), diarrhoea (72.2% vs. 11.9%) and paronychia (nail infection) (14.4% vs. 0%), and with chemotherapy compared to afatinib were stomatitis (43.1% vs. 39.1%), fatigue (31.9% vs. 24.7%) and nausea (22.5% vs. 20.0%). There were fewer drug-related dose reductions and discontinuations for patients taking afatinib compared to chemotherapy.
• • On January 26, 2012, Boehringer Ingelheim has announced  the initiation of two phase III clinical trials, LUX-Head & Neck 1 and LUX-Head & Neck 2. These trials evaluate afatinib* in patients with metastatic and recurrent head and neck cancer, and in patients with locally advanced disease, respectively.
• The initiation of these phase III clinical trials expands the phase III clinical trial programme for Boehringer Ingelheim Oncology which currently includes trials with afatinib in NSCLC and breast cancer and nintedanib* (BIBF 1120) in NSCLC and ovarian cancer.

Is general: Yes