daNIS-3: A phase II platform study of NIS793 and anti–PD-1 combined with standard of care (SoC) anti-cancer therapy for the second-line (2L) treatment (tx) of microsatellite-stable colorectal cancer (MSS CRC).

3529 Background: Despite advances in tx of MSS CRC including targeted tx, the prognosis remains poor. The daNIS-3 study (NCT04952753) evaluated efficacy and safety of anti-TGFß monoclonal antibody NIS793 (NIS) and anti-PD1 tislelizumab (TISLE) with SoC as 2L tx for MSS CRC patients (pts). Methods: This open-label, multicenter study included safety run-in (SRI) Arm 1a: NIS + SoC (bevacizumab [Bev] + FOLFIRI), Arm 1b: NIS + SoC (Bev + mFOLFOX6) followed by Arm 2a: NIS + TISLE + SoC (Bev + FOLFIRI), Arm 2b: NIS + TISLE+ SoC (Bev + mFOLFOX6) to determine NIS recommended phase 2 dose (RP2D) for expansion phase (EP). FOLFIRI and mFOLFOX6 were evaluated independently. While EP included same investigational arms as SRI (Arm 2b not opened for enrollment), additional SoC arm was added. Primary endpoint was progression-free survival (PFS) in EP; secondary endpoints were PFS for SRI, overall response rate (ORR), disease control rate (DCR), duration of response (DOR) and time to response (TTR) using RECIST V1.1, pharmacokinetics (PK), immunogenicity, safety, and tolerability. Based on data monitoring committee recommendation, study was terminated on 31-07-2023 due to unfavorable benefit-risk profile. Results: As of 20-01-2025, median (95% CI) PFS in EP was 5.1 months (mo) (3.6–5.7), 3.7 mo (2.2–5.6), and 7.4 mo (5.5–9.4) for Arms 1a&b, Arm 2a, and SoC, respectively (HR vs SoC [95% CI]: Arms 1a&b, 2.06 [1.34–3.18]; Arm 2a, 1.65 [0.90–3.02]). Secondary endpoints are summarized in Table. PK of NIS and other drugs were similar in EP and SRI. All pts were ADA negative at baseline and during the study. NIS RP2D for Arms 1a&b, and 2a was 2100 mg Q2W. In SRI and EP, overall adverse events (AEs) were comparable across all arms. In EP, grade ≥3 AEs were higher in Arm 1a (67.7%) and 1b (66.7%) compared to Arm 2a (55.2%) and SoC (58.7% & 42.9%). Higher incidence of serious AEs was reported in Arm 1a (49.2%) compared to Arm 2a (31%) and SoC (30.4% & 42.9%). Higher deaths were observed in Arm 1a (50.8%) and 1b (60.0%), mostly attributed to underlying malignancy (MSS CRC). Most common AEs of special interest of NIS were infusion-related reactions, hemorrhage, and skin toxicity, consistent with known safety profile of NIS. Conclusions: Overall AEs were comparable, but a higher incidence of grade ≥3 AEs vs SoC were observed. NIS arms showed a deleterious PFS outcome in MSS CRC pts. Clinical trial information: NCT04952753 . Secondary endpoints * SRIArms 1a (N = 13) & 1b (N = 9) SRIArms 2a (N = 10) & 2b (N = 8) EPArms 1a (N = 67) & 1b (N = 13) EPArm 2a (N = 29) SoC(N = 53) mPFS, mo (95% CI) 3.6 (1.9, 7.3) 2.1 (1.8, 4.3) – – – ORR, n (%) 1 (4.5) 0 7 (8.8) 4 (13.8) 8 (15.1) DCR, n (%) 14 (63.6) 8 (44.4) 53 (66.3) 19 (65.5) 42 (79.2) mDOR, mo (95% CI) 9.4 (NE, NE) NE 9.5 (4.0, NE) NE 11.1 (3.8, NE) mOS, mo (95% CI) 10.2 (5.8, 20.8) 11.0 (6.2, 15.7) 12.8 (8.0, 14.2) 10.9 (6.1, NE) NE (11.6, NE) *SoC+FOLFIRI/mFOLFOX6 presented together due to similar efficacy.