Pembrolizumab and Chemotherapy in Newly-Diagnosed, Early Unfavorable or Advanced Stage Classic Hodgkin Lymphoma: The Phase 2 Keynote-C11 Study

Introduction: In a recent study, pembrolizumab followed by doxorubicin, vinblastine, and dacarbazine (AVD) had promising efficacy in patients (pts) with newly-diagnosed, early unfavorable, or advanced-stage classic Hodgkin lymphoma (cHL) (Allen et al. 2021; Blood 137:1318-26). The current phase 2 KEYNOTE-C11 study (NCT05008224) evaluates the safety and efficacy of pembrolizumab followed by AVD chemotherapy and pembrolizumab consolidation in pts with untreated, early unfavorable or advanced-stage cHL without radiotherapy. Here, we present results of a protocol-specified interim efficacy analysis.

Methods: Eligible pts aged ≥18 years with newly-diagnosed, early unfavorable or advanced stage cHL received induction with pembrolizumab 200 mg IV on d1 every 3 weeks (Q3W) for 3 cycles. Pembrolizumab monotherapy was followed by PET2 to assess response. All pts then received 2 cycles of standard dose AVD on d1 and 15 for 2 cycles (chemotherapy phase 1), followed by PET3. PET3-negative pts (Deauville score 1-3) received 2-4 additional cycles AVD based on stage/bulk. Pts aged ≤60 yrs who were PET3-positive (Deauville score 4-5) received 2-4 cycles of escalated bleomycin plus etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (esc BEACOPP, chemotherapy phase 2). At the end of chemotherapy, all pts received consolidation with 4 cycles pembrolizumab 400 mg Q6W. A post-hoc interim analysis was performed for pts who had either reached or had discontinued treatment prior to PET3 response assessment. The primary analysis endpoints for this interim analysis were PET3 response (negativity rate) by investigator. The data cutoff date for the interim analysis reported here is July 15, 2022.

Results: A total of 146 pts with untreated cHL were enrolled. The median (range) age was 34.5 yrs (18-78); 29 (20%) pts had bulky disease, 81 (55%) and 61 (42%), respectively, had advanced and early unfavorable disease, and 4 (3%) had missing data regarding disease group. At data cut-off, the median (range) follow-up was 3.2 mo (1.0-8.9). Of 146 pts, 46 (32%) were on pembrolizumab monotherapy, 42 (29%) were on chemotherapy phase 1, 34 (23%) were on chemotherapy phase 2, and 7 pts were on pembrolizumab consolidation. A total of 101 pts reached PET2 assessment or discontinued pembrolizumab monotherapy for any reason before PET2. Of these 26 (26%) were PET2-negative by investigator, 53 (52%) were PET2-positive, 9 (9%) discontinued treatment, and 13 (13%) had missing data. A total of 56 pts reached PET3 assessment or discontinued during chemotherapy phase 1. Of these, 38 (68%) were PET3-negative, 4 (7%) were PET3-positive, 11 (20%) had discontinued treatment, and 3 (5%) pts had missing data. Adverse events (AEs) of any grade occurred in 108 of 146 (74%) pts who received pembrolizumab monotherapy or consolidation, 63 of 89 (71%) who received AVD, and 1 of 2 (50%) who received BEACOPP. Grade ≥3 drug related adverse events were reported in 20 of 146 (14%) pts who received pembrolizumab monotherapy or consolidation, 48 of 89 (54%) pts who received AVD, and in 1 of 2 pts who received escBEACOPP. There were no deaths due to drug-related events. Immune mediated events were reported in 28 (19%) pts who received pembrolizumab monotherapy or consolidation. Most were low-grade 1-2 events reported in 20 (14%) pts, most commonly hyperthyroidism (5%) and hypothyroidism (3%). There were no deaths due to immune-mediated events.

Conclusion: Pembrolizumab induction followed by chemotherapy was well tolerated in pts with newly-diagnosed, early unfavorable, or advanced-stage cHL, with 26% of pts achieving a PET2-negative response following the initial course of pembrolizumab alone and 68% having a PET3-negative response as assessed by investigator following the initial chemotherapy phase. Data from this PET-adapted regimen show promising antitumor activity and no safety concerns mid-treatment, indicating that this regimen may be an effective treatment option in this patient population. Data from the full preplanned protocol-specified interim futility analysis will be presented at the meeting.

Advani:ADC Therapeutics, Cyteir, Daiichi Sankyo, Gilead, Merck, Regeneron, Roche, Seattle Genetics: Research Funding; ADC Therapeutics, BMS, Daiichi Sankyo, Epizyme, Gilead, Incyte, Merck, Roche, Sanofi: Consultancy. Avigdor:Takeda, Gilead, Novartis, Roche, BMS: Consultancy; AbbVie: Honoraria. Sureda:ROCHE: Consultancy, Honoraria; MSD: Honoraria; JANSSEN: Consultancy, Honoraria; BMS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria; SANOFI: Consultancy, Honoraria; TAKEDA: Consultancy, Honoraria, Speakers Bureau; GILEAD: Consultancy. Hohaus:Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Zaucha:Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; BMS: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Zilioli:Gentili: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: travel expenses, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Speakers Bureau. Gazitua:Janssen: Other: Support for attending meetings and/or travel; Abbvie: Other: Support for attending meetings and/or travel; Roche: Other: Support for attending meetings and/or travel. Özcan:Roche: Other: travel expenses, Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Jazz: Other: Travel expenses, Research Funding; Bayer: Research Funding; MSD: Research Funding; Janssen: Research Funding; AbbVie: Other: travel expenses, Research Funding; Reddy's: Research Funding; Acerta: Research Funding. Odeleye-Ajakaye:Merck & Co., Inc.: Current Employment, Current holder of stock options in a privately-held company. Ogbu:Merck & Co., Inc.: Current Employment, Current equity holder in publicly-traded company. Nahar:Merck & Co., Inc.: Current Employment. Winter:Daiichi Sankyo: Other: for Spouse, to the University of Chicago, Research Funding; Forty Seven/Gilead: Other: For Spouse, to University of Chicago, Research Funding; Astellas: Other: For Spouse, to University of Chicago, Research Funding; Rafael: Other: For Spouse, to University of Chicago, Research Funding; CVS/Caremark: Consultancy, Other: For Spouse; Servier: Consultancy, Other: For Spouse; Cellectis: Other: for Spouse, to the University of Chicago, Research Funding; Novartis: Consultancy, Other: for Spouse, to the University of Chicago, Research Funding; Merck & Co., Inc.: Honoraria, Research Funding.