Oncologists Respond Rapidly to Labeling Changes for Immunotherapy

Roxanne Nelson, RN, BSN

October 23, 2019

Oncologists appear willing to change clinical practice quickly in response to safety announcements, a new study suggests.

A few years ago, the US Food and Drug Administration (FDA) changed its labeling on first-line immunotherapy for bladder cancer. The study found that use of these therapies among oncologists dropped by about 50% within 6 months of the revised labeling.

The findings were published online September 24 in the Journal of the American Medical Association.

"Our study suggests that oncologists move quickly to incorporate safety data into their practice, even when such data has not been formally published," lead author Ravi B. Parikh, MD, MPP, an instructor in medical ethics and health policy at the University of Pennsylvania, Philadelphia, said in a statement. "The FDA label restriction had not been incorporated into guidelines from most payers and other bodies by the end of our study, which was January 2019."

It is also possible, Parikh told Medscape Medical News, that oncologists' experience with immunotherapies could have contributed to the decline. "However, the sharp decline that we saw right after the date of the label restriction suggests that the FDA policy contributed most to the decline," he said.

Study Details

About half of patients with advanced bladder cancer are ineligible for standard treatment with a cisplatin-based regimen, and in 2017, the FDA granted accelerated approvals to two immunotherapies acting on the programmed cell death pathway. These approvals of pembrolizumab (Keytruda, Merck) and atezolizumab (Tecentriq, Genentech) for first-line treatment of cisplatin-ineligible patients was based on single-group phase 2 studies.

However, subsequent data from ongoing phase 3 trials showed that patients with bladder cancer with PD-L1–negative tumors who were treated with immunotherapy had worse survival as compared to those who received the standard chemotherapy regimens, as reported previously by Medscape Medical News.

Alerts Issued

The FDA sent an alert on this finding to healthcare professionals, oncology clinical investigators, and the public in May 2018, and then moved to restrict the use of these immunotherapy agents to patients with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing therapy.

In August 2018, the FDA updated the prescribing information to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels for selection of patients being treated in the first-line setting who are cisplatin-ineligible.

The second-line indications in urothelial carcinoma for both drugs remained unchanged.

Parikh and colleagues point out that the "FDA’s decision to restrict the indication after accelerated approval based on early review of confirmatory trial data was unique."

However, given the speed in which the use of immunotherapy was embraced in oncology, it was unclear how quickly the FDA label restriction would affect clinical practice. Hence, Parikh and colleagues set out to examine usage rates of pembrolizumab and atezolizumab after the FDA restrictions.

Oncologist Compliance

The team turned to the Flatiron Health database, which is derived from deidentified electronic health records of patients with cancer with both public and commercial insurance who received care in more than 280 geographically diverse US clinics.

In this database, they identified 1965 patients with advanced bladder cancer.

Of this group, 645 patients received first-line immunotherapy and 1147 initiated first-line chemotherapy. The median age was 73 years and nearly all patients (94%) received their care at community practices.

Their results showed that the FDA label change was associated with reversals in immunotherapy and chemotherapy trends along with increases in PD-L1 testing.

Between May 2018 and January of this year, the rate of immunotherapy use declined from 51.9 to 30.3 per 100 patients; at the same time, rates of chemotherapy use increased from 37.0 to 60.6 per 100 patients. Rates of PD-L1 testing also increased from 9.3 to 21.2 per 100 patients.

After adjusting for patient- and practice-related factors, as of January 31, the FDA label change was associated with a decrease in immunotherapy use (marginal effect, −37.4%), and an increase in chemotherapy use (marginal effect, 34.4%) and in PD-L1 testing (marginal effect, 12.7%) (all P < .001).

Parikh pointed out that they did not have the ability to look at PD-L1 expression in the patient population. "Thus, it is difficult to ascertain whether oncologists were restricting immunotherapy use for the right patients — those whose tumors tested negative for PD-L1 expression," he said. "It is possible that oncologists reduced immunotherapy use indiscriminately, but the sharp rise in PD-L1 testing that we found suggests that many are appropriately using biomarker testing to guide treatment selection."

He added that since studies suggest that approximately 70% of urothelial tumors test negative for PD-L1, "we can reasonably assume that the majority of the decline that we saw was appropriate."

This study was supported by the Conquer Cancer Foundation and the National Cancer Institute of the National Institutes of Health. Parikh has disclosed no relevant financial relationships. Several of the coauthors report relationships with industry and can be found with the original article.

JAMA. Published online September 24, 2019. Research Letter

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