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Going Off-Label

Physicians are legally permitted to prescribe drugs approved for one purpose to be used for another, a practice called off-label prescribing. The rise of targeted therapies and immunotherapies is creating new challenges for navigating off-label options. By Kate Yandell

When Tori Tomalia’s oncologist gave her a new prescription for pills to treat her stage IV non–small cell lung cancer (NSCLC) in November 2013, she expected it would be filled routinely. Instead, the pharmacist told the 37-year-old that her insurance company had declined to cover the prescription and that she would need prior authorization for the medication.

Exploring Trials
Clinical trials are testing off-label use in patient with advanced cancers who have exhausted standard treatments.

Assessing Therapies
Know what tips to follow when considering off-label drug use with your physician.
Her new therapy, Xalkori (crizotinib), had been approved by the U.S. Food and Drug Administration (FDA) in 2011 to treat advanced NSCLC patients with ALK gene mutations in their tumors. Tomalia, a mother of three and the owner of a brewery and theater in Ann Arbor, Michigan, instead had learned her cancer had a mutation in the gene ROS1. Clinical trial data had indicated that patients like Tomalia whose cancers had the ROS1 mutation did well on Xalkori, so her oncologist prescribed it. This practice, called off-label treatment, is legal and common in medicine. 

Tomalia’s insurer ended up covering her Xalkori prescription off-label for more than two years. In March 2016, the drug was approved by the FDA to treat ROS1-positive metastatic NSCLC patients. Tomalia is still taking Xalkori to keep her tumors at bay, except for brain metastases, which are being treated separately. Meanwhile, oncologists are now prescribing Xalkori off-label to a new group of NSCLC patients whose tumors have alterations in the MET gene based on promising clinical trial results.

The rise of immunotherapies and targeted agents is complicating off-label treatment, making it more attractive, but also providing opportunities for patients to try drugs that have not been well-tested in their type of cancer. And while using a new therapy off-label before it has been fully investigated can extend life for some patients, off-label use can come with financial and logistical hurdles.

A Cancer Treatment Staple
Off-label use of drugs can be cutting-edge or routine. Studies suggest that historically, from 30 to 50 percent of prescriptions in oncology in the U.S. have been off-label. Off-label uses that become standard-of-care treatments are listed in treatment guidelines, such as those compiled by the National Comprehensive Cancer Network (NCCN). Patients might not even know that the drug they are using is not technically approved by the FDA for their cancer type.

When Larry Simpson of Mobile, Alabama, was first diagnosed with stage IV head and neck cancer in 2014 at age 70, he was given radiation and chemotherapy with carboplatin and Taxol (paclitaxel). Both drugs had been originally approved for treating ovarian cancer: carboplatin in 1989 and Taxol in 1992. Today, Taxol is approved for several additional cancer types, and the NCCN guidelines support off-label use of carboplatin, Taxol or both to treat more than a dozen cancer types, including head and neck cancer like Simpson’s. 

In January 2015, Simpson completed chemotherapy and radiation treatment, but by the summer, a positron emission tomography (PET) scan revealed that his cancer was growing aggressively. He consulted with a local doctor, who suggested he travel to the University of Texas M.D. Anderson Cancer Center in Houston, more than 450 miles from his home.

At M.D. Anderson, Simpson was enrolled in IMPACT2, an initiative in which patients get their tumors sequenced and are funneled into clinical trials based on the results. Simpson learned his cancer had a mutation in the gene PIK3CA, and he was enrolled in a trial testing a combination of Torisel (temsirolimus), which targets a pathway of which PIK3CA is a part, and Avastin (bevacizumab), which slows growth of blood vessels that feed tumors. Torisel is approved for kidney cancer. Avastin is approved, alone or in combination with other drugs, for some patients with colorectal, lung, brain, kidney, cervical and ovarian cancers. Neither drug has been approved for head and neck cancer, and the NCCN does not include these therapies in its guidelines for head and neck cancer treatment.

A Dose of Caution
Some patients, like Simpson, receive approved drugs as part of clinical trials testing whether the drug could be useful for patients beyond the group identified in the drug’s FDA label. In other cases, patients may be prescribed drugs off-label by their physician outside the context of a clinical trial. Despite some encouraging outcomes, physicians and scientists urge caution in choosing off-label treatments outside of a trial that are not considered standard and are not listed in the NCCN guidelines. “As physicians, we are in a tough spot,” says Jonas de Souza, a medical oncologist specializing in head and neck cancer at the University of Chicago Medicine. “We want to treat our patients, provide them the best care available. With all the advances in oncology, there is the potential to start prescribing things we don’t have evidence for yet.”

Immunotherapy drugs, which unleash the body’s immune system to treat cancer, are attractive for off-label use, both because they achieve notable results in some people and because for many, the side effects are easier to control than those of chemotherapy. “There’s a high potential of [saying], ‘Oh, let’s try Keytruda in this cancer’ before the evidence is there,” de Souza says.

In a poster presented in March 2017 at the American Society of Clinical Oncology (ASCO) Quality Care Symposium in Orlando, Florida, de Souza and his colleagues assessed data from insurance claims for off-label use of Keytruda, which is approved for treating advanced NSCLC, melanoma, classical Hodgkin lymphoma and squamous head and neck cancer. Looking at data from private insurance and Medicare and Medicaid claims from January 2015 to September 2016, the researchers found that 292 out of 871 patients who put in claims for Keytruda were taking the drug off-label. 

Anecdotal evidence that someone with a certain condition has benefited from a drug is not sufficient to conclude it will help other people with that condition, says George Demetri, a medical oncologist specializing in sarcoma at the Dana-Farber Cancer Institute in Boston. He recently published a case study on a patient with leiomyosarcoma who was treated with Keytruda and had a very positive response. But other patients with the same disease treated with Keytruda did not benefit. Even in cancers for which immunotherapy drugs have been approved, not all patients respond to treatment, Demetri says.  


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