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The prognosis for patients with metastatic urothelial carcinoma (mUC) remains dismal, with a 5-year survival of approximately 5% in stage IV disease. Currently, platinum-containing chemotherapy remains the standard of care in first-line treatment, but highly potent targeted therapies, including (ADCs), show promise in .

Recently, a combined analysis of data from two sequential, open-label, single-arm phase II clinical trials demonstrated meaningful clinical activity in 107 patients with chemotherapy-refractory mUC following treatment with the novel ADC disitamab vedotin (RC48-ADC). The humanized anti-HER2 monoclonal antibody is conjugated with monomethyl auristatin E (MMAE).

The analysis of data from the and trials showed an overall response rate (ORR) of 50.5%. The median progression-free survival (mPFS) was 5.9 months, and median overall survival (mOS) was 14.2 months, said Xinan Sheng, MD, of Peking University Cancer Hospital & Institute in Beijing, China, and colleagues.

Notably, they explained in the , the findings were consistent across patient subgroups regardless of primary tumor location, presence of HER2-positive disease, liver metastasis, or progression after both chemotherapy and anti–PD-1/L1 therapy.

The authors were not available for interviews, and the following highlights are excerpted from the study and edited for length and clarity.

Why a combined analysis?

The RC48-C005 trial was initiated as a pivotal phase II study to assess the efficacy and safety of disitamab vedotin in 43 patients with advanced HER2-positive UC. We observed an ORR of 51.2% and a PFS of 6.9 months. Enrollment in this trial was terminated, as recommended by the regulatory authority in China, and the RC48-C009 trial was conducted to confirm these preliminary outcomes. (Based on results from the RC48-C009 trial, China approved the use of disitamab vedotin in platinum-refractory metastatic UC in January 2022.)

Regarding the patient population, almost 75% of the patients were male with a median age of 63. All had metastatic disease. The primary tumor originated in the bladder in 51.4% of patients, in the renal pelvis in 26.2%, and in the ureter in 28.2%. Of the 90.7% of patients with visceral metastasis, liver metastasis accounted for almost half the cases.

What was the treatment regimen?

Patients received disitamab vedotin (2.0 mg/kg) as an intravenous infusion once every 2 weeks until disease progression, intolerable toxicity, death, or withdrawal of consent. The median treatment duration was 21.3 weeks, with a median dose intensity of 96.0%.

How was clinical response evaluated?

A blinded independent review committee evaluated the clinical response, according to RECIST [Response Evaluation Criteria in Solid Tumors] version 1.1, at baseline and every 6 weeks, regardless of dose delays or interruptions, until documented disease progression or death.

Of the 54 patients with a confirmed objective response, two were complete responders and 52 were partial responders. In addition, 34 patients (31.8%) experienced stable disease, and 88 (82.2%) had a decrease in target lesions from baseline.

What were the treatment-related adverse events [TRAEs]?

About 54% of patients experienced grade ≥3 TRAEs. These included peripheral sensory neuropathy, increased AST [aspartate aminotransferase], and neutropenia. Most TRAEs were clinically manageable with supportive care, and we think the majority were likely related to toxicity associated with the disitamab vedotin payload, MMAE. We did not observe any grade 4 or 5 TRAEs.

Did the findings indicate that disitamab vedotin might be effective in HER2-negative disease?

We did observe a moderate ORR of almost 40% in patients with low or even negative HER2 expression. As a result, the was developed to examine the use of disitamab vedotin in patients with HER2-negative mUC.

Any early findings?

Our show antitumor activity with the use of disitamab vedotin in HER2-negative mUC. We have a confirmed ORR of 26.3%, an mPFS of 5.6 months, and an mOS of 16.4 months.

Is there a clinical takeaway?

These emerging data suggest that HER2 screening might not be needed for the use of disitamab vedotin in the future, but more clinical trials are needed to test this hypothesis.

What's next for this research?

Given that this ADC achieved success in chemotherapy-refractory mUC settings, the next step is to move it to the frontline treatment setting for evaluation.

Are any trials currently doing this?

The phase II was developed to investigate the use of disitamab vedotin alone or in combination with pembrolizumab (Keytruda) in patients with HER2-positive or HER2-low mUC. In addition, the ongoing is evaluating the use of disitamab vedotin plus toripalimab (Loqtorzi) in mUC regardless of HER2 expression status. Toripalimab is an anti-PD-1 antibody with a durable antitumor effect in mUC, so the combination may have a synergistic antitumor effect.

Read the study here.