Association Between FDA Label Restriction and Immunotherapy and Chemotherapy Use in Bladder Cancer

Abstract

Approximately half of patients with advanced bladder cancer are ineligible for standard management with cisplatin-based chemotherapy. In 2017, based on single-group phase 2 studies, the US Food and Drug Administration (FDA) granted accelerated approvals to 2 anti-programmed cell death protein (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapies, pembrolizumab and atezolizumab, for first-line treatment of any cisplatin-ineligible patients. 1,2 However, data from ongoing phase 3 trials showed that patients with PD-L1-negative tumors who received immunotherapy had decreased survival relative to those receiving platinum-based chemotherapy. In June 2018, the FDA limited the indication for the 2 first-line immunotherapies to cisplatin-ineligible patients with PD-L1-positive tumors. The FDA's decision to restrict the indication after accelerated approval based on early review of confirmatory trial data was unique. 3 Given the rapid uptake of immunotherapies in oncology, 4 whether or how quickly the FDA label restriction would affect clinical practice was unclear. Methods | This interrupted time-series analysis included patients diagnosed as having advanced bladder cancer between January 1, 2016, and January 31, 2019, who were treated with at least 1 line of systemic therapy. We used data from the Flatiron Health database, derived from deidentified electronic health records of commercially and publicly insured patients with cancer receiving care in more than 280 geographically diverse US clinics. 5 We excluded patients who received therapies not listed in National Comprehensive Cancer Network guidelines for bladder cancer. Outcome utilization rates were calculated among patients initiating first-line therapy each calendar month. Multivariable logistic regression models were fit for 3 outcomes (utilization of first-line immunotherapies, cisplatinor carboplatin-based chemotherapy, and PD-L1 testing), adjusted for race, age, smoking status, performance status, region, practice type, and year of diagnosis. Each model included an exposure variable indicating whether first-line treatment started before or after June 1, 2018, and an interaction variable with time. Because oncologists may use immunotherapies interchangeably, all immunotherapies with bladder cancer indications available at the time (pembrolizumab, atezolizumab, nivolumab, avelumab, and durvalumab) were included. We estimated the average marginal effect of the FDA label change on the rates of each outcome evaluated on

DNA Repair Gene Mutations as Predictors of Immune Checkpoint Inhibitor Response beyond Tumor Mutation Burden

“… 2 , 7 However, overtreatment with ICIs remains a considerable concern, particularly when some patients demonstrate greater benefit from other modalities. 8 Clearly, improved predictive biomarkers of ICI response are needed to advance precision medicine and improve patient outcomes.…”

Comparison of Population Characteristics in Real-World Clinical Oncology Databases in the US: Flatiron Health, SEER, and NPCR

“…SEER and NPCR have been well established as research resources since their inception in 1973 and 1992, respectively. As the most recent of the three sources, data derived from Flatiron Health have become a research resource in the last five years (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18); therefore, it has become increasingly critical to understand their features. SEER and NPCR collect specific incident disease data points in a systematic and ordered fashion, fulfilling a public health reporting mandate justified by the public health burden of cancer as a disease.…”

Correlations between glycolysis with clinical traits and immune function in bladder urothelial carcinoma

“…Up to 25% of patients were identified as muscle-invasive bladder cancer (MIBC) for the first diagnosis, which usually leads to distant metastasis and dismal prognosis [ 3 ]. Although radical cystectomy is the standard treatment for MIBC, the U.S. Food and Drug Administration (FDA) granted approvals to two immune checkpoint inhibitors (ICIs), pembrolizumab and atezolizumab, for first-line treatment of cisplatin-ineligible patients with PD-L1-positive bladder cancer in 2018 [ 4 ]. Due to its limited application scope, new systemic therapeutic approaches are urgently needed for BLCA patients.…”