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

Terence W. Friedlander, MD

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.¹ 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.²

“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 OncologyLive. 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).¹

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 OncologyLive. “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.”

Neal Shore, MD, FACS

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.”

A Novel Mechanism of Action

“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 OncologyLive. “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.”

Srikala Sridhar, MD, MSc, FRCPC

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.³ 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.^3,4

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/m² given weekly as well as 6 mg/m² 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.⁴ 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).²

“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).²

“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.”

Diving Into Duravelo-2 Enrollment

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 (FIGURE).^2,4

Figure. Duravelo-2 Enrollment Criteria

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.²

“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.⁵

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

References

1. 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. Ann Oncol. 2024;35(suppl 2):S515-S516. doi:10.1016/j.annonc.2024.08.718
2. 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
3. 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).J Clin Oncol. 2023;41(suppl 6):498. doi:10.1200/JCO.2023.41.6_suppl.498
4. 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. J Clin Oncol. 2024;42(suppl 16):TPS4619. doi:10.1200/JCO.2024.42.16_suppl.TPS4619
5. 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