First-Line Disitamab Vedotin/Toripalimab Shows Benefit in HER2+ la/mUC

Bladder cancer stages: © pikovit - stock.adobe.com

Statistically significant and clinically meaningful progression-free survival (PFS) and overall survival (OS) benefits were seen with disitamab vedotin (RC48) in combination with toripalimab-tpzi (Loqtorzi) vs standard chemotherapy when used as a first-line treatment for patients with HER2-expressing locally advanced or metastatic urothelial carcinoma (la/mUC), meeting the 2 primary end points of the phase 3 RC48-C016 trial (NCT05302284).¹

Compared with the strongly positive findings of a prespecified interim analysis by the independent data monitoring committee, the combination demonstrated notable advantages. Key subgroup analyses showed that disitamab vedotin plus toripalimab significantly improved both PFS and OS over standard chemotherapy, regardless of cisplatin eligibility or HER2 expression.

Looking at safety, the combination elicited a manageable safety profile with tolerable adverse events reported.

"We, once again, jointly witnessed a strong positive result of [disitamab vedotin] combined with toripalimab in the first-line treatment of advanced urothelial carcinoma. Regardless of whether the patients are suitable for cisplatin treatment and regardless of patients' HER2 expression status, [disitamab vedotin] combined with toripalimab significantly improved PFS and OS. This outstanding efficacy proves the success of the 'HER2-[antibody-drug conjugate (ADC)] + immunotherapy' combination treatment concept and is also a major breakthrough in the global treatment of urothelial carcinoma,” said Guo Jun, principal researcher of the study and professor from Peking University Cancer Hospital, in a press release.

Detailed findings from the study are expected to be presented at international medical conferences later in 2025. RemeGen, the drug developer, also plans to file a biologic license application for disitamab vedotin as a treatment for la/mUC to the Center of Drug Evaluation of National Medical Products Administration in China.

Disitamab vedotin is the first domestically approved ADC in China. Toripalimab is a PD-1 inhibitor. The combination is being evaluated for the treatment of patients with la/mUC in the randomized, multicenter, active-controlled, phase 3 RC48-C016 trial.

The phase 3 RC48-C016 trial is evaluating the efficacy and safety of disitamab vedotin when given with toripalimab vs gemcitabine in combination with cisplatin/carboplatin in systemic treatment-naive patients with HER2-expressing la/mUC. The study was initiated in June 2022 and is being conducted in 74 sites across China.²

A total of 484 patients are enrolled in the trial. Enrollment was open to patients with locally advanced, unresectable or metastatic UC with histopathological confirmation, including UC originating from the renal pelvis, ureters, bladder, or urethra. Patients were required to not have received prior systemic therapy for la/mUC. Further, patients must have had an expected survival of 12 weeks or more; at least 1 measurable lesion based on RECIST v1.1; HER2-expressing status determined by the central laboratory to be IHC 1+, 2+ or 3+; an ECOG performance status score of 0 or 1; and adequate cardiac, bone marrow, hepatic, renal, and coagulation functions.

Aside from the primary end points of OS and PFS, the study is evaluating objective remission rate, duration of relief, and disease control rate as secondary end points.

“We look forward to the excellent performance of [disitamab vedotin] in subsequent studies which should provide better decision-making basis for clinicians, bring more benefits to patients, and reshape the global treatment landscape of urothelial carcinoma with the 'Chinese approach,’” added Jun in the press release.¹

Additional Research on Disitamab Vedotin

According to long-term data from a phase 1b/2 clinical trial (NCT04264936) published in Annals of Oncology, disitamab vedotin plus toripalimab led to encouraging efficacy signals and a manageable safety profile in patients with la/mUC.^3,4 With a median follow-up of 33.2 months, the confirmed objective response rate was 73.2% (95% CI, 57.1%-85.8%), including 9.8% complete and 63.4% partial responses, with benefits observed across subgroups. The disease control rate was 90.2%. Median PFS was 9.3 months (12-month rate: 34.6%), and median duration of response was 8.6 months. Median OS reached 33.1 months (36-month rate: 49.2%).

Initial data from this trial were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.⁵

Results from a small study shared during the 2025 American Urological Association (AUA) Annual Meeting also showed disitamab vedotin’s promise. Here, the combination of disitamab vedotin with Bacillus Calmette-Guérin led to promising efficacy with manageable toxicity in patients with HER2-expressing, high-risk, non-muscle-invasive bladder cancer.⁶

For patients unable to undergo complete tumor resection or had carcinoma in situ, the clinical complete response rates were 100% for both the 11 patients evaluable at 3 months and 5 patients evaluable at 6 months. Among the 3 evaluable patients who underwent complete tumor resection, the event-free survival rate at 6 months was 100%.

REFERENCES:

1. Poised to reshape treatment landscape: the phase 3 clinical trial of disitamab vedotin as a first-line therapy for HER2-expressing locally advanced or metastatic ‌urothelial carcinoma reached its primary endpoints of PFS and OS. News release. RemeGen Co., Ltd. May 12, 2025. Accessed May 12, 2025. https://tinyurl.com/33t96pjv

2. A study of RC48-ADC combined with toripalimab For first-line treatment of urothelial carcinoma. ClinicalTrials.gov. Updated December 18, 2023. Accessed May 12, 2025. https://clinicaltrials.gov/study/NCT05302284

3. 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

4. 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

5. Shen Y, Peng L, Lu X, et al. Preliminary efficacy and safety of disitamab vedotin (dv) combined with Bacillus Calmette-Guérin (BCG) in the treatment of high-risk non-muscle invasive bladder cancer with HER2 expression: a prospective, open label, single-center study. J Urol. Published online April 26, 2025. doi:10.1097/01.JU.0001109848.08748.9e.09

6. A study of RC48-ADC combined with toripalimab for first-line treatment of urothelial carcinoma. ClinicalTrials.gov. Updated February 13, 2025. Accessed May 12, 2025. https://clinicaltrials.gov/study/NCT05302284