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FDA approval of Lumakras was contingent on a trial testing lower doses. It could usher in a new era of optimal dosing instead of the maximum tolerated dosing.
The world of oncology treatment may have just course corrected — slightly. The change? The FDA is signaling to pharmaceutical companies a shift from maximum tolerated dosing (MTD) to optimal dosing.
What’s at stake for pharmaceutical companies is lower doses that could affect pricing and income. Drug developers may also need to tweak clinical trial designs. For patients, a new framework based on optimal dosing may mean fewer side effects and same efficacy. For payers, there is the prospect of lower drug costs.
The FDA sent a strong signal about optimal dosing in the first half of 2021 when Amgen sought approval for its KRAS inhibitor Lumakras (sotorasib) as therapy for adults with non-small cell lung cancer whose tumors have a KRAS G12C genetic mutation and who have received at least one prior systemic therapy. The FDA granted approval in late May 2021 but required the pharmaceutical company to conduct a post-approval randomized clinical trial comparing the approved dose of 960 mg daily with a 240-mg dose.
The FDA’s director of the Oncology Center of Excellence, Richard Pazdur, M.D., also stated during Stat’s recap of the 2021 meeting of the American Society of Clinical Oncology that the agency wants other pharmaceutical companies to conduct randomized phase 2 trials such as this prior to registration studies. The goal would be for phase 1 trials to identify the range of doses to study in later trials, instead of just identifying the MTD. This move toward closer study of dosing is a win for the Optimal Cancer Care Alliance (OCCA), which has been pushing for several years for the medical community to find ways to avoid relying only on the MTD as a dosing strategy.
Optimal dosing used to be called interventional pharmacoeconomics, explains Mark Ratain, M.D., OCCA treasurer and director of the Center for Personalized Therapeutics at the University of Chicago. The group has been pushing stakeholders to develop new oncology dosing regimens. \The strategies include lowering dosing, less frequent dosing, shortening the duration of treatment and, in some cases, substituting one therapy for another.
The oncology community has been slow to accept the optimal dosing concept. Clinicians prefer to adhere to the prescribing guidelines, according to Ratain.
“Oncologists believe in the dogma that more is better,” Ratain says. “The FDA finally said more is not better.”
Although the post-approval dosing trial for Lumakras was a new mandate, there are other obvious candidates for testing lower doses, Ratain says. Those include Opdivo (nivolumab), Keytruda (pembrolizumab), Imbruvica (ibrutinib) and Tecentriq (atezolizumab), for which, Ratain says, “doses are excessive.”
Challenges exist for lowering doses in a manner supported by data from trials. The biggest issue involves paying for the trials. “Pharma certainly is not going to fund them,” Ratain says. “The NIH (National Institutes of Health) has not shown any interest in funding these trials. The people interested in developing new drug treatments aren’t interested.” But NIH would be a reasonable funder, Ratain says. Research of this kind has been funded by the United Kingdom’s National Health Service. Ratain says the trials would pay for themselves because of the savings in drug costs, which would benefit payers and healthcare systems such as Kaiser Permamente.
Deborah Abrams Kaplan writes about medical and practice management topics.