Abstract

e16591 Background: The current standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy (RC). However, more than 40% patients are ineligible for cisplatin-based chemotherapy. The adverse reactions, comorbidities and high recurrence rate also limited the implementation of neoadjuvant cisplatin-based chemotherapy. The combination application in perioperative of RC48-ADC and PD-1/CTLA-4 antibody may have synergistic anti-tumor effects and achieve more clinical benefit. Methods: This single arm, open-label, multicenter study evaluates the effectiveness and safety of disitamab vedotin (RC48-ADC), a humanized anti-HER2 antibody conjugated with monomethyl auristatin E, plus cadonilimab (AK104, PD-1/CTLA-4 bispecific antibody) 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 RC and RC48-ADC (2.0 mg/kg D1 Q3W, 6 cycles) + AK104 (10.0 mg/kg D1 Q3W, 14 cycles) of adjuvant treatment post-surgery. The primary end point was pathologic complete response (pCR, pT0N0M0). Secondary end points were pathologic downstaging rate, disease-free survival, overall survival, objective response rate, and safety. Results: As of January 2024, 18 (16 males, 2 Females) out of the planned 36 pts have been enrolled in the study with median age of 65.5 (44-80) years. HER2 expression was positive (IHC 2+ or 3+) in 84.6% pts, and PD-L1 positive (CPS ≥ 10) in 50%. Five pts had completed neoadjuvant therapy, and 2 pts (2/5) achieved partial response (PR), while 3 (3/5) stable disease (SD), with 100% (5/5) disease control rate (DCR). Four pts underwent RC and 1 refused, all 4 pts (100%) were pathologic downstaging to ≤ypT1N0M0, and 2 of them (2/4, 50%) achieved pCR who were both assessed as SD by imaging techniques before. The most common TRAEs in 14 pts who had undergone more than 1 cycle treatment was pruritus (35.7%). Two cases of Grade ≥3 TRAEs were observed (14.3%), a patient bearing background disease of hypertension experienced grade 4 myocarditis, and another patient with underlying renal insufficiency experienced grade 3 diarrhea. Conclusions: This is the first study to evaluate the effectiveness and safety in perioperative of HER2 targeting ADC plus PD-1/CTLA-4 bispecific antibody in HER2-expressing MIBCs. And neoadjuvant RC48-ADC combined with AK104 showed promising anti-tumor activity with high pCR rate and well tolerance in MIBC pts. More specific pathological assessment results and long-term survival data post adjuvant therapy are worth anticipating. Clinical trial information: NCT06074484 .