Phase Ib study of afatinib plus standard-dose cetuximab in patients with advanced solid tumours

Background: Afatinib in combination with cetuximab has demonstrated activity in patients (pts) with EGFR mutation-positive NSCLC and acquired resistance to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib (Janjigian. Cancer Discov 2014). Targeting the ErbB pathway may also be of benefit in the treatment of other tumour types; for example, in squamous cell cancers, which have high levels of EGFR overexpression. This multicentre, open-label, Phase lb study (NCT02020577) assessed afatinib plus standard-dose cetuximab in pts with advanced solid tumours, including squamous NSCLC and squamous cell carcinoma of head and neck (HNSCC). Material and Methods: In Part A of the study, a 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) of afatinib (from 30 to 40 mg daily) plus standard-dose cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly). Treatment was administered in 21-day cycles until disease progression or unacceptable toxicity. MTD was defined as the highest dose at which fewer than 2 of 6 pts experienced a dose-limiting toxicity (DLT) during Cycle 1. In Part B, safety, tolerabilrty and preliminary anli-tumour activity was assessed in 3 expansion cohorts (squamous NSCLC. HNSCC and other tumours) at the MTD determined in Part A. Results: In Part A, 3 pts received afatinib 30 mg. and 6 received afatinib 40 mg. No DLTs were observed in either dose cohort; the MTD was defined as afatinib 40 mg once daily plus standard-dose cetuximab. In Part B. 49 pts have been treated at the MTD (12 with squamous NSCLC, 15 with HNSCC and 22 with other tumours); these pts were heavily pre-treated (median 3 lines of prior therapy). Among all 58 treated pts, the most common drug-related adverse events (AEs; all grades [G], n [%]) were classified as skin and subcutaneous disorders (48 [83%]) and gastrointestinal disorders (45 [78%]). The most frequently reported drug-related AEs were diarrhoea (37 pts [64%]) and dermatitis acneiform (25 pts [43%]). 18 pts (31%) had drug-related G3 AEs, most commonly dermatitis acneiform and rash (each 3 pts). There were 2 drug-related G4 AEs (hyperlipasaemia and hypersensitivity, each 1 pt) and no drug-related G5 AEs. Efficacy results showed that 27 pts (55%) in the expansion cohort (Part B) had stable disease (SD>; 9/12 pts (75%) with squamous NSCLC. 10/15 (67%) with HNSCC and 8/22 (36%) with other tumours. No confirmed objective responses have been reported. Mean duration of disease control in