Allen S. Lichter, MD, FASCO
Mark J. Ratain, MD
IT IS TIME for value-based prescribing—the reduction of prescribing costs using basic pharmacologic principles—to be tested and deployed in oncology. The savings are real and there for the taking. If you are concerned about the high costs in cancer care, here is a chance to get maximum value for the dollars spent.
When manufacturers develop drugs for human use, they start by testing a range of doses and schedules. In essence, they are looking to balance toxicity and efficacy. A higher dose may produce more biologic activity but at a cost of increased toxicity. A lower dose may be safer but might give up some biologic activity. If the drug is rapidly cleared, then more frequent dosing might be desirable. If the drug has a long half-life or has irreversible binding to the target, less frequent dosing may suffice.
From a multitude of possibilities, the manufacturer picks a dose and schedule and takes that choice forward into phase II and III studies. (Although phase IIb randomized dose-ranging studies—to identify the optimal dose and/or schedule—are routine in other therapeutic areas, they are rarely utilized in oncology.) If the results are convincing, the drug will receive U.S. Food and Drug Administration (FDA) approval, and the dose used for those pivotal trials will become the labeled dose. What are the chances that the manufacturer picked precisely the best dose and schedule right from the start? We have set out to ask that question, and the answers are of great importance.
Systematic Assessment
“This investigation identified 34 agents—61% of the patent-protected oral oncology drugs in use today—for which particular clinical trial strategies could reduce prescribing costs in the United States by at least 33%.”— Allen S. Lichter, MD, FASCO, and Mark J. Ratain, MD
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THERE ARE 56 patent-protected oral oncology drugs on the market today. Using publicly available data, including FDA clinical pharmacology reviews supplemented by full publications of phase I and II clinical trials, we sought to identify all the agents for which there could be a legitimate test of a different dosing or frequency of administration other than what appears on the FDA label. To make our list, the value-based prescribing change would have to lower prescribing costs by at least 33% without compromising efficacy.
For each drug, we then calculated the potential cost savings based on the published U.S. price for the drug. Finally, we estimated the global savings by multiplying the potential savings by the annual global sales figures, as published in corporate financial disclosure statements from the pharmaceutical companies. The results are eye-opening.
This investigation identified 34 agents—61% of the patent-protected oral oncology drugs in use today— for which particular clinical trial strategies could reduce prescribing costs in the United States by at least 33% (range = 33%–89%). They include 21 drugs where dose reduction should be tested, 12 where frequency reduction should be tested, and 1 where a straight therapeutic substitution (sirolimus vs everolimus) could be tested. From the original list, 11 drugs appeared to have an optimal dose and schedule, whereas another 11 did not have enough data to draw a conclusion.
Potential Cost Savings
WHAT ARE the cost implications? If all these strategies were successfully tested, documented, and deployed, the worldwide, annual savings would exceed $16 billion per year based on published 2017 sales figures. In the United States, the savings would be, on average, $94,000 per course of treatment, with a standard deviation of $37,000. Almost 60% of the savings come from three drugs: ibrutinib, abiraterone acetate, and enzalutamide.
“If all these strategies were successfully tested, documented, and deployed, the worldwide, annual savings would exceed $16 billion per year based on published 2017 sales figures.”— Allen S. Lichter, MD, FASCO, and Mark J. Ratain, MD
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Ibrutinib irreversibly binds to Bruton’s tyrosine kinase. At an ibrutinib dose of 2.5 mg/kg, Bruton’s tyrosine kinase occupancy is 98%, strongly suggesting that a single 140-mg capsule is more than sufficient for treatment, rather than the labeled doses of 420 mg and 560 mg, depending on the indication. This would save at least two-thirds of the drug’s cost.
The labeled dose of abiraterone is 1,000 mg fasting, even though the drug is far better absorbed with food. Szmulewitz and colleagues recently published a 72-patient study where the labeled dose was compared to a dose of 250 mg taken with a low-fat breakfast.1 The biochemical results (prostate-specific antigen [PSA] and androgen synthesis) and clinical findings (time to PSA progression) were indistinguishable between the two groups.
Enzalutamide’s labeled dosage is 160 mg/d—four 40-mg capsules taken with or without food. At the labeled dosage, there is no relationship between exposure to enzalutamide (and/or an active metabolite) and survival, despite an almost twofold difference in exposure between the highest and lowest quartiles. This suggests that a dose of 80 mg daily may provide comparable benefit to the standard 160-mg dose, and potentially less toxicity as well.
Other drugs with meaningful cost-saving opportunities include nilotinib, dasatinib, osimertinib, erlotinib, pazopanib, and olaparib. The largest percentage savings (89%) is through substitution of the generic drug sirolimus for everolimus, whereas the strategies for the other specified drugs include reduction of dose or frequency.
In addition to reducing costs, lowering the dose or frequency of oral oncology drugs can be expected to have important effects on minimizing off-target toxicity for many of these agents. After all, once a drug like ibrutinib fully saturates its target, higher concentrations only result in off-target toxicities.
In short, the development, testing, and deployment of value-based prescribing strategies have the potential to powerfully impact prescribing costs for many oral oncology drugs. Our estimates are likely conservative, given the expanding indications and prolonged treatment associated with many of these agents. This cost reduction can help make these drugs far more accessible and reduce their financial toxicity. Similar opportunities may exist for parenteral monoclonal antibodies such as nivolumab.
The Challenge Ahead
WE ARE ATTEMPTING to raise the funds to perform the necessary clinical trials, although that has not been easy. It seems we are prepared as a nation to spend hundreds of millions of dollars to develop the next high-priced oncology drug but unwilling to spend a few million dollars to learn how to use our existing drugs far more effectively and efficiently. For example, spending $5 million on an ibrutinib trial has the potential for saving billions of dollars in unnecessary cost and toxicity.
When faced with a similar issue in age-related macular degeneration, the ophthalmology community, assisted by funding from the National Eye Institute, did a study of ranibizumab vs bevacizumab. No one was suggesting bevacizumab was better in this setting. In fact, it was more cumbersome to use since it has to be compounded into small doses for use in the eye.
“It is time to gather the resources needed to do these studies and make oncology the leader in bringing value-based prescribing to the forefront of patient care.”— Allen S. Lichter, MD, FASCO, and Mark J. Ratain, MD
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But at $50 per dose for bevacizumab vs $2,000 per dose for ranibizumab, the trial was demanded by the clinical community. Since that study proved the two agents were equivalent in efficacy, Medicare has saved at least $17 billion on treatment costs for age-related macular degeneration and possibly up to $30 billion when other uses for these agents are included.
If the ophthalmology community can carry out value-based studies, so can oncology. It is time to gather the resources needed to do these studies and make oncology the leader in bringing value-based prescribing to the forefront of patient care. ■
Dr. Lichter is Senior Partner with TRG Healthcare, Philadelphia, and Chair of the Board of Directors at the Value in Cancer Care Consortium (vi3c). He served as Chief Executive Officer of ASCO from 2006 to 2016. Dr. Ratain is Leon O. Jacobson Professor of Medicine at the University of Chicago and Treasurer of vi3c.
Disclaimer: This commentary represents the views of the authors and may not necessarily reflect the views of ASCO or The ASCO Post.
DISCLOSURE: Dr. Lichter has a leadership role in LifeLink and Cellworks; is a consultant/advisor for Integra, Ascentage Pharma, and L-Nutra; and has received reimbursement for travel, accommodations, and expenses from Cellworks. He is also Chair of the Board of Directors at the Value in Cancer Care Consortium. Dr. Ratain has provided expert testimony and patent litigation consulting on behalf of multiple generic pharmaceutical companies; has served as a consultant to AbbVie, Amgen, Aptevo, Ascentage, BioMarin, Cyclacel, Elion Oncology, Genentech, Portola, and Shionogi; and has been a principal investigator for AbbVie and Genentech. In addition, Dr. Ratain is a Director and Treasurer of the Value in Cancer Care Consortium.
REFERENCE
1. Szmulewitz RZ, Peer CJ, Ibraheem A, et al: Prospective international randomized phase II study of low-dose abiraterone with food versus standard dose abiraterone in castration-resistant prostate cancer. J Clin Oncol 14:1389-1395, 2018.
