Heath Discusses Utility of NECTIN-4 as a Target in Urothelial Carcinoma

Elisabeth I. Heath, MD, FACP

NECTIN-4 has emerged as a treatment target for patients with urothelial carcinoma, with recent findings from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) providing further evidence of the promising activity of this agent class, according to Elisabeth I. Heath, MD, FACP.

“NECTIN-4 is a transmembrane member of the nectin family of cell adhesion molecules,” Heath said. “The big take-home point that everyone’s still trying to digest is that the NECTIN-4 directed antibody-drug conjugate [ADC] enfortumab vedotin is truly a different standard of care [SOC].”

Enfortumab vedotin-ejfv (Padcev) is the first NECTIN-4–targeted ADC to receive FDA approval and was granted accelerated approval from the agency in December 2019 for the treatment of patients with locally advanced or metastatic urothelial cancer who received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. The indication was expanded by the FDA in July 2021 for the treatment of adult patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1/L1 inhibitor and platinum-containing chemotherapy, or are ineligible for cisplatin-containing chemotherapy and have received at least 1 prior line of therapy.¹

Then, in October 2023, during the 2023 ESMO Congress, investigators made a splash when they presented findings from EV-302/KEYNOTE-A39, which examined enfortumab vedotin plus pembrolizumab (Keytruda) in locally advanced or metastatic urothelial carcinoma. The median progression-free survival (PFS) with the combination (n = 442) was 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy (n = 444; HR, 0.45; 95% CI, 0.38-0.54; P < .00001). Notably, this was the first investigational regimen that showed superiority over SOC platinum-based chemotherapy in this patient population.²

In December 2023, the FDA approved enfortumab vedotin plus pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial cancer based on findings from EV-302/KEYNOTE-A39.³

In an interview with OncLive®, Heath, associate director of translational science and professor of hematology-oncology at Karmanos Cancer Institute at Wayne State University in Detroit, Michigan, discussed what makes NECTIN-4 an attractive target in drug development, the significance of the EV-302/KEYNOTE-A39 findings, and the future of NECTIN-4-directed agents in urothelial cancer and beyond.

OncLive: What makes NECTIN-4 an attractive pathway for the development of anticancer therapeutics?

Heath: From a drug development [standpoint], it’s something that you can see, and you can target. It’s not intracellular, it’s a transmembrane member of this cell adhesion family of molecules. In that sense, you can see it, stain it, and find it in a cell.

More importantly, it has so many [key] roles [such as] with metastasis and migration—anything that’s in that transmembrane family is usually a target that we like because it impacts cellular signaling. A big part of it is how it impacts cellular signaling and metastasis pathways, and that’s what makes it an interesting target for drug development.

What impact have the EV-302/KEYNOTE-A39 findings had on the urothelial oncology community?

When Thomas B. Powles, MBBS, MRCP, MD, presented this data at ESMO [in 2023], it truly was a game changer. For decades as an oncologist in metastatic urothelial cancer we treated patients [in that population] with standard chemotherapy. Having enfortumab vedotin and pembrolizumab [as an option] for that group where you normally reach for a cisplatin-based [chemotherapy] has completely rewritten the SOC.

It’s a lot to digest and unpack because we’ve been doing this the same way globally for decades. This is the first time where we’re almost in shock that something was positive, and it’s not just a little bit positive, it’s very positive. Those of us who have been in the development path for enfortumab vedotin, and I was fortunate to work with this compound way back in the beginning, are astonished to see that this is now the new SOC.

Beyond urothelial cancer, what disease settings could NECTIN-4-directed agents be effective in and what does the future hold for these drugs?

There are a lot of other cancers that have NECTIN-4 positivity, although probably not as high [as urothelial cancer], and [the positivity is determined by] immunohistochemistry stains, so it depends on who’s doing the staining. At the beginning of the development of enfortumab vedotin, we tested everybody with a central laboratory, and everyone’s [samples] were positive. We got to the point where we were [asking] “Why am I waiting for these results when most everyone is positive?” We know pancreatic cancer also has high expression, [as well as] breast, esophageal, lung, and head and neck cancers. But we don’t test NECTIN-4 status in urothelial cancer [now]—it’s just an assumption.

The drug development space is moving towards other ADCs still targeting NECTIN-4. In oncology, when there’s 1 [agent developed] usually several others follow. There are trials [of other agents] now, a couple of them we have opened at our center, and other companies have taken on this path and are developing their own drugs.

[New drugs] are going for [improvements in terms of] adverse effects [AEs]. One of the AEs is a rash that you have to be quite familiar with handling. We know there is overexpression on skin—is that an off-target effect and will other companies further developing this try to minimize that? Are they trying to get better potency for their payload? It’s not really changing the target, it’s [determining] how you’re going to deliver your drug with more potency and less toxicity.

References

1. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. FDA. July 9, 2021. Accessed March 6, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-enfortumab-vedotin-ejfv-locally-advanced-or-metastatic-urothelial-cancer
2. 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 4):1557-1558. doi:10.1016/j.annonc.2023.10.347
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed March 6, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer