Pembrolizumab and Chemotherapy As First-Line Treatment of Patients with Newly Diagnosed Early Unfavorable or Advanced-Stage Classical Hodgkin Lymphoma: The Phase 2 Keynote-C11 Study

Background: Immunotherapeutic strategies targeting the PD-1/PD-L1 pathway have become part of standard of care for patients with classical Hodgkin lymphoma (cHL). Recent studies have investigated combinations of anti-PD-1 antibodies with conventional chemotherapy and demonstrated significant clinical benefits in the first-line setting. A phase 2 trial demonstrated that induction with pembrolizumab monotherapy followed by chemotherapy was highly effective and safe in patients with newly diagnosed, early unfavorable, or advanced-stage cHL (Allen PB et al. Blood. 2020;137[10]:1318-1326). The KEYNOTE-C11 open-label phase 2 study will build on this concept by evaluating the safety and efficacy of sequential pembrolizumab monotherapy and chemotherapy followed by pembrolizumab consolidation in adult patients with newly diagnosed, early unfavorable, or advanced-stage cHL.

Study Design and Methods: Patients must have newly diagnosed, histologically confirmed, untreated (no prior chemotherapy, immunotherapy, or other systemic therapy for cHL), early unfavorable cHL (Ann Arbor stage I/II plus ≥1 National Comprehensive Cancer Network unfavorable risk factor) or advanced-stage cHL (Ann Arbor stage III/IV) and measurable disease per Lugano 2014 classification. Approximately 140 patients will be enrolled. All patients will receive pembrolizumab 200 mg IV every 3 weeks (Q3W) for 3 cycles followed by PET to determine response to pembrolizumab monotherapy. After pembrolizumab induction, all patients will receive 2 cycles of AVD (day 1 and day 15 Q4W) and undergo another assessment by PET (PET 3) to determine the next treatment course. Patients with negative findings on PET 3 (≤3 on the Deauville 5-point scale) will receive 2-4 additional cycles of AVD, depending on stage and bulk of disease; those with nonbulky early unfavorable disease will receive 2 cycles, and all others will proceed to 4 cycles of AVD chemotherapy. Patients who are PET 3+ (≥4 on the FDG-PEG 5-point scale) and aged <60 years will transition to 2-4 cycles of escBEACOPP; those with nonbulky early unfavorable disease will receive 2 cycles, and all others will receive 4 cycles. Patients aged ≥60 years who are PET 3+ will not transition to escBEACOPP and will continue to receive AVD. Finally, all patients will receive 4 cycles of pembrolizumab 400 mg Q6W after the completion of chemotherapy. They will remain on study treatment until disease progression, unacceptable toxicity, illness preventing continuation, investigator's decision, or maximum duration of treatment, which will include 4 cycles of pembrolizumab consolidation. Adverse events will be graded per CTCAE version v5.0. The primary end point is complete response assessed by blinded independent central review (BICR) per Lugano 2014 response criteria. Secondary end points include complete response by investigator per Lugano 2014 response criteria, BICR-assessed PET negativity (score of 1, 2, or 3 per FDG-PET 5-point scale), BICR-assessed duration of complete response per Lugano 2014 response criteria, and safety and tolerability. Exploratory end points include modified progression-free survival and overall survival. The efficacy and safety analysis population will consist of all patients who received ≥1 dose of pembrolizumab. The complete response rate with 95% CI will be reported per the Clopper-Pearson exact binomial method. Duration of complete response, progression-free survival, and overall survival will be evaluated using Kaplan-Meier method. Counts and percentages of patients with adverse events will be provided.