The push to rethink cancer drug dosing has gained momentum as more patients endure severe side effects from immunotherapy and other treatments, only to find their doctors cannot point to clear evidence that the approved dose is the right one for them.
Uncertainty Built Into Approval
Chuck Manski, an economist at Northwestern University who studies decision-making under uncertainty, found himself uniquely positioned to question his own cancer care. During six months of treatment in 2022, Manski received monthly infusions of nivolumab, an immunotherapy drug. The treatment made him very ill.
When Manski asked his oncologist whether a full year of immunotherapy was provably better than six months, the doctor could not provide clear evidence. “There is incredible uncertainty in drug dosing,” Manski said. His professional expertise in navigating uncertain decisions prepared him to press for answers that many patients, overwhelmed by a diagnosis, might never think to ask.
That uncertainty is not accidental. Cancer drug dosages are typically established during clinical trials that are designed primarily to demonstrate that a drug works and to win regulatory approval as quickly as possible. Researchers and patient advocates say this process often settles on the highest dose patients can tolerate — known as the maximum tolerated dose — rather than the lowest dose that is effective.
Why Doses Were Set High
The maximum tolerated dose model dates back to an era when most cancer drugs were cytotoxic chemotherapies, where pushing the dose to the limit of what the body could withstand was considered the best way to attack tumors. But immunotherapy works differently. These drugs harness the immune system rather than poisoning cancer cells directly, meaning more is not necessarily better.
Despite that biological shift, many immunotherapy drugs were still approved at doses derived from the older framework. Trial designers, eager to move drugs through the approval pipeline, often did not test multiple dose levels against one another. The result is a landscape in which the FDA-approved dose for a given cancer drug may reflect what was fastest to validate, not what is optimal for long-term patient health.
Patients who suffer severe side effects from these doses sometimes reduce or stop treatment on their own, with their doctors’ quiet blessing. But doing so places them outside the evidence base that regulators used to approve the drug, leaving both patients and physicians in a gray zone of informed guesswork.
Researchers Push for Dose Optimization
A growing number of researchers are now calling for dose optimization studies — trials specifically designed to compare different doses of an already-approved drug to find the one that balances effectiveness against toxicity. The concept has support within parts of the FDA, which has issued guidance encouraging drugmakers to conduct such studies, though uptake has been slow.
Critics note that pharmaceutical companies have little financial incentive to test whether a lower dose works. A lower dose could mean smaller sales, and dose-finding trials cost money without producing a new product to market. Without regulatory pressure, voluntary industry action has been limited.
Patient advocates argue that the burden of uncertainty falls most heavily on those least equipped to bear it. Patients without Manski’s analytical training may not realize that the dose on their infusion bag is not a medical certainty but a regulatory compromise shaped by trial design choices and commercial incentives.
What Happens Next
Watch for whether the FDA moves from encouraging dose optimization to requiring it. The agency has already signaled interest in post-approval dose studies, but binding requirements would force drugmakers to act. Congress could also weigh in by tying reimbursement or approval conditions to dose-finding evidence.
Meanwhile, patient groups are beginning to organize around the issue, pushing for clearer labeling that discloses how a drug’s approved dose was determined and whether lower doses have been studied. If that pressure grows, cancer drug dosing could shift from a question patients never think to ask into a standard part of the treatment conversation — one where uncertainty is acknowledged rather than hidden behind an FDA-approved number.
— Aisha Mensah, health desk, AXO News