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]

A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab

“…Afatinib showed a manageable side effect profile in this study. Similar to previous studies with afatinib, the most frequently reported AEs were diarrhea and rash [ 18 , 19 , 25 , 26 ]. These AEs were generally manageable with appropriate treatment pause, supportive care, and dose reductions.…”

“…Evidence of clinical activity of afatinib monotherapy has also been demonstrated in phase I dose-escalation studies in advanced solid tumors. Stable disease (SD) was achieved in five of 14 BC patients participating in phase I monotherapy trials for up to 12 weeks (three patients) and up to 24 weeks (two patients) [ 18 – 20 ].…”

Pharmacological characterization of MP‐412 (AV‐412), a dual epidermal growth factor receptor and ErbB2 tyrosine kinase inhibitor

“…BIBW‐2992 and HKI‐272 are irreversible‐type inhibitors in phase II studies. Dose‐limiting toxicities for BIBW‐2992 were diarrhea and skin rash, ( 32 ) whereas the most frequent severe adverse events for HKI‐272 were diarrhea and asthenia, surprisingly lacking skin rash. ( 33 ) Canertinib is also an irreversible‐type inhibitor and effective in preclinical cancer models, ( 34 ) but phase II studies were eventually disappointing, and further development was precluded.…”

The Role of EGFR Inhibition in the Treatment of Non-Small Cell Lung Cancer

“…BIBW 2992, an anilinoquinazoline designed to irreversibly bind EGFR and HER-2, suppresses the kinase activity of EGFR and HER-2 in tumor cells, including those with erlotinib-resistant isoforms (e.g., T790M) [95]. In phase I studies, BIBW 2992 has a demonstrated safety profile similar to that of other EGFR TKIs; associated AEs include rash and diarrhea [102,103]. In a single-arm phase II study (LUX-Lung 2) with a primary endpoint of RR, BIBW 2992 was administered to patients with advanced lung adenocarcinoma harboring activating EGFR mutations who are chemotherapy-naive (including patients who had received neoadjuvant/adjuvant chemotherapy) or who had experienced failure with first-line chemotherapy.…”