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3051 High Rates of Undetectable MRD By Phased-Seq on Interim and End of Treatment Timepoints in Untreated Advanced Stage Chl Treated with Pembrolizumab + AVD

Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphomas: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Hodgkin lymphoma, Research, Clinical trials, Lymphomas, Clinical Research, Diseases, Lymphoid Malignancies, Measurable Residual Disease
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Ryan C Lynch, MD1, Stefan K. Alig, MD2, Chaitra S. Ujjani, MD1, Christina Poh, MD1, Edus H. Warren, MD, PhD1, Stephen D. Smith, MD1, Mazyar Shadman, MD, MPH1, Brian G. Till, MD3, Vikram Raghunathan, MD1*, Yolanda D Tseng, MD4*, Susan Ottemiller1*, Bonnie Joy1*, Melissa Mary Fessel, ANP, BSN, RN1*, Hongyan Du1*, Jacquelin Vandermeer, BS1*, Alyssa Kelly1*, Heather Rasmussen1*, Jenna M. Voutsinas, MPH5*, Ash A. Alizadeh, MD, PhD6 and Ajay K. Gopal, MD1

1Fred Hutchinson Cancer Center, Seattle, WA
2Stanford University, Stanford, CA
3Fred Hutchinson Cancer Center, University of Washington, Seattle, WA
4Department of Radiation Oncology, University of Washington and Fred Hutch Cancer Center, Seattle, WA
5Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA
6Department of Medicine, Divisions of Oncology and Hematology, Stanford University, Stanford, CA

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.

Disclosures: 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: Dren Bio: Research Funding; Astex: Research Funding; Ipsen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Seagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Acrotech: Consultancy, Membership on an entity's Board of Directors or advisory committees. 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: Bristol Myers Squibb: Research Funding; Mustang Bio: Consultancy, Patents & Royalties, Research Funding; Proteios Technology: Consultancy, Honoraria. 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.

*signifies non-member of ASH