Director Department of Oncology/Haematology
Division of Medical Oncology
SG Moscati Hospital
The chemotherapy-based treatment of metastatic solid tumours has reached a plateau in improving survival in cancer patients. Advances in the identification of molecular targets for cancer treatment have led to the development of several new biological molecular targeted agents (see Table 1). Several targeted agents have been investigated in cancer clinical trials, mainly in advanced disease. Clinically meaningful advances have already been achieved in advanced nonsmall-cell lung cancer (NSCLC), breast cancer and colorectal cancer. Among the novel biological agents targeting selective molecular mechanisms involved in cancer cell progression, small-molecule tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR), anti-EGFR monoclonal antibodies (MAbs), anti-HER2 MAbs and anti-vascular endothelial growth factor (VEGF) antibodies are the most interesting, with extensive clinical data supporting their efficacy.
The EGFR plays an essential role in normal cell growth and differentiation, and in the survival of healthy and cancerous cells. EGFR expression is a common feature of nonhaematological malignancies and is associated with poor clinical prognosis. The main approaches to blocking the EGFR are small-molecule tyrosine kinase inhibitors and MAbs.(1,2)
EGFR tyrosine kinase inhibitors
The small-molecule EGFR tyrosine kinase inhibitors (EGFR-TKIs) are reversible competitors with ATP for binding to the intracellular catalytic domain of the tyrosine kinase. They inhibit tyrosine kinase autophosphorylation in the intracellular domain and downstream intracellular signalling. These agents are administered orally and are generally well tolerated.
Gefitinib (ZD1839, Iressa), a low-molecular-weight anilinoquinazoline, is an orally available selective and reversible EGFR inhibitor. Two large randomised phase II trials of gefitinib as monotherapy, IDEAL 1 and 2 (Iressa Dose Evaluation in Advanced Lung cancer), were conducted in patients with advanced NSCLC progressed after one or more chemotherapy regimens. About 200 patients were enrolled in each trial and received gefitinib (250 or 500mg) daily. Overall response rates of 10–20% and symptom improvement rates of about 40% were observed. The 250mg dose was as active as the 500mg dose. However, the tolerability of the 250mg dose was significantly better in terms of acne-like skin rash and diarrhoea, the main adverse events associated with gefitinib use.(3,4) On the basis of these clinical trials, gefitinib has been licensed for third-line treatment of platinum- and docetaxel-refractory advanced NSCLC in several countries, including Japan, Australia and the USA.
Erlotinib (OSI-774, Tarceva) is another orally available small molecule designed to target EGFR-TK reversibly. Its toxicity profile is similar to that of gefitinib. In a phase III randomised placebo-controlled trial, erlotinib was shown to prolong survival (6.7 months, versus 4.7 months for placebo; p=0.001) in NSCLC patients after first- or second-line chemotherapy. The analysis of quality of life and time to deterioration showed statistically and clinically meaningful benefit for patients randomised to erlotinib. Moreover, erlotinib was shown to be active (response rate of 8.9%) and safe (only 5% of patients discontinued treatment due to toxicity).(5)
MAbs prevent ligand binding to the extracellular domain of EGFR and subsequent activation of the receptor. Cetuximab (IMC-C225, Erbitux), a human–mouse chimeric monoclonal antibody, is highly EGFR-selective. In a recent phase II randomised study in patients with irinotecan-refractory metastatic colorectal cancer expressing EGFR, cetuximab (400mg/m(2) initial dose, followed by 250mg/m(2)) weekly plus irinotecan produced a greater rate of partial response and disease control (partial response plus stable disease) and an increased time to disease progression, compared with cetuximab monotherapy. The most common adverse events associated with cetuximab were acne-like rash, asthenia, abdominal pain and nausea/vomiting.(6) Cetuximab has been approved, in combination with irinotecan, for chemorefractory advanced colorectal cancer in Switzerland and the USA. The drug is currently being investigated in other tumours, such as head and neck cancer and NSCLC.
HER-2/neu is a tyrosine-kinase membrane receptor that, when activated, induces a phosphorylation cascade in cytoplasmic kinases, leading to increased transcription of nuclear proteins and cellular growth. Trastuzumab is a humanised MAb developed to target the HER2 receptor, which is overexpressed in some cancers (including 25–30% of breast cancers). Trastuzumab binds with high affinity to the extracellular domain of HER2, thus inhibiting the proliferation of tumour cells that overexpress HER2.
A large, well-designed, multicentre study found that the addition of trastuzumab to an anthracycline plus cyclophosphamide regimen or to paclitaxel as first-line therapy for metastatic breast cancer overexpressing HER2 significantly increased time to disease progression, rate of objective response, duration of response and survival compared with chemotherapy alone (median survival time of 25.1 months vs 20.3 months; p=0.01).(7)
Trastuzumab is generally well tolerated by most patients; the most significant adverse effects are acute fever and/or chills and the potential to cause cardiac dysfunction. Trastuzumab is indicated for use with paclitaxel as first-line therapy, or as a single agent in second- or third-line treatment regimens for patients with metastatic breast cancer overexpressing HER2. Adjuvant trials with trastuzumab in early breast cancer are ongoing.
VEGF is the single most commonly upregulated angiogenic factor in both grafted and naturally occurring tumours. Thus, it is a prime target for antivascular therapy. Bevacizumab (Avastin) is an anti-VEGF recombinant humanised MAb that blocks the binding of all VEGF isoforms to the receptors, inhibiting the biological activities of VEGF.
A phase III randomised trial enrolling 813 patients recently demonstrated that the addition of bevacizumab to fluorouracil-based combination chemotherapy (irinotecan plus fluorouracil plus leucovorin) resulted in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer. The median duration of survival was 20.3 months in the chemotherapy plus bevacizumab group, compared with 15.6 months in the group given chemotherapy alone (hazard ratio for death of 0.66; p<0.001).(8) Phase III randomised trials of bevacizumab in advanced NSCLC are ongoing.
The first clinical trials with targeted agents in cancer treatment have been conclusive, with survival improvement achieved in the treatment of some metastatic solid tumours. Hospital and prescribing practice policy may be extensively affected by the approval of molecular targeted anticancer therapies in a near future, due to much higher costs compared with traditional chemotherapeutics.
- Ciardiello F, Tortora G. Clin Cancer Res 2001;7:2958-70.
- Mendelsohn J, Baselga J. J Clin Oncol 2003;21:2787-99.
- Fukuoka M, Yano S, Giaccone G, et al. J Clin Oncol 2003;21:2237-46.
- Kris MG, Natale RB, Herbst RS, et al. JAMA 2003;290:2149-58.
- Shepherd FA, Pereira J, Ciuleanu E, et al. Proc Am Soc Clin Oncol 2004;23:7022.
- Reynolds NA, Wagstaff AJ. Drugs 2004; 64:109-18.
- Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med 2004;350:2335-42.
- Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. N Engl J Med 2001;344:783-92.
11th World Conference on Lung
3–6 July 2005