1. EVOLUZIONE DEL RAPPORTO COSTO/EFFICACIA DELLA
TERAPIA DI SUPPORTO
Fausto Roila
Struttura Complessa di Oncologia, Terni

2. TOPICS
THE NK1 RECEPTOR ANTAGONISTS (for prevention of chemotherapy-induced emesis)
THE OSTEOCLAST INHIBITORS ( for prevention of skeletal-related events in pts with bone metastases from breast, prostate and other solid tumors)

3. MASCC/ESMO 2010 RECOMMENDATIONS ON ANTIEMETIC PROPHYLAXIS
ACUTE DELAYED
Cisplatin HT3+DEX+Apr DEX+Apr

4. TWO RCT ON APREPITANT (2003)
day days day 4
Aprepitant mg mg
Ondansetron mg
Desametasone mg mg mg
Dexamethasone mg mg bid mg bid
Aprepitant p.o. Ondansetron i.v. Dexamethasone p.o.

5. RESULTS Protocol 052 Protocol 054 AOD OD AOD OD
No. pts
Complete response (%)
Day % %
Day % %
no nausea (%)

6. NEWS FOR ACUTE EMESIS
FOSAPREPITANT 150 mg iv in 2247 pts same results than with 3-doses aprepitant
NEPA (netupitant + palo): dose-finding su 694 pts; 300 mg mg significantly superior with respect to palo alone (plus DEX in both arms)
Rolapitant: Two RCT on 555 e 532 pts with increase of 4% and 10% of complete response

7. CONCLUSIONS
- The addition of an NK1 receptor antagonists in pts submitted to cisplatin chemotherapy increased the complete response on day 1 from 4% to 15

8. RESULTS WITH NK-1 RECEPTORS ANTAGONISTS ON DAYS 2-5
- Complete response increased from 19% and 21% in the two aprepitant studies, from 10.3% with NEPA and from 9% and from 14.3% in the two studies with rolapitant. An increase with respect to the arm without NK1 antagonist from 9% to 21%
- Of course, part of this increase is due to a dependence effect (the better results achieved on the day 1 which induced an increase of the complete responses on days 2-5)

9. NEWS FOR DELAYED EMESIS
METOCLOPRAMIDE + DEXAMETHASONE induced similar complete response to APREPITANT + DEXAMETHASONE against cisplatin-induced delayed emesis

10. MASCC/ESMO 2015 RECOMMENDATIONS
ACUTE DELAYED
Cisplatin HT3+DEX+NK DEX
5HT3+DEX+APR DEX+APR or MTC

11. MASCC/ESMO 2010 RECOMMENDATIONS
ACUTE DELAYED
AC HT3+DEX+Apr Apr

12. Aprepitant registrative study in breast cancer treated with CTX ± DOX or EPI
day days 2-3
Aprepitant mg mg
Ondansetron /8 mg
Desametasone mg
Ondansetron /8 mg /8 mg
Dexamethasone mg
Aprepitant p.o. Ondansetron p.o. Dexamethasone p.o.

13. *Complete response: no vomiting and no rescue therapy
RESULTS*
AOD OD P
No. pts
Day
Day %
Day %
No nausea days n.s.
*Complete response: no vomiting and no rescue therapy

14. NEWS FOR ACUTE EMESIS
NEPA: a RCT in 1455 pts increased the complete response of 3.4%
Rolapitant: RCT in 1332 pts increased the complete response of 3.2%

15. CONCLUSIONS
- The addition of an NK1 receptor antagonists increased the complete response in pts submitted to AC/EC on day 1 from 3% to 7%

16. RESULTS WITH NK-1 RECEPTOR ANTAGONISTS ON DAYS 2-5 ON THE 4 STUDIES WITH AC/EC
- Complete response increased from 6% in the aprepitant study, from 7.4% in the NEPA study and from 9.7% in the rolapitant study. An increase with respect to the arm without NK1 antagonist from 6% to 10%
- Even in this case, part of this increase is due to a dependence effect (the better results achieved on the day 1 which induced an increase of the complete responses on days 2-5)

17. NEWS FOR DELAYED EMESIS
DEXAMETHASONE induced similar complete response to APREPITANT against AC/EC-induced delayed emesis

18. MASCC/ESMO 2015 RECOMMENDATIONS
ACUTE DELAYED
Cisplatino 5HT3+DEX+NK DEX
5HT3+DEX+APR DEX+APR or MTC
AC HT3+DEX+NK
5HT3+DEX+APR APR or DEX

19. NK-1 RECEPTOR ANTAGONISTS
- No comparative studies have been carried out to identify differencies in efficacy and toxicity between the three NK-1 receptor antagonists.
- Therefore, when availables, the choice should be based on their respective cost.

20. NK-1 RECEPTOR ANTAGONISTS COST
- APREPITANT (3 tablets) €
FOSAPREPITANT (150 mg iv) €
NEPA (1 tablet) €
(netupitant +palonosetron)
- ONDANSETRON (8 mg iv) €
ROLAPITANT (not yet available in European market)

21. CONCLUSIONS
At present the only difference between the three NK1 receptor antagonists approved by regulatory agencies is the cost.
We have not the necessity of a pharmacoeconomic analysis but only of a cost minimization analysis (use the less expensive NK1 antagonist)

22. INTRODUCTION
In patients with bone metastases from castration-resistant prostate cancer zoledronic acid was shown superior to placebo for the prevention of skeletal-related events
Skeletal-related events is a composite endpoint of skeletal complications represented by pathological fracture, spinal cord compression and radiotherapy or surgery to bone

23. DENOSUMAB
An excess of osteoclastic activity is the cause of bone destruction in bone metastases
RANKL is the main driver of osteoclast formation, function and survival
Denosumab is a monoclonal antibody against RANKL

24. Fizazi K et al, Lancet 2011; 377: 813-22
DENOSUMAB VERSUS ZOLEDRONIC ACID FOR THE TREATMENT OF BONE METASTASES IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER: A RANDOMIZED, DOUBLE-BLIND STUDY
Fizazi K et al, Lancet 2011; 377:

25. THE STUDY
Phase III randomized, double-blind study comparing denosumab (120 mg subcutaneously) versus zoledronic acid (4 mg iv) for the treatment of bone metastases in men with castration-resistant prostate cancer
patients enrolled in the study: 1904
primary endpoint: time to first on-study skeletal-related event

26. RESULTS
the median time to first on-study skeletal-related event was significantly longer with denosumab (20.7 vs 17.1 months)
time to disease progression and overall survival was not significantly different in the two groups of patients as well as the occurrence of adverse events and serious adverse events

27. RESULTS
Hypocalcaemia more frequent with denosumab than with zoledronic acid (13% vs 6%)
Osteonecrosis of the jaw occurred infrequently (2% vs 1%)
More acute (after the first 3 days of treatment) phase reaction symptoms were observed in patients submitted to zoledronic acid

28. Stopeck AT et al, J Clin Oncol 2010; 28: 5132-29
DENOSUMAB COMPARED WITH ZOLEDRONIC ACID FOR THE TREATMENT OF BONE METASTASES IN PATIENTS WITH ADVANCED BREAST CANCER. A RANDOMIZED DOUBLE-BLIND STUDY
Stopeck AT et al, J Clin Oncol 2010; 28:

29. THE STUDY
Phase III randomized, double-blind study comparing denosumab (120 mg subcutaneously) versus zoledronic acid (4 mg iv) for the treatment of bone metastases in pts with breast cancer
patients enrolled in the study: 1026
primary endpoint: time to first on-study skeletal-related event

30. RESULTS
the median time to first on-study skeletal-related event was significantly superior with denosumab (not yet reached vs 26.4 months)
time to disease progression and overall survival was not significantly different in the two groups of patients as well as the occurrence of adverse events and serious adverse events

31. RESULTS
Hypocalcaemia more frequent with denosumab than with zoledronic acid (1,6% vs 1,2%)
Osteonecrosis of the jaw occurred infrequently (2% vs 1.4%)
More acute (after the first 3 days of treatment) phase reaction symptoms were observed in patients submitted to zoledronic acid (27.3% vs 10.4%) as well as serious renal adverse effects (2.2% vs 0.4%).

32. Henry DH et al, J Clin Oncol 2011; 29: 1125-32
RANDOMIZED DOUBLE-BLIND STUDY OF DENOSUMAB VERSUS ZOLEDRONIC ACID IN THE TREATMENT OF BONE METASTASES IN PATIENTS WITH ADVANCED CANCER (EXCLUDING BREAST AND PROSTATE CANCER) OR MULTIPLE MYELOMA
Henry DH et al, J Clin Oncol 2011; 29:

33. THE STUDY
Phase III randomized, double-blind double-dummy study comparing denosumab (120 mg subcutaneously) versus zoledronic acid (4 mg iv) in pts with advanced cancer and bone metastases (excluding breast and prostate) or myeloma (40% NSCLC, 10% myeloma, 50% other tumor types)
patients enrolled in the study: 1776
primary endpoint: time to first on-study skeletal-related event

34. RESULTS
the median time to first on-study skeletal-related event was longer but not significantly with denosumab (20.6 vs 16.3 months)
time to disease progression and overall survival was not significantly different in the two groups of patients as well as the occurrence of adverse events and serious adverse events

35. RESULTS
Hypocalcaemia more frequent with denosumab than with zoledronic acid (10.8% vs 5.8%)
Osteonecrosis of the jaw occurred infrequently and not significantly different.
More acute (after the first 3 days of treatment) phase reaction symptoms were observed in patients submitted to zoledronic acid (14.6% vs 6.9%) as well as renal toxicity (10.9% vs 8.3%).

36. CONCLUSIONS
Denosumab significantly increases the median time to first skeletal-related event.
no benefits on time to disease progression and overall survival.
Hypocalcemia was more frequent with denosumab while acute-phase reactions and renal adverse effects were more frequent with zoledronic acid.

37. CONCLUSIONS Similar incidence of osteonecrosis of the jaw.
Denosumab offers the convenience to patients and treating centers of a subcutaneous injection
denosumab will cost nearly twice as much as zoledronic acid (before generic zoledronic acid)

38. OSTEOCLAST INHIBITORS COST
- ZOLEDRONIC ACID (4 mg iv) €
PAMIDRONATE (90 mg iv) €
DENOSUMAB (120 mg sc) €

39. CONCLUSIONS
Denosumab results in a greater (albeit modest) reduction in the risk of skeletal-related events compared with zoledronic acid
The subcutaneous mode of administration may be more convenient, especially in pts not receiving systemic intravenous chemotherapy

40. COST EFFECTIVENESS ANALYSES
8 cost-effectiveness studies have been carried out.
5 studies concluded that denosumab is not a cost-effective choice when compared to zoledronic acid.
3 studies indicated that denosumab it a more cost-effective choice when compared to zoledronic acid

41. COST EFFECTIVENESS ANALYSES
All studies received funding from Novartis or from Amgen (trying to favourite its drug)
Cost-effectiveness analysis carried out today could give different results considering the generic price of zoledronic acid