Oncologists quickly react to label changes for immunotherapies, a study by Penn, Flatiron shows

Cancer Letter

In an unprecedented use of real-world data, researchers at the University of Pennsylvania and Flatiron Health have determined that oncologists are responding quickly to label restrictions announced by FDA.

Researchers found that, in treatment of advanced bladder cancer, there was an adjusted 50% reduction in the use of two immuno-oncology agents within six months after issuance of a safety alert.

The study’s findings, published in JAMA Sept. 24, come at a time when oncologists have to keep up with the rapid pace of approval of new therapies. This is especially important in the context of FDA’s accelerated approval program, which approves therapies based on metrics that are “reasonably likely to predict” patient benefit.

Using de-identified data from more than 280 oncology clinics across the United States, the study analyzed data on utilization of first-line immunotherapies and chemotherapy in patients with advanced bladder cancer between January 2016 and January 2019. The majority of the patients, 94%, were treated in community practices, with the remaining 6% receiving care at academic medical centers.

The study, Association Between FDA Label Restriction and Immunotherapy and Chemotherapy Use in Bladder Cancer, examined usage rates of PD-1 inhibitor pembrolizumab and PD-L1 inhibitor atezolizumab in advanced bladder cancer patients who are not eligible for standard cisplatin-based chemotherapy.

The two checkpoint inhibitors, manufactured by Merck and Roche, received accelerated approval in 2017 based on phase II studies. However, data from ongoing phase III studies showed patients with PD-L1-negative tumors had decreased survival when taking these drugs, compared to first-line chemotherapy.

This led FDA to issue a safety alert in May 2018, and subsequently restrict the label indications for patients with locally advanced or metastatic urothelial carcinoma. In August 2018, FDA updated the prescribing information for pembrolizumab and atezolizumab to require oncologists to determine PD-L1 levels in tumor tissue of these patients.

“I think in terms of the near 50% reduction in use of immunotherapy, it’s encouraging from the perspective that physicians rapidly respond to FDA guidance, which is based on real-time changes in the evidence,” Ravi Parikh, lead author of the study, and an instructor in medical ethics and health policy at the University of Pennsylvania, said to The Cancer Letter.

“So, in this case, the FDA warning was based on early reporting of two ongoing clinical trials that looked at the effectiveness of immunotherapy monotherapy as a first-line therapy for bladder cancer versus chemotherapy.”

While it wasn’t possible to conclusively determine whether all PD-L1-negative patients in the study cohort stopped receiving pembrolizumab and atezolizumab—because not all patients received biomarker testing—the results showed that most oncologists, especially in the community setting, are making clinical decisions that align with evidence-based announcements by FDA.

“The FDA is not mandated to collect information about how providers are using drugs,” Blythe Adamson, co-lead author of the study, and senior quantitative scientist at Flatiron Health, said to The Cancer Letter. “Before this study, they really haven’t been able to understand whether or not their guidances are being rapidly absorbed, understood, and changing clinical practice to improve patient outcomes.”

The study found that rates of PD-L1 testing more than doubled within the same six-month period, from 9.3% to 21.2% per 100 patients.

“That increase in testing is corresponding to the decrease in immunotherapy over time, with the mix of chemo and IO that we’re seeing now,” Adamson said. “We really hope it’s corresponding to the patients who are PD-L1-positive getting the immunotherapy, and the PD-L1-negative patients getting chemo.

“The decrease of 50% [in utilization of first-line immunotherapies for advanced bladder cancer] doesn’t mean there’s still 50% room to get better. Because the percentage that’s left, that doesn’t mean that those oncologists are not prescribing the best care. It means that those might be the PD-L1-positive.”