Efficacy and safety of cadonilimab combined albumin-paclitaxel, cisplatin and fluorouracil (APF) in neoadjuvant therapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC): Results from the CAPITAL trial

BackgroundNeoadjuvant therapy with Docetaxel, Cisplatin, and 5-FU (DCF) is established as the standard treatment for LA-ESCC as per JCOG1109. Immunotherapy for LA-ESCC has been rapidly explored. Cadonilimab (AK104), a first-in-class bispecific antibody targeting PD-1 and CTLA-4, has shown promising efficacy and tolerability. This study aimed to assess the efficacy and safety of AK104 combined with modified APF in neoadjuvant therapy for LA-ESCC.MethodsIn this prospective, single-arm, phase II clinical trial (NCT05947201), we enrolled patients (pts) aged 18-75 with histologically diagnosed with ESCC and primary lesion located within the thoracic esophagus (cT1N1-3M0/cT2-3N0-3M0, AJCC 8th). Pts received 2–3 cycles of neoadjuvant therapy with AK104 combined with modified APF (AK104 [day 1]: 10 mg/kg, nab-PTX [day 1/8]: 100 mg/m2, CDDP [day 1-3]: 20 mg/ m2, 5-FU [continuous infusion on days 1-5]: 600 mg/m2, every 3 weeks). Surgery was performed 4-6 weeks after the last cycle. The primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included major pathologic response (MPR), tumor regression grade, R0 resection rate, non-surgery-delay rate, event-free survival, disease-free survival, overall survival, and toxicities.ResultsTwenty-one pts were enrolled and received neoadjuvant therapy between May, 2023 and May, 2024, 11 of whom proceeded to surgical resection. The rate of pCR and MPR were 36% (4/11) and 54% (6/11), respectively. R0 resection rate was 100%, with all surgical procedures conducted as scheduled. No treatment-related death has occurred so far. Treatment-related adverse events (TRAEs) were observed in 80.9% (17/21) of pts, with 28.5% (6/21) experiencing grade ≥3 events. Immune related adverse events included skin rash (4 pts grade 1/2; 1 pt grade 3/4) and hypothyroidism (3 pts grade 1/2).ConclusionsAK104 combined with modified APF is a promising neoadjuvant treatment for resectable LA-ESCC, demonstrating antitumor activity and an acceptable safety profile. Meanwhile, long-term survival outcomes are pending further follow-up.Clinical trial identificationNCT05947201.Legal entity responsible for the studyThe authors.FundingAkeso Pharmaceuticals, Inc. provided the study drug AK104.DisclosureAll authors have declared no conflicts of interest.