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-HT 3 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-HT 3 receptor antagonist without an FDA safety warning about QTc interval prolongation • Oral version never marketed in the USA • NCCN: the preferred 5-HT 3 RA for highly and moderately emetogenic chemotherapy (HEC, MEC) • The leading 5-HT 3 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-HT 3 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 What about absolute differences in nausea and vomiting? Popovic, Warr, DeAngelis et al, Support Care Cancer 2014
Absolute differences/95% Confidence Intervals Absolute differences Palonosetron is superior (NNT:10) Not simply due to a longer T 1/2 – smaller but still statistically significant difference in the first 24 hrs Popovic, Warr, DeAngelis et al, Support Care Cancer 2014
A reality check for palonosetron • Slow uptake in guidelines as the preferred 5-HT 3 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-HT 3 RA was used beyond d1 1 • It is possible that, had the palonosetron trials included administration of the other 5-HT 3 RA beyond 24 hours, much of the 10% advantage would have disappeared 1 Geling 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-HT 3 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 chemo 1 • 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) 1 Celio 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 P 1 • 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 cisplatin 2 . All received d1-4 dexamethasone * approved by FDA Oct 10, 2014 1 Rojas Pharmacol Exp Ther. 2010;335:362-8, , 2 Hesketh Ann Oncol 2014; 25:1340-6
Hesketh Ann Oncol 2014; 25:1340-6
A true pre-NK 1 RA standard arm i.e. dex d1-4 A true pre-NK 1 RA standard arm i.e. dex d1-4 FDA approved NK1+5-HT 3 RA combination + dex FDA approved NK1+5-HT 3 RA combination + dex Hesketh Ann Oncol 2014; 25:1340-6
Results from 0-120 hrs Palo NEPA 300 N=136 N=135 CR 76.5% 89.6%* No Emesis 76.5% 91.1%* An NK 1 RA adds to palonosetron 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
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- HT 3 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 100 80 68% did not get aprepitant 68% did not get aprepitant 55% did not get dexamethasone 55% did not get dexamethasone Percent 60 43,1 40 25 20,1 11,7 20 0 5HT 3 5HT 3 +Dex 5HT 3 +NK 1 Triple Based upon Hatoum Support Care Cancer 2012;20(5):941-9
Antiemetic use for Cisplatin (lung cancer) N=1692 100 20% rate of visits to 20% rate of visits to 80 68% did not get aprepitant 68% did not get aprepitant 60% did not get dexamethasone 60% did not get dexamethasone Emergency Dept for vomiting! Emergency Dept for vomiting! 60 46,8 40 20,3 19,3 13,6 20 0 5HT 3 5HT 3 +Dex 5HT 3 +NK 1 Triple Based upon Hatoum Support Care Cancer 2012;20(5):941-9
In contrast . . . INSPIRE 1 • 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-HT 3 RA prescribed (93.6%) • 90.7% of HEC (including AC) had an NK 1 RA+ 5-HT 3 RA + at least d1 dexamethasone • 73.1% of MEC (AC ≠ MEC) received this same triple therapy! (overtreatment??) 1 Gilmore, 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
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