S204: pembrolizumab in children and young adults with newly diagnosed classical hodgkin lymphoma with slow early response to frontline chemotherapy: the phase 2, open-label, keynote-667 study

Background: Patients with classical Hodgkin lymphoma (cHL) with slow early response (SER) to initial chemotherapy (chemo) are at higher risk of relapse, and the burden of late organ toxicities may be higher after dose intensification and radiotherapy (RT). The phase 2, open-label KEYNOTE-667 (NCT03407144) study is evaluating the efficacy and safety of pembrolizumab (pembro) plus chemo in patients with cHL and SER to frontline chemo. Aims: To present results of an interim analysis of efficacy and safety in patients with high risk cHL (Group 2) who were SER. Methods: In Group 2, eligible patients aged 3-17 (children) or 18-25 years (young adults) with newly-diagnosed stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL were enrolled to receive induction with vincristine, etoposide, prednisone/prednisolone, doxorubicin (OEPA) for 2 cycles. Response assessment after induction (early) and consolidation (late) therapy was done by PET/MRI/CT. After induction treatment, patients with rapid early response (RER) received non-study therapy and patients with SER received consolidation with 4 cycles cyclophosphamide, vincristine, prednisone/prednisolone, dacarbazine (COPDAC-28) plus pembro 2 mg/kg up to 200 mg IV Q3W (3-17 years of age) or 200 mg IV Q3W (18-25 years of age). After consolidation therapy, patients with PET-positivity (Deauville score 4-5) received modified involved-site RT to late PET-positive residua; RT was omitted in patients with PET-negativity. All patients with SER received maintenance pembro Q3W, for a total of 17 doses. Safety analyses included all patients with SER treated with pembro, while efficacy analyses was based on all patients who had completed late response assessment. All patients provided informed consent. The primary endpoint was ORR by BICR per Cheson 2007 IWG criteria in patients with SER. Secondary endpoints included rate of PET-negativity after consolidation, details of RT, and safety. Data cut-off was Nov 22, 2021. Results: At data cut-off, median (range) follow-up was 9.6 mo (2.5-21.2). A total of 30 patients with high-risk cHL with SER were included. Median (range) age was 15y (6-19), 13 (43%) had bulky disease, 19 (63%) had Ann Arbor stage IV disease. A total of 6 (20%) patients had completed, and 24 (80%) were ongoing on treatment, with median time on treatment of 3.3 mo (range, 0-11.8). Of 30 patients, 25 (83%) had a late response assessment, of which 17 (68%) were PET-negative by BICR; 18 (72%) PET-negative by investigator. All cause AEs occurred in 23 (77%) patients, with 14 (47%) having a treatment-related AE. Grade ≥3 AEs occurred in 6 (20%) patients, with 3 (10%) having an SAE. Grade ≥3 treatment-related AEs occurred in 2 (7%) patients. One (3%) pt had a grade 2 immune-mediated AE of hypothyroidism. Summary/Conclusion: In pediatric patients with high-risk cHL and SER to standard OEPA induction, pembro in combination with COPDAC 28 consolidation therapy was well tolerated and resulted in 68% of patients having a PET-negative response at end of chemo, and being spared RT. This early data suggests that addition of pembro potentially may have the ability to augment responses in this high-risk subgroup of patients.