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ONCAlert | 2018 SGO Annual Meeting on Women’s Cancer

Immune Checkpoint Blockade for the Treatment of Advanced Urothelial Cancer: A New Era in Systemic Therapy

Matthew D. Galsky, MD
Published Online: Dec 28,2017

Matthew D. Galsky, MD
Abstract

In this review, the emerging arena of checkpoint inhibitors and immunotherapy in the treatment of urothelial carcinomas is explored and discussed. In particular, the article covers the recent groundbreaking data in this space. As immunotherapies become more popular and clinically available, and more data emerge in support of them, it is essential to understand the science and the justification for using these agents in clinical practice.

Introduction

Metastatic urothelial cancer (UC) is a relatively chemotherapy-sensitive malignancy. With contemporary cisplatin-based combination chemotherapy regimens, objective responses are achieved in approximately 50% to 60% of patients and complete radiographic responses are achieved in approximately 10% to 20% of patients.1 Unfortunately, response durations are typically short with only 5% to 10% of patients achieving durable disease control.

Decades of clinical trials exploring modifications of cytotoxic regimens, including the use of different or more drugs, demonstrated that a therapeutic plateau had been reached with conventional chemotherapeutic agents, highlighting the need for novel approaches. Central to the immune system is a set of inhibitory pathways regulated by proteins commonly referred to as immune checkpoints among which cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death-1 (PD-1), and the programmed death ligand 1 (PD-L1) are the most well characterized.2 Instead of a dysfunctional immune system as a general explanation of the lack of effective anticancer immune responses in patients with cancer, it is now understood that in at least a subset of patients, these immune checkpoints are co-opted by cancers to dampen antitumor immunity. Data in model systems, and in patients, now demonstrate that the administration of blocking antibodies to these checkpoints can overcome such adaptive immune resistance.

Clinical Experience With Single-Agent Immune Checkpoint Blockade in UC

Anti–CTLA-4 antibodies were the first immune check- point inhibitors to be widely explored in cancer, and ipilimumab (Yervoy) is approved for the treatment of metastatic melanoma by the FDA. Studies in syngeneic mouse model systems of bladder cancer have demonstrated anticancer activity providing a rationale for clinical testing of CTLA-4 blockade.3 Despite such data, there have been very few completed clinical trials exploring CLTA-4 blockade in UC.

Bradley C. Carthon, MD, PhD, and colleagues performed a “window of opportunity” study of precystectomy ipilimumab in patients with invasive UC of the bladder as a means to study the pharmacodynamic effects of treatment; that is, the investigators compared changes in the immune microenvironment in the posttreatment cystectomy specimens with the pretreatment transurethral resection specimens.4 Interestingly, in this study of 12 patients treated with 2 doses of ipilimumab prior to cystectomy, patients receiving a higher dose of ipilimumab demonstrated a robust infiltration of T cells in the posttreatment cystectomy specimen.

A phase II study explored treatment with 2 cycles of gemcitabine plus cisplatin followed by 4 cycles of gemcitabine, cisplatin, and ipilimumab in chemotherapy-naïve patients with metastatic UC.5 The combination regimen was devised based on the hypothesis that initial chemotherapy would induce the killing of cancer cells and the release of tumor antigen (ie, immunogenic cell death), which could then be exploited by introduction of immune checkpoint blockade.5

Although the overall outcomes of patients treated with this regimen were similar to historical controls treated with gemcitabine plus cisplatin alone, an exploratory analysis revealed an intriguing improvement in survival in the subset of patients demonstrating a post-ipilimumab increase in peripheral blood T cells compared with the subset not demonstrating such an increase. Though PD-1/ PDL1 rapidly surpassed CTLA-4 as an attractive therapeutic target in UC, several studies are now exploring combination regimens involving CTLA-4 blockade plus PD-1/PD-L1 blockade or are revisiting the potential role of single-agent CTLA-4 blockade. 

In the initial phase I studies exploring PD-1 and PD-L1 antibodies, it was apparent early on that the spectrum of anticancer activity was broader than had been the experience of CTLA-4 blockade; objective responses were seen in cancers commonly considered “immune responsive,” such as melanoma and renal cancer, but also somewhat unexpectedly in other solid tumors such as non–small cell lung cancer.6,7 These findings, as well as data demonstrating that tumor-infiltrating lymphocytes are prognostic in UC specimens, provided the impetus to expand phase I cohorts to include UC. Initial proofof-concept for PD-L1 and PD-1 blockade in UC came from expansion cohorts of phase I studies of atezolizumab (Tecentriq) and pembrolizumab (Keytruda), respectively.8,9 Both studies demonstrated durable objective responses in a subset of heavily pretreated patients with metastatic UC, with a generally favorable adverse event (AE) profile compared with historical patients treated with cytotoxic chemotherapy, serving as the basis for much more extensive investigation.

As of May 2017, 2 PD-1 inhibitors, pembrolizumab (Keytruda) and nivolumab (Opdivo), and 3 PD-L1 inhibitors, atezolizumab, durvalumab (Imfinzi), and avelumab (Bavencio), have been approved by the FDA for the treatment of metastatic UC (Table 1). The datasets leading to approval of these therapies’ range from expansion cohorts of phase I studies to large randomized phase III studies (Table 2). 

 


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Immune Checkpoint Blockade for the Treatment of Advanced Urothelial Cancer: A New Era in Systemic Therapy
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