Biomarker-Guided Therapies, Novel Combos Take Center Stage in Urothelial Carcinoma

Jason Zhu, MD

Although platinum-based chemotherapy was once the standard of care for patients with previously treated locally advanced or metastatic urothelial carcinoma, novel antibody-drug conjugates (ADCs), innovative combinations, and promising targeted therapies have since gained prominence, according to Jason Zhu, MD.

“Bladder cancer is a very exciting field. We have really moved beyond platinum-based chemotherapy or chemotherapy alone to biomarker-guided therapies with FGFR3 inhibitors to ADCs—not 1 but 2—with combination therapies also being studied,” Zhu explained. “This [research has been] really beneficial for our patients, as [these agents allow] them to live longer and better.”

In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on genitourinary malignancies, Zhu, a medical oncologist at Levine Cancer Institute, part of Atrium Health, discussed several approaches under exploration in the treatment of patients with previously treated, locally advanced, or metastatic urothelial carcinoma.

OncLive®: Why is enfortumab vedotin-ejfv (Padcev) a unique agent in bladder cancer treatment?

Zhu: Enfortumab vedotin is an ADC, and ADCs are a unique class of compounds that are really exciting right now. Enfortumab vedotin’s antibody is Nectin-4, and the payload is in monomethyl auristatin E. Enfortumab vedotin looks for tumors that harbor Nectin-4, which is present in all patients with bladder cancer.

EV-201 was a single-arm, phase 2 study evaluating enfortumab vedotin. Cohort 1 [consisted of] patients who were treated previously with an immune checkpoint inhibitor [ICI] and a platinum-based chemotherapy; these are the patients we’re seeing [in practice], those who have received a platinum-based chemotherapy and immunotherapy.

In this study, patients [who received enfortumab vedotin experienced] an objective response rate of about 55%, with 12% of patients having a complete response [CR]. [These f indings] compare very favorably with historical data [that we have for] chemotherapy like docetaxel in this setting, where response rates are typically 10% or less.

What did the extended follow-up from the trial reveal?

The extended follow-up data were presented during the 2020 European Society for Medical Oncology Virtual Congress. [The agent] continued to demonstrate favorable efficacy; about one-third of patients were still alive at 18 months and a median overall survival [OS] of 12.4 months [was reported], which is remarkable for this heavily pretreated population.

Is enfortumab vedotin currently being examined in combination?

The data for enfortumab vedotin are really exciting in bladder cancer. Any time we achieve a good result [with an agent], we’re always thinking of ways to make it more effective. One way, of course, is to combine it with another therapy.

We know that immunotherapy works well in bladder cancer. As such, we are currently evaluating enfortumab vedotin plus pembrolizumab [Keytruda] in the EV-103 study [NCT03288545]. Data [from this research] presented during the 2020 American Society of Clinical Oncology Virtual Scientific Program were pretty exciting. [We saw that] 93% of patients experienced some kind of tumor reduction with the combination, with 73% having a confirmed objective response and 16% having a CR. Of course, any time you combine therapies, you have to worry about toxicity; that is something we’re going to need to look out for.

The current standard of care for neoadjuvant therapy is platinum-based chemotherapy. The real question is whether enfortumab vedotin can also be used in the neoadjuvant setting. Right now, studies such as EV-103 and EV-303 [NCT03924895] are evaluating this question. It’s worth noting that we have EV-103 open at Levine Cancer Institute with a few spots remaining; this trial is looking even further up in the lines to see whether we can help our patients prior to surgery.

Another key trial was COSMIC-021, which examined the combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) for those with advanced solid tumors. What was the rationale for this research?

COSMIC-021 [NCT03170960] had many arms, but the one that I’m going to talk about here is the arm for bladder cancer. Cabozantinib, as we know, is a well-established multikinase inhibitor regulating VEGFR2, AXL, and MET. [The agent] has already been approved as a monotherapy for [patients with] renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer.

The thought was to [take] cabozantinib and combine it with an ICI because [the former] promotes an immunepermissive environment, which enhances tumor responses to ICIs. We have seen this with the CheckMate 9ER trial [NCT03141177], where the combination of cabozantinib and nivolumab [Opdivo] significantly improved progression-free survival [PFS] and OS over a single tyrosine kinase inhibitor [TKI]. We have seen this not only with cabozantinib, but other TKIs, as well. It’s a fairly [well-] understood theory.

Have we seen any data to support the use of cabozantinib plus atezolizumab in this patient population?

Right now, the data are still very early, as this was a phase 1 study. The main end point [of this research] was safety. [Results] showed that cabozantinib and [atezolizumab) were safe. No patient had to discontinue both drugs during the treatment. About one-third of patients had to dose- reduce cabozantinib due to toxicity, [although] grade 3/4 adverse effects were rare. [This approach] deserves further study, but is the combination better than a single agent alone? That question remains.

How has erdafitinib (Balversa) performed in this patient population?

Erdafitinib is a really exciting drug. It’s our first FDA-approved biomarker-guided therapy for patients with bladder cancer who have a pathogenic FGFR3 mutation. We know that about 20% of patients with bladder cancer have an FGFR mutation; maybe up to one-third of patients with upper-tract disease [harbor this mutation]. The agent provides several advantages. For one, erdafitinib is an oral therapy; as such, it does not require a lot of time in clinic for infusions, which is an important quality-of-life [QOL] factor for our patients, especially during the coronavirus disease 2019 pandemic.

We see a reasonable response of around 40% with erdafitinib in this patient population. The median PFS with erdafitinib was around 5.5 months and the median OS was 11.3 months in BLC2001 [NCT02365597]. Because it is a biomarker-guided therapy, my colleagues and I send for next-generation sequencing very early on. [This way,] we know what is available for this patient down the road; [this also helps us] screen for potential clinical trials.

Are any other biomarkers under investigation showing promise?

Right now, no other FDA-approved biomarker-based therapies for bladder cancer [exist]. Of course, for any patients who [have] microsatellite instability–high [disease], it’s always reasonable to try immunotherapy; we know that those patients have a higher response rate, including in bladder cancer, although it’s a rare patient population. HRAS-targeted therapies are in the pipeline and are being developed right now; those agents are interesting.

ADCs play a big role [in treatment]. We talked about enfortumab vedotin, but we haven’t spoken about sacituzumab govitecan-hziy [Trodelvy], which is another ADC. It’s exciting because [we have] a different antibody in a different payload [than EV], so there may not be cross-resistance. We may potentially be able to use both therapies back-to-back. Sacituzumab govitecan targets Trop-2 and uses SN-38 as the cytotoxic payload.

What data have we seen to support the use of sacituzumab govitecan in these patients?

Even in the very heavily pretreated postplatinum, postimmunotherapy population, we’re seeing an ORR of around 27% [with this agent], with 5% of patients achieving a CR. [The ADC has led to] a median PFS of 5.5 months and an OS of 10.5 months; it compares very favorably with enfortumab vedotin.

We don’t have data yet on how to sequence these therapies, but that would be exciting to see in a realworld study. How are patients doing when they get to this therapy? They’ll be very heavily pretreated, so we’ll also have to be watching toxicity and QOL very closely. Sacituzumab govitecan is being studied in the large phase 3 TROPiCS-04 study [NCT04527991], which is comparing the agent with standard-of-care chemotherapy.

What are the goals and design of the TROPiCS-04 study?

TROPiCS-04 is a confirmatory phase 3 study that is currently underway; it is looking at patients who have locally advanced or metastatic, unresectable urothelial carcinoma. [Patients with] other histologies are permitted to enroll on this study. The investigators are looking at the patients who are post platinum and post PD-1/PD-L1 therapy, and they [aim] to enroll around 482 patients. In one arm, [patients will receive] sacituzumab govitecan, which is given on day 1 and day 8 of every 3-week cycle, [while] the standard-of-care [arm] will receive the typical docetaxel, paclitaxel, or vinflunine therapy. [Treatment will] continue until disease progression. [The trial has] a strong primary end point of OS.

What are some areas of research that need further exploration?

It would be nice to prevent patients from developing metastatic disease. How do we do that? Can we have more effective neoadjuvant or adjuvant therapies following surgery? We’re all excited [to see] topline data with adjuvant nivolumab following cystectomy. I’ll be interested in reviewing those data closely to see [which patients are] really benefiting [from this approach].

I’m also excited about the neoadjuvant studies with EV and pembrolizumab. I can’t wait to see what those pathologic CRs are going to be and if we can really improve [those responses] and cure more patients.