FDA Label Change Takes a Bite Out of Prescriptions

OncologyLive, Vol. 20/No. 23, Volume 20, Issue 23

Immunotherapy prescriptions for patients with metastatic bladder cancer declined rapidly after the FDA altered the indications of 2 drugs, suggesting that oncologists can keep pace with changes associated with the agency’s accelerated approval program.

Ravi B. Parikh, MD, MP

Immunotherapy prescriptions for patients with metastatic bladder cancer declined rapidly after the FDA altered the indications of 2 drugs, suggesting that practicing oncologists can keep pace with changes associated with the agency’s accelerated approval program. Data published in JAMA showed that usage rates for pembrolizumab (Keytruda) and atezolizumab (Tecentriq) in this population dropped by approximately 40% within 8 months of a label change.1,2

The uptake of immune checkpoint inhibitors has been rapid. Results from a 2018 study of 3089 patients with melanoma, nonsmall cell lung cancer (NSCLC), or renal cell carcinoma (RCC) showed that more than 60% of those eligible in each group were assigned to PD-1 inhibitors within 4 months of FDA approval. Anti—PD-1 therapies were administered to 79.1% of eligible patients with melanoma, 65.6% with NSCLC, and 71.2% with RCC.3

Supporters say the accelerated approval program is an important tool to get vital medications to patients quickly. Critics argue that these agents should be evaluated for safety and efficacy in randomized phase III clinical trials before going to market.

Ravi B. Parikh, MD, MPP, an instructor in Medical Ethics and Health Policy at the University of Pennsylvania in Philadelphia, and colleagues wanted to determine the response to emerging safety data and whether new information affected clinical practice.

“Given the rapid expansion of approvals for immunotherapies, understanding how oncologists react to postapproval safety concerns is crucial,” Parikh said in a news release.2 “Our study suggests uptake of these changing recommendations can occur very quickly.”

Based on findings from phase II studies, the FDA in 2017 granted accelerated approval to both pembrolizumab and atezolizumab for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based therapy. The approvals were based on tumor response rate and duration of response.

However, early reviews from data monitoring committees in the ongoing phase III KEYNOTE-361 and IMvigor130 trials found patients in the monotherapy arms of both trials with PD-L1—low expression had decreased survival compared with patients who received cisplatin- or carboplatin-based chemotherapy. As a result, the FDA in June 2018 restricted the indications for the immunotherapeutic agents to cisplatin-ineligible patients with PD-L1positive tumors.4 (Both agents also are approved for patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status and for those with disease progression during or following chemotherapy).

Parikh and colleagues analyzed health records for 1965 patients with advanced bladder cancer collected at more than 280 oncology clinics across the United States. The study period lasted from May 2018 to January 2019.1

The rate of immunotherapy usage per 100 patients decreased from 51.9 to 30.3 during the study period while the rate of chemotherapy usage increased from 37.0 to 60.6. By January 2019, patients were more than twice as likely to undergo PD-L1 testing (21.2 vs 9.3 per 100 patients).

After adjusting for patient and practice factors, investigators concluded that the marginal effect of the label change was a 37.4% decrease in immunotherapy use with a 34.4% increase in chemotherapy use and a 12.7% increase in PD-L1 testing.1

The study could not determine how many practitioners changed treatment in response to the label change or how many patients were still receiving therapy not in accordance with the approved label.

Rapid adherence to label changes is crucial following accelerated approval because the performance of anticancer drugs is mixed in confirmatory trials. In results published in JAMA Internal Medicine in May 2019, investigators analyzed 93 anticancer agents granted accelerated approval from December 1992 through May 2017. Only 20% of confirmatory trials showed an improvement in overall survival.5

“Until the requirements to transition from accelerated approval to regular approval are met, the clinical community will have less information about the risks and benefits of drugs approved by the accelerated approval program,” wrote Bishal Gyawali, MD, PhD, and colleagues. “Appropriate use of this pathway will require that confirmatory trials are conducted in a timely fashion, using clinically meaningful or validated end points.”


  1. Parikh RB, Adamson BJS, Khozin S, et al. Association between FDA label restriction and immunotherapy and chemotherapy use in bladder cancer. JAMA. 2019;322(12):1209-1211. doi: 10.1001/ jama.2019.10650
  2. Oncologists respond swiftly to FDA safety alerts, Penn study finds [news release]. Philadelphia, PA; Penn Medicine; September 24, 2019. bit.ly/2OaLfuK. Accessed September 30, 2019.
  3. O’Connor JM, Fessele KL, Steiner J, et al. Speed of adoption of immune checkpoint inhibitors of programmed cell death 1 protein and comparison of patient ages in clinical practice vs pivotal clinical trials. JAMA Oncol. 2018;4(8):e180798. doi: 10.1001/ jamaoncol.2018.0798.
  4. FDA alerts health care professionals and oncology clinical investigators about an efficacy issue identified in clinical trials for some patients taking Keytruda (pembrolizumab) or Tecentriq (atezolizumab) as monotherapy to treat urothelial cancer with low expression of PD-L1 [news release]. Silver Spring, MD: FDA; August 16, 2018. bit.ly/2yJSWiV. Accessed September 30, 2019.
  5. Gyawali B, Hey SP, Kesselheim AS. Assessment of the clinical benefit of cancer drugs receiving accelerated approval. JAMA Intern Med. 2019;179(7):906-913. doi: 10.1001/jamainternmed.2019.0462.