publication date: Mar. 29, 2019

Guest Editorial

NCCN validates path toward de-escalated doses and reduced costs of cancer drugs

From the Value in Cancer Care Consortium (Vi3C)

Allen_Lichter_web

Allen Lichter

Chair,
Value in Cancer Care Consortium

Former CEO (2006-2016), ASCO

 

Mark J. Ratain

Mark Ratain

Treasurer, Value in Cancer Care Consortium

Leon O. Jacobson Professor of Medicine, director, Center for Personalized Therapeutics, associate director for Clinical Sciences, Comprehensive Cancer Center, University of Chicago

 

Leonard Saltz

Leonard Saltz

Secretary, Value in Cancer Care Consortium

Executive director for Clinical Value & Sustainability; Head, Colorectal Oncology Section, Memorial Sloan Kettering

 

Michael Stebbins

Michael Stebbins

Member-at-large, Value in Cancer Care Consortium

President, Science Advisors 

 

David Hyman

David Hyman

Member-at large, Value in Cancer Care Consortium

Professor of law, Georgetown University

 

The ever-rising cost of oncology drugs is doing damage to cancer care on many levels.

Annual total cost increases are projected to be as much as 20 percent annually. The intense financial pressure these costs place on our patients, even well-insured patients, is well documented.

Patient access and adherence to therapy is threatened due to excessive and unaffordable costs.

If these cost increases are unabated, not only will individual patients suffer now, but there will be permanent harm to the infrastructure of oncology, as there will be insufficient resources to balance the books.

The Value in Cancer Care Consortium was founded in 2016 around the premise that the same clinical and translational investigative techniques and scientific reasoning that helped to create the newer but expensive therapies could be used to help address and control their resultant financial toxicities, both to patients and to society.

One of our lines of investigation posits that many of the newer targeted cancer drugs are being given in doses far in excess of what is needed to achieve the desired therapeutic effect. We proposed using the best pharmacological reasoning possible to select drugs that could be subjected to clinical trials of de-escalation in dose, schedule, or duration.

In so doing, we theorized that the resulting savings would be in the billions of dollars per year. While many colleagues supported this concept, it is not a stretch to say that most were skeptical that such a plan could succeed.

We don’t blame them. Taking on the financial toxicity of cancer therapy is a heavy lift, but recent developments show that we may be on the right track.

The prostate cancer drug abiraterone, labeled to be taken fasting at a dose of 1,000 mg daily despite much better absorption with food, was studied as proof of concept.

A 72-patient international randomized study—including investigators from The University of Chicago, the NCI, Emory University and the National University Cancer Institute in Singapore— comparing a 75 percent dose reduction (250 mg with food) to standard dosing was published in the Journal of Clinical Oncology in May 2018.

The study demonstrated that the lower dose was noninferior in regard to PSA metrics, including PSA progression-free survival.

The accompanying editorial by Kolesar and Liu criticized the work, arguing that the evidence was non-compelling, the primary endpoints of PSA response and duration were questionable, and the trough concentrations of abiraterone were too low (although they were identical in both groups).

Subsequently, several Letters to the Editor were published, some supporting the work and others more critical. The study authors and the editorial authors responded to the letters. Then, nothing happened.

There were the occasional emails from patients who were on the lower dose thanking us for the effort that saved them a small fortune in cost, but that was about it.

However, two recent events have made us believe that this work has a bright future. In a recent viewpoint in JAMA Oncology, Klaassen and colleagues remind us that full-dose abiraterone can likely be used in nonmetastatic castrate-resistant prostate cancer at slightly less cost than enzalutamide or apalutamide.

However, the authors note that low-dose abiraterone with food is another option, one whose hypothetical cost over an average 40.5-month time period ($2,580/month and $104,490 for a full treatment course) would be about 75-80% less than enzalutamide’s $491,000 and apalutamide’s $440,000.

They also note that a generic version of abiraterone is now on the market, which is currently priced around $3,000/month for the 1000 mg dose. If generic abiraterone were used at a dose of 250 mg with food, the total cost of 40.5 months of treatment would be $30,000.

That is still a great deal of money but is a small fraction of the cost of other antiandrogen drugs (ranging up to $500,000), and thus is a huge step forward. However, the authors note that this method of administration “has not been endorsed as a routine substitute for standard dose.”

That is no longer true.

With the release of the latest NCCN Prostate Guideline (NCCN Clinical Practice Guidelines in Oncology-Prostate Cancer. Version 1.2019 – March 6, 2019)such endorsement has now been achieved.

The guideline states: “Abiraterone with prednisone can be administered at a dose of 250 mg/day following a low-fat breakfast, as an alternative to the dose of 1000 mg/day after an overnight fast. The cost savings from this dosing may reduce financial toxicity and improve compliance.”

We are not ready to claim: “Mission Accomplished.” There is far more work to be done.

Will oncologists use the lower dose regimen?

Off-label prescribing of compendium-listed indications is a standard of care in oncology, although it has not been previously utilized to reduce costs of care. In contrast, prescribing of low-dose intravitreal bevacizumab for age-related macular degeneration is widely utilized, and has already saved Medicare billions of dollars.

Thus, we hope that low-dose abiraterone with food will be broadly considered to be an acceptable alternative to full-dose abiraterone.

Additionally, there are dozens of oral and biological agents for which randomized de-escalation trials appear appropriate. We are determined to carry out those studies.

These recent developments establish that de-escalation studies can be done, and their results endorsed.

The field of oncology will benefit as we lower drug spend and, in many cases, reduce not only financial toxicity but other toxic side effects as well.

Society will benefit in the long run, but most importantly, our patients and their families can benefit now.

Copyright (c) 2019 The Cancer Letter Inc.