High Rates of Undetectable MRD By Phased-Seq on Interim and End of Treatment Timepoints in Untreated Advanced Stage Chl Treated with Pembrolizumab + AVD

Introduction

We previously reported initial (n=30) efficacy results of a frontline study of pembrolizumab + AVD (Lynch et al Blood 2023, ASH 2023) in classic Hodgkin lymphoma (CHL). Despite finding surprisingly high rates of positive interim and EOT PET/CT compared to historical data, observed outcomes were excellent. Herein we present updated clinical data for our full 50-patient study including interim and end of treatment (EOT) MRD testing by PhasED-Seq

Methods

We examined additional long-term follow up of patients with pembrolizumab combined with concurrent AVD in previously untreated CHL as previously described (NCT03331341). Samples were analyzed for ctDNA at baseline, post cycle 1 (if available), post cycle 2, and end of treatment. ctDNA levels were quantified as haploid genome equivalents/mL plasma using PhasED-Seq (Kurtz et al. Nat Biotech 2021).

Results

50 patients were enrolled between Feb 1, 2019, and Apr 13, 2023, with a median follow up of 3.1 years; 3-year PFS and OS were 98% and 100%, respectively. Among advanced stage patients (n=38), 3-year PFS and OS were 97% and 100%, respectively.

In patients where samples were available for analysis, baseline ctDNA was detectable in 11/12 (92%) of early-stage patients, and 36/37 (97%) of advanced stage patients. 7/8 (88%) early-stage patients had undetectable MRD (uMRD) at C3D1, and all cleared ctDNA by EOT and none have relapsed to date. Among advanced stage patients, 22/29 (76%) of samples at C2D1 and 29/35 (83%) samples at C3D1 had uMRD. In contrast, the PET CR rate at C3D1 in advanced stage patients was only 58%. At EOT, 31/34 (91%) advanced stage samples had uMRD compared to a PET CR rate of 73%. The only patient in the study to relapse had a negative interim PET but did not clear ctDNA at any timepoint. Two additional patients had minute amounts of ctDNA detectable at the end of treatment after levels dropped >20,000 fold when compared to baseline. Both patients have not relapsed 3 years and 14 months after completion of treatment, respectively. Some timepoints did not have plasma samples available, and no samples were drawn for sequencing during follow-up,

Conclusion

Pembrolizumab + AVD continues to demonstrate durable efficacy in previously untreated CHL. No patient who has cleared ctDNA as measured by PhasED-Seq has relapsed to date despite high rates of interim-PET and EOT PET positivity. The role of PhasED-Seq will be further examined in the upcoming Phase 2 MRD-adapted PRECISE-HL study in untreated advanced stage CHL.

Lynch:Merck: Honoraria; SeaGen, Foresight Diagnostics, Abbvie, Janssen: Consultancy; TG Therapeutics, Incyte, Bayer, Cyteir, Genentech, SeaGen, Rapt, Merck, Janssen: Research Funding. Alig:Foresight Diagnostics: Consultancy. Ujjani:AbbVie, Astrazeneca, Lilly, PCYC: Research Funding; Abbvie, Astrazeneca, Beigene, Genentech, Jansen, Lilly, Pharmacyclics: Honoraria. Poh:Incyte: Research Funding; Seagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Acrotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ipsen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dren Bio: Research Funding. Warren:Roche Diagnostics: Other: Travel Support. Smith:Kymera Therapeutics: Research Funding; Millenium/Takeda: Consultancy; De Novo Biopharma: Research Funding; Coherus Biosciences (spouse): Consultancy; Beigene: Consultancy, Research Funding; Merck Sharp and Dohme Corp: Research Funding; AstraZeneca: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Bayer: Research Funding; KITE pharma: Consultancy; Enterome: Research Funding; Epizyme: Consultancy; abbvie: Consultancy; BMS (spouse): Research Funding; ADC therapeutics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Ignyta (spouse): Research Funding; Karyopharm: Consultancy; Lumanity: Consultancy. Shadman:Vincerx, Janssen: Research Funding; Merck, Nurix, Fate Therapeutics, Eli Lilly, Kite Pharma, Bristol Myers Squibb: Consultancy; Koi Biotherapeutics: Current holder of stock options in a privately-held company; Bristol Myers Squibb (spouse): Current Employment; Morphosys/Incyte, Beigene, Genmab, AstraZeneca, Genentech, Abbvie: Consultancy, Research Funding. Till:Mustang Bio: Consultancy, Patents & Royalties, Research Funding; Bristol Myers Squibb: Research Funding. Alizadeh:Gilead: Consultancy; Forty Seven: Other: stock; Roche: Consultancy; CiberMed: Consultancy, Other: Scientific Co-founder; Foresight: Consultancy, Other: Scientific Co-founder; Pharmacyclics: Consultancy; CARGO Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; ADC Therapeutics: Consultancy; Adaptive Biosciences: Consultancy; BMS: Research Funding. Gopal:Merck: Consultancy, Honoraria, Research Funding; I-Mab bio: Research Funding; IgM Bio: Research Funding; Takeda: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; SeaGen: Research Funding; Teva: Research Funding; Genmab: Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Morphosys/Incyte: Consultancy, Honoraria; ADCT: Consultancy, Honoraria; Acrotech: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Compliment: Consultancy, Current holder of stock options in a privately-held company, Honoraria; Epizyme: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Caribou: Consultancy, Honoraria; Fresenius-Kabi: Consultancy, Honoraria; Scitek: Consultancy, Honoraria; Sana: Consultancy, Honoraria.