Disitamab vedotin plus toripalimab shows promise for advanced urothelial carcinoma

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

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.

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:

• HER2 IHC (2+/3+), PD-L1 (+): 8 patients; 75% ORR
• HER2 IHC (2+/3+), PD-L1 (-): 16 patients; 87.5% ORR
• HER2 IHC (1+), PD-L1 (+): 4 patients; 50.0% ORR
• HER2 IHC (1+), PD-L1 (-): 10 patients; 70% ORR
• HER2 IHC (0), PD-L1 (+): 1 patient; 0% ORR
• HER2 IHC (0), PD-L1 (-): 2 patients; 50% ORR

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

References

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.