Herceptin

1. Herceptin Summarising the evidence

2. The facts not under debate • Herceptin (trastuzumab) indicated for metastatic HER2+ breast cancer and now HER2+ early breast cancer • One of a new class of medicines, a monoclonal antibody • Given as an infusion –hospital setting • Funded for metastatic breast cancer by district health boards • Drug cost for 12 month sequential treatment approx $70,000 per person (or approx $20-$25 million /yr, total DHB cancer spend approx $50million currently) • Drug cost for 9 week concurrent treatment approx $15,000 per person (or approx $5 million/yr)

3. 12 months sequential treatment declined July 2006 • Cost effectiveness • Cost • Clinical Benefit and Clinical Risks • Cost Offsets (prevention of progression) • 12 months sequential cost/QALY approx $70K (range $20K-$140K) • If data to be updated with 2 year HERA data cost effectiveness would look worse • If N9831 are B data were included cost effectiveness would look worse • DHB resources

4. The Evidence • Herceptin is an add-on treatment, not stand alone so relationship with the other cancer medicines in the overall treatment of the patient is important. • Two variables: • Which order?: Sequential versus concurrent treatment; and • Which duration?: Long (12 months) versus short (9 weeks) treatment • Six trials: need to think about what they as a group are telling us, not just one trial (HERA or FinHer) on its own.

5. About “12,000 patients taking Herceptin” • ‘Data from >12,000 patients support 12 months treatment’ • NZ indication for ‘trastuzumab given following completion of chemotherapy’ (sequential) • In fact 12 month sequential Herceptin data only available from 2,679 patients • HERA = 1694 patients = Positive result • N9831 Arm B = 985 patients = Negative result

6. 13,609 patients in all Clinical trials Herceptin treated (8724) Concurrent therapy(with chemotherapy) Data from 4351 patients reported Sequential treatment (post-chemotherapy) Data from 2679 patients reported HERA 1 year treatment arm 1694 patients (12 months Post-chemo) HERA 2 year treatment arm 1694 patients (not yet reported) N9831 arm B 985 patients 12 months post-chemo N9831 arm C 840 patients 52 weeks B31 1019 patients 52 weeks BCIRG 006 2149 patients 52 weeks Finher 116 patients 9 weeks Sledge 227 patients 52 weeks or 10 weeks a ? r r a a a a a a

7. HERA – 2-year follow-up (Disease- Free Survival) 3 years In other words for every 100 women treated… 6 benefited from Herceptin treatment (94 did not benefit) 4 suffered cardiac damage severe enough to require discontinuation of Herceptin

8. N9831 – sequential treatment worse than concurrent Sequential Herceptin no better than normal chemo Sequential Herceptin worse than concurrent Herceptin Romond ‘delayed administration of trastuzumab may be less effective than concurrent administration’….’ further follow-up of groups B and C in trial N9831 is necessary for an adequate evaluation of the efficacy of concurrent as compared with sequential administration of trastuzumab’

9. Data for 12 months sequential worse than 12 months concurrent - meta-analysis across studies Above the line = Herceptin no better than normal chemo Below the line = Herceptin better than normal chemo

10. Sequential vs Concurrent summary • Roche’s indication is for 12 months sequential herceptin • sequential data available from 2,679 patients • HERA 2 yr FU recurrence decreased by 6.4% • Arm B of N9831 – no better than normal chemo • 12 months concurrent appears to be better than 12 months sequential

11. Data for concurrent - data for short and long duration similar Above the line = Herceptin no better than normal chemo Below the line = Herceptin better than normal chemo

12. Short duration concurrent – ‘FinHer’ • The 9-week regimen • Good efficacy • comparable to studies that used 12-mo duration of administration (Joensuu H et al. NEJM 2006:354:809-20) • patient friendly: chemo+Herceptin completed in 18 weeks (vs. 60 weeks) • More patients would get treated • no cardiotoxic anthracyclines given before Herceptin • Might be less cardiotoxic • Would spare hospital resources (6 visits vs. 20 visits + extra cardiac monitoring + blood tests) • A more compact platform for further development of BC management • Cost effective (<$20K per QALY) • Affordable and managable for DHBs (cost/resources) • Supported by ’Sledge’ study (10 weeks concurrent)

13. Summary • There are doubts over 12 months sequential treatment • Concurrent treatment IS proven (and approved for use in USA, Australia) • Exactly how long to use concurrent treatment has NOT been established • Efficacy seen with 12 months, 9 weeks and 10 weeks • But 12 month concurrent (post anthracyclines) increases cardiotoxicity • The international trial (SOLD) is planned to address the question – does 12 months treatment add any benefit over concurrent 9 week treatment?

14. Some Overseas commentary • Cancer Research UK’s director of clinical trials, during an appearance on a BBC Radioshow January 2007: • "Currently we give Herceptin for a year and there is no good evidence why it should be given for a year. It is what the drug company decided upfront. We are now doing trials in the UK that are following some done in Finland that look as though nine to ten weeks would be sufficient.“ • The Belgian Health Care Knowledge Centre June 2006: • “The KCE wonders why there is no comparative trial with a shorter and possibly more safe treatment regimen.” • Daniel Hind, The Lancet January 2007 Editorial: • “NICE might never have deemed the HERA schedule to be cost effective if the FinHer study had been assessed as a comparator…”