A phase I dose-escalation study to evaluate safety and feasibility of neoadjuvant camrelizumab with palbociclib for the treatment of resectable esophageal squamous cell carcinoma (ESCC).

e16114 Background: Immune checkpoint inhibitors (ICIs) have enhanced treatment outcomes for patients with esophageal squamous cell carcinoma (ESCC) in both advanced and perioperative stages. However, existing evidence suggests that the efficacy of combination strategies for neoadjuvant immunotherapy remains contentious. CDK4/6 inhibitors have demonstrated potential efficacy in preclinical ESCC models in our published study (Liu et al., Cancer Cell 2023). Moreover, our previous preclinical research revealed that CDK4/6 inhibitors can synergize with ICIs (Deng et al., Cancer Discov. 2018). Thus, we designed a phase I clinical study to perform neoadjuvant treatment for resectable ESCC patients using the PD-1 inhibitor camrelizumab in combination with CDK4/6 inhibitor palbociclib. Methods: Patients with resectable ESCC were enrolled in a 3+3 dose escalation phase 1 study and treated with palbociclib and camrelizumab before radical surgery. Camrelizumab will be given twice at a dosage of 200 mg every three weeks on day 23 within a scheduled 28-day cycle. Patients were orally administered palbociclib at a dose of 100/125 mg every day, following a schedule of three weeks on and one week off for three cycles. The primary endpoints of this trial are to evaluate the safety and feasibility of neoadjuvant camrelizumab with palbociclib for the treatment of resectable ESCC. Safety will be evaluated through assessing the number of participants who experience adverse events by CTCAE version 5.0 criteria. Results: Six patients with resectable ESCC were enrolled and treated with palbociclib at dosages of 100 mg (n = 3) and 125 mg (n = 3). In the 100mg palbociclib group, 2 of 3 patients developed treatment-related adverse events (TRAEs), including leukopenia(n = 2), thrombocytopenia(n = 1) and elevated AST/ALT(n = 1). No Grade ≥3 TRAEs were observed in this group. In the 125 mg palbociclib group, 2 out of 3 patients experienced TRAEs, including leukopenia (n = 2), thrombocytopenia (n = 1), and pruritus (n = 1). One patient in this group developed Grade ≥3 leukopenia. All patients finished the study treatment and achieved R0 surgical resection. In the 100 mg group, 1 of 3 patients had a partial response (PR), while 2 patients had stable disease (SD). In the 125 mg palbociclib group, 2 of 3 patients achieved PR, and 1 had SD. All 6 patients exhibited a postoperative pathological assessment of TRS2. Based on a comprehensive evaluation of TRAEs and therapeutic efficacy, the recommended Phase 2 dose of palbociclib was determined to be 125 mg. Conclusions: Neoadjuvant combination treatment of camrelizumab and palbociclib showed promising efficacy and safety in patients with resectable ESCC. An RP2D of 125 mg dosage of palbociclib in combination was selected to be explored in further phase II study. Clinical trial information: NCT06654297 .