Disitamab vedotin is a HER2-targeted antibody-drug conjugate and toripalimab is a PD1-inhibitor.
The novel combination of the HER2-targeted antibody-drug conjugate disitamab vedotin (RC48) and the PD-1 inhibitor toripalimab demonstrated promising clinical activity with a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma, according to findings from a phase 1b/2 study presented at the 2023 ASCO Annual Meeting.1,2
At a median follow-up of 13.5 months, the confirmed investigator-assessed objective response rate (ORR) was 73.2%, including 4 complete responses and 26 partial responses among a total of 41 patients. The disease control rate was 90.2%. Among treatment-naïve patients (n = 25), the ORR was 76%. The median time to response was 1.8 months and the median duration of response was 8.2 months.
The median progression-free survival was 9.2 months overall and 9.0 months in the treatment-naïve subgroup. The median overall survival (OS) was not reached in the overall population and the 24-month OS rate was 63.2%.
"Treating locally advanced or metastatic urothelial carcinoma remains a substantial unmet clinical need. In clinical practice, we find that approximately 90% of locally advanced or metastatic urothelial carcinoma patients show HER2 expression at IHC 1+ or above. It is gratifying to showcase the updated long-term survival data at this year's ASCO Annual Meeting, highlighting the impressive efficacy of disitamab vedotin across varied HER2 or PD-L1 expression levels," professor Guo Jun, Peking University Cancer Hospital, principal investigator of the study, stated in a press release.2
At a data cutoff date of November 18, 2022, there were 41 evaluable patients in the open-label phase 1b/2 study. At baseline, the median age of these patients was 66 years (range, 42-76), 22 patients were male, and 19 patients were female. The ECOG performance status was 0 for twelve patients and 1 for twenty-nine patients. Regarding histology, 25 patients had pure urothelial carcinoma, 12 patients had other variants, and 4 patients had urothelial carcinoma with squamous differentiation. Patients had metastatic lesions in the lung (41.5%), liver (24.4%), and bone (22.0%). Twenty-five patients had not received prior systemic treatment and 16 patients had received 1 or more lines of systemic therapy.
Patients were treated with disitamab vedotin at 1.5 mg/kg or 2 mg/kg (recommended phase 2 dose) plus 3 mg/kg of toripalimab every 2 weeks.
The breakdown of HER2 and PD-L1 expression by population size and ORR was as follows:
Regarding safety, treatment-related adverse events (TRAEs) across all grades occurring in at least half of the patients included AST increase (68.3%), ALT increase (63.4%), peripheral sensory neuropathy (61.0%), asthenia (61.0%), GGT increase (56.1%), hypertriglyceridemia (53.7%), and appetite decrease (51.2%). Fifteen patients overall experienced at least 1 grade ≥3 TRAE. Grade ≥3 TRAEs occurring in at least 3 patients included GGT increase (n = 5), asthenia (n = 4), ALT increase (n = 3), and hypertriglyceridemia (n = 3).
The FDA previously granted disitamab vedotin (RC48) a breakthrough therapy designation for the treatment of patients with HER2-positive locally advanced or metastatic urothelial carcinoma following treatment with platinum-based chemotherapy. The designation is intended to expedite the development and review of disitamab vedotin in this setting.3
"We're thrilled to share updates on disitamab vedotin research at the 2023 ASCO Annual Meeting. The study further underscores the potential of disitamab vedotin, in combination with PD-1 inhibitors, for treating urothelial carcinoma. Currently, we are conducting a prospective phase III study (NCT04264936.) to investigate the safety and efficacy of this combination therapy. The encouraging outcomes seen so far suggest a promising avenue for exploring disitamab vedotin across different indications," Fang Jianmin, CEO and chief scientific officer of RemeGen, the developer of disitamab vedotin, stated in a press release.2
1. 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
2. ASCO 2023: RemeGen Exhibits Promising Results of Disitamab Vedotin in Bladder Cancer. Published online June 5, 2023. https://tinyurl.com/yc7mbews
3. RemeGen Announces US FDA Has Granted Breakthrough Therapy Designation for Disitamab Vedotin (RC48) in Urothelial Cancer. Posted online September 25, 2020. https://bit.ly/3n6jbYz.