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

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.

Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

“…Avelumab is also currently being evaluated in patients with non-muscle invasive UC in combination with BCG (NCT03892642). In patients with advanced UC, combinations of Avelumab with radiation (NCT03747419) and KHK2455 (an indoleamine 2,3-dioxygenase inhibitor; NCT03915405) are also being tested [ 38 ]. ( Table 1 ).…”

“…Response to treatment with Atezolizumab was present in all TCGA molecular subtypes, but a higher response rate was noted in the subtype defined by the luminal cluster 2 ( p = 0.0017, ORR = 34%) compared to the other clusters, luminal cluster 1, basal cluster 1, and basal cluster 2 (ORR 10%, 16%, and 20% respectively). The subsequent analysis of cohort 1 of IMvigor reported the highest response rate in the luminal cluster 2 group ( n = 11/37, seven partial responses and four complete responses) after treatment with Atezolizumab [ 38 ].…”

“…RNA-based immune-gene expression profiling has the advantage of providing and quantifying data from multiple tumor cells in a given sample, thus providing more fully representative information of the tumor microenvironment. Therefore, immune-gene expression profiling identifies more accurately the inflammatory status of a tumor by quantifying mRNAs to indirectly assess the status of cell surface proteins, cytokines, and chemokines that define “hot” tumors better than using only the expression of PD-L1 by immunohistochemistry [ 38 ].…”

2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology

“…Adverse events were frequent, often grade 3 or higher, and mandated close monitoring [ 233 ]. Despite this promising evidence of efficacy in trials [ 234 ], immunotherapies have to date largely outcompeted FGFR-based approaches for second-line palliation of platinum-refractory urothelial cancer [ 235 ].…”

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“…SG has undoubtedly provided a new option for treating patients with mTNBC. However, SG treatment was associated with significantly higher costs, which might limit its access in many countries (11). There are currently no economic evaluations of SG for its use in the treatment of mTNBC.…”