Second-line afatinib significantly improves progression-free survival in recurrent or metastatic head and neck cancer
The tyrosine kinase inhibitor afatinib significantly improves progression-free survival (PFS) compared to methotrexate in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after failure of platinum-based chemotherapy. Results of the phase III Lux-Head & Neck 1 trial showed that patients who received treatment with 40mg/day oral afatinib had a 20% reduction in risk of progression or death compared to patients who received methotrexate, with a median progression-free survival of 2.6 months. Moreover, the improvement in PFS was associated with a significantly delayed worsening of symptoms (such as pain, swallowing and global health status) versus chemotherapy.
Recurrent or metastatic squamous cell carcinoma of the head and neck often has a poor outcome. Moreover, these patients often present with severe co-morbidities and social problems such as alcoholism and excessive tobacco use. Frequently, a relapse in the head and neck area is seen. This location is responsible for many symptoms that are difficult to palliate: pain, breath disorder and swallowing difficulties. For these patients currently no standard therapy is available.
Afatinib is a compound that irreversibly blocks the ErbB family of cell surface receptors, which includes epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), HER3 and HER4. Around 90% of squamous cell carcinomas of the head and neck overexpress EGFR making afatinib an interesting agent to test in this setting. In the Lux-Head & Neck 1 trial, researchers aimed to see if inhibiting multiple ErbB receptors simultaneously would improve the clinical efficacy of EGFR-targeted therapy. In total, data of 483 patients with recurrent or metastatic head and neck squamous cell carcinoma whose cancer had progressed despite treatment with platinum-based therapy were analyzed. Overall, 322 patients received 40 mg/day oral afatinib and 161 were given 40 mg/m2/week intravenous methotrexate (MTX). Given the different administration route of both agents in the trial (oral and intravenously), it was impossible to keep the study blinded.
The study met its primary endpoint with afatinib significantly improving the primary endpoint of PFS versus MTX (median 2.6 vs. 1.7 months; HR=0.80 [95% CI 0.65–0.98; p=0.03]). This PFS advantage did however not translate in a significant improvement in overall survival (OS) (median OS 6.8 vs. 6.2 months; HR[95%CI]= 0.94[0.75–1.18]). Disease control rate was higher with afatinib as compared to MTX (49.1% vs. 38.5%; p=0.04); the overall response rate (ORR) was 10.2% with afatinib and 5.6% with MTX (p=0.10). Tumour shrinkage from baseline was observed in 34.8% of afatinib-treated patients compared to 22.4% of MTX-treated patients. Importantly, afatinib significantly delayed deterioration of global health status, pain and swallowing vs. MTX (all p≤0.03) and provided improvement in pain (p=0.03). The toxicity profile of afatinib was acceptable and manageable with the most frequent grade 3/4 drug-related adverse events being rash/acne (9.7%) and diarrhea (9.4%). Less treatment-related dose reductions, discontinuations and fatal events were seen with afatinib as compared to MTX.
In summary, afatinib improved PFS and delayed worsening of symptoms and as such is the first tyrosine kinase inhibitor to demonstrate a significant benefit in this disease. The trial was not able to demonstrate that afatinib improves survival. However, the fact that 50% of the patients in both arms received subsequent therapies may have influenced the survival benefit, for example a significant number of patients in the MTX arm received subsequent anti-EGFR therapies.
References
Machiels J-P, Haddad R, 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. Presented at ESMO 2014; Abstract 29LBA.
