OS no-show for afatinib in PhIII head and neck trial
This article was originally published in Scrip
Boehringer Ingelheim has reported data from a Phase III trial with afatinib (Gilotrif/Giotrif) that met its primary endpoint of significantly delaying tumor growth versus chemotherapy in patients with recurrent and/or metastatic (R/M) head and neck squamous cell cancer after failure of previous therapy. However, some observers have raised concerns over the failure of the trial to demonstrate overall survival benefit.
The data was presented as a late-breaking abstract at the European Society for Medical Oncology (ESMO) 2014 congress over the weekend.
The LUX-Head & Neck 1 trial met its primary endpoint of progression-free survival (PFS) by showing that patients taking afatinib, after failure of previous platinum-based chemotherapy, experienced a significant delay in tumor growth of 2.6 months versus 1.7 months with chemotherapy. "This translated into a 20% reduction in risk of disease progression," said Boehringer.
With regard to secondary endpoints, afatinib significantly improved the disease control rate (DCR: the percentage of patients whose tumor 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%). However, no significant difference between afatinib and chemotherapy was observed regarding overall survival (median 6.8 vs. 6.0 months).
"Although this large study technically met its primary endpoint, the failure to demonstrate an OS benefit is concerning," noted analysts from BioMedTracker. However, "Three other large head and neck trials are ongoing, so there should be additional readouts of Gilotrif [afatinib] potential in this indication. For now, though, we are lowering our likelihood of approval by 2% based on the minimal OS benefit."
Afatinib is a once-daily, irreversible ErbB blocker and the first tyrosine kinase inhibitor (TKI) to show that it can significantly delay tumor growth versus chemotherapy in patients with head and neck squamous cell cancer after failure of previous therapy.
Professor Jan Vermorken from department of medical oncology at Antwerp University Hospital in Belgium, noted that in addition to achieving the primary endpoint, "there were some favorable patient reported outcomes with respect to pain, swallowing and global health status when compared to standard chemotherapy. These data provide additional insight into evaluating this agent in this difficult-to-treat disease."
The most frequent drug-related severe adverse events (> grade 3) were rash/acne (9.7%) and diarrhea (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%), diarrhea (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.
LUX-Head & Neck program
The LUX-Head & Neck clinical trial program 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, Phase III trials that investigate afatinib in patients with R/M head and neck squamous cell cancer who have progressed on/after platinum-based chemotherapy. Estimated study completion dates: July 2015 and April 2016 respectively.
LUX-Head & Neck 2 and 4, Phase III trials that evaluate afatinib in patients with locally advanced head and neck cancer after chemo-radiotherapy. Estimated study completion dates: May 2019 and August 2020 respectively.
Lung data
Also at ESMO, Phase III data from Boehringer's LUX-Lung 8 trial, the first study to directly compare the efficacy of two different targeted agents in patients with advanced squamous cell carcinoma (SCC) of the lung, demonstrated better PFS of afatinib compared to Roche's erlotinib (Tarceva). Afatinib showed significant improvement across several measures of efficacy, in particular for the primary endpoint of PFS compared to erlotinib in patients after failure of first-line chemotherapy.
LUX-Lung 8 demonstrated that afatinib significantly reduced the risk of disease progression by 18% when compared to erlotinib, and delayed tumor growth (PFS) by 2.4 vs. 1.9 months. In addition, afatinib showed an improvement in the secondary endpoint of DCR. The ORR was numerically higher with afatinib compared to erlotinib (5% vs. 3%).
Afatinib's mode of action differs from other EGFR TKIs such as erlotinib, which target EGFR (ErbB1) only, in that it targets the complete ErbB family, according to Boehringer.
LUX-Lung 7, a second head-to-head trial evaluating afatinib versus gefitinib as a first-line treatment in EGFR mutation-positive NSCLC patients, is currently ongoing.
Afatinib is currently indicated for specific forms of treatment of EGFR mutation positive locally advanced or metastatic non-small cell lung cancer (NSCLC).