SI-B003 (PD-1/CTLA-4) in patients with advanced solid tumors: A phase I study

e14668 Background: Although marketed antibodies against PD-1/L1 or CTLA-4 have been shown to be efficacious in a variety of tumors, the overall response rate (ORR) remains low. SI-B003 is a PD-1/CTLA-4 bispecific antibody. We hypothesized that co-targeting PD-1 and CTLA-4 simultaneously could achieve a better anti-tumor activity due to cooperative binding to exhausted T-cell subsets. Methods: Patients with recurrent or metastatic solid tumors who had failed standard therapy were eligible to participate. SI-B003 was administered intravenously every other week (Q2W) in a four-week cycle. The phase Ia dose escalation consisted of an accelerated titration phase (the first 2 dose levels) and a mTPI-2 with a total of five dose levels: 0.1, 0.3→1.0, 3, 5 and 10 mg/kg. The phase Ib consisted of a dose expansion and indication expansion cohorts with 5, 10 mg/kg Q2W and 7.5mg/kg Q3W. The primary objectives of phase Ia were to assess dose-limiting toxicity (DLT), maximum tolerated dose (MTD) or maximum administration dose (MAD), and treatment emergent adverse events (TEAEs). The primary objectives of phase Ib included safety, tolerability, and identification of the recommended phase 2 dose (RP2D). Results: As of December 31, 2022, 60 patients with solid tumors received SI-B003 at six different dose levels (14 in Ia, 46 in Ib). Median age was 55.5 years. The median PFS (95%CI) was 3.7 (1.6~5.7) months. Among 56 evaluable patients, the objective response rate (ORR) (n/N, 95%CI) was 16.1% (9/56, 7.6~28.3%) and disease control rate (DCR) was 50.0% (28/56). Confirmed ORR, DCR, median duration of response (DoR) and median progression free survival (PFS) were 9.5% (2/21, 1.2~30.4%), 42.9% (9/21), NR and 2.1 (95%CI, 1.4~NA) months in the 5mg/kg Q2W group and 8.3% (2/24, 1.0~27.0%), 62.5% (15/24), 7.1 (95%CI, 1.9~NA) and 5.7 (95%CI, 1.9~8.7) months in 10mg/kg Q2W group respectively. One patient received 7.5mg/kg Q3W had a confirmed response and was still under treatment. Among 21 evaluable patients who had received prior PD-1/L1 treatment, the ORR and DCR were 14.3% (3/21, 3.1~36.3%) and 52.4% (11/21). The mDoR (95%CI) and mPFS (95%CI) were 4.2 (NA) months and 4.1 (1.4, 5.7) months. The most common TRAEs were rash (35%), AST increased (28%), ALT increased (28%). The most common grade ≥3 TRAEs were AST increased (3%). One patient died from an immune-mediated pneumonia. Conclusions: SI-B003 demonstrated a tolerable safety profile and preliminary anti-tumor activity in patients with recurrent or metastatic solid tumors. Anti-tumor effects of SI-B003 were observed in patients who had progressed on prior PD-1/L1 immunotherapy suggesting that SI-B003 may be beneficial for patients who have developed resistance to PD-1/L1 drugs. Clinical trial information: NCT04606472 .