FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy

Abstract

The U.S. Food and Drug Administration (FDA) granted accelerated approval to atezolizumab and pembrolizumab in April and May 2017, respectively, for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin‐containing chemotherapy. These approvals were based on efficacy and safety data demonstrated in the two single‐arm trials, IMvigor210 (atezolizumab) and KEYNOTE‐052 (pembrolizumab). The primary endpoint, confirmed objective response rate, was 23.5% (95% confidence interval [CI]: 16.2%–32.2%) in patients receiving atezolizumab and 28.6% (95% CI: 24.1%–33.5%) in patients receiving pembrolizumab. The median duration of response was not reached in either study and responses were seen regardless of PD‐L1 status. The safety profiles of both drugs were generally consistent with approved agents targeting PD‐1/PD‐L1. Two ongoing trials (IMvigor130 and KEYNOTE‐361) are verifying benefit of these drugs. Based on concerning preliminary reports from these trials, FDA revised the indications for both agents in cisplatin‐ineligible patients. Both drugs are now indicated for patients not eligible for any platinum‐containing chemotherapy or not eligible for cisplatin‐containing chemotherapy and whose tumors/infiltrating immune cells express a high level of PD‐L1. The indications for atezolizumab and pembrolizumab in patients who have received prior platinum‐based therapy have not been changed. This article summarizes the FDA thought process and data supporting the accelerated approval of both agents and the subsequent revision of the indications. Implications for Practice The accelerated approvals of atezolizumab and pembrolizumab for cisplatin‐ineligible patients with advanced urothelial carcinoma represent the first approved therapies for this patient population. These approvals were based on single‐arm trials demonstrating reasonable objective response rates and favorable durations of response with an acceptable toxicity profile compared with available non‐cisplatin‐containing chemotherapy regimens. However, based on concerning preliminary reports from two ongoing phase III trials, the FDA revised the indication for both agents in cisplatin‐ineligible patients. Both are now indicated either for patients not eligible for any platinum‐containing chemotherapy or not eligible for cisplatin‐containing chemotherapy and whose tumors have high expression of PD‐L1.

Personalisierte Medizin im Urothelkarzinom der Harnblase

“…Patienten mit einer niedrigen PD-L1-Expression (PD-L1-Expression < 5 % bzw. CPS [combined positivity score] < 10), die mit einem Immuncheckpoint-Inhibitor behandelt wurden, wiesen im Vergleich zu Patienten mit einer Platin-basierten Erstlinientherapie ein schlechteres Gesamtüberleben auf [27,28]. Auch in 2 Phase-II-Studien zum Einsatz von Immuncheckpoint-Inhibitoren in der neoadjuvanten Therapiesituation konnte das Tumoransprechen mit dem PD-L1-Status korreliert werden.…”

Oral immune‐related adverse events associated with PD‐1 inhibitor therapy: A case series

“…The use of such agents has resulted in prolonged disease‐free remission and overall survival in malignancies that were previously fatal (Freeman et al, ; Hanahan & Weinberg, ; Iwai et al, ). To date, PD‐1 inhibitors have been approved for the treatment of advanced and refractory cancers including melanoma, non‐small‐cell lung cancer, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, urothelial cancer, cervical cancer, and gastric cancer; their use is expected to continue to increase with additional approvals (Chen et al, ; Chung et al, ; Fashoyin‐Aje et al, ; Finkelmeier, Waidmann, & Trojan, ; Hauschild & Schadendorf, ; Hodi et al, ; Larkins et al, ; Printz, ; Suzman et al, ).…”

“…To date, PD-1 inhibitors have been approved for the treatment of advanced and refractory cancers including melanoma, non-smallcell lung cancer, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, urothelial cancer, cervical cancer, and gastric cancer; their use is expected to continue to increase with additional approvals Chung et al, 2019;Fashoyin-Aje et al, 2019;Finkelmeier, Waidmann, & Trojan, 2018;Hauschild & Schadendorf, 2016;Hodi et al, 2010;Larkins et al, 2017;Printz, 2017;Suzman et al, 2018).…”

Illumination of a Vision 2020—Urinary Based Biomarkers for Bladder Cancer on the Way to Clinical Decisions—Dream or Nightmare?

“…In the past, more and more genetic and epigenetic markers could show its predictive and/or prognostic value regarding overall survival and even cancer specific survival. As an example of how a tumor marker can predict therapeutic success, the results of the phase 2 KEYNOTE-052 (NCT02335424) study showed how a marker could influence therapeutic decisions on one hand, and that negative marker results were also not a certain predictor of therapeutic success [22]. PD-L1 positive is defined as a combined positive score (CPS) ≥10.…”