MB BS FRACP
Medical Oncologist/Cancer Geneticist
Murdoch Children’s Research Institute
Royal Children’s Hospital
In an era of molecular medicine, targeted biological therapies are the focus of much research and development. As mechanisms of specific tumour development are unravelled, new targets become available for rational drug design to block the growth of both haematological and solid tumours.
Chronic myeloid leukaemia
Imatinib, a dramatic success story as a targeted therapy, is an orally active tyrosine kinase inhibitor (TKI) that is the standard of care as initial treatment of choice for most patients with chronic myeloid leukaemia (CML).(1) In CML, a translocation between chromosomes 9 and 22 creates the novel fusion gene BCR-ABL. The protein product, BCR-ABL, is a tyrosine kinase (an enzyme that phosphorylates proteins) with constitutive activity with deregulation of signalling pathways and increased tumour cell growth. Imatinib inhibits the BCR-ABL tyrosine kinase by competing with the transfer of phosphate from ATP. Initial studies of imatinib in patients with interferon-resistant chronic phase CML and blast crisis showed significant activity, with haematological and cytogenetic responses superior to those of other medical therapies.(2,3) In a phase III study, imatinib was superior to the standard first-line chemotherapy for chronic phase CML in terms of cytogenetic responses and progression-free survival, but complete molecular remissions remain elusive.(4) No overall survival benefit has been demonstrated to date. Resistance to imatinib occurs when resistant clones arise due to random mutation in the kinase domain of the enzyme.
Gastrointestinal stromal tumours
Imatinib mesylate inhibits a small number of other receptor tyrosine kinases, including kit (CD117) and platelet-derived growth factor receptor (PDGFR). A gastrointestinal stromal tumour (GIST) is a mesenchymal tumour of the gut that is distinguishable from other similar tumours by the expression of kit (CD 117). Activation of the kit receptor tyrosine kinase occurs early in the development of most GISTs, due to a gain of function mutation in the c-kit gene with constitutive enzyme activation and increased downstream signalling. Most c-kit mutations occur in exon 11.(5) A small number of GISTs result from mutational activation of the tyrosine kinase PDGFRa.(6) Imatinib has a dramatic effect on previously treatment-refractory metastatic and unresectable GIST tumours, with 54% of patients obtaining a partial response and 82% obtaining clinical benefit.(7) There is a strong association between clinical response to imatinib and the tumour genotype in c-kit, with response rates highest in those with exon 11 mutations.(8) Daily dosing of imatinib is 400, 600 or 800mg orally. Treatment is well tolerated, with only mild side-effects, including oedema, fatigue, nausea, neutropenia and skin rash. Few patients experience significant toxicity. Tumour-associated bleeding can occur in patients with bulky GIST disease who have a rapid treatment response. SU11248 is a novel multitargeted tyrosine kinase inhibitor with activity in patients with imatinib-resistant GIST, and also shows promise in the treatment of metastatic renal cell cancer.
EGFR tyrosine kinases
The epidermal growth factor receptor (EGFR) is overexpressed in 40–80% of nonsmall-cell lung cancer (NSCLC) and in other epithelial cancers (eg, breast, colorectal, glioblastoma or head and neck). Overexpression correlates with poor outcome.(9) When EGF and other ligands bind this receptor, a cascade is initiated, with recruitment of downstream effectors and activation of cell survival signals. Gefitinib (Iressa) and erlotinib (OSI-774, Tarceva) compete with ATP to bind the tyrosine kinase portion of EGFR, thereby reducing the receptor’s activity with cell cycle arrest, potentiation of apoptosis and inhibition of angiogenesis.
In phase II studies (IDEAL 1 and 2), gefitinib (250–500mg oral daily) has shown activity in patients with previously treated advanced NSCLC, with response rates of 10–18% and significant improvements in disease symptoms.(10) However, two phase III trials (INTACT 1 and 2) of this agent in combination with chemotherapy (carboplatin–paclitaxel and cisplatin–gemcitabine) failed to show improvements in progression-free survival, overall survival or time to worsening of symptoms.(11) Bronchoalveolar cell carcinoma and being a never-smoker are associated with gefitinib response.
Specific mutations in the EGFR gene correlate with clinical responsiveness to gefitinib; thus, screening lung cancers for this mutation may identify patients who will be responders to this agent.(12) Single-agent activity has been shown in phase II studies for head and neck cancer, but not in patients with hormone-refractory prostate cancer and previously treated colorectal cancer. Toxicity includes diarrhoea and skin rash. Interstitial lung disease rarely occurs.
Erlotinib also demonstrated activity in phase II studies conducted in patients with NSCLC, head and neck and ovarian cancers. Response rates of 12% were obtained in previously treated patients with advanced stage NSCLC at an oral dose of 150mg daily. Phase III studies with chemotherapy as first-line treatment of NSCLC found that combination treatment was not superior to chemotherapy alone.(13,14) A phase III study in patients with refractory NSCLC in which patients were randomised to erlotinib or placebo found a superior median survival (statistically significant) in the erlotinib arm (6.7 vs 4.7 months) and significantly better quality of life in the treatment arm. Side-effects included skin rash and diarrhoea, with no evidence of an increased incidence of interstitial lung disease.(15)
Early antibody constructs were of murine nature and induced strong immune responses in humans, which limited their use. Genetic engineering has enabled the development of chimeric (65–90% human) and humanised antibodies (95% human) with fewer side-effects and an enhanced capacity to recruit the human immune system (complement and cytotoxic cells) to target tumour cells. Monoclonal antibodies affect tumour cell apoptosis by activation of the human immune system or by delivery of radioisotopes, toxins or drugs to tumour sites.
Rituximab is a chimeric antibody that targets the CD20 cell surface protein present on most B-cell lymphomas. Initial activity of this construct was demonstrated in patients with relapsed low-grade lymphoma who were given a 375mg/m(2) intravenous (IV) course weekly for four weeks, with half of the patients responding and a median response duration of one year.(16)
In a phase III study in untreated patients with follicular non-Hodgkin’s lymphoma (NHL), rituximab administered on day 1 of eight cycles of CVP chemotherapy (cyclophosphamide, vincristine and prednisolone) was compared with CVP alone. A superior response rate (81 vs 57%) and time to treatment failure (27 vs 7 months) were observed in the combination arm, without increased side-effects.(17) In the phase III GELA study, patients aged 60 and over with stages II–IV diffuse large B-cell lymphoma (DLBCL) received first-line treatment with eight cycles of R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine and prednisolone) compared with eight cycles of chemotherapy alone. A higher complete response rate was observed in the combination arm (76 vs 63%) and at median follow-up of three years, higher event-free survival (53 vs 35%) and overall survival (62 vs 51%), all statistically significant, were seen in the combination arm.(18) Similarly, in patients aged 60 and under, the Mabthera International Trial (MinT) study was terminated at its first preplanned interim analysis in December 2003, when the combination treatment achieved significantly superior complete response rates, time to treatment failure and overall survival.(19)
R-CHOP is superior to chemotherapy alone in the first-line treatment of mantle cell lymphoma. Rituximab has activity in chronic lymphocytic leukaemia and hairy-cell leukaemia, and has been used during stem cell mobilisation before and after autologous bone marrow transplantation for NHL.(20–23) The toxicity of rituximab includes infusion reactions, which are usually mild and consist of fever, chills and rash. Rarely, a severe cytokine release syndrome can occur, especially in patients with high tumour burdens. Significant myelosuppression rarely occurs.
(90)Y ibritumomab tiuexetan (Zevalin) and (131)I tositumomab (Bexxar) are two constructs (each consisting of an antibody linked to a radionuclide, 90-yttrium and 131-iodine, respectively) that target radiation to CD20-positive cells. These radiopharmaceuticals are administered in a single course of treatment, and have been studied in pretreated patients with low-grade NHL, where they have demonstrated significant activity in comparison with, and in patients refractory to, rituximab.(24,25) Myelosuppression due to bone marrow targeting is frequently of grade 3–4 in severity. Myelodysplasia and acute leukaemia have been reported; however, most patients had received prior alkylator therapy.
These agents are now being used in combination with chemotherapy as first-line treatment of patients with low-grade lymphoma, and their place in the treatment of high-grade lymphoma remains undefined.
Trastuzumab is a humanised antibody that targets and blocks signal transduction by HER2, a tyrosine kinase receptor that is overexpressed in 30% of breast cancers and in NSCLC, ovarian and prostate cancers. Tumours with high HER2 overexpression or with gene amplification derive most clinical benefit from trastuzumab.(26) Single-agent use in pretreated patients with metastatic breast cancer (4mg/mg IV week 1; 2mg/kg weekly thereafter) results in a 15% response rate, with median response duration of nine months.(27) In a phase III study, HER2-positive metastatic breast cancer patients were randomised to antibody and chemotherapy (paclitaxel or doxorubicin and cyclophosphamide), or to chemotherapy alone. The combination treatment arm achieved significantly superior response rates (49 vs 32%), median duration of response (9.3 vs 5.9 months) and a better overall median survival (25.4 vs 20.3 months), with superior gains in quality of life.(28) International adjuvant trials of this agent are ongoing.
Toxicity includes infusion reactions and cardiotoxicity, with cardiac dysfunction in 3–7% of patients receiving antibody monotherapy and in up to 27% of patients receiving concurrent anthracycline. Most cases improve with treatment, but monitoring of cardiac function is important at baseline and during treatment.(29)
Bevacizumab is a humanised monoclonal antibody that binds with vascular endothelial growth factor (VEGF), thus preventing interaction with its receptors, VEGFR1 and VEGFR2. VEGF is essential for tumour growth as a proangiogenic growth factor that regulates vascular proliferation and permeability and acts as an antiapoptotic factor for new blood vessels. In the first-line treatment of metastatic bowel cancer, bevacizumab was the first antiangiogeneic agent to produce a survival benefit in the treatment of cancer. Patients were randomised to antibody (5mg/kg IV once every two weeks) and chemotherapy (Saltz regimen of bolus 5-fluorouracil, folinic acid and irinotecan) or to chemotherapy alone. Combination treatment produced higher response rates (45 vs 35%), median progression-free survival (10.6 vs 6.2 months) and median overall survival (20.3 vs 15.6 months), all of which were statistically significant. Side-effects included an increased incidence of hypertension, treated with oral medications in the antibody arm.(30) Studies in combination with oxaliplatin and in the adjuvant setting will follow. This construct has also shown activity in metastatic carcinoma of the kidney and advanced NSCLC.(31,32)
Cetuximab is a chimeric antibody that blocks signal transduction through EGFR (or ERBB1) by competing with endogenous ligands (including EGF) for its receptor. This construct has activity in EGFR-positive irinotecan-refractory metastatic bowel cancer. Retreatment of these patients with cetuximab (400mg/m(2) IV week 1; 250mg/m(2) weekly thereafter) and irinotecan produced superior results compared with treatment with cetuximab alone. Response rate (23 vs 11%), median time to progression (4.1 vs 1.5 months) and median overall survival (8.6 vs 6.9 months) all favoured the combination arm. However, the survival advantage was not statistically significant.(33) Activity has also been demonstrated in head and neck and pancreatic cancers, as well as NSCLC.
A phase III study has demonstrated that use of cetuximab in combination with high-dose radiotherapy compared with radiation alone significantly prolongs survival in patients with locoregionally advanced squamous cell carcinoma of the head and neck. Side-effects consist of infusion reactions and a rash, the rash being predictive of a favourable treatment response.(34)
Bortezomib (PS-341, Velcade) is a member of a novel class of anticancer drugs that inhibit the proteosome. The proteosome is a multi-subunit protein complex present in the nucleus and cytoplasm of eukaryotic cells. It degrades cellular proteins and regulates levels of short-lived cell-regulatory proteins, and in particular a protein inhibitor of nuclear factor kB (NFkB), which is a transcription factor. When not bound by its inhibitor, NFkB activates the transcription of genes whose proteins promote proliferation.(35) Bortezomib has been studied as a single agent administered IV (1.3mg/m(2) twice weekly for two weeks with one week off) for eight cycles in patients with refractory multiple myeloma with significant activity. Thirty-five percent of patients responded, 10% with a complete response, and median duration of response was 12 months. Toxicity included neutropenia, thrombocytopenia and peripheral neuropathy.(36) A phase III trial compared this agent with dexamethasone in patients with relapsed myeloma. Bortezomib demonstrated superior efficacy, with significant improvement in time to progression (5.7 vs 3.6 months), with a trend for a lesser number of significant infections.(37) Phase I and II trials of this agent are ongoing, both as a single agent and in combination with other agents in the treatment of a number of haematological and solid tumours.
Raf pathway/BRAF inhibitor
Ras genes are mutated in a range of human cancers. Mutant Ras proteins activate the Raf/MAPK (mitogen-activated protein kinase) pathway, with subsequent activation of cell proliferation. Farnesyl transferase inhibitors block the activation (farnesylation) of Ras, and have been studied in early phase studies, showing limited clinical activity. The BRAF gene is also activated by mutation in a number of cancers, particularly in melanoma and papillary carcinoma of the thyroid. BAY 43-9006 blocks the Raf pathway, which controls tumour growth and proliferation, as well as the VEGF angiogenic pathway. This oral agent, administered in a phase I/II study dosed at 100–400mg twice daily in combination with carboplatin and paclitaxel in patients with metastatic melanoma, resulted in 40% of patients obtaining a partial response and 80% of patients achieving clinical benefit, with a favourable safety profile. Median time to progression was not reached at five months follow-up. Further randomised trials are planned in melanoma. Activity has also been demonstrated in patients with ovarian and pancreatic cancer in phase I/II studies of the drug in combination with gemcitabine; further studies are planned.(38,39)
Cell cycle inhibitors
Mammalian target of rapamycin (mTOR) is an essential protein kinase that acts as a gatekeeper for cell cycle progression from the G1 to the S phase. The TOR pathway is upregulated in many cancers. Rapamycin and its analogues are specific inhibitors of TOR, and are in phase I–III clinical trials. CCI-779 is an mTOR kinase inhibitor that inhibits cell cycle progression. It has demonstrated activity in renal cell carcinoma, and phase III studies are planned. Phase II studies are ongoing in prostate, breast and pancreatic cancers. Side-effects include rash, mucositis and nausea.(40)
Cyclooxygenase-2 (cox-2), an enzyme of the arachidonic acid cascade, is upregulated and overexpressed in many cancers. This is associated with aggressive tumour behaviour. Cox-2 inhibitors reduce polyp formation in familial adenomatous polyposis (FAP), and may enhance responses to radiotherapy and chemotherapy.
These agents are being studied in phase III trials in colorectal, breast and lung cancers, with proof of their benefit as cancer therapeutics yet to be demonstrated.41
Overexpression of Bcl-2 protein makes cancers resistant to apoptosis. This protein is a target for antisense molecules such as G3139. This antisense oligonucleotide targets specific Bcl-2 RNA sequences with complementary oligonucleotides to reduce the translation of the Bcl-2 mRNA message into a protein, thereby limiting bcl-2 gene and protein expression.
Early-phase studies have been carried out with this agent in diverse tumour types, including small-cell lung cancer and NHL.
Targeted therapies have expanded treatment options for cancer patients. Selecting patients who are most likely to respond to these therapies and establishing how best to combine these agents with each other and with chemotherapy and radiotherapy for maximal antitumour efficacy and optimal patient benefit remains to be defined. How to afford many of these novel agents is another problem that will be difficult to solve.
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Cancer trials National Cancer Institute of America