O3.5A Phase Ib dose escalation study of afatinib in combination with standard-dose cetuximab in patients with advanced solid tumours

ABSTRACT Background: Afatinib in combination with cetuximab has demonstrated robust activity in patients (pts) with EGFR mutation-positive lung cancer with acquired resistance to the EGFR tyrosine kinase inhibitors erlotinib/gefitinib. 1 This Phase I study was conducted to establish a maximum tolerated dose (MTD) of the combination using standard weekly doses of cetuximab in pts with other advanced solid tumours. Methods: A standard 3 + 3 Phase I design was utilized. Cohorts with escalating afatinib doses (from 30 to maximum 40 mg once daily) were combined with cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly). Study treatment was administered in 3-week cycles and continued until disease progression or unacceptable toxicity. Safety and antitumour activity were assessed. Dose limiting toxicities (DLTs) in cycle 1 served as the basis for dose escalation between cohorts and in determination of MTD. Results: 9 pts with a variety of heavily pre-treated advanced solid tumours were included: median age: 64 years; male: 6. 3 pts received afatinib 30 mg in cohort 1 and 6 received afatinib 40 mg in cohort 2 in combination with cetuximab. No DLTs were observed in cycle 1 in either cohort. MTD was defined as afatinib 40 mg once daily plus standard-dose cetuximab. The most frequent treatment-related adverse events (AEs; all grades [G], n [%]) were rash/acne (8 [89%]), diarrhoea (5 [56%]), stomatitis (5 [56%]) and dry skin (3 [33%]). 3 treatment-related G3 AEs occurred in 3 pts in the afatinib 40 mg group only (stomatitis, aspartate/alanine aminotransferase increased, and fatigue). There were no G4 or 5 treatment-related AEs. 5 pts (56%) had stable disease; no objective responses were observed. Median duration of disease control was 17 weeks. Further assessment of the combination is ongoing in pts with squamous cell carcinomas of lung, head and neck and in other solid tumours and will be reported at the meeting. Conclusions: Afatinib 40 mg in combination with cetuximab 250 mg/m2 weekly (after 400 mg/m2 loading dose) was established as the MTD. Disease stabilization was observed in pts with varied tumour types and no unexpected AEs were observed. Further assessment of the MTD, and its activity, via expansion cohorts is ongoing.