Disitamab Vedotin Plus Toripalimab Elicits Responses, Safety in Metastatic Urothelial Carcinoma

The combination of disitamab vedotin (RC48-ADC) with toripalimab (JS001) generated responses and displayed a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma, irrespective of HER2 expression, according to data from the phase 1b/2 RC48-C014 trial (NCT04264936) presented at the 2023 ASCO Annual Meeting.

Findings showed that at a median follow-up of 13.5 months, patients who underwent at least 2 tumor assessments (n = 41) experienced a confirmed investigator-assessed objective response rate (ORR) of 73.2% (95% CI, 57.1%-85.8%), including a complete response rate of 9.8%, a partial response rate of 63.4%, and a disease control rate of 90.2% (95% CI, 76.9%-97.3%).

Regarding safety, all patients experienced at least 1 treatment-related adverse effect (TRAE); however, the rate of grade 3 or higher TRAEs was 36.5%.

“Disitamab vedotin in combination with toripalimab had a good tolerance. Most of the TRAEs were grade 1/2. The most common TRAEs were increased aspartate transaminase [AST] and increased alanine transaminase [ALT],” lead study author Xinan Sheng, MD, of Peking University Cancer Hospital and Institute, in Beijing, China, and colleagues, wrote in a poster presentation of the data.

Disitamab vedotin is an anti-HER2 antibody-drug conjugate, and investigators hypothesized that adding it to immunotherapy with the anti–PD-1 antibody toripalimab could create a synergistic antitumor effect.

The investigator-initiated trial enrolled patients with treatment-naïve or previously treated unresectable, locally advanced or metastatic urothelial carcinoma. Key inclusion criteria included measurable lesions per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and tissue samples for the detection of PD-L1 and HER2.

During the dose-escalation portion of the study, patients received 1.5 mg/kg (n = 3) or 2.0 mg/kg (n = 3) of disitamab vedotin in combination with 3 mg/kg of toripalimab every 2 weeks. In the dose expansion, patients received the 2.0 mg/kg of disitamab vedotin plus 3 mg/kg of toripalimab. Treatment continued until disease progression or unacceptable toxicity. Notably, no dose-limiting toxicities were observed in the dose-escalation cohorts.

The primary end point of the trial was AEs. Secondary end points included ORR, progression-free survival (PFS), overall survival (OS), and pharmacokinetics.

The median age was 66.0 years (range, 42-76), 53.7% of patients were male, and 70.7% of patients had an ECOG performance status of 1. Histology included pure urothelial carcinoma (60.9%), other variants (23.9%), and urothelial carcinoma with squamous differentiation (9.8%). Metastatic lesions were observed in the lung, liver, and bone of 41.5%, 24.4%, and 22.0% of patients, respectively.

Moreover, 61.0% of patients had 0 prior lines of systemic therapy, and 39.0% had 1 or more.

HER2 expression of immunohistochemistry (IHC) 3+, IHC 2+, IHC 1+, and IHC 0 was seen in 12.2%, 46.3%, 34.1%, and 7.3% of patients, respectively. Notably, 68.3% of patients were PD-L1–negative. HER2 and PD-L1 expression groups included HER2 IHC 2+/3+ and PD-L1 positive (19.5%), HER2 IHC 2+/3+ and PD-L1 negative (39.0%), HER2 IHC 1+ and PD-L1 positive (9.8%), HER2 IHC 1+ and PD-L1 negative (24.4%), HER2 IHC 0 and PD-L1 positive (2.4%), and HER2 IHC 0 and PD-L1 negative (4.9%).

Additional data showed the 12-month PFS rate was 30.7% (95% CI, 16.6%-45.9%). The 12- and 24-month OS rates were 78.3% (95% CI, 60.9%-88.6%) and 63.2% (95% CI, 40.7%-79.1%), respectively. Notably, the median OS was not reached.

The median duration of response was 8.2 months, and the median PFS was 9.2 months. Notably, the median PFS for treatment-naïve patients was 9.0 months.

The confirmed ORR for patients with treatment-naïve locally advanced or metastatic urothelial carcinoma was 76%. The confirmed ORRs were 75.0%, 87.5%, 50%, 70%, 0%, and 50% for patients who were HER2 IHC 2+ or 3+/PD-L1 positive, HER2 IHC 2+ or 3+/PD-L1 negative, HER2 IHC 1+/PD-L1 positive, HER2 IHC 1+/PD-L1 negative, HER2 IHC 0/PD-L1 positive, and HER2 IHC 0/PD-L1 negative, respectively.

Regarding safety, the most common any-grade TRAEs reported in at least 20% of patients included increased AST (68.3%), increased ALT (63.4%), peripheral sensory neuropathy (61.0%), asthenia (61.0%), increased γ-glutamyl transferase (53.7%), hypertriglyceridemia (53.7%), and decreased appetite (51.2%).

Reference

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. 2023;41(suppl 16):4566. doi:10.1200/JCO.2023.41.16_suppl.4566