|| FOCUS ON OSI-774
OSI-774 (Tarceva, erlotinib):
The Drug Development Program currently has 5 studies that are ongoing,
or will be opening presently, with the new drug; OSI-774. They are as
- PHL 002 (open Nov 01)
A phase I/II study of OSI-774 in combination with cisplatin in patients
with recurrent or metastatic squamous cell cancer of the head and neck.
- PHL 003 (closed to accrual
for interim analysis)
A phase II study of OSI-774 in metastatic colorectal cancer.
- PA.3 (open Nov 01)
A randomized placebo controlled study of OSI-774 plus gemcitabine in
patients with locally advanced, unresectable, or metastatic pancreatic
- IND.148 (open June 02)
A phase II study of OSI-774 in patients with locally advanced and/or
metastatic carcinoma of the endometrium.
- IND.149 (open June 02)
A phase II study of OSI-74 given in combination with carboplatin in
patients with advanced and /or recurrent metastatic epithelial ovarian
OSI-774 is one of a number of epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitors. Such inhibitors have stemmed from a better
understanding of cancer cell biology, thereby rationally interfering with
the process of malignancy.
The EGFR is a transmembrane receptor, which has been found to play an
important role in cancer development and progression, including cell proliferation,
apoptosis, angiogenesis and metastatic spread. Stimulation of the receptor
activates a receptor linked tyrosine kinase enzyme, which will in turn
trigger a chain of biochemical reactions, which transmit the growth stimulus
to the cell nucleus. Several mechanisms are proposed for suppression of
apoptosis via EGFR signaling, including activation of the ras/raf/MEK
pathway (Fig 1). EGFR overexpression has been identified in a number of
tumour types, such as prostate, ovary, breast, lung, brain and the gastrointestinal
tract. This overexpression has been linked with a poor prognosis.1
OSI-774 is an orally active tyrosine kinase inhibitor. It inhibits EGFR
tyrosine phosphorylation and blocks transduction of proliferative signals
mediated by the EGFR in a concentration-dependent manner. OSI-774 was
selected for development as it is 1,000-fold more potent against EGFR
tyrosine kinase with negligible activity against other receptor and nonreceptor
Fig. 1. Simplified schematic
illustration of the EGFR system depicting EGFR, mitogen-activated protein
kinase signal transduction cascade to the nucleus, and stimulation of
cell cycle machinery. [reproduced with permission from Huang and Harari
and the American Association for Cancer Research, Inc.4].
A recent phase I study investigated a number of dosing schedules in patients
with advanced solid malignancies.3
Forty patients, received a total of 123 28-day course of OSI-774. The
median number of courses administered per patient was two (range, 1 to
20+). Thirty-seven patients had received cytotoxic therapy previously,
including 8 patients who had been treated with both chemotherapy and radiotherapy.
The maximum tolerated dose was found to be 150 mg /day as a continuous
daily dose schedule. At this dose level, dose-limiting toxicity occurred
in one of 12 patients. The principal toxicities of OSI-774 were cutaneous
and diarrhea. Although the rash and diarrhea seemed to be caused by inhibition
of the EGFR, the precise pathogenic mechanisms for these toxic effects
- Rash skin rash or dermatosis has been observed during the first
several days of treatment with OSI-774 in approximately 50% patients,
and has been observed to diminish in severity after 4 or more weeks
of treatment in many patients. The rash typically involves the face
in a periorificial distribution, as well as the upper trunk. The rash
has been characterized by clusters of monomorphic pustular lesions that
have resembled an acneiform-type drug eruption. In some patients, the
rash appeared to be treatable with standard acne therapies. Anecdotal
improvements have occurred with several agents, such as silver sulfadiazine
cream (flamazine® 10%) and oral minocycline.
- Diarrhea this has been observed in approximately 50% patients.
The frequency and severity of diarrhea has rarely hindered administration
of OSI-774. Symptoms are usually managed successfully with symptomatic
measures, such as loperamide.
- Keratitis ocular changes have been observed in animal studies.
The final 16 patients enrolled onto the study underwent serial ophthalmologic
examinations to evaluate potential corneal effects. Only 1 patient,
who wore contact lenses and had a normal examination immediately before
treatment, was found to have corneal edema, subepithelial infiltrates,
and a minimal decrement in visual acuity after a single 28-day course
of OSI-774 150 mg/day. These effects are probably related to the contact
lenses and resolved shortly after both treatment and contact lens use
- Nausea this is commonly observed, and is usually transient
in nature. Routine premedication is unnecessary, but symptomatic patients
should be treated with standard therapies.
Other toxicities include pruritus, mucositis, fatigue, transient elevations
of serum transaminases, hyperbilirubinemia and headache, which were
generally mild to moderate in severity.
Since cutaneous toxicity is presumably related to EGFR inhibition, skin
can be used as a pharmacodynamic marker to assess the relevant pathologic
and biologic effects of OSI-774. Skin biopsies will be performed in
two of the above studies. The relation of effects in the skin to inhibition
of the EGFR and the antitumour effect, may lead to the development of
assays to predict possible benefit from treatment. This would increase
the therapeutic index of OSI-774.3
- Wikstrand CJ,
Bigner DD: Prognostic applications of the epidermal growth factor receptor
and its ligand, transforming growth factor-alfa. J Natl Cancer Inst
- Moyer JD, Barbacci
EG, Iwata KK, et al: Induction of apoptosis and cell cycle arrest by
OSI-774, an inhibitor of epidermal growth factor receptor tyrosine kinase.
Cancer Res 57:4838-4848, 1997
- Hidalgo M,
Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774,
an epidermal growth factor receptor tyrosine kinase inhibitor, in patients
with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001
- Huang SM, Harari
PM: Modulation of molecular targets to enhance radiation. Clin Cancer
Res 6:323-325, 2000