Disitamab vedotin/toripalimab shows encouraging efficacy in urothelial carcinoma

The combination of disitamab vedotin plus toripalimab-tpzi (Loqtorzi) demonstrated encouraging efficacy with a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma (la/mUC), according to long-term data from a phase 1b/2 clinical trial (NCT04264936; RC48-C014) published in Annals of Oncology.¹

The multicenter trial enrolled 41 patients with la/mUC.

Initial data from the trial were presented at the 2023 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.²

The trial was conducted as a dose-escalation/dose-expansion study. In phase 1, patients received disitamab vedotin at the dose levels of 1.5 mg/kg and 2.0 mg/kg in combination with 3.0 mg/kg toripalimab once every 2 weeks. No dose-limiting toxicities were observed during this phase.

Thus, the recommended phase 2 dose (RP2D) was determined to be 2.0 mg/kg disitamab vedotin plus 3.0 mg/kg toripalimab, which was explored in phase 2 of the trial.

At a median follow-up of 33.2 months, the confirmed objective response rate (ORR) was 73.2% (95% CI, 57.1%-85.8%). This was comprised of 4 (9.8%) complete responses and 26 (63.4%) partial responses. ORR benefits were noted across all subgroups of patients, irrespective of prior lines of systemic treatments, HER-2 expression status, and PD-L1 expression status.

Additionally, the disease control rate was 90.2%, attributed to 17.1% of patients achieving stable disease.

Data also showed a median progression-free survival (PFS) of 9.3 months (95% CI, 5.7-11.2 months). At 12-month follow-up, the PFS rate was 34.6%. The median duration of response was 8.6 months (95% CI, 7.2-16.8 months).

Further, the median overall survival (OS) was 33.1 months (95% CI, 16.5 months-not estimated). The OS rate at 36 months was 49.2%.

Regarding safety, all patients experienced a treatment-related adverse event (TRAE). The most common TRAEs were an increase in aspartate aminotransferase (65.9%), an increase in alanine aminotransferase (63.4%), and peripheral sensory neuropathy (63.4%).

TRAEs of grade 3 or higher were reported in 51.2% of patients. The most common TRAEs of grade 3 or higher were an increase in γ-glutamyltransferase (12.2%), asthenia (9.8%), and alanine aminotransferase increased (7.3%).

At the time of data cutoff in March 2024, 95.1% of patients had discontinued treatment. This was primarily due to disease progression (61%) or adverse events (14.6%).

One treatment-related death due to pneumonitis was reported.

In total, the open-label, multicenter trial enrolled 41 patients with la/mUC. Of those, 6 patients were enrolled in the dose-escalation phase and 35 patients were enrolled in the dose-expansion phase.

The median age of patients was 66 years. Among all participants, 53.7% were male, 70.7% had an ECOG performance status of 1, and 61% of patients were treatment-naïve. In the study, patients received treatment for a median duration of 8.0 months (95% CI, 5.5-11 months).

The primary end points for the trial were safety and the determination of a RP2D. Secondary end points included ORR, PFS, and OS.

Based on these findings, the authors concluded, “This combination represents a promising first-line option for la/mUC.”

They also note that 2 randomized phase 3 trials of disitimab vedotin plus toripalimab are currently underway. These include a phase 3 study in China (RC48-C016, NCT05302284) of disitamab vedotin plus toripalimab vs platinum-based chemotherapy in patients with untreated HER2-expressing la/mUC, as well as a global phase 3 study (DV-001, NCT05911295) of disitamab vedotin plus pembrolizumab (Keytruda) vs chemotherapy in patients with untreated, HER-2 expressing la/mUC.

Both studies are expected to reach primary completion in 2026.^4,5

Disitimab vedotin currently has a breakthrough therapy designation in the US for HER2-positive la/mUC that was previously treated with platinum-based chemotherapy.

References

1. Zhou L, Yang KW, Zhang S, et al. Disitamab vedotin plus toripalimab in patients with locally advanced or metastatic urothelial carcinoma (RC48-C014): a phase Ib/II dose-escalation and dose-expansion study. Ann Oncol. 2024:S0923-7534(24)04977-9. doi:10.1016/j.annonc.2024.12.002

2. Sheng X, Zhou L, Yang K, et al. Disitamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate (ADC), combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma: An open-label phase 1b/2 study. J Clin Oncol 41, 2023 (suppl 16; abstr 4566). doi:10.1200/JCO.2023.41.16_suppl.4566

3. Published in Annals of Oncology: Disitamab vedotin combined with PD-1 inhibitor is a promising treatment for locally advanced or metastatic urothelial carcinoma. News release. RemeGen Co, Ltd. Published online and accessed January 8, 2025. https://www.prnewswire.com/news-releases/published-in-annals-of-oncology-disitamab-vedotin-combined-with-pd-1-inhibitor-is-a-promising-treatment-for-locally-advanced-or-metastatic-urothelial-carcinoma-302345663.html

4. A Study of RC48-ADC Combined With Toripalimab For First-line Treatment of Urothelial Carcinoma. ClinicalTrials.gov. Last updated December 18, 2023. Accessed January 8, 2025. https://clinicaltrials.gov/study/NCT05302284

5. Disitamab Vedotin With Pembrolizumab vs Chemotherapy in Previously Untreated Urothelial Cancer Expressing HER2. ClinicalTrials.gov. Last updated January 2, 2025. Accessed January 8, 2025. https://clinicaltrials.gov/study/NCT05911295