Palonosetron/NEPA from a North American Perspective David Warr - - PowerPoint PPT Presentation

Palonosetron/NEPA from a North American Perspective

David Warr

University of Toronto david.warr@uhn.on.ca

Princess Margaret Cancer Center

Outline

• Palonosetron facts
• Why care about a USA perspective and an “old”

drug like palonosetron (FDA approval 11 years ago)?

• Why has palonosetron dominated the USA 5-HT3

receptor antagonist market despite its high cost?

• What does the combination of palonosetron +

netupitant offer? (“NEPA” - FDA approval in October)

Palonosetron Facts

• Long half life 40 hrs (ondansetron 5 hrs, granisetron 9 hrs)
• The only 5-HT3 receptor antagonist without an FDA

safety warning about QTc interval prolongation

• Oral version never marketed in the USA
• NCCN: the preferred 5-HT3 RA for highly and

moderately emetogenic chemotherapy (HEC, MEC)

• The leading 5-HT3 RA despite a listed cost higher than

aprepitant (>$300). Estimated 50% USA market share

Why care about a USA perspective on palonosetron?

• The NCCN guidelines which endorse palonosetron

influence oncologists around the world (easy to apply, comprehensive, many oncologists trained in the USA)

• Historically the USA has been ~ half of the global 5-HT3

RA antiemetic market

• Freedom to prescribe (wealthy enough to allow)
• Incentives to prescribe expensive IV drugs in clinics
• Large use of preoperative palonosetron (~35% of

the total market)

• Patent expiry in North America is 2024!

No emesis over first five days

Popovic, Warr, DeAngelis et al, Support Care Cancer 2014 epub

No emesis over first five days

Popovic, Warr, DeAngelis et al, Support Care Cancer 2014

What about absolute differences in nausea and vomiting?

Absolute differences

Palonosetron is superior (NNT:10) Not simply due to a longer T1/2 – smaller but still statistically significant difference in the first 24 hrs

Popovic, Warr, DeAngelis et al, Support Care Cancer 2014

Absolute differences/95% Confidence Intervals

A reality check for palonosetron

• Slow uptake in guidelines as the preferred 5-HT3 RA
• Only one of those trials allowed dexamethasone and

none allowed aprepitant (no “standard therapy” arm)

• Another meta-analysis pre-palonosetron found that if

dexamethasone was not prescribed beyond d1, 8% fewer vomited if a 5-HT3 RA was used beyond d11

• It is possible that, had the palonosetron trials included

administration of the other 5-HT3 RA beyond 24 hours, much of the 10% advantage would have disappeared

1Geling J Clin Oncol 2005;23:1289-94

Was palonosetron successful in the USA because oncologists actually read antiemetic trials?

Not likely

• The USA reimbursement scheme is complicated (Dr.

Gralla will correct any inaccuracies)

• There is a $20 fee for the injection of palonosetron
• Medicare allows an additional 6% markup over the

“average sales price” (adds another ~$11)

• For outpatients there is an incentive to prescribe an

expensive intravenous 5-HT3 RA rather than an inexpensive oral one

Also effective marketing

Fears of dexamethasone

• Many physicians are reluctant to prescribe

dexamethasone especially for women with breast cancer (weight gain/insomnia/bone loss)

• Two randomized trials with palonosetron evaluated

the contribution of dexamethasone beyond day1 for anthracycline plus cyclophosphamide chemo1

• A combined analysis concluded that there was no

benefit to giving dexamethasone beyond day1

• (Whether ANY chemotherapy other than cisplatin

benefits much from dex beyond day1 is unclear)

1Celio Support Care Cancer. 2013;21:565-73

Palonosetron already acting via substance P?

• An in vitro and in vivo (NON antiemetic) study

suggested palonosetron “crosstalk” with substance P1

• No published clinical trials address whether adding

palonosetron to aprepitant is helpful (mixed results in

hospital and population series, tiny positive result in an unpublished clinical trial)

• A randomized trial evaluated the role of adding

netupitant to palonosetron (NEPA)* in the setting of high dose cisplatin2. All received d1-4 dexamethasone

* approved by FDA Oct 10, 2014

1Rojas Pharmacol Exp Ther. 2010;335:362-8, , 2Hesketh Ann Oncol 2014; 25:1340-6

Hesketh Ann Oncol 2014; 25:1340-6

FDA approved NK1+5-HT3 RA combination + dex FDA approved NK1+5-HT3 RA combination + dex A true pre-NK1 RA standard arm i.e. dex d1-4 A true pre-NK1 RA standard arm i.e. dex d1-4

Hesketh Ann Oncol 2014; 25:1340-6

Results from 0-120 hrs

Palo

N=136

NEPA300

N=135

CR 76.5% 89.6%* No Emesis 76.5% 91.1%* No Sig Nausea 79.4% 89.6%*

• Delta emesis = 14.6% - less than in aprepitant trials because fewer

patients vomited with non NK1 therapy but > MASCC standard for changing practice

• Delta nausea = 10.2%

Adapted from Hesketh Ann Oncol 2014; 25:1340-6

An NK1 RA adds to palonosetron

Does having the resources to prescribe expensive antiemetics AND a popular NCCN guideline translate into better antiemetic prescriptions?

• Not necessarily – two dramatically different

examples within the USA

Antiemetic use versus Admissions

• Used USA insurer database for 2005-2008 (~ 100 plans)
• Billing codes for type of cancer, type of chemotherapy,

antiemetics and emergency department visits for nausea, vomiting or dehydration

• 38% of AC patients and 23% of cisplatin patients

received palonosetron

• Fewer emergency department visits for those patients

who received palonosetron as compared to other 5- HT3 RA

• But did patients get best standard therapy? (No)

Hatoum Support Care Cancer. 2012;20:941-9

Antiemetic use for AC (breast cancer) N=4868

20 40 60 80 100

43,1 25 11,7 20,1

Percent

Based upon Hatoum Support Care Cancer 2012;20(5):941-9 5HT3 5HT3+Dex 5HT3+NK1 Triple

68% did not get aprepitant 68% did not get aprepitant 55% did not get dexamethasone 55% did not get dexamethasone

Antiemetic use for Cisplatin (lung cancer) N=1692

20 40 60 80 100

46,8 20,3 13,6 19,3

Based upon Hatoum Support Care Cancer 2012;20(5):941-9

20% rate of visits to Emergency Dept for vomiting! 20% rate of visits to Emergency Dept for vomiting!

5HT3 5HT3+Dex 5HT3+NK1 Triple

60% did not get dexamethasone 60% did not get dexamethasone 68% did not get aprepitant 68% did not get aprepitant

In contrast . . . INSPIRE1

• Observational study within four oncology practice

networks in the southeastern states (Apr 2011- Mar 2012)

• N=1292
• NCCN guideline compliant Rx was associated with

significantly better control of vomiting (an old message)

• Palonosetron was the most common 5-HT3 RA

prescribed (93.6%)

• 90.7% of HEC (including AC) had an NK1 RA+ 5-HT3

RA + at least d1 dexamethasone

• 73.1% of MEC (AC≠MEC) received this same triple

therapy! (overtreatment??)

1Gilmore, J Oncol Pract.2014; 10:68-74

Summary

• Palonosetron has been commercially extremely

successful (patient expiry 2024) due to:

• A favorable USA reimbursement scheme
• Somewhat superior results in clinical trials that

may or may not have been due to trial design and consequent adoption by NCCN for MEC to HEC

• Supportive results from health care utilization data
• Skillful marketing
• Practice in the USA, as in many other countries, does

not necessarily reflect guidelines

• There is no such thing as an “American” (or “Canadian”)

approach to prescribing antiemetics