A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in patients with advanced solid tumours

Abstract

3027 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of EGFR and HER2 receptor tyrosine kinases with IC50 values of 0.5 and 14 nM, respectively. Methods: Patients (pts) with advanced solid malignancies were enrolled. BIBW 2992 was given orally as a continuous once daily dose from 10 mg, doubled in successive cohorts until drug-related toxicity > grade 2, when escalation of no more than 50% was allowed. All pts had pharmacokinetic sampling and pre- and post-treatment skin biopsies. DNA sequencing of tumour cell EGFR and HER2 was performed on pts achieving objective response. Results: Twenty-six pts were treated (14 M/11 F). Median age: 53 (range: 30–68). ECOG PS 0/1: 7/19. 19 pts completing ≥ 28 days were evaluable for adverse events (AEs). Three dose-limiting toxicities (DLT) were seen. One pt with HER2+ breast cancer who had previously received trastuzumab and lapatinib treated at 30 mg of BIBW 2992 developed dyspnoea with radiological interstitial changes, which fully recovered on drug discontinuation. The 2 other DLTs were grade 3 acneiform skin rash, at doses of 40 mg and 50 mg daily. AEs resolved on drug discontinuation and the pts were dose reduced to 30 mg and 40 mg, respectively. The 50 mg dose level is being expanded. One pt treated at 50mg developed grade 3 diarrhoea in cycle 2 and was dose reduced to 40mg with resolution of the AE. Other AEs were mild (CTCAE v3 grade 1 or 2); nausea, diarrhoea, mucositis and fatigue. Two female pts with lung adenocarcinoma treated with 10 mg and 40 mg daily had confirmed partial responses (PR) and remain on study after 14 and 5 months, respectively. The pt with PR at 10mg has a complex heterozygous EGFR mutation in tumour cells, including a deletion and missense mutations of 4-amino acids (WT: KELREATSPKANKEILD; Patient: KEP—-SPRANKEILD) in the kinase domain, but a wildtype HER2 domain. One pt with cervical and one pt with colorectal cancer had stabilization of disease and tumour markers for 6 and 4 months, respectively. Conclusions: BIBW 2992 shows promising activity with skin rash as the main AE. Maintained PR seen in lung adenocarcinoma indicates effective mutated EGFR kinase modulation at the lowest evaluated dose level. Exploration of BIBW 2992 in Phase II is warranted. [Table: see text]