Yusuf, Rushdia Z.

Background: Overall survival rates now exceed 90% for children, adolescents, and young adults with cHL, but patients with slow early response (SER) to front-line chemotherapy are at an increased risk of relapse. The approaches used historically to treat patients with SER included dose intensification and radiotherapy (RT), which can be associated with long-term toxicity. The open-label, phase 2 KEYNOTE-667study (NCT03407144) is designed to evaluate the efficacy and safety of consolidation with pembrolizumab plus chemotherapy with or without RT followed by pembrolizumab maintenance in patients with cHL and SER to front-line chemotherapy. The study includes 2 groups: patients with low-risk cHL (stage IA, IB, or IIA without bulky disease) and patients with high-risk cHL (stage IIEB-IVB). Prior analysis of the high-risk group showed that consolidation with pembrolizumab plus cyclophosphamide, vincristine, prednisone/prednisolone, and dacarbazine (COPDAC-28) followed by pembrolizumab maintenance had manageable safety and promising activity in patients with high-risk cHL and SER to front-line vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). Here, we present updated results for patients with high-risk cHL and SER to OEPA. Methods: Patients eligible for the high-risk group were aged 3-25 years and had newly diagnosed stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL; measurable disease; and a Lansky Play-Performance Scale (aged <16 years) or a Karnofsky Performance Status (aged ≥16 years) score of ≥50. All patients in the high-risk group received 2 cycles of OEPA followed by early response assessment (PET and CT/MRI). Patients with a rapid early response (ie, Deauville score [DS] 1-3) received nonstudy therapy. Patients with a SER (ie, DS 4 or 5) received consolidation therapy with pembrolizumab 2 mg/kg up to 200 mg (aged 3-17 years) or 200 mg (aged 18-25 years) IV Q3W plus COPDAC-28 for 4 cycles. Patients then underwent late-response assessment (LRA; PET and CT/MRI). Patients with PET-positive disease at LRA (ie, DS 4 or 5) received RT (28.8 Gy) to late PET-positive residua. Patients with PET-negative disease (ie, DS 1-3) received no RT. All patients received maintenance pembrolizumab for up to 17 cycles. The primary end point was objective response rate (ORR) by blinded independent central review (BICR) per Cheson 2007 IWG criteria. Secondary end points included the rate of PET negativity after consolidation and safety. Results: 84 patients with high-risk cHL and SER to front-line OEPA received consolidation with pembrolizumab plus COPDAC-28. Median time from treatment allocation to data cutoff (Feb 29, 2024) was 24.3 months (range, 5.7-48.4). As of the data cutoff, 55 patients had completed consolidation and maintenance therapy, 20 were ongoing, and 9 had discontinued treatment (due to adverse events [AE], n = 3; progressive disease, n = 2; withdrawal by patient, n = 2; complete response [CR], n = 1; physician decision, n = 1). Patients received a median of 17 doses of pembrolizumab (range, 2-17) and the median time on pembrolizumab was 11.1 months (range, 0.5-11.8). The median age of patients was 14 years (range, 4-22), 78 (93%) were aged 3-17 years, 45 (54%) were male, 44 (52%) had bulky disease, and 53 (63%) had Ann Arbor stage IV disease. Of 84 patients who received consolidation, 80 (95%) had an LRA. The ORR among these patients was 99% (95% CI, 93-100; 57 CR and 22 partial response). 56 patients (70%) with a LRA were PET negative by BICR; 55 (69%) were PET negative by investigator review and did not receive RT. Treatment-related AEs were reported in 61 patients (73%); grade 3 or 4 treatment-related AEs occurred in 16 patients (19%). Three patients (4%) discontinued treatment due to treatment-related AEs. No patients died due to treatment-related AEs. Immune-mediated AEs occurred in 10 patients (12%). Conclusion: After additional follow up, consolidation with pembrolizumab plus COPDAC-28 with or without RT followed by pembrolizumab maintenance continued to demonstrate promising activity and manageable safety in patients with high-risk cHL and SER to front-line OEPA. Among the 80 patients with an LRA, 70% were PET negative by BICR and 69% were PET negative by investigator review and were spared RT. These results continue to support pembrolizumab plus COPDAC-28 consolidation as a treatment option that may augment response in patients with high-risk CHL and SER to front-line OEPA.

Background: Cure rates for children, adolescents, and young adults with cHL are high, but patients with a slow early response (SER) to front-line chemotherapy are at an increased risk of relapse compared with patients who have a rapid early response (RER). To avoid long-term toxicity while optimizing outcomes, treatment for pediatric cHL is now shifting to a response-adapted approach. KEYNOTE-667 (NCT03407144) is an open-label phase 2 study designed to evaluate the efficacy and safety of pembrolizumab plus chemotherapy consolidation with or without radiotherapy (RT) followed by pembrolizumab maintenance in patients with cHL and SER to front-line chemotherapy. The study includes 2 groups of patients: those with low-risk cHL (stage IA, IB, and IIA without bulky disease) and those with high-risk cHL (stage IIEB-IVB cHL). Prior analysis of the low-risk group showed that consolidation with pembrolizumab plus doxorubicin, vinblastine, and dacarbazine (AVD) and RT followed by maintenance pembrolizumab had manageable safety and promising antitumor activity in patients with low-risk cHL and SER to front-line doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). We present updated results for patients with low-risk cHL and SER to ABVD. Methods: Patients eligible for the low-risk group were aged 3-25 years and had newly diagnosed stage IA, IB, or IIA cHL without bulky disease, measurable disease, and a Lansky Play-Performance Scale score of ≥50 (aged <16 years) or a Karnofsky Performance Status score of ≥50 (aged ≥16 years). All patients in the low-risk group received 2 cycles of ABVD followed by early response assessment (PET and CT/MRI). Patients with a RER (ie, Deauville score [DS] 1-3) received nonstudy therapy. Patients with SER (ie, DS 4 or 5) received consolidation with pembrolizumab 2 mg/kg up to 200 mg (aged 3-17 years) or 200 mg (aged 18-25 years) IV Q3W plus 2 cycles of AVD. Patients then underwent late response assessment (LRA; PET and MRI/CT). All patients with SER received involved-site RT: 21.6 Gy for complete PET response (ie, DS 1-3) or 30.6-36 Gy for partial PET response (ie, DS 4 or 5). All patients received maintenance pembrolizumab for up to 17 cycles. The primary end point was objective response rate (ORR) by blinded independent central review (BICR) per Cheson 2007 IWG criteria. Secondary end points included PET negativity after consolidation and safety. Results: 78 patients with low-risk cHL received front-line ABVD. As of the data cutoff date (February 29, 2024), 10 of 78 patients had SER to ABVD and received consolidation with pembrolizumab plus AVD; 4 had completed consolidation and maintenance, 1 was continuing to receive treatment, and 5 had discontinued because of complete response (CR). Median time from allocation to data cutoff was 19.9 months (range, 5.6-44.8). Patients had received a median of 11.5 doses of pembrolizumab (range, 5-17) and the median time on pembro was 7.4 months (range, 3.5-11.3). The median age of patients was 16 years (range, 7-20), 6 (60%) were male, and 8 (80%) had Ann Arbor stage II disease. Of 10 patients who received consolidation, all (100%) had an LRA. The ORR was 100% (95% CI, 69-100; 9 CR and 1 partial response). Six patients (60%) were PET negative by BICR. Seven patients (70%) were PET negative by investigator review, all of whom received a reduced dose of RT. During consolidation, treatment-related adverse events (AEs) were reported in 8 patients (80%); grade 3 or 4 treatment-related AEs occurred in 4 patients (40%). No patients discontinued or died due to treatment-related AEs. Seven patients (67%) had pembrolizumab-related AEs, 3 of whom (30%) had a grade 3 event (vomiting, lymphocyte count decreased, white blood cell count decreased). Immune-mediated AEs occurred in 3 patients (30%; all grade 1 or 2 hypothyroidism). Conclusion: After additional follow-up, consolidation withpembrolizumab plus AVD and RT followed by pembrolizumab maintenance continued to demonstrate promising activity and manageable safety in patients with low-risk cHL and SER to ABVD. Of patients with a LRA, 60% were PET negative by BICR; 70% of patients were PET negative by investigator review and received a reduced dose of RT. These results support further evaluation of pembrolizumab plus AVD consolidation as a treatment option for patients with low-risk CHL and SER to front-line ABVD.