Sintilimab (anti-PD-1) plus ifosfamide, carboplatin, and etoposide (ICE) in second-line classical Hodgkin lymphoma (cHL): Results of a multicenter, randomized, controlled, double-blind phase 3 study (ORIENT-21).

Abstract

7007 Background: Sintilimab monotherapy for cHL in third-line setting and beyond has been evaluated in a single-arm, phase 2 study ORIENT-1. Here, we present results of the phase 3 study ORIENT-21 evaluating sintilimab plus ICE versus placebo plus ICE as the second-line treatment for cHL. Methods: This study enrolled cHL pts who have failed first-line standard chemotherapy. The study has a safety run-in phase to enroll pts receiving sintilimab plus ICE, followed by a randomized phase in which pts were assigned in a 1:1 ratio to receive either sintilimab plus ICE (experimental arm) or placebo plus ICE (control arm) for 6 cycles. Patients without disease progression continued either sintilimab or placebo monotherapy. Stratification factors were age (<50 vs ≥50), disease status (relapsed vs refractory), and international prognostic score (IPS, <3 vs ≥3). Primary endpoint was complete remission rate (CRR) assessed by investigators according to Lugano 2014 criteria. Secondary endpoints included progression-free survival (PFS), duration of complete remission (DoCR) and safety. Results: As of Nov 21, 2024, 81 pts (ITT set: 10 in safety run-in, 34 in experimental arm, 37 in control arm) were enrolled (age≥50: 12.3%, IPS≥3: 18.5%, relapsed: 56.8%, refractory: 43.2%) with a median follow-up of 38.4 months (range: 0-58). In mITT set (randomized pts, n=71), significant higher CRR was observed in the experimental arm than the control arm (61.8% vs 32.4%, p=0.0295). Consistent results were also observed in ITT set (CRR: 61.4% vs 32.4%, p=0.0105). In mITT and ITT sets, median DoCR was not reached in sintilimab plus ICE (events in 28.6% and 22.2% pts), and was 20.7 months in placebo plus ICE. There were 16 pts in control arm switching to sintilimab monotherapy after disease progression. In ITT set, median PFS was not reached in sintilimab plus ICE (events in 34.1% pts), and was 9.0 months in placebo plus ICE (HR: 0.48, 95% CI: 0.23-1.00). Favorable PFS was observed in CR pts than non-CR pts with either sintilimab plus ICE (HR: 0.22, 95% CI: 0.08-0.63) or placebo plus ICE (HR: 0.15, 95% CI: 0.04-0.52). In safety set (n=80), all pts had treatment-emergent adverse events (TEAEs) while ≥grade 3 TEAEs occurred in 81.4% pts with sintilimab plus ICE (n=43) and in 97.3% pts with placebo plus ICE (n=37). Most common ≥grade 3 TEAEs were neutrophil count decreased (62.8% vs 70.3%), white blood cell count decreased (53.5% vs 64.9%) and platelet count decreased (51.2% vs 67.6%). TEAEs led to treatment discontinuation in both arms (18.6% vs 13.5%). No TEAE led to death. Conclusions: Sintilimab plus ICE significantly improved CRR and showed a trend of favorable PFS compared with placebo plus ICE. The safety profiles were manageable and no new safety signal was observed. Clinical trial information: NCT04044222 .