New treatments in oncology

1. New treatments in oncology Priya Shah 7th November 2012

2. Imatinib • Dasatanib • Nilotinib • Erlotinib • Gefitinib • Lapatinib • Sorafenib • Sunitinib • Pazopanib • Vemurafenib • Rituximab • Trastuzumab • Pertuzumab • Ofatumumab • Ipilimumab • Cetuximab • Bevacizumab • Alemtuzumab • Panitumumab

3. Issues with traditional chemotherapy • Act on all rapidly dividing cells - non-selective - toxic to normal cells - often IV treatments - finite number of cycles

4. Targeted therapies • Targeted cancer therapies block the growth and spread of cancer by interfering with specific molecules involved in tumour growth and progression • Ideal target: key proteins or pathways that are present in cancer cells and absent in normal cells

5. Targeted therapies • Small molecules • Antibodies • Vaccines

6. Monoclonal antibodies

7. Mechanisms of action of targeted therapies • Interfere with cell growth signalling • Interfere with tumour blood vessel development • Promote specific death of cancer cells • Stimulate the immune system to destroy cancer cells • Deliver toxic drugs to cancer cells

8. Molecular markers

9. Role of molecular markers • Early detection/diagnosis • Prognosis • Prediction of toxicity, response, relapse

10. Prognostic versus predictive markers Prognostic Provides information on outcome, regardless of which treatment is used Predictive Provides information on outcome with regards to a specific therapy

11. Epidermal Growth Factor Receptor (EGFR) • Cell surface receptor for growth factors that has an important role in controlling cell growth and proliferation • Uncontrolled signalling from EGFR has been implicated in the pathogenesis of many human tumours

12. EGFR tyrosine kinase inhibitors • Erlotinib, gefitinib • High response rate in EGFR mutation positive lung cancer patients • Approved by NICE for 1st line use

13. EGFR inhibitors

14. EGFR inhibitors • Rash • Diarrhoea • Drug interactions

15. Crizotinib • Oral ALK (anaplastic lymphoma kinase) inhibitor • 5% NSCLC patients have an overactive ALK protein • Objective response rate of 57% • Responses have been durable (up to 15 months) • > 90% of patients had tumour shrinkage

16. Angiogenesis • Creation of new blood vessels • Once a tumour reaches a certain size (1 cubic millimetre), it requires a blood supply to continue growing • Many tumours release proteins such as vascular endothelial growth factor (VEGF) that bind to and activate endothelial cells of nearby existing blood vessels

18. Bevacizumab • Binds to VEGF and keeps it away from receptors on the surface of endothelial cells • Existing blood vessels no longer receive signals for increased blood flow so new blood vessels are not formed • Used in metastatic colorectal and breast cancer

19. Pazopanib • NICE approved first line treatment in patients with renal cell carcinoma • Activity against VEGFR, PDGF, c-kit • Overall progression free survival of 9.2 months versus 4.2 months in placebo arm • Common toxicities: hypertension and diarrhoea

20. Multi-targeted tyrosine kinase inhibitors

21. PARP inhibitors • PARP = poly ADP ribose polymerase 1 = a protein involved in DNA repair • PARP helps cancer cells avoid apoptosis • PARP inhibitors → prevent DNA repair → cancer cells more likely to undergo apoptosis • Use alongside standard chemotherapy • Olaparib is an example of a PARP inhibitor currently in clinical trials in breast and ovarian cancers

22. EMILIA study (2012) • Trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in HER2 positive locally advanced or metastatic breast cancer • T-DM1 is a 3 part immunoconjugate comprising trastuzumab, a stable linker and the potent cytotoxic agent DM1 • 978 patients

23. EMILIA study (2012) • 9.6 months PFS in the T-DM1 arm compared with 6.4 months in the capecitabine + lapatinib arm • 16.3% patients needed a dose reduction in the T-DM1 arm compared with 53.4% for the capecitabine dose and 27.3% for the lapatinib dose • Median overall survival has not been reached

24. Human Epidermal Growth Factor Receptor (HER2) • HER2 gene amplified in 20% of breast cancers • HER2 interacts with other receptors on the cell surface, activating signalling pathways that cause the cell to proliferate • Trastuzumab works by binding to HER2 and prevents it from interacting with other receptors • Trastuzumab also causes antibody-dependent cell mediated cytotoxicity • T-DM1: using targeted treatment to deliver a microtubule-disrupting cytotoxic agent to cancer cells whilst reducing normal tissue exposure

25. Ipilimumab • Treatment of advanced (unresectable or metastatic) melanoma • Stimulates the immune system to attack and destroy cancer cells by inhibiting CTLA-4 receptor on T cells • Median overall survival of 10 months in ipilimumab arm versus 6 months in vaccine arm • Immune-related adverse reactions

26. Ipilimumab

27. Summary of targeted therapy actions

28. Risks of targeted therapies

29. Cancer vaccines • Prophylactic vaccines e.g. Gardasil®, Cervarix® • Therapeutic vaccines: - delay or stop cancer cell growth - cause tumour shrinkage - prevent cancer from recurring - eliminate cancer cells not killed by other forms of treatment

30. Provenge® vaccine • Licensed for metastatic prostate cancer in USA • Designed to stimulate an immune response by T-cells to prostatic acid phosphatase, an antigen found on most prostate cancer cells

31. Vaccines in development • Telo Vac: immune response against the protein telomerase which is widely expressed in pancreatic cancer • IMA901 in combination with sunitinib in renal cell carcinoma to see if overall survival is improved • TroVax stimulates the immune system to destroy cancer cells that express the 5T4 tumour antigen, which is present in approximately 85% of solid tumours

32. Impact of targeted therapies • Personalised medicine - given until progression - additional to existing therapy - extending life - improving quality of life

33. Personalised medicine • Body Surface Area • Renal Function • Liver function • Performance status • Biomarkers • Tumour genetics • Pharmacogenomics