6.2.5. Avelumab

Avelumab has been studied and deemed that its use would have a cost-neutral impact within a US commercial and a Medicare health plan [87]. Based on that it is the lowest priced drug on the list (Table 3), and the positive data from the phase III JAVELIN Bladder 100 trial, avelumab is a relatively affordable and a cost-effective option.

### 6.2.6. Nivolumab and Durvalumab

NICE did not recommend nivolumab as an option for treating locally advanced, unresectable or metastatic bladder cancer who have had platinum-containing therapy [88]. The cost-effectiveness was not better than cisplatin plus gemcitabine. Nivolumab was also shown to not be cost-effective in the US economic healthcare system [76]. This may be due to nivolumab having the highest relative toxicity profile among the ICIs. For durvalumab, AstraZeneca advised that they would not be pursuing a licensing application from the European Medicines Agency for a bladder cancer indication and, thus, NICE has suspended its cost-effectiveness appraisal [89].

#### 6.2.7. ADCs and Erdafitinib

There are currently no cost-effective appraisals for EV or for SG (for its current approval for use in triple-negative breast cancer). For erdafitinib, NICE is currently appraising its cost-effectiveness and results are to come [90].

#### **7. Discussion**

Patients with metastatic or advanced bladder cancer once had limited options after failed chemotherapy leading to disease progression and death. Active application and examination of immune checkpoint inhibition has provided new therapeutic possibilities for patients with metastatic bladder cancer. Today, patients typically receiving ICI therapy do not have to withstand the severe toxicity associated with chemotherapy. In addition, patients who respond typically have long-lasting responses and increased survival. However, the median ORR from the clinical trials evaluating the described ICIs was 20.9% (13.4–28.6%). In contrast for the two approved targeted therapeutics, EV and erdafitinib, the ORR values were increased by factors of 2.1 and 1.9, respectively. In addition, ICI affordability, not only for patients, but also for national health care systems threatens patient access to these drugs. However, the targeted therapeutics are even more expensive than the ICIs. The findings that avelumab and atezolizumab (for cisplatin-ineligible patients only) are most likely the only cost-effective ICIs provides a wake-up call to develop strategies to make these drugs more affordable and/or how to improve patient responses.

As described in this review, in general, it is difficult for physicians to identify patient groups that will benefit from ICI therapy based on PD-L1 tumor expression and has previously been discussed [91]. Some patients have demonstrated strong responses under ICI therapy whose tumors express relative 'high' levels of PD-L1, such as in the JAVELIN Solid Tumor (avelumab) and in the Checkmate 275 (nivolumab) trials. However, in general PD-L1-specific responses were not better than in patients regardless of PD-L1 expression, or PD-L1 associated responses were not reproducible in larger randomized trials or when responses were evaluated at longer follow-up periods. The major reason for these scattered results, in the context of PD-L1 expression, is that PD-L1 is an unreliable marker to predict treatment response. One major challenge for PD-L1 as a biomarker is the different assays and expression scoring systems used, as described in the above ICI clinical trials. Currently, different IHC

assays have different PD-L1 expression cutoffs and scoring is either only on tumor cells (nivolumab, durvalumab, avelumab), only on tumor-infiltrating ICs (atezolizumab), or on the combination of tumor cells and ICs (pembrolizumab). Attempts to standardize PD-L1 expression evaluation using IHC are underway. Preliminary harmonization studies have indicated that the assays 22C3, SP263 and, 28–8 (used for pembrolizumab, durvalumab and avelumab, respectively) can be comparable, additional research is needed regarding the interchangeability of the assays as it pertains to response and once a universal assays is in place, what will be the PD-L1 expression thresholds required to achieve robust responses [92].

ADCs and small molecules have given another life-saving chance to patients with advanced and metastatic bladder cancer, and have demonstrated a higher ORR in clinical trials, compared to ICI therapies, but increased frequency of any-grade treatment-related AE (Table 2) and high cost (Table 3) remain a serious barrier for mainstream application in patients. In addition, these results are early and longer follow-up analyses are needed. Nonetheless, EV and erdafitinib are effective for treating bladder cancer and, hence, inaugurated the era of targeted therapy for bladder cancer.

#### **8. Future**

#### *8.1. Improved Biomarkers*

Biomarkers are needed that will be able to identify patients for treatment-specific responses. Unlike, other tumor types, there remains no biomarker in the clinic that allows physicians to determine which patients are most likely to benefit from immuno- or targeted therapeutics. As described in the Checkmate 275 trial, TMB appears to be a promising biomarker. There are active investigations for developing bladder cancer-specific biomarkers and reviewed in [12,93].

The antigens Nectin-4 and Trop-2 as biomarkers to identify patients to respond to EV and SG, respectively, appear promising. Specifically, the fact that all patients were positive for Nectin-4 and that the majority of these patients had 'strong' expression is highly encouraging. Although, the EV-201 trial performed many subgroup analyses, it did not report patient responses based on 'low', 'moderate', and 'high' Nectin-4 expression. [34] This was most likely because the majority of patients had 'high' Nectin-4 expression and there may have been too few patients with 'low' and 'moderate' expression. A larger phase II EV-202 trial (NCT04225117) is currently recruiting and estimates to enrol 240 patients and perhaps they will determine patient responses based on Nectin-4 tumor expression.

#### *8.2. Additional Targeted Therapeutics in the Pipeline*

Emerging targeted therapies that have reached the clinic include inhibitors against angiogenesis, FGFR, HER2, phosphoinositide 3 kinase, protein kinase B, mammalian target of rapamycin, and epigenetic targets and are nicely described by Mendiratta and Grivas [12]. Notably, many of the investigational drugs have not shown significant activity reinforcing the difficulty with the targeted therapy approach for bladder cancer.

MAbs make up a large portion of these investigational drugs. For example, mAbs such as bevacizumab and ramucirumab that target vascular endothelial growth factor (VEGF) have been evaluated. Bevacizumab failed to improve OS relative to placebo in a phase III study, and caused grade ≥3 AEs in 83.4% of patients [94]. In the RANGE phase III trial, ramucirumab did not significantly improve OS in patients who had previously been treated with platinum-containing chemotherapy and/or ICI therapy [95]. The mAb trastuzumab that targets HER2 has also been extensively evaluated in the clinic against bladder cancer. Unfortunately, trastuzumab has also not had any significant clinical impact. One of the great examples of antibody-targeted therapy for cancer is the story of HER2 [54]. Trastuzumab in combination with paclitaxel is standard practice for patients with HER2-positive breast cancer. Initially, a phase II study showed a remarkable ORR of 70% in patients with advanced bladder cancer treated with trastuzumab plus chemotherapy [96]. However, a larger trial that evaluated

chemotherapy with and without trastuzumab did not show a difference between the two arms for bladder cancer patients [97].

ADCs may be the best option for antibody-based therapies relative to unmodified mAbs. The ICIs and the above described mAbs targeting VEGF and HER2, and mAbs in general, that are reliant on an antagonistic (blockade or receptor-ligand or receptor-receptor interactions) mechanism of action may show some therapeutic potency—the effects tend to be various and ultimately not curative [98]. The strategy of conjugating chemotherapy drugs to mAbs to generate ADCs appears to be the more clinically successful approach for antibody-based treatment of metastatic bladder cancer. Hence, future research directions should discover additional antigens that are overexpressed on the surface of bladder cancer, and for the development of ADCs that deliver highly cytotoxic payloads. One example is the discovery of the interleukin-5 receptor α-subunit (CD125) as being preferentially overexpressed in MIBC tumors but not on superficial bladder tumors or normal urothelium [99]. An anti-CD125 ADC has potent cytotoxicity against MIBC cells [99]. Additional target with accompanying ADCs that have shown promise in preclinical models of bladder cancer include The Slit- and Trk-like receptor family, transmembrane glycoprotein epithelial cell-adhesion molecule, and Thomsen-Fridenreich antigen and are described in further detail in [100].

#### **9. Conclusions**

ICIs have greatly reduced AEs compared to traditional chemotherapy. However, their relatively low response rates make it unclear on their ability to increase the therapeutic window relative to traditional chemotherapy remains unclear. In addition, their high cost makes ICIs, with the exception of avelumab and atezolizumab (for cisplatin-ineligible patients), not cost-effective. Based on the evidence described in this review, newly diagnosed patients with advanced bladder cancer will most likely significantly benefit from avelumab plus cisplatin-containing or carboplatin-containing chemotherapy. The targeted therapeutics EV, SG, and erdafitinib still have to demonstrate their worth in randomized phase III testing. If successful, it is likely patients who have relapsed after traditional chemotherapy or ICI therapy will benefit from these targeted therapeutics. Bladder cancer therapy has advanced tremendously in a short period of time since the first ICI approval, and the future looks hopeful as science will increase knowledge to make responses more robust to ICI therapy or new targetable biomarkers will be discovered.

**Author Contributions:** O.B. carried our literature studies and wrote the manuscript. J.V.L. conceived of the review topic and helped in drafting the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Canadian Institutes of Health Research, grant number 201610PJT-378389-PJT-CFDA-190713 and Fonds de recherche Quebec—Santé.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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