NECTIN-4 Offers Attractive Target in Urothelial Cancer and Beyond

Elisabeth I. Heath, MD

As the treatment paradigm in urothelial cancer continues to expand with the addition of agents directed at various targets, including FGFR, TROP-2, and VEGFR-2, nectin cell adhesion protein 4 (NECTIN-4) has emerged as a promising treatment target for patients with urothelial carcinoma.

“NECTIN-4 is a transmembrane member of the nectin family of cell adhesion molecules,” Elisabeth I. Heath, MD, associate director of translational science and professor of hematology- oncology at Karmanos Cancer Institute, Wayne State University in Detroit, Michigan, said in an interview with OncologyLive. “The nectin family plays a critical role in cell activities such as movement, organization, and survival. There are several mechanisms where NECTIN-4 plays a significant role in cancer development including overexpression of NECTIN-4 in cancer cells, impact on cellular signaling, and promotion of metastasis. NECTIN-4 is highly overexpressed in urothelial, breast, pancreatic, esophageal, and lung cancers. NECTIN-4 can serve as a potential biomarker as it has been found to be overexpressed in many cancers and can also serve as a therapeutic target with various anticancer agents such as antibody-drug conjugates [ADCs].”

Urothelial carcinoma accounts for approximately 2.9% of the global mortality and is the sixth most common cancer in the United States. Specifically, patients with noninvasive urothelial bladder cancer, who make up approximately 75% of newly diagnosed patients with urothelial carcinoma, have an increased risk of disease recurrence and advancement, even though strides have been made in improving localized therapy. Patients with invasive urothelial bladder cancer often require surgery and/or radiation and can still have poor outcomes, even with systemic therapies. The lack of effective treatment options for these patients, especially following recurrence, underscores the need for the continued development of effective novel therapies with new targets.

Enfortumab Vedotin Breaks Ground as First Approved NECTIN-4–Directed ADC

The NECTIN-4–targeted ADC that has made recent waves in the oncology community is enfortumab vedotin-ejfv (Padcev). Enfortumab vedotin is a humanized IgG1 ADC directed against NECTIN-4 that is made up of the microtubule-disrupting small molecule monomethyl auristatin E (MMAE) attached to an antibody via a cleavable linker. Nonclinical findings suggested that treatment with enfortumab vedotin led to anticancer activity by disrupting the microtubule network within the cell following binding of the ADC to NECTIN-4-expressing cells and the release of the MMAE, leading to cell cycle arrest and apoptotic cell death.²

Enfortumab vedotin first received accelerated approval from the FDA in December 2019 for the treatment of patients with locally advanced or metastatic urothelial cancer who have received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/ adjuvant, locally advanced or metastatic setting. In July 2021, the agency expanded the indication for enfortumab vedotin to include patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/L1 inhibitor and platinum-containing chemotherapy or those who are ineligible for cisplatin-containing chemotherapy and have previously received at least 1 prior line of therapy.³

The approval of enfortumab vedotin monotherapy was supported by findings from the phase 3 EV-301 trial (NCT03474107), which enrolled patients with locally advanced or metastatic urothelial cancer who received a prior PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Patients were randomly assigned 1:1 to receive enfortumab vedotin (n = 301) or investigator’s choice of chemotherapy (n = 307). The primary end point was overall survival (OS) per RECIST 1.1; secondary end points included progression-free survival (PFS), overall response rate (ORR), and safety.^2,3

At the time of the July 2021 FDA approval, findings from EV-301 demonstrated that patients who received the ADC achieved a median OS of 12.9 months (95% CI, 10.6-15.2) compared with 9 months (95% CI, 8.1-10.7) among patients in the chemotherapy arm (HR, 0.70; 95% CI, 0.56-0.89; P = .0014). Moreover, the median PFS durations were 5.6 months (95% CI, 5.3-5.8) vs 3.7 months (95% CI, 3.5-3.9), respectively (HR, 0.62; 95% CI, 0.51-0.75; P < .0001). The ORRs were 40.6% (95% CI, 34.9%-46.5%) vs 17.9% (95% CI, 13.7%-22.8%), respectively (P < .0001), including respective complete response (CR) rates of 4.9% vs 2.7%.²

Additionally, the efficacy of enfortumab vedotin for the treatment of cisplatin-ineligible patients was examined in cohort 2 of the phase 2 EV-201 study (NCT03219333). EV-201 enrolled patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1/ L1 inhibitor. Cohort 2 of the trial (n = 89) examined patients who received prior treatment with a PD-1/L1 inhibitor but were ineligible for cisplatin and did not receive platinum-based chemotherapy in the locally advanced or metastatic setting. The ORR by blinded independent central review (BICR) was 51% (95% CI, 39.8%-61.3%), including a 22% CR rate; the median duration of response (DOR) was 13.8 months (95% CI, 6.4-not estimable [NE]).²

More recently, investigators presented data from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), which evaluated enfortumab vedotin in combination with the anti–PD-1 antibody pembrolizumab (Keytruda) for the treatment of patients with treatment-naive locally advanced or metastatic urothelial carcinoma. The standard of care in this patient population for many years has been platinum-based chemotherapy, but 5-year survival rates remain poor and multiple trials of chemotherapy in combination with PD-1/L1 inhibition did not show improved survival. Updated findings from EV-302 were presented during the 2023 European Society for Medical Oncology Congress, which took place in October in Madrid, Spain.⁴

The open-label study enrolled patients with locally advanced or metastatic urothelial carcinoma who were eligible for platinum-based chemotherapy and PD-1/L1 inhibitor naive. Eligible patients also needed to have an ECOG performance status of 2 or less and a glomerular filtration rate of at least 30 mL/min. Patients were randomly assigned 1:1 to receive enfortumab vedotin plus pembrolizumab (n = 442) or chemotherapy with either cisplatin or carboplatin plus gemcitabine (n = 444). The coprimary end points were PFS by BICR and OS; secondary end points included ORR per RECIST 1.1 and safety.⁴

Findings from EV-302 showed that the median PFS in the combination and chemotherapy arm was 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5), respectively, conferring a 55% reduction in the risk of progression or death with enfortumab vedotin plus pembrolizumab vs chemotherapy (HR, 0.45; 95% CI, 0.38-0.54; P < .00001). The 12-month PFS rates were 50.7% vs 21.6%, respectively, and the 18-month PFS rates were 43.9% vs 11.7%, respectively.⁴

The median OS in the combination arm was 31.5 months (95% CI, 25.4-NE) vs 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm (HR, 0.47; 95% CI, 0.38-0.58; P < .00001). The 12-month OS rates were 78.2% vs 61.4%, respectively, and the 18-month rates were 69.5% vs 44.7%, respectively. In response-evaluable patients in the combination arm (n = 437), the confirmed ORR was 67.7% (95% CI, 63.1%-72.1%), with a 29.1% CR rate, compared with 44.4% (95% CI, 39.7%-49.2%), with a 12.5% CR rate, in the chemotherapy arm (n = 441; 2-sided P < .00001).⁴

“[These are] the most significant data in bladder cancer in at least a generation, certainly since I’ve been doing this,” Brian I. Rini, MD, FASCO, chief of clinical trials at Vanderbilt-Ingram Cancer Center and Ingram Professor of Cancer Research at Vanderbilt University, both in Nashville, Tennessee, said in an interview with OncologyLive. “The initial chemotherapy for bladder cancer was always somewhat unsatisfying. [Additionally,] a lot of patients couldn’t get cisplatin, and we would argue over cisplatin versus carboplatin. We finally got some movement with avelumab [Bavencio] as maintenance therapy, but this [combination] is sort of the best of both worlds where you’re combining a potent ADC with immunotherapy, which had not been successful in the other trials with non-ADC chemotherapy, but it was wildly successful here. It absolutely is the standard of care.”

Notably, the combination of enfortumab vedotin and pembrolizumab led to a significant OS benefit over chemotherapy in both cisplatin-eligible (HR, 0.53; 95% CI, 0.39-0.72) and cisplatin-ineligible patients (HR, 0.43; 95% CI, 0.31-0.59). Moreover, an OS benefit was observed with the combination in PD-L1–high patients (HR, 0.49; 95% CI, 0.37-0.66) and PD-L1–low patients (HR, 0.44; 95% CI, 0.31-0.61).⁴

Enfortumab vedotin plus pembrolizumab displayed a generally manageable safety profile, with no new safety signals being reported. Grade 1 or 2 treatment-related adverse effects (TRAEs) occurred in 97% of patients in the combination arm (n = 440) vs 95.6% of patients in the chemotherapy arm (n = 433). Common grade 1 or 2 TRAEs in the combination arm included peripheral sensory neuropathy (50%), pruritus (39.8%), and alopecia (33.2%). Common grade 1 or 2 TRAEs in the control arm included anemia (55.6%), neutropenia (41.6%), and thrombocytopenia (34.2%). Grade 3 or higher TRAEs were present at rates of 55.9% vs 69.5% and serious TRAEs occurred at rates of 27.7% vs 19.6%, in the combination and chemotherapy arms, respectively.⁴

In their conclusion, study authors noted that EV-302 was the first instance in which platinum- based chemotherapy was surpassed in terms of OS in patients with previously untreated locally advanced or metastatic urothelial carcinoma.⁴ On December 15, 2023, the FDA granted regular approval to the combination of enfortumab vedotin and pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial cancer. The regulatory decision was supported by findings from EV-302.⁵

“The combination of enfortumab vedotin and pembrolizumab has revolutionized the treatment landscape for patients with metastatic urothelial carcinoma,” Heath commented. “The findings from EV-302 have been pivotal in shifting the paradigm of care, steering away from the long-established cisplatin-based combination chemotherapy that has been the cornerstone of treatment for the last 3 decades.”

Excitig Future on the Horizon For NECTIN-4–Directed Agents

Beyond urothelial cancer, NECTIN-4-directed agents are currently under clinical development in a variety of solid tumor types. “NECTIN-4 is an interesting target for drug development in that it’s something you can see and target. It’s not intracellular; it’s a transmembrane member of this cell adhesion family of molecules. You can see it, you can stain it, and you can find it on the cell membrane. But more importantly, it has so many roles, [such as] metastasis and migration, that [make it] an appealing target because it impacts cellular signaling,” Heath said.

In the phase 1/2 Duravelo-1 study (NCT04561362), investigators are examining the safety and efficacy of the novel bicycle toxin conjugate BT8009 in patients with NECTIN-4–expressing advanced solid tumors. BT8009 is a NECTIN-4– directed agent that is designed with high specificity to reduce toxicity, particularly those of the skin and eyes. The agent is composed of a novel bicycle molecule selective to NECTIN-4 attached via a cleavable protease linker to MMAE that is inactive when bound to the bicycle molecule.⁶

At the November 16, 2023, data cutoff, updated findings from Durvaleo-1 showed that patients with enfortumab vedotin–naive metastatic urothelial carcinoma who received BT8009 at the recommended phase 2 dose of 5 mg/m² weekly (n = 26) achieved an ORR of 38% (95% CI, 20%-59%), with 1 patient experiencing a CR. Notably, BT8009 also displayed initial antitumor activity in patients with triple-negative breast cancer (TNBC; n = 15), ovarian cancer (n = 10), and non–small cell lung cancer (NSCLC; n = 16), with respective ORRs of 20%, 20%, and 13%. The median DORs were 4.2 months, 1.8 months, and 3.4 months, respectively.⁶

References

1. Shafique MA, Haseeb A, Siddiq MA, Mussarat A, Rangwala HS, Mustafa MS. Current and emerging treatments for urothelial carcinoma: a focus on enfortumab vedotin. Cancer Manag Res. 2023;15:699-706. doi:10.2147/CMAR.S418009
2. Padcev. Prescribing information. Astellas Pharma; 2021. Accessed December 21, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761137s006s008lbl.pdf
3. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. FDA. July 9, 2021. Accessed December 21, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-enfortumab-vedotin-ejfv-locally-advanced-or-metastatic-urothelial-cancer
4. Powles TB, Valderrama BP, Gupta S, et al. EV-302/KEYNOTE-A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34(suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106
5. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed December 21, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
6. R & D Day. Bicycle Therapeutics. December 14, 2023. Accessed January 2, 2024. https://investors.bicycletherapeutics.com/static-files/46599fde-67dc-40a8-9dcb-10ed8444f31e