Background: Patients (pts) with cHL with SER to initial chemo are at higher risk of relapse, and chemo dose intensification and radiotherapy (RT) can increase the burden of late organ toxicities. The open-label, phase 2 KEYNOTE-667 study (NCT03407144) is evaluating pembro plus chemo in pts with cHL and SER to front-line chemo. Results of an interim analysis in pts with high-risk cHL (group 2) and SER are presented. Methods: Pts were aged 3-17 (children) or 18-25 y (young adults) with newly diagnosed stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL. Pts received induction with 2 cycles of vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). Response was assessed after induction (early) and consolidation (late) therapy by PET/MRI/CT. After induction, pts with rapid early response at the early response assessment (ERA) received nonstudy therapy and pts with SER at ERA received consolidation with 4 cycles cyclophosphamide, vincristine, prednisone/prednisolone, dacarbazine (COPDAC-28) plus pembro 2 mg/kg up to 200 mg IV every 3 weeks (Q3W; aged 3-17 y) or 200 mg IV Q3W (aged 18-25 y). Pts with PET positivity (Deauville score 4-5) after consolidation (late response assessment [LRA]), received involved-site RT (28.8 Gy) to late PET-positive residua; RT was omitted in pts with PET negativity. All pts with SER received maintenance pembro Q3W for a total of 17 doses. Primary end point was ORR by blinded independent central review (BICR) per Cheson 2007 International Working Group criteria in pts with SER. Secondary end points included PET negativity after consolidation and safety. Results: At data cutoff (Sep 02, 2022), median follow-up was 15.3 mo (range, 3.2-30.5); 49 pts with high-risk cHL with SER were included. Median age was 15 y (range, 6-22), 24 (49%) pts had bulky disease, and 31 (63%) had Ann Arbor stage IV disease. 22 (45%) pts completed treatment and 24 (49%) were ongoing on consolidation/maintenance treatment. Median time on pembrolizumab was 10.4 mo (range, 0.5-11.8). 42 (86%) of 49 pts had a LRA, of whom 27 (64%) were PET negative by BICR (30 [71%] PET negative by investigator). All-cause adverse events (AEs) occurred in 42 (86%) pts, with 30 (61%) having a treatment-related AE. Grade ≥3 AEs occurred in 13 (27%) pts, with 7 (14%) having a serious AE. Grade ≥3 treatment-related AEs occurred in 6 (12%) pts. 4 (8%) pts had immune-mediated AEs (2 grade 1 hypothyroidism; 2 grade 2 hypothyroidism). Conclusions: In pediatric pts with high-risk cHL and SER to standard OEPA induction, pembro plus COPDAC-28 consolidation had manageable safety and resulted in 64% of pts having a PET-negative response at end of chemo and being spared RT. These results suggest adding pembro to COPDAC-28 consolidation may augment responses in this high-risk population. Clinical trial information: NCT03407144.