Rapid Advances Change the Paradigm in Bladder Cancer

Arjun V. Balar, MD

A greater understanding of not only tumor biology and driver mutations but also targeted therapy has led to unprecedented precision and efficacy in treating bladder cancer, Arjun V. Balar, MD, said in an interview with OncLive about major advances in the disease over the past 20 years.

The advent of next-generation sequencing (NGS), a new standard in bladder cancer, has simplified mutation detection, making therapeutic approaches tailored to a patient’s genomic profile a reality. With the April 2019 FDA approval of erdafitinib (Balversa), an oral fibroblast growth factor receptor (FGFR) kinase inhibitor indicated for patients with locally advanced or metastatic bladder cancer harboring activating FGFR2/3 mutations or fusions, the bladder cancer armamentarium gained its first precision therapy.¹

The second precision therapy arrived in December 2019, when enfortumab vedotinejfv (Padcev) received FDA approval for patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant, adjuvant, locally advanced, or metastatic setting. Enfortumab vedotinejfv targets nectin-4, a protein that is highly expressed in bladder cancer.² It is the first nectin-4—directed antibody-drug conjugate (ADC) to gain FDA approval.

Erdafitinib and enfortumab vedotin-ejfv will not be the last targeted options to gain clearance in this space, said Balar, director of the genitourinary medical oncology program at NYU Langone’s Perlmutter Cancer Center in New York, New York. Instead, they will prompt further genomic sequencing and translational study to better comprehend bladder cancer and develop additional targeted and immunotherapy approaches.

Treatment options in bladder cancer began to expand with the first immunotherapeutic approvals in this disease type between 2016 and 2017. In this period, 5 immune checkpoint inhibitors received approval for the treatment of platinum-resistant metastatic disease: atezolizumab (Tecentriq), nivolumab (Opdivo), durvalumab (Imfinzi), avelumab (Bavencio), and pembrolizumab (Keytruda). On January 8, 2020, pembrolizumab was cleared for use in the treatment of patients with bacille Calmette-Guérin (BCG)—unresponsive, high-risk, non–muscle-invasive bladder cancer with carcinoma in situ with or without papillary tumors who do not qualify for cystectomy.³

In the interview, Balar also discussed how immunotherapy options are helping to reduce reliance on platinum chemotherapy and cystectomy, as well as further efforts to engage the immune system in the fight against bladder cancer and other pathways toward greater treatment efficacy and quality of life for patients.

OncLive: What have been the biggest improvements in the treatment of urothelial carcinoma over the past 20 years?

Balar: The first is our understanding of tumor biology, specifically as it relates to the host’s immune system. In just the past 5 years, so many significant advances have added to our understanding of immunotherapy. Comprehending how the immune system interacts with cancer has completely changed the way we look at bladder cancer. We used to focus exclusively on treating the tumor. Now we’re looking at it from 2 different directions: How can we treat the cancer, and how can we elicit an immune response that will target the cancer? Using both approaches seems to be a way to extend survival and perhaps cure patients with advanced bladder cancer.

We also have a better understanding of tumor biology and driver mutations. For years now, we’ve been perfecting our ability to sequence the DNA of cancers to better understand the genetic mutations that drive these cancers. One of the areas that has been particularly interesting is the FGFR3 pathway. We have known for at least 10 or 15 years that FGFR mutations, specifically FGFR3 activating alterations, are present in 15% to 20% of high-grade and invasive urothelial cancers. Historically, we were not very good at identifying which mutations were most important, nor were we good at identifying the best drugs to target those mutations. In trials dating back 10 years, we didn’t see much mutation targeting activity with drugs that were developed in the late 2000s. Now we have [NGS] and other ways of detecting these mutations in a highly reliable way.

Table. Enfortumab Vedotin + Pembrolizumab Shows Promise in Advanced Urothelial Cancer⁴ (Click to Enlarge)

Older and frailer patients can receive the treatment more safely than with nonspecific chemotherapy, such as platinum. Cisplatin, especially, was feasible only in a very [limited] population. The convergence of all 3 treatment modalities—immunotherapy, targeted therapy, and ADCs—has quickly changed how we treat advanced urothelial cancer. Some of these approaches, immunotherapy in particular, have found their way into localized disease, in which the standard of care has been neoadjuvant cisplatin chemotherapy followed by cystectomy. We’re starting to challenge that treatment paradigm. Perhaps some patients can receive systemic immunotherapy for nonmuscleinvasive bladder cancer, and some can receive chemoradiation and systemic immunotherapy for muscle-invasive bladder cancer—and in both settings avoid cystectomy entirely. The advent of these new drugs is really reshaping how we think about this disease.

Please comment on the progress of targeted therapy in this setting.

I think the approval of erdafitinib in April 2019 was a very critical step; it was the first approval of a targeted agent in advanced bladder cancer.¹ I think some might say, “Well, it’s only applicable to patients who have activating mutations or fusions in FGFR2 and FGFR3, and that’s only 15% to 20% of the population.” Yes, that’s true. However, it opens the door for more genomic sequencing and translational efforts to further understand the disease.

Historically, [NGS] was not considered a standard [in this setting], but we’ve been doing it. Investigators like me who want to advance the field have pushed hard for sequencing. Now it’s a standard of care. Every patient with advanced bladder cancer will be allowed to have or should be allowed to have sequencing of their tumor to identify these alterations, and it should be included [as part of the therapeutic process].

That will ultimately lead to more research efforts to better understand FGFR signaling, find other targets, hopefully, and help us understand mechanisms of resistance because not all patients with FGFR3-mutated cancer respond to treatment. There’s primary resistance, and then there’s acquired resistance. And that story of primary versus acquired resistance has already unfolded in lung cancer, in which EGFR mutations, for instance, are identified very early. And I suspect that we will have a very similar path forward in bladder cancer: FGFR3 mutations are just the beginning of a better understanding of oncogenic drivers and how to treat them. I’m very confident that our understanding of the genomics of bladder cancer is going to evolve rapidly over the next few years.

What pivotal trial data have emerged recently that might change the paradigm?

I think some of the most promising data I’ve probably ever seen in advanced bladder cancer were from the EV-103 trial [NCT03288545], presented at the European Society for Medical Oncology 2019 Congress. Investigators presented preliminary data from the first 45 cisplatin-ineligible patients with advanced bladder cancer treated with first-line combination enfortumab vedotinejfv and pembrolizumab.

The objective response rate was an eye-popping 71%, and 93% of the patients had at least some [effect on] their target lesions [Table].⁴ It’s incredible to see such a high percentage of patients achieve an objective response. Anytime you see a response rate this high, it’s quite noteworthy. If we can confirm these data in a much larger and randomized setting, and I’m optimistic that we will, we may completely reshape not only advanced bladder cancer treatment but also [treatment for] localized disease, specifically muscleinvasive bladder cancer.

What are the prospects for improving treatment in earlierstage disease?

The most important advancement that I expect to see in the next 4 to 5 years is a higher proportion of patients who will be effectively treated and cured of their disease without needing cystectomy. Current practice patterns in the United States demonstrate that the vast majority of patients who are eligible for surgery for muscle-invasive bladder cancer undergo radical cystectomy. I believe that the number of patients who will have a radical cystectomy as their only option will be vastly reduced, primarily because of advancements in the drugs and the pathways I’ve just described.

We also know that the standard of care in patients with nonmuscle-invasive bladder cancer whose disease has become unresponsive to BCG is also cystectomy. Data from a single-agent immunotherapy trial of pembrolizumab, KEYNOTE-057 [NCT02625961], showed that about 40% of these patients can achieve a complete response if they have had carcinoma in situ that does not respond to BCG. About half of those responses are durable beyond a year. This tells us that a systemic checkpoint inhibitor can also induce complete responses in carcinoma in situ, indicating that we can systemically activate the immune system against cancer that is restricted to the lining of the bladder, which is incredible in terms of understanding how a systemic immune activation can penetrate very early-stage disease. It also means that we may be able to spare these patients’ bladders.

Preserving the bladder is important to work toward because radical cystectomy is a highly morbid surgery. It’s permanent, and it has a significant impact on a patient’s quality of life, sexual function, intimacy, and sense of self. I hope that we can change the conversation and afford patients options to effectively treat their cancer that don’t require cystectomy.

How can we keep up the momentum of these advances?

Every single time [we] hear about ADCs or a targeted therapy or the next immunotherapy, we are excited because there is a need to be addressed, right? And I think we’re doing a pretty good job of doing it. I joke around with my colleagues that after 30 years of a lack of advancements, we’re doing a really good job of making up for lost time. The pace of discovery and the development of new drugs in bladder cancer right now are simply unprecedented.

I think what will continue to be a focus in the future—and I think this is shared by many investigators across the world— is enhancing our knowledge of how the immune system interacts with cancer because our best chance of curing patients with muscle-invasive and metastatic bladder cancer is going to come through the immune system. We will need to evaluate novel therapies through an immune “lens” to arrive at effective, long-term cures.

We need to figure out why, in the combination immunotherapy trials so far, only 38% of patients, at most, who are treated are responding. What about the remaining patients? How do we get the immune system to work for them? What is missing, and what are the key components? Answering these questions will require not only a better understanding of tumor biology and the host immune system but also the subsequent development of different drugs that target immune pathways.

References

1. Balversa [prescribing information]. Beerse, Belgium: Janssen; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/ 2019/212018s000lbl.pdf. Accessed January 20, 2020.
2. Padcev [prescribing information]. Northbrook, IL: Astellas Pharma US Inc; 2019. www.accessdata.fda.gov/drugsatfda_docs/ label/2019/761137s000lbl.pdf. Accessed January 20, 2020.
3. Keytruda [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; 2020. www.accessdata.fda.gov/drugsatfda_docs/ label/2020/125514s066lbl.pdf. Accessed January 20, 2020.
4. Hoimes CJ, Rosenberg JE, Srinivas S, et al. EV-103: initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. Ann Oncol. 2019;30(suppl 5):v356-v402. doi: 10.1093/annonc/mdz249.

I think the third part is a convergence of modern technology and so-called traditional chemotherapy. We have developed highly specific ADCs to help deliver chemotherapy directly to the cancer. ADCs have been in use for years in other cancer types, such as advanced HER2-positive breast cancer. However, we didn’t have a good therapeutic target in bladder cancer until recently, when we identified nectin-4. By targeting this protein, we can deliver very potent chemotherapies directly to the cancer, and drugs like enfortumab vedotin-ejfv are rapidly changing how we treat this disease. These allow us to deliver cytotoxic treatment to the cancer cell in a very targeted way, leading to higher response rates.