Neoadjuvant mFOLFOXIRI chemotherapy with or without cadonilimab versus mFOLFOX6 alone in locally advanced colorectal cancer: A randomized phase II study (OPTICAL2).

Abstract

3599 Background: The current standard treatment for locally advanced rectal cancer is chemoradiotherapy (CRT) followed by total mesorectal excision (TME) . For locally advanced colon cancer, neoadjuvant FOLFOX is also an option. In the era of immunotherapy, several studies have explored the efficacy of CRT combined with immunotherapy treatment. However, no studies have yet investigated the efficacy and safety of chemotherapy combined with immunotherapy in locally advanced colorectal cancer. We aim to explore the efficacy of mFOLFOXIRI with or without cadonilimab (AK104) compared to mFOLFOX6 neoadjuvant chemotherapy in locally advanced colorectal cancer (LACRC). Methods: OPTICAL-2 was a randomized, phase II trial in patients with II/III rectal ancer and locally advanced colon cancer (T3 ≥5 mm or T4). Patients were randomly assigned (1:1:1 ) to 3 groups: preoperative mFOLFOXIRI plus AK104 for 6 cycles or mFOLFOXIRI for 6 cycles, or mFOLFOX6 alone for 6 cycles, followed by TME and adjuvant chemotherapy. The primary endpoint was pCR rate in mITT population, and the secondary endpoint was major pathological response (MPR) rate, 3-year disease-free survival, overall survival and safety. Results: From July 2023 to August 2024, 123 patients with LACRC were enrolled, with 41 patients in each group, including 22 colon cancer and 101 rectal cancer. As the data cutoff, 121 patients had underwent surgery (41 in mFOLFOXIRI plus AK104, 39 in mFOLFOXIRI group and 41 in mFOLFOX6 group). Preoperative radiotherapy was added after induction treatment in 5 (12.2%), 4 (9.7%) and 3 (7.3%) patients among the 3 groups. In the mITT analysis, the pCR rate was 26.8% vs. 15.4% vs. 9.8% among the 3 groups, respectively. The downstaging (ypStage 0 to 1) was 65.9%, 46.2% and 41.5%, respectively. The MPR rate was 68.3%, 48.7% and 43.9%, respectively. While in the PP analysis (completed 6 cycles of preoperative treatment), the pCR rates were 30.6%, 17.1%, and 10.8%, respectively. The downstaging was 63.8%, 45.7% and 37.8%, respectively. Safety assessments was generally well-tolerated. Conclusions: mFOLFOXIRI with AK104 demonstrated a higher pCR rate, downstaging rate and MPR rtae compared with FOLFOX chemotherapy in patients with LACRC. This study suggests that the combination of Intensified chemotherapy and dual immunotherapy may be a promising approach for improving treatment outcomes. Clinical trial information: NCT05571644 . Pathologic outcome and surgical parameters. Characteristics mFOLFOXIRI+AK104 (A) mFOLFOXIRI (B) mFOLFOX6 (C) P1 (A vs. C) mITT analysis n=41 n=39 n=41 pCR 11 (26.83%) 6 (15.38%) 4(9.76%) 0.046 ypStage 0-I 27 (65.9%) 18 (46.2%) 17 (41.5%) 0.026 MPR 28 (68.3%) 19 (48.7%) 18 (43.9%) 0.026 PP analysis n=36 n=35 n=37 pCR 11 (30.6%) 6 (17.1%) 4 (10.8%) 0.036 ypStage 0-I 23 (63.8%) 16 (45.7%) 14 (37.8%) 0.026 Footnote: pCR, pathological complete response; MPR, major pathological response.