Nectin-4, Variant Histology, and What Comes Next: Benjamin Garmezy, MD

Metastatic bladder cancer being one of the worst diagnoses in oncology is no longer the case, says Benjamin Garmezy, MD, of Sarah Cannon Research Institute, who believes targeted antibody-drug conjugate (ADC) and immunotherapy combinations may now be curing upward of 20% to 25% of patients with true stage 4 disease.

How Progress Is Moving Backward Through Stages

In perioperative therapy for muscle-invasive stage 2 and 3 disease, these regimens are outperforming chemotherapy, and Garmezy expects the majority of those patients may eventually be cured. In stage I, the conversation turns to agents delivered inside the bladder rather than systemically, sparing toxicities seen at higher stages, though durability is still unknown. Although Bacillus Calmette-Guerin (BCG) was the standard for a long time, better post-BCG options could delay surgery or radiation, preserving not just the bladder but bladder quality of life.

What EV-303 and EV-304 Established

Both the EV-303 (NCT03924895) and the EV-304 (NCT04700124) trials examined perioperative therapy in cisplatin-eligible and cisplatin-ineligible patients, a distinction Garmezy expects to fade. The intervention arm, enfortumab vedotin plus pembrolizumab, pairs an ADC targeting Nectin-4 with a monomethyl auristatin E payload and a PD-1 inhibitor. This payload, he explains, matters and may be immunogenic. The combination beat cisplatin and gemcitabine and beat cystectomy alone in the respective populations, making it standard of care for eligible patients with conventional histology, in his view. The NIAGARA regimen was not the control arm in either trial, since both were designed under a different standard.

Why Variant Histology Remains the Open Question

Variant histology is where more data are needed. Squamous cell and plasmacytoid disease retain Nectin-4 expression, sarcomatoid is less clear, and small cell neuroendocrine does not. Beyond target expression, the question is whether the payload still works. Garmezy calls the combination transformational in plasmacytoid disease and ineffective in neuroendocrine disease, which is treated differently. Squamous and micropapillary are more controversial, and he offers a personal impression that these patients fare worse, while noting he lacks data and that they also do poorly on alternatives. For mixed histology, he leans toward the combination while for fully squamous disease he declines to advocate either way.

What Comes After the Current Backbone

Future work will build on the existing backbone, Garmezy says, reducing toxicity through approaches such as induction followed by immunotherapy maintenance. He points to T-cell engagers and radioligands as possibilities, including for PD-1–refractory patients, a group nothing currently cures. Because the transformational change arrived in the past 24 months, he expects the next leap in a decade rather than 5 years.