Preliminary results from a phase II study to evaluate the efficacy and safety of perioperative disitamab vedotin (RC48-ADC) plus cadonilimab (AK104, PD-1/CTLA-4 bispecific antibody) for HER2-expressing muscle-invasive bladder cancer (MIBC).

person Sujun Han Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China info_outline Sujun Han, Yong Zhang, Xiongjun Ye, Hongzhe Shi, Bolin Jia, Feiya Yang, Xingang Bi, Xin Wang, Wasilijiang Wahafu, Hongsong Bai, Linjun Hu, Nianzeng Xing

Authors person Sujun Han Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China info_outline Sujun Han, Yong Zhang, Xiongjun Ye, Hongzhe Shi, Bolin Jia, Feiya Yang, Xingang Bi, Xin Wang, Wasilijiang Wahafu, Hongsong Bai, Linjun Hu, Nianzeng Xing Organizations Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, Department of Urology, National Cancer Center & National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, Oncology, Shanxi Cancer Hospital, Taiyuan, China, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, General Internal Medicine, Beijing, China, Cancer Hospital of HuanXing ChaoYang District Beijing, Beijing, China, Urinary Surgery Center, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China Abstract Disclosures Research Funding Remegen Akesobio 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.