ADCs Usher in a Complex New Era of Disease and Toxicity Management in Bladder Cancer

A plethora of antibody-drug conjugates (ADCs) have made their way into the urothelial carcinoma treatment paradigm, raising the bar for efficacy in ways that surpass that of prior standard chemotherapy regimens, according to Jacqueline Brown, MD. However, the toxicity profiles associated with ADCs reinforce the importance of stringent patient selection to identify the most fit patients for these therapies, she emphasized.

In an interview with OncLive^®, Brown discussed the nuanced potential role of dual-ADC combinations in bladder cancer, preliminary efficacy data with disitamab vedotin (RC48) in this disease, and what the future may hold for the treatment of patients with HER2-positive disease now that fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) has made its way onto the bladder cancer arsenal.

She highlighted questions regarding the efficacy of immunotherapy plus cisplatin vs carboplatin, as well as patient populations for whom platinum-based chemotherapy may be a preferred treatment option, in another article.

Brown is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as the associate medical director of the Ambulatory Infusion Center at the Winship Cancer Institute of Emory University in Atlanta, Georgia.

OncLive: How do findings from the phase 1 DAD trial (NCT04724018) indicate the potential efficacy of an ADC-ADC combination in metastatic bladder cancer?

Brown: Findings from the DAD trial were initially presented by Bradley McGregor, MD, of Dana-Farber Cancer Institute [DFCI] in Boston, Massachusetts, at the 2023 ESMO Congress. [Dr McGregor presented] longer-term results at the 2024 ESMO Congress. This trial was novel because it investigated the combination of 2 ADCs: enfortumab vedotin-ejfv [Padcev] and sacituzumab govitecan-hziy [Trodelvy], [the latter of] which targets TROP2 and currently has an accelerated FDA approval for patients with later-line urothelial carcinoma. The idea was: Can we put these 2 drugs together? They have different payloads and different targets in the form of the antibody, so can we get some synergy between them?

Ninety-six percent of the patients in this trial had received prior immunotherapy and prior platinum chemotherapy. [Among the] 23 patients [enrolled in] this trial, the overall response rate [ORR] in this heavily pretreated population was 70%, which is notable. [Although it is] fantastic to have achieved such a response in these heavily pretreated patients, with that response comes more toxicity. [Patients were at risk for experiencing toxicities associated with] enfortumab vedotin, which include cytopenias, fatigue, gastrointestinal symptoms, rashes, neuropathy, and hyperglycemia. [They were also exposed to adverse effects (AEs) from] sacituzumab govitecan, most significantly, cytopenias and diarrhea.

When you combine those agents, you get an overlay of AEs, [so the efficacy of this regimen] comes at a cost. Regardless, the data are compelling. They prove it’s possible to [combine 2 ADCs in this setting] and give us a basis for how we can improve future first-line therapies.

If we’re giving patients enfortumab vedotin plus pembrolizumab, can they be also given sacituzumab govitecan? Dr McGregor [is also conducting an] ongoing [portion of the DAD trial], DAD-IO trial, which is combining enfortumab vedotin with sacituzumab govitecan and pembrolizumab [Keytruda]. With more efficacy, we must be worried about more toxicity. However, a patient traveling to DFCI for a clinical trial is fit [if they are] able to do that and may be different than the average patient with advanced urothelial carcinoma. We always have to keep those differences [between clinical trial and real-world patient populations] in mind.

Data from cohort C of the phase 2 RC48G001 trial (NCT04879329) of disitamab vedotin plus pembrolizumab were presented at the 2024 ESMO Congress. What might be the role of this combination in the urothelial carcinoma treatment paradigm?

Disitamab vedotin is another ADC that targets HER2, a cell surface marker on urothelial carcinoma. We often [associate HER2] with gastric and breast cancer, but [we’re realizing] that it is an important target in urothelial carcinoma as well. [In RC48G001], disitamab vedotin was combined with pembrolizumab [in patients with previously untreated, HER2-expressing, locally advanced or metastatic urothelial carcinoma]. [In the] safety run-in portion, data from which were presented at the 2024 ESMO Congress, the ORR in this [pretreated] population was 75.0%. [In the phase 3 EV-302 trial (NCT04223856), the ORR] with enfortumab vedotin plus pembrolizumab was 67.7%, so [that 75% ORR with disitamab vedotin plus pembrolizumab is] excellent.

Remarkably, responses [with disitamab vedotin plus pembrolizumab] were seen in patients who had HER2-positive [tumors] and those who had HER2-low disease by immunohistochemistry [IHC]. [These data show] that patients don’t necessarily have to have high expression of this antigen to benefit from the drug, which speaks to the nature of the bystander effect from ADCs. These are promising data.

At the 2023 ASCO Annual Meeting, similar results were presented with the first-line combination of disitamab vedotin and toripalimab-tpzi [Loqtorzi]. [Toripalimab] is a checkpoint inhibitor that is different from pembrolizumab, but [its use in combination with disitamab vedotin is based on] a similar concept. [Disitamab vedotin] will be promising going forward, and HER2 will continue to be an important target in urothelial cancer.

How has T-DXd performed in patients with HER2-positive bladder cancer?

[Primary findings from] the phase 2 DESTINY-PanTumor02 trial [NCT04482309] were published [in October 2023]. This trial investigated T-DXd in patients with HER2-expressing tumors in later-line settings. This was a basket trial that enrolled lots of different non–breast and gastric cancer tumors to see the efficacy of this drug [in solid tumors broadly]. It enrolled patients with endometrial, cervical, ovarian, and bladder cancers.

Forty-one heavily pretreated patients with bladder cancer were enrolled in this trial, and they were treated with this ADC. The ORR in all-comers [with bladder cancer] was 39.0%. Patients with [bladder cancer with] high HER2 expression of 3+ by IHC had an ORR of 56.3%. Those [with HER2 expression of 2 by IHC] had an ORR of 35.0%.

These data show, [at the same time] as we’re investigating disitamab vedotin plus immunotherapy in the first-line setting, that T-DXd may be an option for patients with high HER2 expression who [experience] progression after platinum-based chemotherapy and after enfortumab vedotin, who maybe don’t have an FGFR mutation that qualifies them for erdafitinib [Balversa]. [The efficacy of T-DXd in bladder cancer is notable] in this treatment desert, where we don’t know how to treat later-line patients because of the paradigm shift [that happened after the FDA approval of enfortumab vedotin plus pembrolizumab for all patients with bladder cancer]. The FDA approved T-DXd for the treatment of patients with tumors with high HER2 expression, regardless of histology. That indication includes urothelial cancer. T-DXd is another important tool for oncologists who treat patients with bladder cancer.