*Review* **Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?**

**Olga Bednova <sup>1</sup> and Je**ff**rey V. Leyton 1,2,\***


Received: 24 August 2020; Accepted: 30 September 2020; Published: 1 October 2020

**Abstract:** The fact that there are now five immune checkpoint inhibitor (ICI) monoclonal antibodies approved since 2016 that target programmed cell death protein 1 or programmed death ligand-1 for the treatment of metastatic and refractory bladder cancer is an outstanding achievement. Although patients can display pronounced responses that extend survival when treated with ICIs, the main benefit of these drugs compared to traditional chemotherapy is that they are better tolerated and result in reduced adverse events (AEs). Unfortunately, response rates to ICI treatment are relatively low and, these drugs are expensive and have a high economic burden. As a result, their clinical efficacy/cost-value relationship is debated. Long sought after targeted molecular therapeutics have now emerged and are boasting impressive response rates in heavily pre-treated, including ICI treated, patients with metastatic bladder cancer. The antibody-drug conjugates (ADCs) enfortumab vedotin (EV) and sacituzumab govitecan (SG) have demonstrated the ability to provide objective response rates (ORRs) of 44% and 31% in patients with bladder tumor cells that express Nectin-4 and Trop-2, respectively. As a result, EV was approved by the U.S. Food and Drug Administration for the treatment of patients with advanced or metastatic bladder cancer who have previously received ICI and platinum-containing chemotherapy. SG has been granted fast track designation. The small molecule Erdafitinib was recently approved for the treatment of patients with advanced or metastatic bladder cancer with genetic alterations in fibroblast growth factor receptors that have previously been treated with a platinum-containing chemotherapy. Erdafitinib achieved an ORR of 40% in patients including a proportion who had previously received ICI therapy. In addition, these targeted drugs are sufficiently tolerated or AEs can be appropriately managed. Hence, the early performance in clinical effectiveness of these targeted drugs are substantially increased relative to ICIs. In this article, the most up to date follow-ups on treatment efficacy and AEs of the ICIs and targeted therapeutics are described. In addition, drug price and cost-effectiveness are described. For best overall value taking into account clinical effectiveness, price and cost-effectiveness, results favor avelumab and atezolizumab for ICIs. Although therapeutically promising, it is too early to determine if the described targeted therapeutics provide the best overall value as cost-effectiveness analyses have yet to be performed and long-term follow-ups are needed. Nonetheless, with the arrival of targeted molecular therapeutics and their increased effectiveness relative to ICIs, creates a potential novel paradigm based on 'targeting' for affecting clinical practice for metastatic bladder cancer treatment.

**Keywords:** bladder cancer; antibodies; immune checkpoint inhibitors; antibody-drug conjugates; sacituzumab govitecan; enfortumab vedotin; erdafitinib; cost-effectiveness

#### **1. Introduction**

Urothelial cancer typically arises from the transitional cells in the urothelium of the bladder, renal pelvis, ureter, and urethra and is commonly referred to as bladder cancer. According to the World Health Organization, bladder cancer represents the 10th most diagnosed and 13th most deadly malignancy worldwide [1]. Bladder cancer is a particular challenge to treat as it is most frequent (>50%) within the elderly and these patients often have underlying comorbidities and reduced functional status [2]. Bladder cancer is a heterogeneous disease, with 70% of cases diagnosed with superficial (non-invasive) tumors and 20% and 10% present as muscle-invasive bladder cancer (MIBC) and metastatic disease, respectively [3]. Importantly, 50–70% of superficial tumors will recur and 10–20% will progress to MIBC [3]. Despite therapy, MIBC progresses to incurable metastatic disease in about half of cases [4]. Cisplatin-containing chemotherapy regimens are the current standard-of-care for the treatment of metastatic bladder cancer. Unfortunately, the 5-year survival rate of metastatic patients treated with regimens consisting of cisplatin plus gemcitabine and methotrexate/vinblastine/doxorubicin/cisplatin is poor [5]. Chemotherapy is also related to high toxicity and has caused adverse events (AEs) of grade ≥3 in up to 82% of cases [6]. In addition, treatment related death occurs in 3–4% of cases [7]. Due to the frailty of many elderly patients, there are significant proportions of cases that are ineligible for platinum-containing chemotherapy. In these patients, carboplatin-based regimens are typically used. However, carboplatin-based chemotherapy is considered limited as the overall survival (OS) rate for these patients is approximately 9 months [5,8]. Patients who relapse after platinum-containing chemotherapy and are treated with second-line chemotherapy, have even more limited responses and poor survival [9,10]. Thus, there are unmet needs for effective and tolerable therapies for patients that are cisplatin-ineligible or for those with metastatic tumor recurrences after receiving platinum-containing chemotherapy.

In concept, precision-based therapy is the systemic administration of a drug that specifically targets tumors and, as a result, reduces nonspecific toxicities while maximizing tumor killing. Although the paradigm of targeted therapeutics has been effective and part of the standard of care for certain tumor types, it has been a challenge to accomplish in the clinic for bladder cancer [11–13]. The inability of targeted therapeutics to provide patients with robust patient responses or significant responses relative to chemotherapy is the major reason why chemotherapy has been the primary option for systemically treating advanced or metastatic bladder cancer for the past three decades, until the approval of immunotherapy and targeted therapeutics starting in 2016.

The advent of immunotherapies in the form of immune checkpoint inhibitors (ICIs), which are monoclonal antibodies (mAbs) that target specific factors that regulate the immune response, has dramatically changed the landscape of bladder cancer treatment. In general, ICIs work well—but only for a minority of patients providing them with long-lasting immunologic memory [14]. However, the majority of patients treated with ICIs fail to ever respond, and those that initially respond eventually develop resistance and disease progression. Unlike targeted therapeutics, there remains no predictive molecular biomarker to determine the patients who are most likely to benefit from ICI therapy.

In other tumor types, ICIs have been incredibly successful and have helped patients who have previously received not only traditional chemotherapy, but also targeted therapies [15–17]. A unique aspect of bladder cancer, ICIs have provided benefit in a tumor type where targeted therapy is inexistent. Bladder cancer is a unique case study because it is now targeted therapies that are coming to the rescue of patients who have previously received ICIs. Many of the ICIs have now provided results with follow-up periods that provide data with increased insight on important phase II/III trials. Thus, we provide a timely analysis of the latest clinical effectiveness of the five ICIs that are currently approved by the U.S. Food and Drug Administration (FDA). We also describe AEs, drug price, and cost-effectiveness in order to integrate important health economic insight. We found that, with some exceptions, the clinical effectiveness of ICIs is marginal and if it is worth paying a high price is justifiably questionable. In essence, the current paradigm of ICIs for bladder cancer is somewhat of a mixed fortune.

In contrast, our review of the key trials for the targeted therapeutics enfortumab vedotin (EV), sacituzumab govitecan (SG), and erdafitinib show these agents are proving more effective than the current ICIs. EV and erdafitinib are (SG has only fast track designation) approved and now available. However, the cost of these targeted therapeutics is significantly more expensive, than the already high cost of ICIs. We also caution that these clinical results are early. This review hopes to provide clinicians and patients with the up-to-date facts in order to help decide on the best-value option for treating patients with advanced or metastatic bladder cancer. The approval process timeline is shown in Figure 1.

**Figure 1.** FDA approval timeline for ICIs, EV, and Erdafitinib against bladder cancer.
