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 follows:

  • 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 cancer.
  • 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 cancer.

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 tyrosine kinases.2

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 are unknown.

Adverse Events3

  • 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 were discontinued.
  • 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


  1. Wikstrand CJ, Bigner DD: Prognostic applications of the epidermal growth factor receptor and its ligand, transforming growth factor-alfa. J Natl Cancer Inst 90:799-800, 1998
  2. 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
  3. 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
  4. Huang SM, Harari PM: Modulation of molecular targets to enhance radiation. Clin Cancer Res 6:323-325, 2000