More is not always better with targeted cancer drug dose selection

Oncologists at the FDA have warned that higher doses of targeted drugs and biologic therapies for solid and haematological cancers are not necessarily more effective than lower doses.

Writing in a Perspective article in the NEJM, they said it was not unusual for doses and schedules of oncology drugs to be inadequately characterised before sponsors initiate registration trials.

They gave several examples of drugs where doses or schedules were modified for safety or tolerability after approval.

For example, there was a 40% reduction in the dose of ceritinib across the ASCEND program of trials for non-small-cell lung cancer – from 750 mg to 450 mg in order to lower GI side effects.

Similarly the 45mg dose of ponatinib in the PACE trial for CML and ALL was reduced to 15 mg (once ≤1% BCR-ABL is achieved) in the OPTIC trial in order to reduce vascular occlusive events.

“The default decision to select the highest dose that has been evaluated reflects both the desire to make oncology drugs rapidly available to patients who have limited options and the belief that higher drug doses will have better therapeutic activity,” they said.

However targeted drugs were different from cytotoxic drugs.

“With targeted drugs, increasing doses beyond a certain level may not enhance antitumor activity, dose-limiting toxic effects may not be observed at clinically active doses, and serious toxic effects may occur only after multiple cycles of experimental treatment.”

“And yet, the “more is better” paradigm is still used for dose selection for new oncology drugs, despite the recognition that alternative approaches to dose optimisation are needed for these targeted therapies.”

They said initial trials of both pembrolizumab and nivolumab included an examination of wide dose ranges.

“Dose- and exposure-response data from these trials and modelling led sponsors to select doses lower than the highest dose studied, while preserving efficacy.”

“Early assessment of dose- and exposure-response data related to safety and efficacy could guide dose selection based on drug exposure for specific populations, including patients with organ dysfunction and those taking additional medications.”

They noted that enrolling more patients from racial and ethnic minority groups and elderly patients in early trials could also provide additional data on dosing and safety.

“Sponsors should carefully evaluate exposure-response, efficacy, and safety data from early trials to inform dose selection, rather than automatically selecting the maximum tolerated dose.”

“The answer to the dose-selection conundrum may sometimes be that less is more,” they concluded.

Professor John Simes, Senior Associate Director of the NHMRC Clinical Trials Centre at the University of Sydney, told the limbic that clinicians did have to be aware that for some of these therapies, the recommended dose may not necessarily be the optimal dose.

He said it could be more of a challenge getting the right dose with some of the targeted therapies and immunotherapy due to their different mechanisms of action.

“Cytotoxic drugs often have a quick effect in terms of side effects and in terms of an early indication of activity. Toxicity might be within days in terms of nausea and vomiting or low blood counts. You often get an early indication of activity and an early indication of toxicity.”

“With targeted therapies you tend to get less side effects but some of the side effects may be delayed and immunotherapy likewise has less side effects and some of those may be delayed and also sometimes more idiosyncratic.”

He said triallists were often focused on showing proof of efficacy for any dose.

“If you have the luxury of doing very large studies and have lots of time, then doing a trial with a more moderate dose might be effective but if you did that as a screening approach to try to come up with a new therapy, and it turned out that treatment you tested was negative then you may have failed to identify a promising therapy.”

Professor Simes said that once a treatment has been shown to be effective at a certain dose, it was often hard to do a subsequent trial to vary that dose.

He said further studies may be worth doing but often the pharmaceutical  companies wouldn’t be as interested in funding them.

“There might still be a societal benefit for doing the follow-up studies but there may not be a commercial benefit so in some ways that may be more of an onus on the government and the community to do those trials.”

He said as an example, being able to prove that 6 months versus 12 months of therapy produced the same benefit to a patient, could potentially save money for the government or the patient.

“But why would pharma pay for a study to show we only need 6 months of treatment?”

However, he said the costs to government of running a trial for some of these expensive therapies could be paid for by that extra 6 months of therapy saved.


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