Updated results from a phase II study of perioperative disitamab vedotin (RC48-ADC) plus cadonilimab (AK104) for HER2-expressing muscle-invasive bladder cancer (MIBC).

4588 Background: Several current ongoing clinical trials have shown promising efficacy and safety of antibody-drug conjugates (ADCs) alone and in combination with immune checkpoint inhibitors (ICIs) as neoadjuvant treatment for patients with MIBC (ASCO 2024). Disitamab vedotin (RC48-ADC) is a novel humanized anti-HER2 ADC. RC48-ADC combined with cadonilimab (AK104), known as the PD-1/CTLA-4 bispecific antibody ICI, may have enhanced synergistic anti-tumor effects attributed to the mechanism of action and achieve more clinical benefit. Here, we report updated results from a phase II study of perioperative RC48-ADC plus AK104 in HER2-expressing MIBC (NCT06074484). Methods: This single-arm, open-label, multicentre study evaluates the efficacy and safety of RC48-ADC plus AK104 as a novel neoadjuvant and adjuvant therapy in patients (pts) with treatment-naïve HER2-expressing (immunohistochemistry, IHC 1+, 2+, 3+) MIBC (T2-T4a, N0-1, M0; ECOG PS score 0-1). Eligible pts received neoadjuvant RC48-ADC (2.0 mg/kg D1 Q2W, 4 cycles) + AK104 (6.0 mg/kg D1 Q2W, 4 cycles) followed by radical cystectomy and pelvic lymph node dissection (RC+PLND), and postoperative adjuvant RC48-ADC (2.0 mg/kg D1 Q3W, 6 cycles) + AK104 (10.0 mg/kg D1 Q3W, 14 cycles). The primary endpoint was pathologic complete response (pCR, pT0N0M0). Secondary endpoints were pathologic downstaging rate (pDS, yp≤T1N0), disease-free survival (DFS), overall survival (OS), objective response rate (ORR), and safety. Results: By January 2025, 43 pts had been successfully enrolled. Of these, 81.4% (35/43) were male and 18.6% (8/43) were female, with a median age of 65 years (range, 44-78). HER2 expression was positive (IHC 2+ or 3+) in 72.1% of pts and PD-L1 positive (CPS ≥ 10) in 34.9%. The pCR rate was 64.71% (22/34, 95% CI, 47.85-78.58) in all evaluable pts, 81.82% (9/11) in HER2 1+ and 56.57% (13/23) in HER2 2+/3+ pts, meanwhile 77.78% (14/18) in cT2, 30.00% (3/10) in cT3, and 83.33% (5/6) in cT4a/N1 pts. The overall pDS rate was 76.47% (26/34). Treatment-related adverse events (TRAEs) of any grade occurred in 90.7% of pts (39/43), with ≥ Grade 3 TRAEs in 18.6% (8/43), including fever, rash, bone marrow hypocellular, alanine aminotransferase increased, and immune-mediated myocarditis or pneumonitis. No Grade 4 or Grade 5 TRAEs occurred. At a median follow-up of 11.3 months (95% CI, 9.0-12.1), 2 pts had died, but the median DFS and OS were not reached which remained stable on study and would be updated. Conclusions: Neoadjuvant and adjuvant RC48-ADC plus AK104 demonstrated favorable efficacy and a manageable safety profile, supporting its potential as a valuable treatment modality for HER2-expressing MIBC. Long-term benefits and further understanding the role of this combination therapy in the perioperative setting of MIBC will be critical to advance treatment strategies. Clinical trial information: NCT06074484 .