CANCER

LUNG CANCER is a form of cancer which can be very difficult to treat, with average survival time from diagnosis of approximately six months to one year. Platinum compounds (carboplatin, cisplatin), anti-metabolites (gemcitabine, methotrexate), microtubule inhibitors (vincristine, vinorelbine, paclitaxel, docetaxel) and the topoisomerase inhibitor etoposide are often used for chemotherapy, usually in combination, but side-effects can limit therapy.

One promising new class of medicines that may help to extend survival is the kinase inhibitors. These inhibit enzymes closely involved in key cell functions and their effects vary according to which enzymes they inhibit. Many, but not all, of them are given orally. Erlotinib (Tarceva, Roche) has already shown a survival benefit in advanced non-small cell lung cancer (NSCLC) and is indicated for use in advanced disease where chemotherapy has failed. It is now in Phase 3 trial to see whether it is also effective in those who have not already undergone chemotherapy. AZD2171 (AstraZeneca), which works in a similar way, is in Phase 2/3 trial. AstraZeneca also has ZD6474 in Phase 3 trial for NSCLC. Another multi-kinase inhibitor that targets an even wider range of enzymes is sorafenib, from Bayer and Onyx, which has now entered Phase 3 study. Other kinase inhibitors in Phase 2 development include Cyclacel's seliciclib, XL999 (Exelixis), sunitinib malate (Sutent, Pfizer) and Wyeth's HKI-272.

Several monoclonal antibodies are being investigated in NSCLC. Cetuximab (Erbitux, Merck Pharmaceuticals) and bevacizumab (Avastin, Roche) are in Phase 3 trial, while mapatumumab (Human Genome Sciences) and matuzumab (Merck Pharmaceuticals) are at Phase 2. Others in development include CDP-791 (UCB, Phase 2), nimotuzumab (YM Biosciences, Phase 2) and panitumumab (Amgen, Phase 1).

A variety of cell cycle-disrupting agents are in Phase 2 development, including E7389 and E7070 (Eisai), Tasidotin (Genzyme) and ispinesib (Cytokinetics).

Vaccine approaches are also being tried. Aphton Biopharma's IGN101 stimulates an immune response against a protein on some tumour cells (EpCAM) and is in Phase 2/3 trial. Merck Pharmaceuticals is developing a vaccine (L-BLP25, Stimuvax), which has entered Phase 3 trial. In a Phase 2 trial, patients with stage IIIB NSCLC given the vaccine showed an average survival time of 30.6 months, compared with 13.3 months in those not given the vaccine. GlaxoSmithKline also has a therapeutic vaccine which is in Phase 2 study.

Among other advanced projects are pemetrexed (Alimta, Eli Lilly; Phase 3), Pfizer's PF-3512676 (Phase 3), Telik's TLK-286 (Phase 3), Antisoma's AS1404 (Phase 3), Introgen's Advexin (Phase 2), Millennium's bortezomib (Phase 2), Schering's MS-275 and ZK-EPO (both Phase 2) and Sunesis Pharma's SNS-595 (Phase 2).

With such a large array of new initiatives under development, it must be hoped that survival rates in non-small cell lung cancer, which have hardly risen over the last twenty years, can be substantially improved.

OVARIAN CANCER is less common than lung cancer, but is still a significant cause of death. New therapies are needed, as five year survival rates are still below 30 per cent and relatively few medicines are authorised for use in ovarian cancer. GlaxoSmithKline's topotecan (Hycamtin) is in Phase 3 trial for first-line use, as is Roche's bevacizumab (Avastin) and the microtubule stabiliser patupilone (EPO 906) of Novartis. A completely new agent also at Phase 3 is PharmaMar's trabectedin, a molecule originally discovered in a marine organism, that inhibits cell division and DNA repair.

Compounds in Phase 2 trials include Eli Lilly's pemetrexed, Antisoma's AS1404, ispinesib (Cytokinetics), Schering's ZK-EPO and Roche's pertuzumab (Omnitarg). OSI Pharmaceuticals is testing a form (OSI-211) of lurtotecan in Phase 2 for relapsed ovarian cancer. Menarini's abagovomab is being prepared for Phase 3 studies in prevention/delay of relapse.

PANCREATIC CANCER is another condition with very poor treatability. 5-FU and gemcitabine (Gemzar, Lilly) are the main chemotherapy medicines used, often together with radiotherapy, but response rates are not encouraging and survival is usually only a matter of months. The first agent to have shown a significant increase in survival when added to standard gemcitabine chemotherapy is erlotinib (Tarceva, Roche). However, the survival rate was still low, with only 24 per cent of patients alive after one year.

Phase 3 trials in progress include studies of the monoclonal antibodies cetuximab (Erbitux, Merck Pharmaceuticals) and bevacizumab (Avastin, Roche) and of the cytotoxic agents (those that kill the cancer cells) capecitabine (Xeloda, Roche), tegafur-uracil (Uftoral, Merck Pharmaceuticals) and a new microtubule inhibitor XRP 9881 (Larotaxel, sanofi-aventis). Among new cytotoxic agents at Phase 2 is Eisai's cell cycle disrupting agent E7070 (indisulam) and Pfizer's multi-targeted kinase inhibitor AG 13736 (axitinib).

Also at Phase 2, GenVec is exploring a gene therapy approach. Direct injection of this material (TNFerade) into the tumour, followed by chemotherapy, causes the generation of an anti-cancer substance called tumour necrosis factor-alpha (TNF) in the tumour itself. Oxford BioMedica is also using a gene therapy approach with their agent MetXia, which delivers a gene into the tumour, where it stimulates local production of a cytotoxic substance. It is hoped that this strategy will result in enhanced elimination of tumour cells.

PROSTATE CANCER has a much better prognosis than pancreatic cancer. While a tumour confined within the prostate itself is usually treated by surgery (radical prostatectomy) or radiation therapy, about half of all cases have already metastasised by the time they are discovered and require additional treatment. This usually involves therapy with hormonal agents such as gonadotrophin releasing hormone (GnRH) agonists triptorelin (Decapeptyl, Ipsen), leuprorelin (Prostap, Wyeth), buserelin (Suprefact, sanofi-aventis) or goserelin (Zoladex, AstraZeneca) or anti-androgens, e.g. flutamide, bicalutamide or cyproterone acetate. Typically, these are prescribed for advanced disease. However, bicalutamide (Casodex, AstraZeneca) is also used in non-metastatic disease. Docetaxel (Taxotere, sanofi-aventis) is also available for treatment of metastatic disease that has not responded to hormonal treatment.

Medicines development has tended to concentrate on agents for treating late-stage disease. A number of new small molecule agents are in Phase 2 development, including:

• Ambrilia Biopharma's Laminin receptor binding peptide PCK3145
• Antisoma's vascular targeting agent DMXAA (AS1404)
• Astellas's survivin expression inhibitor YM-155
• AstraZeneca's endothelin-A receptor antagonist ZD 4054
• Genzyme's tubulin-disrupting dolastatin analogue Tasidotin
• OncoGenex's clusterin-inhibiting antisense oligonucleotide OGX-011
• Pfizer's multi-targeted kinase inhibitor sunitinib malate (Sutent)
• PharmaMar's marine-derived cyclic peptide Aplidin
• YM BioScience's chemopotentiator tesmilifene.

These compounds are generally at too early a stage of development for their efficacy to be judged. However, some encouraging data on efficacy are available for a number of anti-tumour vaccines that have progressed further in development. Cell Genesys has a vaccine (GVAX) comprised of two genetically modified prostate cancer cell lines. It is in Phase 3 trials in patients with metastatic disease. Dendreon Corp is also developing a prostate cancer vaccine (sipuleucel-T, PROVENGE) and has reported results from a Phase 3 trial in patients with hormoneresistant metastatic cancer. In this study, 34 per cent of those who had received the vaccine were alive at 36 months as compared with 11 per cent who had been given placebo. Onyvax has started a Phase 3 trial of its Onyvax-P vaccine, which contains antigens from three prostate cancer cell lines. In addition, Oxford bioMedica is studying its TroVax vaccine in prostate cancer (Phase 2). Results from these various projects so far suggest that vaccines may represent a promising new approach to the treatment of advanced prostate cancer.

Monoclonal antibodies are also being explored in prostate cancer. Bevacizumab (Avastin, Roche) has reached Phase 3 trial, as has denosumab (Amgen), which is being studied for its effects on bone metastases. Monoclonal antibodies in Phase 2 study include MDX-070 (Medarex), adecatumumab (MT201, Serono), and MLN2704. In addition, Merck Sharp & Dohme is developing AGS-PSCA in Phase 1 trial and Pfizer is developing CP-751871, a monoclonal antibody to IGF-1R, at the same stage.

While some prostate tumours progress only slowly, others are much more invasive, giving rise to bone metastases and markedly reducing survival. Unfortunately, tests are not yet available to determine the risk of progression. The commonly-measured prostate specific antigen (PSA) has been found to be an unreliable marker of the progression of malignancy. Several genes have now been suggested to be better markers, including the E2F3 gene identified by researchers at the Institute of Cancer Research of the University of London, and development of a reliable diagnostic test would be a great advance in managing this common cancer.

OTHER TUMOUR TYPES are less common, but the need to improve chemotherapy is just as acute and pharmaceutical companies have included them in their development programmes. There are development projects in many more areas than just the six detailed above.

• Recent positive developments in kidney cancer include the introduction of sorafenib (Nexavar, Bayer) and sunitinib (Sutent, Pfizer), while Wyeth's temsirolimus, GlaxoSmithKline's lapatinib and pazopanib, Novartis's rapamycin derivative RAD 001 (everolimus) and Roche's bevacizumab are all in Phase 3 trial.
• In brain cancer, temozolomide (Temodal, Schering- Plough), for newly-diagnosed glioblastoma, and carmustine implants (Gliadel implants, Link Pharmaceuticals) for malignant glioma have increased the therapeutic options available, while Eli Lilly's enzastaurin and Novartis's imatinib (Glivec) are in Phase 3 trials for glioblastoma.
• The arrival of cetuximab (Erbitux, Merck Pharmaceuticals) for locally advanced squamous cell carcinoma of the head and neck is a welcome advance and Amgen is studying panitumumab for this use (Phase 3).

Supportive treatment

Improved supportive treatments are also needed for chemotherapy to be applied productively and a range is in development that address the major side effects that can limit therapy.

• Anaemia may develop during chemotherapy and can now be managed using darbepoetin alpha (Aranesp, Amgen) and epoetin beta (Neorecormon, Roche). Roche also has a new preparation (R774, CERA) in Phase 2 trial.
• Mucositis of the mouth and throat is often seen with radiotherapy and high-dose chemotherapy and palifermin (Kepivance, Amgen) is available for treating this. Other compounds in development for this use include RK-0202 (RxKinetix) and ATL-104 (Alizyme), which have both completed Phase 2 studies.
• Nausea and vomiting is also a problem with chemotherapy, especially where it involves platinum compounds. Several effective compounds that much reduce this problem are now available, and Merck Sharp & Dohme has aprepitant (Emend), a new class of anti-emetic. GlaxoSmithKline has a further compound of this type in development: casopitant (Phase 3).

A great deal of effort is being put into researching anti-cancer medicines and there has been real progress over the past decade. Nevertheless, achieving long-term disease-free survival in many solid tumours remains an ambitious goal rather than an accomplished fact. Over time, however, as increasingly selective agents are developed, backed up by growing insight into the biology of cancer, disease management is being improved and patients' quality of life and life expectancy are being continually improved.

FOR FURTHER INFORMATION CONTACT:

Cancerbackup
3 Bath Place, Rivington Street
London, EC2A 3JR
Phone: 0808 800 1234 (Helpline)
Website: www.cancerbackup.org.uk

Macmillan Cancer Relief
89 Albert Embankment
London, SE1 7UQ
Phone: 0808 808 2020 (Helpline)
Website: www.macmillan.org.uk

Beating Bowel Cancer
39 Crown Road
St Margarets
Twickenham, TW1 3EJ
Phone: 020 8892 1331 (Helpline)
Website: www.beatingbowelcancer.org

Bowel Cancer UK
7 Rickett Street
London, SW6 1RU
Phone: 08708 50 60 50 (Helpline)
Website: www.bowelcanceruk.org.uk

Breast Cancer Care
Kiln House, 210 New Kings Road
London, SW6 4NZ
Phone: 0808 800 6000 (Helpline)
Website: www.breastcancercare.org.uk

Prostate Cancer Support Association
BM Box 9434
London, WC1N 3XX
Phone: 0845 601 0766 (Helpline)
Website: www.prostatecancersupport.co.uk

Roy Castle Lung Cancer Foundation
200 London Road
Liverpool, L3 9TA
Phone: 0800 358 7200 (Helpline)
Website: www.roycastle.org