Immunotherapy Propels Urothelial Carcinoma Treatment Advances

The metastatic urothelial carcinoma treatment landscape continues to evolve to reflect potentially practice-changing data with antibody-drug conjugate (ADC)–based combinations and chemoimmunotherapy sequencing strategies, according to Stephanie A. Berg, DO.

“Immunotherapy is playing a role in metastatic urothelial cancer. There have been some recent updates in the news regarding companies withdrawing indications, as well as some trial updates at our big, international meetings in the past year about how we can combine immunotherapy with chemotherapy or [use it] by itself,” Berg said in an interview with OncLive^®.

In the interview, Berg, a medical oncologist at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School, both in Boston, Massachusetts, highlighted ongoing urothelial cancer clinical trials; the role of single-agent immunotherapy and combinations in this disease; and the importance of future research that prioritizes and guides individualized patient care.

The phase 3 IMvigor130 trial (NCT02807636), which evaluated atezolizumab (Tecentriq) alone or with platinum-based chemotherapy vs placebo plus platinum-based chemotherapy, failed to meet its coprimary end points of progression-free survival and overall survival (OS) as first-line therapy in metastatic urothelial cancer.¹ Berg discussed the implications of these findings on the urothelial cancer treatment paradigm and how updated results may further influence the use of immunotherapy combinations in this population. She also explained the rationale for the phase 3 NILE trial (NCT03682068), an extension of the phase 3 DANUBE trial (NCT02516241). In DANUBE, patients with locally advanced or metastatic urothelial carcinoma who received durvalumab (Imfinzi) plus tremelimumab (Imjudo) as frontline therapy had a median OS of 15.1 months vs 12.1 months in those who received chemotherapy.²

OncLive^®: How does immunotherapy fit into the current treatment paradigm for patients with metastatic urothelial cancer?

Berg: The big study we’re looking forward to having OS results from is IMvigor130, led by Matthew D. Galsky, MD, [of The Tisch Cancer Institute at Mount Sinai in New York, New York]. [This trial has been] going on [since 2016] and led to Genentech’s removal of the indication of atezolizumab in metastatic urothelial cancer. [These data will be presented at the 2023] Genitourinary Cancers Symposium. We’ve been looking at this study for a long time, [as it investigated] combination therapies and atezolizumab by itself. The final results from the trial will be interesting to see.

[The phase 3] KEYNOTE-361 trial [NCT02853305] investigated pembrolizumab [Keytruda] in combination with chemotherapy. We have data for that. We’re not quite sure how to use [pembrolizumab], either by itself or in combinations. There weren’t positive data from the combination with chemotherapy, but we know it still has a role to play by itself. We’re still trying to decide [what that is] and will update our guidelines accordingly if any new data come out.

What ongoing studies in this area could potentially change practice?

Many key trials are enrolling right now from different companies and our cooperative groups. [The phase 3] EV-302 trial [NCT04223856] is looking at pembrolizumab plus enfortumab vedotin-ejfv [Padcev]. These drugs have been studied together [previously] and had good efficacy.

Combinations with chemotherapy [are being investigated] as well. The NILE trial, an extension of a previous trial by AstraZeneca, DANUBE, is looking at different immunotherapies, durvalumab and tremelimumab, with or without chemotherapy. That will be interesting to see, although it will not be completed for a few years.

[The phase 3] CheckMate901 trial [NCT03036098] from Bristol Myers Squibb is investigating ipilimumab [Yervoy] and nivolumab [Opdivo] vs nivolumab and chemotherapy vs chemotherapy. Lastly, the [phase 3] MAIN-CAV trial [NCT05092958], ongoing through the Alliance [for Clinical Trials in Oncology], is adding cabozantinib [Cabometyx] to immunotherapy in patients with metastatic bladder cancer [who have] received chemotherapy.

There are different aspects of first-line treatment, maintenance therapy, and how we can combine them [based on] what is best for our patients and what they can tolerate. Sometimes, more is better, but it’s also a safety issue. Many of these studies will give us those answers over the next few years.

What questions remain unanswered for the treatment of patients with metastatic urothelial carcinoma?

[We need to] identify the proper patients to receive which therapies because safety is important. These drugs can have many long-lasting adverse effects [AEs]. Identifying who’s going to benefit from what combination for how long will be important. [For instance, with] dosing: How many cycles do they need? Do they need a lower dose? Could [that achieve] the same efficacy?

Once we establish the best regimens from these trials, [we may be able] to deescalate [treatments] for patients with incurable disease for better quality of life. That will be interesting to see in the future.

What guideline changes do you expect to see in the near future?

Many new treatment options are coming through that will be presented at the 2023 Genitourinary Cancers Symposium. The National Comprehensive Cancer Network [may] change the current version [of its Clinical Practice Guidelines in Oncology], which is almost a year old. Atezolizumab [will be removed], and then, as the role of enfortumab vedotin in combinations [is defined, that may be included], but we’re waiting for an FDA approval [for that regimen].

The guidelines [may] change. Keep an eye out and look for emails and announcements to see when we have all these practice-changing [regimens] to treat our patients with.

What ongoing urothelial carcinoma research at Dana-Farber Cancer Institute are you excited about?

Here at Dana-Farber Cancer Institute, we have an interesting trial investigating the combination of 2 approved ADCs, the [phase 1] DAD trial [(NCT04724018), which stands for] dual ADCs. It’s investigating the combination of enfortumab vedotin and sacituzumab govitecan-hziy [Trodelvy]. These are both approved in urothelial cancer. We’ve had great response rates and safety, with minimal toxicity profiles [consistent with the AEs] we know these drugs can cause. We’re not seeing anything new. We have a few slots left to enroll, and then hopefully we’ll have more data to present [regarding] another potential treatment combination, specifically in this tough patient population.

References

1. Galsky MD, Arija JAA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomized, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-1557. doi:10.1016/S0140-6736(20)30230-0
2. Powles T, van der Heijden MS, Castellano D, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020;21(12):1574-1588. doi:10.1016/S1470-2045(20)30541-6