Moving Targets: Off-Label Prescribing of Targeted Therapies

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By way of the TAPUR study, researchers are attempting to evaluate the activity of targeted therapies when they are used in an off-label setting.
By way of the TAPUR study, researchers are attempting to evaluate the activity of targeted therapies when they are used in an off-label setting.

Off-label prescribing has been a perennial part of cancer practice, and can sometimes begin as soon as reports of the clinical trial results in support of an investigational indication begin to emerge — but the appearance of increasingly pricier targeted therapies has boosted the complexity of therapeutic decisions.

The variability of the underlying evidence, highlighted by a recent study, is just one factor for cancer physicians to consider.1 The patient's financial circumstances and vulnerability to unknown toxicities also must be weighed. Meanwhile, advances in research and an improved ability to screen for mutations have expanded potential drug targets. In late 2017, officials from the US Food and Drug Administration (FDA) approved FoundationOneCDx, which can detect mutations in 324 genes that have been linked to cancer growth.2 (Another test called MSK-IMPACT, which can detect mutations in 468 genes, also was authorized by federal officials in late 2017.)

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Such expansive genetic profiling tests are “intended to be used as a companion diagnostic to screen tumors for genes that are known to be actionable with FDA-approved drugs,” Richard Schilsky, MD, FACP, FASCO, chief medical officer at the American Society of Clinical Oncology (ASCO), told Cancer Therapy Advisor. “But I think it inevitably will lead to off-label prescribing as well,” he said.

Some of the off-label prescribing is appropriate, Dr Schilsky said, as ongoing research identifies new indications and the drug manufacturer might not necessarily update the label right away. Dr Schilsky coauthored a frequently cited analysis, published in 2013 in the Journal of Clinical Oncology, which looked at 10 commonly used chemotherapy drugs and found that overall they were prescribed off-label 30% of the time. Of those 10, gemcitabine (32%) and rituximab (33%) were least likely to be prescribed on-label; trastuzumab (99%) was most likely.3

Overall, 14% of that off-label prescribing was supported by National Comprehensive Cancer Network (NCCN) recommendations. An additional 10% of the time, the drug was prescribed for the same malignancy stated on the FDA label, but not for the same stage or line of therapy.

NCCN guidelines frequently stray beyond FDA-approved indications, Vinay Prasad, MD, MPH, associate professor of medicine, Oregon Health and Science University, Portland, told Cancer Therapy Advisor. In an analysis published earlier this year, Dr Prasad and colleagues looked at 47 cancer drugs approved from 2011 to 2015.1 NCCN recommended these drugs for a total of 113 indications; 44 of them extended beyond FDA-approved indications.

Of those 44, 10 cited evidence from randomized trials, and just 7 of the 44 cited results from phase 3 randomized studies, specifically. Dr Prasad noted that NCCN guidelines are frequently referenced by physicians he's training, and he often urges his students to dig deeper into trial data.

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