When manufacturers develop drugs for human use, they start by testing a range of doses and schedules. In essence, they are looking to balance toxicity and efficacy. A higher dose may produce more biologic activity but at a cost of increased toxicity. A lower dose may be safer but might give up some biologic activity. If the drug is rapidly cleared, then more frequent dosing might be desirable. If the drug has a long half-life or has irreversible binding to the target, less frequent dosing may suffice.
“Patients who respond to nivolumab have an additional benefit because clearance decreases when disease status improves. This means that the trough concentration will increase over time as clearance decreases (mean decrease, approximately 25%) and also implies that a reduction in either dose or frequency of dosing will maintain therapeutic trough concentrations. Patients with a complete response seem to have the greatest decrease in clearance, averaging approximately 40%. This time-dependent change in clearance provides further evidence that the dosage or frequency can be decreased, particularly in responding patients.
"The science behind Imbruvica suggested that it could work at lower doses, and early clinical evidence indicated that patients with chronic lymphocytic leukemia might do just as well on one or two pills a day after completing an initial round of treatment at three pills per day.
The researchers at the Value in Cancer Care Consortium, a nonprofit focused on cutting treatment costs for some of the most expensive drugs, set out to test whether the lower dose was just as effective — and could save patients money."
"In a pilot study involving 72 people, Ratain and his colleague Russell Szmulewitz, a medical oncologist at the University of Chicago, confirmed this warning by showing that a similar amount of the drug was absorbed when taken as a low dose with a low-fat breakfast as was received with a full dose when fasting. Participants could therefore take one-quarter of the normal dose and still receive the same anti-cancer effects after 12 weeks of treatment, as measured by changes in the level of prostate-specific antigen, a proxy for tumour burden."
"Immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 has revolutionized the treatment of a variety of malignancies. Despite recent advances, many outstanding questions, such as the definitions of the optimal dose, schedule, combinations, and duration of therapy; the development of robust predictors of likely benefit; toxicity; and the development of better ways to manage toxicities, still need to be addressed. These questions can only be explored through prospective clinical trials and broad collaborative research."
Vi3C intends to perform research on optimal dose, schedule and duration of immunotherapy agents.
"The Value in Cancer Care Consortium is a group of physicians who have come together to create, design, and implement clinical trials with the goal of increasing the value of cancer therapeutics. Many drugs today are not being used in the ideal dose. They may be given in too large a dose, for example, or too frequently. They may be given in schedules or durations that are not ideal."
"The initiative is the latest response to rising concerns over “financial toxicity,” the economic devastation that can be wrought by the high cost of cancer care. With new oncology therapies routinely debuting at more than $100,000 a year, “lots of people are worried about developing drugs that people can't get,” said Leonard Saltz of Memorial Sloan Kettering Cancer Center in New York, who helped organize the new group."
"According to the results of the Short-HER study, “There may be a protective effect from a shorter duration of trastuzumab therapy” against cardiac toxicity, discussant Carey K. Anders, MD, of The University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center, said.
There was no difference in OS at 5 years, and the smaller subset analysis found that patients with stage III disease with multiple positive lymph nodes “appeared to derive greater benefit from the longer duration of trastuzumab.”