Dr Shore on the Rationale for the Duravelo-2 Trial in Metastatic Urothelial Cancer

Neal D. Shore, MD, FACS, medical director, Carolina Urologic Research Center, Atlantic Urology Clinics, discusses early data from the phase 1/2 Duravelo-1 trial (NCT04561362) investigating zelenectide pevedotin (formerly BT8009) in patients with metastatic urothelial carcinoma. He also highlights the rationale for the ongoing phase 2/3 Duravelo-2 trial (NCT06225596).

In the Duravelo-1 trial, this first-in-class agent, known as a bicycle toxin conjugate, showed efficacy as monotherapy in patients who had not received prior treatment with enfortumab vedotin-ejfv (Padcev). Currently, the Duravelo-2 trial is enrolling patients with locally advanced or metastatic urothelial cancer and will evaluate zelenectide pevedotin as both monotherapy and in combination with pembrolizumab (Keytruda) across different dose levels.

Earlier-phase studies highlighted promising efficacy outcomes, including durable objective response rates with the agent, leading to the development of the Duravelo-2 study, Shore begins. Shore states that his institution was honored to be the first site to enroll a patient to this trial and that enrollment has been progressing well among patients with locally advanced or metastatic urothelial cancer. This study includes 2 cohorts: previously untreated patients and patients who have undergone prior treatment, he reports. Patients in both groups receive treatment with zelenectide pevedotin at doses of 5 mg/m² or 6 mg/m², Shore states, noting that investigators are eager to observe response rates and assess efficacy across dose levels.

According to Shore, an important aspect of advancing bladder cancer research involves examining previous study results, such as those from the randomized, open-label, phase 3 EV-302 trial (NCT04223856), which led to 

the FDA approval of enfortumab vedotin plus pembrolizumab

 for the treatment of patients with locally advanced or metastatic urothelial cancer. Another notable trial is the phase 3 CheckMate 901 study (NCT03036098), which combined nivolumab (Opdivo) with cisplatin and gemcitabine in patients with treatment-naive, inoperable or metastatic urothelial cancer, Shore reports. Investigators are also focused on understanding the role of maintenance therapy with avelumab (Bavencio) in the context of new trial data, as guided by prior findings from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) in patients with advanced urothelial carcinoma who were progression free after frontline chemotherapy, he continues. More data on maintenance therapy strategies and their effects on outcomes are anticipated, Shore adds.

Ultimately, although other targets and treatments are being explored, the Duravelo-2 trial of zelenectide pevedotin remains a current focus in the bladder cancer field, he expands. This trial may provide patients with an additional treatment option and generate deeper insights into managing advanced urothelial cancers, especially with maintenance therapies and targeted drug conjugates, Shore concludes.

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Neal D. Shore, MD, FACS, discusses the Duravelo-1 and Duravelo-2 trials investigating zelenectide pevedotin in metastatic urothelial carcinoma.

Zelenectide pevedotin (formerly BT8009) is part of a new class of investigational agents, bicycle toxin conjugates (BTCs), seeking to improve upon the efficacy and safety profiles of currently available monomethyl auristatin E (MMAE) antibody-drug conjugates (ADCs) for patients with metastatic urothelial carcinoma.

 The first-in-class agent demonstrated early efficacy as monotherapy in patients who had not received enfortumab vedotin-ejfv (Padcev) in the phase 1/2 Duravelo-1 trial (NCT04561362), and the phase 2/3 Duravelo-2 trial (NCT06225596) is currently enrolling patients. Duravelo-2 will examine the agent as monotherapy and in combination with pembrolizumab (Keytruda) at various doses.

“Zelenectide pevedotin is an exciting drug and it provides the opportunity to access a nectin-4 targeted drug conjugate therapy, which we already know is very effective [based on the success of] enfortumab vedotin,” Terence W. Friedlander, MD, said in an interview with 

. Friedlander is chief of Hematology-Oncology and associate director for Cancer Research at Zuckerberg San Francisco General, University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center. He is also an associate clinical professor in the Division of Hematology/Oncology at UCSF.

At a median follow-up of 4.2 months (range, 0.5-28.6), efficacy-evaluable patients with recurrent, unresectable metastatic urothelial carcinoma (n = 38) who received the agent at 5 mg/m2 weekly in Duravelo-1 achieved an objective response rate (ORR) of 45% with a median duration of response (DOR) of 11.1 months (95% CI, 3.9-not reached); 1 patient experienced a complete response and 16 achieved partial response. Additionally, the clinical benefit rate was 61%. Nine patients experienced stable disease whereas 12 patients had progressive disease. Further, the median time on treatment was 16.1 weeks (range, 1.0-101.4).

Early Safety Data With the BTC in Duravelo-1 Shows Promise

“In the early phase studies [of zelenectide pevedotin], patients were heavily pretreated and that’s important—their performance statuses were somewhat compromised, [and] they were heavily pretreated with both platinum- and immuno-oncology–based therapy, especially the patients with urothelial cancer,” Neal Shore, MD, FACS, said in an interview with 

. “It was small numbers, but over a third [of patients] had partial responses [and] a little over a quarter had stabilization of disease. Overall, [zelenectide pevedotin is] fairly well tolerated.”

Regarding safety, the most common treatment-related adverse effects (TRAEs) observed in Duravelo-1 were nausea (33%), asthenia (22%), pyrexia (20%), fatigue (20%), and diarrhea (18%). Patients experienced grade 3 or higher TRAEs at a rate of 22% and grade 3 or higher treatment-emergent AEs (TEAEs) at a rate of 53%. TEAEs led to dose interruption (53%), reduction (27%), and discontinuation (4%) in patients who received zelenectide pevedotin. No treatment-related deaths occurred. TRAEs of specific monitoring related to the therapy included the following grade 1 to 3 toxicities: peripheral neuropathy (36%), skin reactions (18%), peripheral sensory neuropathy (13%), neutropenia (13%), hyperglycemia/diabetes mellitus (7%), and eye disorders (7%).

“What’s always challenging in this patient population is that they tend to be older, both men and women, [who] tend to have a lot of other comorbidities,” said Shore, who is US chief medical officer of surgery and oncology at GenesisCare USA and medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina. “What drew [me to zelenectide pevedotin was its] novel mechanism of action, the early impressive imaging radiographic responses, and the tolerability.”

“This BTC targets nectin-4, so in some ways it is similar to enfortumab vedotin. It is linked to MMAE as well, similar to enfortumab vedotin, but it has a low molecular weight and a short plasma half-life,” Srikala Sridhar, MD, MSc, FRCPC, a clinician investigator in the Cancer Clinical Research Unit at Princess Margaret Cancer Centre in Toronto, Canada, said in an interview with 

. “The hope is that this drug will have a little less toxicity than enfortumab vedotin, and that’s perhaps a distinguishing feature between [zelenectide pevedotin] and enfortumab vedotin. We have to wait for the trials to report out to tell us.”

BTCs such as the first-in-class agent zelenectide pevedotin are distinct from ADCs and have pharmacokinetic properties analogous to small molecules. Bicycles are chemically synthesized molecules that are 50 to 100 times smaller than antibodies, and chemical synthesis allows optimization for affinity, stability, and solubility, according to investigators.

 Zelenectide pevedotin has a total molecular weight of 4.2 kDa and comprises a nectin-4–targetedbicyclic peptide linked to the cytotoxin MMAE via a sarcosine spacer chain and valine-citrulline cleavable linker.

Sridhar added that Duravelo-2 “is going to try to determine a bit about what dosing [is right for the agent as well as] efficacy, and it’ll give us some important information about this new bicycle toxin [and the] new way of delivering this treatment to patients. There’s a bit of comfort here because the target is known—we’ve seen good results with enfortumab vedotin so far—and the chemotherapy backbone seems to be a good, effective backbone. That’s going to be interesting, and it’ll be exciting to see how these results will play out in the future.”

Zelenectide pevedotin, which has a half-life of less than an hour, will be evaluated at a dose of 5 mg/m

 given 2 weeks on and 1 week off in the dose selection portion of the trial; the agent will be administered as monotherapy and in combination with pembrolizumab 200 mg given every 3 weeks.

 Cohort 1 includes patients with untreated disease, and is comprised of 3 arms: zelenectide pevedotin given on days 1, 8, and 15 of every 21-day cycle plus pembrolizumab on day 1 (arm 1), zelenectide pevedotin given on days 1 and 8 of every 21-day cycle plus pembrolizumab on day 1 (arm 2), and gemcitabine plus cisplatin or carboplatin with or without maintenance avelumab (Bavencio)if clinically indicated (arm 3).

“We’re now doing the Duravelo-2 study [at my institution],” Shore said. “We were proud to be the first site to enroll a patient, and it is enrolling very nicely now in patients with locally advanced or metastatic urothelial cancer. There are 2 cohorts in the study, those who have not been previously treated and those treated.”

Cohort 2 of the trial includes patients with previously treated disease and is comprised of 3 arms as well: zelenectide pevedotin given on days 1, 8, and 15 of every 21-day cycle (arm 1), zelenectide pevedotin given on days 1 and 8 of every 21-day cycle (arm 2), and zelenectide pevedotin given on days 1, 8, and possibly 15 of every 21-day cycle with pembrolizumab on day 1 (arm 3; not yet recruiting).

“The thought here is that the BTC molecule may penetrate the tumor microenvironment better, improving the activity of the drug,” Friedlander explained. “It also may be less persistent in the circulation, because it’s a small molecule and not an antibody, so we may see less lingering toxicity, especially skin toxicities.”

The 2 cohorts of Duravelo-2 are enrolling adult patients with histologically or cytologically confirmed locally advanced or metastatic, unresectable urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra. Patients must have measurable disease by RECIST 1.1 criteria and a life expectancy of at least 12 weeks. Those in cohort 1 with previously untreated disease must be eligible to receive platinum-based chemotherapy and could not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with exceptions noted (

Additionally, patients with previously treated disease in cohort 2 must have received at least 1 systemic treatment for locally advanced or metastatic disease including neoadjuvant/adjuvant platinum-based chemotherapy if they experienced recurrence within 12 months of completing therapy. Exclusion criteria noted that patients in cohort 1 could not have received treatment with a checkpoint inhibitor for any other malignancy within the last 12 months; those in cohort 2 are not permitted to have received more than 1 prior platinum-based chemotherapy regimen for locally advanced or metastatic disease and could not have received enfortumab vedotin or any other MMAE-based therapy.

“We don’t yet understand the patterns of resistance,” Sridhar explained. “Potentially, if a patient develops resistance to enfortumab vedotin, we’re not sure what that looks like or why that’s happening, so if you’re using another drug that’s similar to enfortumab vedotin in terms of both its target and its chemotherapy backbone, you may not get the same results as you would in someone who’s never had prior exposure. That’s why [prior use of the agent is] an exclusion criterion on the trial.”

This is especially notable as Sridhar added that enfortumab vedotin may soon become part of the standard of care (SOC) in patients with locally advanced or metastatic, unresectable urothelial carcinoma in Canada.

“Currently in Canada, we’re using platinum-based chemotherapy followed by avelumab if patients have no progression on frontline chemotherapy, but this is going to be set to change,” Sridhar said. “I believe we’ll see the introduction of enfortumab vedotin plus pembrolizumab into the frontline setting. Both enfortumab vedotin/pembrolizumab or gemcitabine/cisplatin/nivolumab [Opdivo] have been shown to be better than our current SOC, which is gemcitabine plus platinum-based chemotherapy.”

Subsequently, in August 2024, Health Canada approved the combination of enfortumab vedotin and pembrolizumab for use in adult patients with unresectable locally advanced or metastatic urothelial cancer who had not previously received systemic treatment for metastatic disease.

Editor’s note: The interview with Sridhar took place prior to the approval of the combination in Canada.

Reig Torras O, Crouzet L, Necchi A, et al. BT8009 monotherapy in enfortumab vedotin (EV)-naïve patients (pts) with metastatic urothelial carcinoma (mUC): updated results of Duravelo-1. 

. 2024;35(suppl 2):S515-S516. doi:10.1016/j.annonc.2024.08.718

Study BT8009-230 in participants with locally advanced or metastatic urothelial cancer (Duravelo-2). ClinicalTrials.gov. Updated September 19, 2024. Accessed September 30, 2024. https://clinicaltrials.gov/study/NCT06225596

Baldini C, Goldschmidt V, Brana I, et al. BT8009-100: a phase I/II study of novel bicyclic peptide and MMAE conjugate BT8009 in patients (pts) with advanced malignancies associated with nectin-4 expression, including urothelial cancer (UC).

. 2023;41(suppl 6):498. doi:10.1200/JCO.2023.41.6_suppl.498

Loriot Y, Siefker-Radtke AO, Friendlander TW, et al. A phase 2/3 study of Bicycle toxin conjugate BT8009 targeting nectin-4 in patients with locally advanced or metastatic urothelial cancer (la/mUC): Duravelo-2. 

 2024;42(suppl 16):TPS4619. doi:10.1200/JCO.2024.42.16_suppl.TPS4619

Padcev (enfortumab vedotin) in combination with pembrolizumab approved by Health Canada to treat advanced bladder cancer. News release. Pfizer Canada. August 22, 2024. Accessed October 3, 2024. https://www.newswire.ca/news-releases/padcev-r-enfortumab-vedotin-in-combination-with-pembrolizumab-approved-by-health-canada-to-treat-advanced-bladder-cancer-862646661.html

Articles

Zelenectide pevedotin, a novel bicycle toxin conjugate, is being investigated for metastatic urothelial carcinoma, aiming to enhance efficacy and safety over existing MMAE ADCs. Early results from the Duravelo-1 trial showed promising efficacy and tolerability, with a 45% ORR and a median DOR of 11.1 months. The ongoing Duravelo-2 trial is exploring its use as monotherapy and in combination with pembrolizumab. Zelenectide pevedotin targets nectin-4, similar to enfortumab vedotin, but with potentially reduced toxicity due to its unique pharmacokinetic properties.

Oncologists detail how zelenectide pevedotin, which is under evaluation in the Duravelo-2 trial, could fill an unmet need in metastatic urothelial carcinoma.

First-in-Class Bicycle Toxin Conjugate Targeting Nectin-4 Generates Excitement in Urothelial Carcinoma

Dr Sridhar on the Use of Zelenectide Pevedotin in Locally Advanced or Metastatic Urothelial Cancer

Srikala Sridhar, MD, MSc, FRCPC, clinician investigator, Cancer Clinical Research Unit, Princess Margaret Cancer Centre, University Health Network, discusses the unique application of the Bicycle® toxin conjugate zelenectide pevedotin (BT8009), which targets nectin-4 in patients with locally advanced or metastatic urothelial cancer. This agent is being evaluated in the phase 2/3 Duravelo-2 clinical trial (NCT06225596).

The target of zelenectide pevedotin makes it somewhat similar to enfortumab vedotin-ejfv (Padcev), Sridhar begins. Like enfortumab vedotin, zelenectide pevedotin is linked to monomethyl auristatin E; however, it has a lowermolecular weight and a shorter plasma half-life, she explains. This difference may lead to reduced toxicity withzelenectide pevedotin compared with enfortumab vedotin, according to Sridhar. Although initial data are promising, trial results are awaited to confirm these benefits, she states.

The Duravelo-2 trial is assessing the efficacy of zelenectide pevedotin in 2 distinct cohorts. The first cohort includes treatment-naive patients, who are being randomly assigned to receive 1 of 2 dosing schedules of zelenectide pevedotin in combination with pembrolizumab (Keytruda), or chemotherapy, Sridhar continues. The second cohort is enrolling patients who have received at least 1 prior treatment, excluding those previously treated with enfortumab vedotin, which is a logical exclusion criterion, Sridhar says. 

This trial will explore dosing strategies, evaluate the drug’s efficacy, and provide essential data on this novel treatment approach, she expands. A notable aspect of the trial is the use of nectin-4, a familiar target that enfortumab vedotin has shown efficacy against in past studies, she notes. Additionally, the chemotherapy backbone used as an active comparator in this trial is well established and considered an effective approach, Sridhar explains, noting that these factors offer some reassurance regarding the potential success of the treatment if proven positive.

The results from the Duravelo-2 trial will be crucial in determining whether this innovative drug delivery method can provide enhanced efficacy with reduced toxicity, she emphasizes. The outcomes will generate significant interest, and further developments are anticipated in the future, Sridhar concludes.

Srikala Sridhar, MD, MSc, FRCPC, discusses the unique application of zelenectide pevedotin, which targets nectin-4 in locally advanced or metastatic urothelial cancer.

Treatment sequencing in bladder cancer has evolved significantly with recent approvals in the first-line setting, with the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) emerging as a dominant frontline therapy. As efforts to leverage a variety of viable targets, such as HER2, FGFR, TROP-2 and TGF-β, through novel drug development continue, there is increasing hope that novel agents will offer less toxic and equally effective alternatives to standard-of-care (SOC) regimens, according to Terence Friedlander, MD.

Among these promising contenders is the Nectin-4–targeted bicycle toxin conjugate zelenectide pevedotin. Although zelenectide pevedotin has the same target and payload as SOC enfortumab vedotin, its incorporation of small molecule therapy could allow for improved drug activity, reduced persistence in circulation, and fewer off-target toxicities, Friedlander explained.  

Updated results from the phase 1/2 Duravelo-1 trial (NCT04561362) presented at the 

showed that zelenectide pevedotin was tolerable and produced preliminary antitumor activity in patients with advanced urothelial cancer without prior exposure to enfortumab vedotin (n = 45). At a median follow-up of 4.2 months (range, 0.5-28.6), efficacy-evaluable patients who received one of the two recommended phase 2 doses (RP2Ds) of 5 mg/m2 weekly (n = 38)––the other being 7.5 mg/m2 on days 1 and 8 of a 21-day cycle––experienced an overall response rate (ORR) of 45% (n = 17). This comprised 1 complete response (CR) and 16 partial responses; 9 patients maintained stable disease and 12 patients experienced disease progression. The clinical benefit rate was 61% (n = 23). The median duration of response was 11.1 months (95% CI, 3.9-not reached) among patients with confirmed responses (n = 14).

Results from this study supported the ongoing phase 2/3 Duravelo-2 study (NCT06225596) investigating zelenectide pevedotin alone and in combination with pembrolizumab for patients with locally advanced or metastatic urothelial cancer.

“It’s exciting that zelenectide pevedotin [is being evaluated in] clinical trials,” said Friedlander, who is the chief of Hematology-Oncology and the associate director for Cancer Research at Zuckerberg San Francisco General, University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, as well as an associate clinical professor in the Division of Hematology/Oncology at UCSF. “We’re going to have to see how [zelenectide pevedotin] performs in later stages through phase 2/ 3 trials, but data from the phase 1 trial suggest that this drug may be effective and [could serve as] a kinder, gentler version of enfortumab vedotin.”

®, Friedlander discussed the evolution of treatment sequencing in bladder cancer due to recent approvals, lingering toxicity concerns with standard therapies, and efforts to develop novel therapies and improve upon current regimens through research.

How has treatment sequencing in bladder cancer evolved alongside key approvals in the first-line setting?

: There are a lot of new and exciting developments in the bladder cancer field, both in terms of therapies that have already been approved as well as therapies that are [coming down] the pipeline. How I currently approach therapeutic sequencing of bladder cancer has really evolved over the past few years. For many years, cisplatin-based chemotherapies were SOC. If patients were eligible for cisplatin, that’s what they would get; if not, [they would receive] carboplatin. [Seven] years ago, 

pembrolizumab received FDA approval in the frontline setting

 as monotherapy. I still use it for frail patients who are completely platinum ineligible. After platinum, we would generally use taxanes. Enfortumab vedotin became available in 2019, and FGFR inhibitors were approved as well, so the armamentarium started to increase. We also had a second antibody-drug conjugate [ADC], sacituzumab govitecan-hziy [Trodelvy] receive early FDA approval [in 2021] for later-line settings in bladder cancer.

Last fall, we had 2 major trials in the metastatic space report [data] at the same time [during the 2023 ESMO Congress]. The first study was 

the phase 3 CheckMate 901 study [NCT03036098]

 of gemcitabine, cisplatin, and nivolumab [Opdivo]. This study compared those agents with cisplatin plus gemcitabine and showed that the addition of nivolumab to cisplatin-based chemotherapy was beneficial. There were higher CRs and ORRs with the nivolumab regimen]. That really put gemcitabine, cisplatin, and nivolumab on the map.

the phase 3 EV-302/KEYNOTE-A39 trial [NCT04223856]

 were presented. This study evaluated the combination of enfortumab vedotin and pembrolizumab compared with chemotherapy. It’s little different than the CheckMate 901 study, which was only focused on cisplatin-eligible patients. Data from EV-302 were impressive. We saw dramatic improvements in overall survival [OS], progression-free survival [PFS], and the CR rate. The ORR was [67.7%] with a CR rate of [29.1%]. Approximately 40% of patients were still progression free after 15 months of follow-up. This study established enfortumab vedotin as sort of the dominant frontline therapy in metastatic bladder cancer, where we’re really seeing a lot of benefit in those patients; I generally recommend [that regimen] for my frontline patients. If patients are ineligible for enfortumab vedotin, if they have bad [comorbidities such as] diabetes, or if they have pre-existing grade 2 peripheral neuropathy, then I think there’s a role for platinum-based chemotherapy in the frontline setting.

What questions remain regarding the optimal approach for patients who progress on enfortumab vedotin plus pembrolizumab in the second line?

In the second-line setting, it is less clear as to what to do for patients who progress on enfortumab vedotin plus pembrolizumab. The most empiric option would be to give platinum[-based chemotherapy] in the second line because we know it has activity, although it hasn’t been prospectively evaluated that way. My practice is generally to give cisplatin [provided that] the patients don’t have too much peripheral neuropathy and are still fit to receive cisplatin; if not, I’ll generally use carboplatin and gemcitabine in the second-line setting. Beyond that, it’s hard to know exactly what to do.

What recent developments and approvals have affected the third-line treatment paradigm in bladder cancer?

Previously, we were using a lot of sacituzumab govitecan in the third-line setting. The big challenge was that at the 2024 ASCO Annual Meeting, a press release came out that showed that the [phase 3] TROPiCS-04 study [NCT04527991] comparing sacituzumab govitecan with single-agent chemotherapy was not positive, and that sacituzumab govitecan wasn’t able to outperform standard chemotherapy. The release also said that it was fairly toxic in terms of neutropenia, neutropenic sepsis, and death related to infections. In retrospect, this makes some sense, because sacituzumab is myelosuppressive. Unlike breast cancer, where sacituzumab govitecan is also approved, patients with bladder cancer tend to be older, and are sometimes more frail or more heavily pretreated with cytotoxic agents. That can create a real challenge, [so this study has] opened up space for drug development in the third-line setting. 

We do have some targeted therapies in the third line that are available now. FGFR inhibition with 

erdafitinib [Balversa] is now FDA approved

 based on data from the phase 3 THOR study [NCT03390504], which showed benefit [with the agent] compared with older chemotherapies. This is a small molecule oral pan-FGFR inhibitor, but it’s approved for patients with 

 mutations. It’s nice because it’s oral, and it can be used in the second line after platinum as well. The toxicities [associated with] erdafitinib can be challenging in terms of skin, nail, hair, and eyelash changes. Managing phosphate levels and gastrointestinal adverse effects [AEs] can also be hard. That said, all our other agents also have significant toxicities.

FDA approved in the late-line setting [across tumor types, including bladder cancer]

 is fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd], which is a HER2-targeted ADC approved in the late-line setting for any cancer that has HER2 3+ expression by immunohistochemistry [IHC]. In the [phase 2] DESTINY-PanTumor02 trial [NCT04482309], which evaluated T-DXd across several tumor types, we found that patients who had HER2 3+ IHC, had an ORR of [51.4%]. That is quite good for a monotherapy in that space. We must be careful about myelosuppression with that drug as well, because it’s a topoisomerase-based therapy. There are opportunities for new agents in the third-line setting, especially those that are biomarker driven. We’ll have to see how the drugs develop.

What are some emerging agents of interest within the bladder cancer space?

A number of exciting therapies are coming down the pike in bladder cancer. By far the most well-developed therapies are those targeting HER2. [In addition to T-DXd], disitamab vedotin [Aidixi] is another ADC that has had very strong phase 1/2 data and is now being evaluated in a global phase 3 clinical trial in the frontline setting. Disitamab vedotin is a HER2-targeted ADC with a monomethyl auristatin E [MMAE] payload, which is the same payload as enfortumab vedotin. In earlier studies in patients who were HER2 3+, the ORR was approximately 50% or 60% [with disitamab vedotin] and we think that this agent may be synergistic with pembrolizumab. The phase 3 [DV-001 trial (NCT05911295)] looking at disitamab vedotin plus pembrolizumab is actively accruing. There are other studies looking at [the use of] HER2-targeting agents, including T-DXd, in earlier line settings. We’ll await [data from] those.

The other major agents that are being tested in the metastatic setting include agents targeting FGFR. Erdafitinib was already approved in this space. There are other oral, more selective molecules that target FGFR. Loxo-Lilly has one [LOXO-435], Taiho Oncology has [futibatinib [Lytgobi], which is in clinical trials here at UCSF, and Tyra Biosciences has [TYRA-300, which is being evaluated] in a trial that we’re going to be involved in. 

It’s hard to say that one is necessarily better than the others, but the hope is that if we have more agents targeting FGFR3, we might get less off-target AEs, less toxicity, and hopefully better efficacy. Other agents that are coming down the pike include those targeting TROP-2. We’ve talked a bit about sacituzumab govitecan, which had early, somewhat promising data for unselected patients with metastatic bladder cancer, but just had a negative phase 3 trial, which is very disappointing. [However, that outcome can] probably be attributed more to the toxicity of the payload than to the targeting of TROP-2.

There are a number of other TROP-2–targeted agents being tested. [For example], there’s one from Merck that’s currently in clinical trials. TGF-β is another target [with agents in] very early development, as it may be a mechanism of immunoresistance. There’s an agent from AbbVie that targets part of the TGF-β signaling pathway [and is being assessed in an] earlier phase study. We need more data to understand how this works, but it would be exciting to have drugs that work in patients who’ve already had anti–PD-1 immunotherapy to see if we can re-energize the immune system.

What are some of the lingering toxicity concerns with current therapeutic options, particularly enfortumab vedotin and MMAE-targeted agents, in bladder cancer?

Enfortumab vedotin plus pembrolizumab is really the standard frontline regimen. It’s recommended by the National Comprehensive Cancer Network for both cisplatin-eligible and -ineligible patients, and it can be very effective. One of the challenges is that there are also AEs that practitioners need to know about. By now, most folks are familiar with the AEs [associated with] immunotherapy. Approximately half of patients tolerate it very well and experience no AEs. For most patients who have AEs, they are mild, but they can occur anywhere in the body if the immune system attacks healthy tissues. Approximately 10% of people who get immunotherapy can have severe AEs, including severe rash, diarrhea, pneumonitis, myocarditis, nephritis or hepatitis, or problems with joints or nerve conduction.

Although serious AEs associated with PD-L1 inhibitors [are well-known], it may be less recognized that enfortumab vedotin itself can be associated with serious AEs. [One of the AEs] that I worry about the most is peripheral neuropathy, which generally starts [during the first few cycles] and tends to be progressive. Approximately 50% of patients will have some degree of peripheral neuropathy, a quarter or more will have grade 2 symptomatic peripheral neuropathy, or worse. Generally, I tend to do some combination of dose reduction, delay or hold [when those AEs are reported]; sometimes I even discontinue the dose if the peripheral neuropathy is bad.

The other thing that’s unrecognized or underrecognized is the motor neuropathy that occurs with MMAE therapeutics. This happens in less than 10% of people, but can cause serious problems with handwriting, gait, or other sort of motor activities. It’s important for providers to really assess a patient’s neurologic exam when they’re using enfortumab vedotin because of these neuropathic risks. Skin rash also can be an issue for some patients. There have been severe cases of Stevens-Johnson [syndrome], toxic epidermal necrolysis, erythema multiforme, and other things that require hospitalization or intravenous steroids. Patients have died of AEs related to skin toxicity, so we have to be very careful about that. The last major AE [associated with] enfortumab vedotin is hyperglycemia. For most patients this is mild, but essentially patients who had hemoglobin A1C levels greater than 8% or blood sugar greater than 250 mg/dL were excluded from trials of enfortumab vedotin. There were, in the very early stages, deaths due to hyperglycemia and ketoacidosis related to enfortumab vedotin use, so I’m very cautious about using the agent in diabetic [patients]. I work with their primary care physician or their endocrinologist to make sure that they get good diabetes control.

[Regarding] FGFR3 inhibitors and some of the AEs related to [this drug class], good, multidisciplinary management [is typically all that’s necessary]. Myelosuppression is obviously an issue with sacituzumab and some of our other agents, and we have to think about cardiotoxicity with the HER2-targeting agents as well. Those that contain MMAE [are also associated with some] skin toxicity and peripheral neuropathy. There are opportunities for novel agents that can help preserve the activity of the drug and have less toxicity. We will have to see how many of these studies pan out.

What ongoing research is being conducted to address the need for highly effective, less toxic regimens in bladder cancer?

There are trials of novel agents that have never been seen before, and lot of those are in later-line settings. In addition to FGFR3 inhibitors, HER2-targeted therapies, and TGF-β–targeting therapies, there are other studies looking at CAR T cells and bispecific antibodies. However, those are very [early] in their development in bladder cancer.

The other set of studies are aiming to take therapies that we think are effective and trying to improve upon them. Obviously, we want to have therapies that work for every patient, but it takes time to develop those. If we can improve upon existing therapies, there’s something to be said for that.

The other unmet need is giving these therapies earlier in the disease course. Although we’re focused on locally advanced and metastatic disease, agents such as PD-1 inhibitors and enfortumab vedotin are moving into the perioperative space. We may be able to use these in the perioperative space to help prevent patients from relapsing after they have their bladder removed.

Lastly, there were 2 important studies in the neoadjuvant space that looked at giving therapy but not removing the bladder. [One of these was] the phase 2 HCRN GU 16-257 trial [NCT03558087], presented at the 2023 Genitourinary Cancers Symposium in which patients received neoadjuvant nivolumab plus platinum-based chemotherapy, and then, if they had a complete clinical response, were allowed to keep their bladders. Most patients did very well in terms of not having metastatic relapse if they achieved a complete clinical response, so avoiding cystectomy would be a great win.

The last [area for improvement in bladder cancer is the] treatment of patients with radiation. Concurrent radiation therapy is typically administered alongside platinum-based chemotherapy or 5-fluorouracil, but there are a number of studies now looking at adding PD-1 inhibitors and/or enfortumab vedotin to concurrent radiation as another form of bladder preservation. We’ll have to see how those studies play out.

What is unique about the mechanism of action of zelenectide pevedotin, and how might this agent improve upon standard approaches in advanced bladder cancer?

One of the exciting studies that I’m part of is the phase 2/3 Duravelo-2 study investigating zelenectide pevedotin [BT8009]. This agent is similar to an ADC, but it’s actually a small molecule drug conjugate. The idea here is that the small molecule is a bicyclic peptide rather than being an antibody. It [functions as] a fixed scaffold for which certain protein sequences can be designed so that the drug can [bind to its] target [with high specificity]. In this case, zelenectide pevedotin targets Nectin-4, which is the same target as enfortumab vedotin. Although [enfortumab vedotin is composed of] an antibody as opposed to a small molecule, their payloads are both MMAE, which is a small molecule microtubule stabilizer.

The thought here is that the BTC molecule may penetrate the tumor microenvironment better, improving the activity of the drug. It also may be less persistent in the circulation, because it’s a small molecule and not an antibody, so we may see less lingering toxicity, especially skin toxicities. That seems to be borne out in the initial phase 1/2 trial, where we saw less toxicity with zelenectide pevedotin [in patients with Nectin-4–expressing advanced malignancies]. 

What is the study design and methodology of Duravelo-2?

Duravelo-2 is an open-label, randomized, global, multicenter combined phase 2/3 trial. Cohort 1 is going to include approximately 640 patients. [Investigators plan to] to have a 30-patient run-in to evaluate 5 mg/m2 or 6 mg/m2 doses of zelenectide pevedotin in different schedules, select the optimal dose, and then move into a phase 3 trial with a primary end point of PFS. The first cohort of the study is evaluating frontline zelenectide pevedotin plus pembrolizumab given every 3 weeks vs gemcitabine plus cisplatin or carboplatin. The second cohort of the study [will evaluate] the activity of zelenectide pevedotin as monotherapy [arms 1 and 2] or [in combination with] pembrolizumab [arm 3] in patients who have already received at least 1 prior systemic therapy. The study has just opened, so we’ll see how it accrues and what the data are in the coming months and years.

Do you anticipate any challenges or barriers to enrollment?

Worldwide, there probably won’t be major challenges because zelenectide pevedotin is an exciting drug and it provides opportunity to access a Nectin-4 targeted ADC, which we already know is very effective [based on the success of] enfortumab vedotin. In the United States [U.S.], there might be challenges to accrual partly because it’s a randomized study in the frontline setting to treatment with zelenectide pevedotin plus pembrolizumab or gemcitabine plus cisplatin or carboplatin. We know that [the latter regimen] is starting to fall out of favor in the U.S. That said, data for giving gemcitabine plus cisplatin or carboplatin followed by avelumab [Bavencio] show that the median OS isn’t that different for patients who make it to maintenance avelumab vs patients who start enfortumab vedotin plus pembrolizumab. There’s an argument to be made for accruing patients to this study and still administering gemcitabine plus cisplatin or carboplatin, followed by avelumab maintenance because we could see somewhat similar long-term outcomes. However, that might slow down [the enrollment of] some patients who just want to come in and get enfortumab vedotin plus pembrolizumab as their frontline regimen.

If the Durvelo-2 study is positive, what might its clinical significance be?

Positive [data from Durvelo-2] would make [zelenectide pevedotin] an option for the frontline setting, which would be exciting. If either of the second-line cohorts of zelenectide pevedotin as monotherapy or in combination are positive, that would open it up as an option to treat those patients. The challenges with zelenectide pevedotin will be that, because it targets Nectin-4 and has the same payload as enfortumab vedotin, we don’t know how this drug will perform in patients who’ve already had enfortumab vedotin. Conversely, [we don’t know] how enfortumab vedotin would perform in patients who already had zelenectide pevedotin. We’re going to have to see, perhaps from real-world evidence, whether you can treat patients with enfortumab vedotin followed by zelenectide pevedotin because they have similar targets and payloads.

Torras OR, Crouzet L, Necchi A, et al. BT8009 monotherapy in enfortumab vedotin (EV)-naïve patients (pts) with metastatic urothelial carcinoma (mUC): updated results of Duravelo-1. 

Loriot Y, Siefker-Radtke A, Friendlander TW, et al. A phase 2/3 study of Bicycle toxin conjugate BT8009 targeting nectin-4 in patients with locally advanced or metastatic urothelial cancer (la/mUC): Duravelo-2. 

 2024;42(suppl 16):TPS4619. doi:10.1200/JCO.2024.42.16_suppl.TPS4619

Terence Friedlander, MD, spotlights emerging agents of interest in advanced bladder cancer, including the Nectin-4–targeted therapy zelenectide pevedotin.

Zelenectide Pevedotin Shows Early Promise as Less Toxic Alternative to Standard Regimens in Bladder Cancer

Dr Friedlander on the Duravelo-2 Trial for Advanced or Metastatic Urothelial Cancer

Terence W. Friedlander, MD, genitourinary oncologist, associate clinical professor, Division of Hematology/Oncology, Robert and Virginia O’Reilly Family Endowed Professor of Medicine,University of California San Francisco (UCSF), UCSF Health; chief, Hematology-Oncology, Zuckerberg San Francisco General; associate director, Cancer Research, Helen Diller Family Comprehensive Cancer Center, discusses the investigation of zelenectide pevedotin (BT8009) in the phase 2/3 Duravelo-2 study (NCT06225596) in patients with advanced or metastatic urothelial cancer.

One study that aims to enhance existing effective therapies for patients with urothelial cancer isDuravelo-2, for which Friedlander is an investigator. This study examines the peptide-drug conjugate zelenectide pevedotin, which may have similar activity to enfortumab vedotin-ejfv (Padcev) but is potentially associated with less toxicity, he begins. The smaller size of the zelenectide pevedotin molecule could allow it to penetrate the tumor microenvironment more effectively, potentially resulting in better drug activity and reduced persistence in circulation, he reports. This smaller size may lead to fewer lingering toxic effects, especially skin toxicity, as indicated by initial phase 1/2 trial (NCT04561362) data in patients with Nectin-4–expressing advanced malignancies, Friedlander explains.

Although developing universally effective therapies takes time, improving upon existing ones is valuable, he says, noting that patients with urothelial cancer may also benefit from receiving these therapies earlier in the disease course. Currently, research is focused on locally advanced and metastatic disease, but agents such as PD-1 inhibitors are moving into the perioperative setting to help prevent relapse after bladder removal, he continues.

Important studies have also been conducted in the neoadjuvant setting, where therapy is given without bladder removal, Friedlander states. One such study, the phase 2 HCRN GU 16-257 trial (NCT03558087), involved patients with muscle-invasive bladder cancer who received neoadjuvant nivolumab (Opdivo) plus platinum-based chemotherapy. Patients with a complete clinical response were allowed to keep their bladders, and most did not experience metastatic relapse, he reports.

The ability to avoid cystectomy would be a significant achievement for the bladder cancer treatment field, Friedlander expands. Improving frontline therapies in metastatic cases and developing novel therapies for later-line treatment are also crucial, he says. Additionally, radiation therapy for bladder cancer is being studied in combination with PD-1 inhibitors or enfortumab vedotin as a form of bladder preservation, according to Friedlander. These studies offer promising new treatment approaches, and their outcomes are highly anticipated, Friedlander concludes.

Terence W. Friedlander, MD, discusses the investigation of BT8009 in the Duravelo-2 study in patients with advanced or metastatic urothelial cancer.

Emerging Novel Therapies in Bladder Cancer | Supplements and Featured Publications

Dr Shore on the Rationale for the Duravelo-2 Trial in Metastatic Urothelial Cancer

First-in-Class Bicycle Toxin Conjugate Targeting Nectin-4 Generates Excitement in Urothelial Carcinoma

Dr Sridhar on the Use of Zelenectide Pevedotin in Locally Advanced or Metastatic Urothelial Cancer

Zelenectide Pevedotin Shows Early Promise as Less Toxic Alternative to Standard Regimens in Bladder Cancer

Dr Friedlander on the Duravelo-2 Trial for Advanced or Metastatic Urothelial Cancer