Many years ago, my patient, a woman in her fifties with chronic myeloid leukemia (CML), got her routine, yearly lab work returned showing a white blood cell count that was 10 times higher than normal.
In my practice, which focuses exclusively on treating patients with leukemias and related myeloid cancers, seeing someone with CML is often the highlight of my day. With the development of tyrosine kinase inhibitors, I believe we have seen one of the greatest, most effective cancer drug interventions over the past 25 years. One study even showed that life expectancy in successfully treated patients is now similar to the age-matched population as a whole who never had a diagnosis of leukemia. The average survival for these patients used to be 3-5 years.
You could argue that these medications are truly miracle cancer drugs.
For my patient, however, our treatment was no walk in the park — unless that park was set in a bleak, Road Warrior-like post-apocalyptic landscape. Her blood counts quickly became devastated, and we went through a series of “hold and restart the drug” interventions. She never felt quite right on the medicine, and complained about fluid retention. She even wondered if she was starting to lose her hair. By this point, her leukemia was in a deep remission, so she didn’t want to change medicines, but her life was in shambles.
“Can we at least lower the drug dose?” she asked me.
A Heretical Idea
At the time, that was considered heretical. Nobody wanted to mess with the FDA- and European Medicines Agency (EMA)-approved drug dose and schedule, for fear of compromising the drug’s impressive efficacy.
Cancer drugs go through a series of trials demonstrating their safety and efficacy before a regulatory body like the FDA will consider approving them for a particular indication. Typically, in phase I trials, a few patients are treated at a given drug dose, adverse events are assessed, and then the drug dose is escalated in another cohort of patients if the initially treated patients tolerated it. Dose-limiting toxicities are identified, and a maximum tolerated dose is established for later-phase trials. While drug efficacy is assessed, it isn’t a primary endpoint — assessing drug safety is the phase I study’s main goal.
And phase I trials, despite their pretenses of having a robust statistical justification, are not an ironclad science. For example, one out of three patients treated at a low dose level, all of whom tolerated the drug, may benefit from tumor shrinkage, while two out of three patients at a dose level three times higher, all of whom also appeared to tolerate the drug, may experience more modest tumor shrinkage. A trial steering committee may conclude that their “gestalt” is to move forward with the higher dose, and that becomes the dose that is eventually recommended to the FDA, and the one that can make it onto a product label.
Not an ironclad science indeed.
When Less Is More
Recognizing the imprecision of establishing a drug dose, the FDA initiated Project Optimus in 2021, the goal of which is “to reform the dose optimization and dose selection paradigm in oncology drug development.” In an editorial, members of the FDA even cited examples of approved drug dosing that was initially too high, including sotorasib (Lumakras) for non-small-cell lung cancers with a KRAS mutation (for which the manufacturer has been reluctant to recommend the lower dose); gemtuzumab ozogamicin (Mylotarg), for the treatment of acute myeloid leukemia; and the tyrosine kinase inhibitor my patient was taking.
I’ve personally studied the “less is more” approach to drug dosing. Azacitidine (Vidaza) is approved by the FDA to treat myelodysplastic syndromes (MDS) with 7-day dosing on a 28-day chemotherapy cycle. It prolongs survival in patients with higher-risk MDS, but the 7-day dosing schedule is probably too toxic for patients with lower-risk MDS. Decitabine (Dacogen) is also approved to treat MDS, with 5-day dosing on a 28-day chemotherapy cycle.
We conducted a trial giving just 3 days of one drug or the other to patients with lower-risk MDS. (The study was funded by a private foundation and our institutions; as you can imagine, it was a nonstarter to approach a pharmaceutical company and ask for trial support to demonstrate that using less of their drug was a good thing.) The results: Response rates, event-free survival, and overall survival appeared just as good, if not better, than what we had seen historically. And adverse events appeared to be lower.
Do Dollars Make a Difference?
So, why have recommended doses remained high? Money could play a role.
After a drug is approved, pricing is set by the pharmaceutical company (as I was reminded frequently during my 5 years on the Oncologic Drugs Advisory Committee of the FDA, “We do not consider drug costs or charges at the FDA.”). But this isn’t like buying a pound of corned beef at the deli, where 240 mg will run you $17.99, but 120 mg only costs $8.99, and please make sure the drug is lean! Each milligram of drug doesn’t have an inherent value.
Drug pricing is complicated, and based on a drug’s uniqueness, effectiveness, competition, along with recoup of research and development costs and what the market will bear. The problem arises when a drug price is set, and less of a drug is found to be as effective and less toxic than more of a drug. It just makes sense that less of a drug should cost less, and that will affect a company’s bottom line.
Around the time my patient with CML and I were struggling with her regimen, a study came out showing that she would benefit just as much from a lower dose of her tyrosine kinase inhibitor as from a higher dose. We made the adjustment, and her blood counts and symptoms improved within a month. She has remained on the drug for years, and her leukemia is undetectable.
For newer drugs, spending the time to optimize drug doses will lead to better patient outcomes, better patient experience, and lower costs to our health system. For older drugs, particularly those with limited dose-finding investigation, re-exploring those doses would be worthwhile for drugs with high rates of adverse events and discontinuation.
It’s the right thing to do for our patients.
Mikkael A. Sekeres, MD, MS, is chief of the Division of Hematology and professor of medicine at the Sylvester Comprehensive Cancer Center at the University of Miami. He is author of the books When Blood Breaks Down: Life Lessons from Leukemia (The MIT Press 2020), and Drugs and the FDA: Safety, Efficacy, and the Public’s Trust (The MIT Press 2022).
Disclosures
Sekeres serves on advisory boards for Bristol Myers Squibb and Kurome Therapeutics.
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