Novel Agents Influence the Development of New Strategies for Treatment of Bladder Cancer

Arlene Siefker-Radtke, MD

Arlene Siefker-Radtke, MD

The population of patients with bladder cancer are predominantly elderly individuals in their mid-70s, said Arlene Siefker-Radtke, MD. This population has difficulty tolerating cisplatin-based chemotherapy, the standard of care for muscle-invasive bladder cancer. Patients with non—muscle-invasive bladder cancer have Bacillus Calmette-Guérin (BCG) as the standard of care. Yet, the ongoing BCG shortage has made it difficult to treat those patients as well.

The ongoing need for new and more effective treatment for bladder cancer is currently being addressed through the use of novel single-agent antibody—drug conjugates like enfortumab vedotin (ASG-22ME) and sacituzumab govitecan (IMMU-132). Recent data on enfortumab vedotin, which is being studied in locally advanced or metastatic urothelial cancer (NCT03219333), shows clinically significant overall response rates (ORRs).

In the cohort of patients in the enfortumab vedotin study who previously had no response to checkpoint inhibition, the ORR was 42%. Patients in cohort 2, who were responders to checkpoint inhibition and had no prior exposure to chemotherapy, showed an ORR of 38%. The study also had a subset of patients with liver metastases who showed a 36% ORR.¹

Enfortumab vedotin was well tolerated in both cohorts and only 3% of the adverse events (AEs) seen were grade 3 or higher. The most common grade 1 and 2 AEs were decreased appetite (41%), fatigue (50%), and alopecia (48%).¹

Another strategy for providing new options for patients with bladder cancer is combination therapies. In the EV-103 study (NCT03288545) combining enfortumab vedotin with an anti—PD-1 immunotherapy agent, pembrolizumab (Keytruda), investigators have seen a higher ORR (62%) than seen with enfortumab vedotin monotherapy. Patients in this trial also had a complete response (CR) rate of 14% and a 90% disease control rate.²

Enfortumab vedotin/pembrolizumab resulted in similar AEs as enfortumab vedotin alone, including fatigue (66%), diarrhea (41%), decreased appetite 52%), and alopecia (45%). However, the combination therapy had more grade 3 or higher AEs. In total, 2 patients (7%) discontinued treatment due to serious AEs. The combination was still considered tolerable and effective.

Other clinical trials are looking at both novel single agents and combination strategies to continue to introduce more options to patients with bladder cancer who are ineligible for chemotherapy or do not have access to BCG.

“When I look at the future of urothelial cancer, I think we'll see combination strategies, and strategies trying to achieve deeper responses. The ability to achieve complete response may be associated with greater longer-term benefit, and my hope is we'll understand the mechanisms of resistance to immunotherapy and find novel agents that can combine and counteract this as well,” said Seifker-Radtke.

In an interview withTargeted Oncology, Siefker-Radtke, professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, examined the treatment landscape for bladder cancer and how factors like BCG shortages and prognoses in the elderly population are causing a shift toward novel immunotherapy agents.

TARGETED ONCOLOGY: What is the current treatment landscape for systemic therapies in bladder cancer in terms of muscle-invasive bladder cancer versus non—muscle invasive bladder cancer?

Siefker-Radtke: With muscle-invasive bladder cancer, the current standard is cisplatin-based chemotherapy for anyone who is a candidate for cisplatin prior to their cystectomy. The biggest difficulty with this strategy is that there's a lot of patients who are not eligible for cisplatin-based chemotherapy. Bladder cancer is a disease of an elderly or geriatric patient population with a typical age in the mid-70s upon diagnosis. A lot of our patients have comorbid medical conditions that make them ineligible for cisplatin due to those conditions affecting their kidney function, heart function, or [causing] neuropathy.

Despite the standard that is in place, there is still a large number of patients who are not eligible and need an alternative to the typical standard-of-care therapy.

BCG remains the standard for superficial high-risk, non—muscle invasive bladder cancer.

TARGETED ONCOLOGY: How are BCG shortages affecting treatment?

Siefker-Radtke: The BCG shortage has impacted patient care, and we've seen multiple national guidelines make recommendations on how to deal with this. One option is to use one vial of BCG for multiple patients, with some guidelines suggesting that one vial can be divided amongst 3 patients with similar efficacy. There's also a lot of discussions ongoing about whether to use BCG for intermediate-risk patients versus intravesical therapy, and I think a lot of groups are going to the use of alternate intravesical agents due to the lack of BCG.

What are some enduring areas of unmet need in bladder cancer?

When we look at the treatment of metastatic bladder cancer the algorithm is still very simple. Frontline patients who are eligible for cisplatin, receive cisplatin-based chemotherapy, most commonly gemcitabine/cisplatin or dose-dense MVAC. However, a lot of patients are not eligible for this type of therapy and in the setting of poor kidney function, PD-L1 expression may be used and, if elevated, we may pick a patient or a group of patients who may benefit from single-agent immune checkpoint inhibition. If their PD-L1 testing is low in the frontline setting, most patients are then recommended to receive chemotherapy. Most commonly, we see gemcitabine carboplatin used, but that still has toxicity and can be difficult for patients to tolerate in the setting of poor kidney function.

When we look at patients who have failed frontline therapy, then the standard of care depends upon whether you have an absence or presence of a mutation. Without anFGFR3mutation, pembrolizumab is the standard that has shown definitive survival benefit over other taxanes. However, there are four other checkpoint inhibitors approved including; nivolumab (Opdivo), atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio). There are multiple checkpoint inhibitors approved for the second-line space. If a patient has anFGFR3mutation present, then they become eligible for treatment with erdafitinib (Balversa), which is a novel agent that targets FGFR3 receptor alteration that can be found in patients with bladder cancer. This mutation is present in approximately 15% to 20% of patients with metastatic urothelial tumors of the bladder and in upward of 35% of patients with metastatic urothelial tumor of the upper tract, which includes renal, pelvis, and ureter. The use of mutation of testing can now provide a personalized care strategy for the treatment of our patients.

TARGETED ONCOLOGY: What treatments are emerging to fill these areas of unmet need?

Siefker-Radtke: There are still many areas of unmet need. There are many patients who do not have these mutations present and require alternate therapies. We current are seeing promising data from enfortumab vedotin, which is an antibody—drug conjugate targeting nectin-4. Nectin-4 is overexpressed on 93% of patients with urothelial cancer. The preliminary results that we've seen so far include a 40% ORR and a median overall survival of around 11 months. The data are promising with enfortumab vedotin, but we're still awaiting FDA approval, which is anticipated sometime within the next year.

There are other agents though that are under development and showing significant promise. We see other antibody—drug conjugates like sacituzumab govitecan, which is also providing a novel way of targeting metastatic urothelial cancer. There are also other combinations that are showing promising by combining FGF-targeted therapy with immune checkpoint inhibitors, enfortumab with checkpoint inhibitors, and even other immuno-oncology (IO) with IO combinations, including bempegaldesleukin plus nivolumab. Bempegaldesleukin is an IL-2 analog which stimulates the proliferation of lymphocytes associated with immune response and does not stimulate the proliferation of the T regulatory cells. So, it provides a differential proliferation of the immune cells needed to attack bladder cancer.

There are certainly many novel agents and many combination strategies that are very exciting, and we'll be awaiting the results of clinical trials to see how we'll be able to pull them into our clinics for the benefit of our patients with bladder cancer.

TARGETED ONCOLOGY: Is there any research you’re particularly excited about in this field?

Siefker-Radtke: I think the field is moving toward novel agents combined with immunotherapy. It seems that immune checkpoint inhibitors are becoming the backbone of the treatment of urothelial cancer. I sometimes joke that immunotherapy is the new Lupron of solid tumors, where we're going to give as long as we’re can still give it without toxicity. We are seeing that with the combinations strategies combing novel agents with immune checkpoint inhibitors.

We saw enfortumab vedotin plus pembrolizumab, which was presenting at ESMO, suggesting a response rate of around 70%, which is very promising in the frontline setting. We see other IO/IO combinations, including bempegaldesleukin plus nivolumab, which, based on small numbers of patients presented on far, had an ORR of around 45% and a CR rate of 19%. In the melanoma data, bempegaldesleukin plus nivolumab has had deeper CRs occurring in up to 35% of patients.

When I look at the future of urothelial cancer, I think we'll see combination strategies, and strategies trying to achieve deeper responses. The ability to achieve a CR may be associated with greater longer-term benefit, and my hope is we'll understand the mechanisms of resistance to immunotherapy and find novel agents that can combine and counteract this as well. One such option may be the trial of erdafitinib with an immune checkpoint inhibitor as part of the NORST trial where patients are randomized to erdafitinib plus cetrelimab (JNJ-63723283) versus erdafitinib alone. Cetrelimab is a PD-1 inhibitor.

Hopefully, these combinations will overcome mechanisms of resistance to the immune system and as we head to personalized therapy, we'll be able to build the best treatment and best sequence of treatments adding to the long-term survival of patients with urothelial cancer worldwide.

References

1. Hoimes Cj, Rosenberg JE, and Petrylak DP, et al. EV-103: Enfortumab vedotin plus pembrolizumab and/or chemotherapy for locally advanced or metastatic urothelial cancer. J Clin Oncol. 37, 2019; DOI: 10.1200/JCO.2019.37.15_suppl.TPS4593. Abstract TPS4593.
2. Hoimes CJ, Rosenberg JE, Srinivas S, et al. EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. Presented at ESMO 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract 9010.