A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours

Abstract

To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.

BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models

“…Daily oral treatment with BIBW2992 at 20 mg/kg for 25 days resulted in dramatic tumor regression with a cumulative treated/control tumor volume ratio (T/C ratio) of 2% (Figure 3a), and downregulation of EGFR and AKT phosphorylation, as detected by immunohistochemical staining of tissue sections ( Figure 3b). With this dose schedule, the animals showed no clinical signs of intolerability and gained weight similar to untreated littermates, with systemic exposure (C max , AUC 0À24 h in Supplementary Table 5) comparable to the pharmacokinetic data seen in Phase I studies with effective doses of BIBW2992 (Eskens et al, 2008). When drugs were given at respective maximum tolerated doses in the A431 model, BIBW2992 was more potent than either gefitinib (T/C ¼ 46% at 75 mg/kg/day) or lapatinib (T/C ¼ 32% at 2 Â 100 mg/kg/day) (data not shown).…”

“…Furthermore, treatment of NIH-3T3 cells expressing the EGFR mutants with BIBW2992 inhibited receptor autophosphorylation at least 100-fold more effectively than erlotinib (Figure 1b). IC 50s for inhibition in these cell-based transformation models are generally well below 300 nM, the maximum achievable drug plasma concentration (Eskens et al, 2008). One notable exception is the A549 cells, which express wild-type EGFR and HER2 and are resistant to BIBW2992.…”

“…inhibits EGFR and HER2 kinase activity in vitro BIBW2992, an anilino-quinazoline designed as an irreversible, dual EGFR/HER2 inhibitor, possesses a functional Michael acceptor group similar to the one found in the quinoline-derived irreversible EGFR inhibitors EKB-569 and HKI-272, allowing covalent modification of the ATP-binding site of the kinase domains of EGFR (Cys 773) and HER2 (Cys 805) (Rabindran et al, 2004;Eskens et al, 2008). In cell-free in vitro kinase assays, BIBW2992 shows potent activity against wild-type and mutant forms of EGFR and HER2, similar to gefitinib in potency for L858R EGFR, but about 100-fold more active against the gefitinibresistant L858R-T790M EGFR double mutant, with an IC 50 of 10 nM (Table 1).…”

Algorithms for Management of Patients With Adverse Events on Therapy With Tyrosine Kinase Inhibitors Egfr

“…Дерматологические НЯ, такие как папуло-пустулезная (угревая) сыпь, зуд, сухость/трещины кожи, алопеция, гипертрихоз и паронихия, описывались у онкологических больных, получавших ИТК-EGFR [29]. В клинических иссле-дованиях ИТК-EGFR III фазы у 54-89% пациентов наблю-дались кожные НЯ любой степени и 0-16,2% -НЯ ≥ 3 степени [29][30][31][32][33][34][35][36][37][38][39][40][41]. Критерии NCI-CTCAE являются стандар-том классификации и методом оценки степени тяжести, широко используемым всем онкологическим сообществом при описании НЯ в клинических исследованиях терапии рака.…”

Radiotherapy and inhibition of the EGF family as treatment strategies for prostate cancer: combining theragnostics with theragates

“…This inhibitor has demonstrated improvements over first-generation EGFR inhibitors in lung cancer and squamous cell carcinoma models [47][48][49]. Tolerability and pharmacokinetics of the inhibitor in patients have recently been investigated in a phase I study by Eskens et al [50], and phase II results reporting clinical activity of the compound have been described [51][52][53].…”