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

Terence Friedlander, MD

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 2024 ESMO Congress 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).¹

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.²

“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.”

In an interview with OncLive®, 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.

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

Friedlander: 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.

At that same meeting, data from 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 FGFR3 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.

The other agent that was just recently 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.

References

1. 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. Annal Oncol. 2024;35(suppl 2):S515-S516. doi:10.1016/j.annonc.2024.08.718
2. 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. J Clin Oncol. 2024;42(suppl 16):TPS4619. doi:10.1200/JCO.2024.42.16_suppl.TPS4619