SKYGLO: A Global Phase III Randomized Study Evaluating Glofitamab Plus Polatuzumab Vedotin + Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) Versus Pola-R-CHP in Previously Untreated Patients with Large B-Cell Lymphoma (LBCL)

Background and Significance: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is a standard first line (1L) therapy for DLBCL but only ~60% of patients (pts) achieve durable remissions. Recently, Pola-R-CHP became the first therapy to be approved by the FDA for 1L treatment of DLBCL in ~20 years, and demonstrated a significant progression-free survival (PFS) benefit (hazard ratio: 0.73; 95% confidence interval 0.57-0.95; p=0.02) over R-CHOP (Tilly, et al. NEJM 2022). Glofitamab is a CD20xCD3 T-cell-engaging bispecific antibody that redirects T-cells to eliminate B-cells and has shown durable responses in pts with relapsed/refractory (R/R) DLBCL (Dickinson, et al. NEJM 2022). Glofitamab is approved in pts with R/R LBCL after ≥2 prior lines of therapy based on data from study NCT03075696. In an ongoing Phase Ib trial (NP40126; NCT03467373), treatment with glofitamab in combination with Pola-R-CHP demonstrated promising efficacy in untreated pts with DLBCL, with a complete metabolic response rate of 91.7%. The safety profile was manageable, and dose intensity was maintained for all glofitamab and Pola-R-CHP components (Topp, et al. ASH 2023. Poster 3085). Glofitamab plus Pola-R-CHP also demonstrated promising efficacy and safety in the Phase I/II COALITION study in pts with high-risk 1L DLBCL (Minson, et al. Hemasphere 2023). Here, we describe the study design of SKYGLO (GO44145; NCT06047080), a Phase III, multicenter, randomized, open-label trial evaluating the efficacy and safety profile of glofitamab plus Pola-R-CHP versus Pola-R-CHP alone in pts with previously untreated CD20-positive LBCL.

Study Design and Methods: Eligible pts are those with previously untreated CD20-positive LBCL according to the 2022 World Health Organization classification of lymphoid neoplasms. Other key eligibility criteria include age 18-80 years, ≥1 bi-dimensionally measurable lesion (>1.5cm in its longest dimension), an International Prognostic Index score of 2-5 and an Eastern Cooperative Oncology Group performance status of 0-2. Key exclusion criteria include current diagnosis of follicular lymphoma grade 3B; transformations of indolent B-cell lymphomas; or active viral infections (including SARS-CoV-2). Approximately 1130 pts will be randomized 1:1 to receive glofitamab plus Pola-R-CHP or Pola-R-CHP alone. Treatment will be administered over 8 cycles of 21 days each. Pts in the glofitamab plus Pola-R-CHP group will receive glofitamab during Cycles (C) 2-8, using a step up-dosing schedule, and Pola-R-CHP in C1-6. Pts in the Pola-R-CHP group will receive Pola-R-CHP during C1-6 and rituximab in C7-8. The primary endpoint is PFS as determined by Independent Review Facility, defined as the time from randomization to the first occurrence of disease progression or relapse, or death due to any cause, whichever occurs first. Treatment comparisons for the primary endpoint, performed in all randomized pts, will be made using a two-sided level 0.05 stratified log-rank test. Secondary endpoints include PFS as determined by the investigator; event-free survival (time from randomization to disease progression, death, initiation of new treatment or positive biopsy for residual disease); objective and complete response (CR) rate at the end of treatment or discontinuation; duration of response; duration of CR; overall survival (OS); disease-free survival; PFS and OS in pts classified as high-risk according to ctDNA; glofitamab pharmacokinetic profile; immunogenicity; and safety. All responses and time-to-event outcomes will be determined according to Lugano criteria (Cheson, et al. J Clin Oncol 2014). Safety endpoints include incidence and severity of adverse events (AEs) as defined by the National Cancer Institute Common Toxicity Criteria for Adverse Events v5.0 (including cytokine release syndrome graded per the American Society for Transplantation and Cellular Therapy [Lee, et al. Biol Blood Marrow Transplant 2019]), and tolerability as assessed by dose interruptions, reductions, study discontinuation and dose intensity. Pts will be enrolled from approximately 260 sites globally. Enrollment began in September 2023.

Advani:Seattle Genetics: Research Funding; Cyteir: Research Funding; Regeneron: Research Funding; Autolus: Honoraria, Other: DSMB/Advisory Boards; Gilead: Research Funding; Merck: Other: Steering committee, DSMB/Advisory Boards, Research Funding; ADCT: Honoraria, Other: DSMB/Advisory Boards; BeiGene: Honoraria, Other: DSMB/Advisory Boards, Research Funding; Roche/Genentech: Honoraria, Other: Steering committee, DSMB/Advisory Boards, Research Funding. Dickinson:Gilead: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Kite: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; Adicet Bio: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Fox:AbbVie, AstraZeneca, Atarabio, BMS, GenMab, Gilead/Kite, Incyte, Janssen, Lilly, Morphosys, Ono, Roche, SERB, SOBI, Takeda: Consultancy, Honoraria; BeiGene, AbbVie: Research Funding. Kahl:BMS, BeiGene, Lilly, Kite, AZ, AbbVie, Merck, Novartis, Genentech, Roche, ADCT: Consultancy; AstraZeneca, BeiGene, Roche: Research Funding. Herrera:Regeneron: Consultancy; Tubulis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Adicet Bio: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Allogene Therapeutics: Consultancy; AbbVie: Consultancy; KiTE Pharma: Research Funding; Karyopharm: Consultancy; Pfizer: Consultancy; Caribou Biosciences: Consultancy; Merck: Consultancy, Research Funding; Gilead Sciences: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; AstraZeneca: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Genmab: Consultancy. Lenz:Constellation: Honoraria; AbbVie, BeiGene, Sobi, Roche, Gilead, BMS: Other: Travel; Roche, Gilead, BMS, Novartis, AstraZeneca, Abbvie, Incyte, Genmab, Constellation, ADC Therapeutics, Miltenyi, PentixaPharm, Sobi, Immagene, Genase, Hexal-Sandoz, Lilly, Beigene, MSD, Pierre Fabre: Membership on an entity's Board of Directors or advisory committees; ELVESCA: Current equity holder in private company; Roche, Gilead, BMS, Novartis, AstraZeneca, Abbvie, Incyte, Genmab, Constellation, ADC Therapeutics, Miltenyi, PentixaPharm, Sobi, Immagene, Genase, Hexal-Sandoz, Lilly, Beigene, MSD, Pierre Fabre: Consultancy; Acerta: Research Funding; Sobi: Honoraria, Speakers Bureau; Pierre Fabre: Honoraria; PentixaPharm: Honoraria; NanoString: Honoraria; MSD: Honoraria; Miltenyi Biotech: Honoraria; Lilly: Honoraria; Karyopharm: Honoraria; Incyte: Honoraria; Immagene: Honoraria; Hexal/Sandoz: Honoraria; Genmab: Honoraria; Genase: Honoraria; Verastem: Research Funding; ADC Therapeutics: Honoraria; AbbVie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; MorphoSys: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BeiGene: Honoraria; BMS: Honoraria; AstraZeneca: Honoraria, Research Funding; AGIOS: Research Funding; AQUINOX: Research Funding; Celgene: Honoraria, Research Funding; Bayer: Honoraria, Research Funding. Tao:Fudan University Shanghai Cancer Center: Current Employment. Kim:IMBDx Inc: Honoraria; Daiichi Sankyo, HK inno.N, F. Hoffmann-La Roche Ltd/Genentech, Yuhan: Consultancy; AstraZeneca/MedImmune: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Samsung Bioepis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Doral:Roche: Current equity holder in publicly-traded company; Genentech: Current Employment. Kaufman:Roche/Genentech: Current equity holder in publicly-traded company; Genentech: Current Employment. Pereira:Roche/Genentech: Current Employment; Roche: Current holder of stock options in a privately-held company. Berthier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Morschhauser:Eisai: Honoraria; Chugai: Honoraria; Roche/Genentech: Consultancy, Honoraria, Other: Payment for Expert Testimony, Honoraria for Scientific Lectures; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Honoraria, 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; Kite/Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

All study therapy constituted investigational or off-label use. Glofitamab (Columvi) is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory DLBCL, NOS or large B-cell lymphoma arising from FL, after two or more lines of systemic therapy. Polatuzumab vedotin (Polivy) is a CD79b-directed antibody-drug conjugate indicated: in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of adult patients who have previously untreated DLBCL, NOS or HGBL and who have an IPI score of 2 or greater; and in combination with bendamustine and a rituximab product for the treatment of adult pts with relapsed or refractory DLBCL, NOS after at least two prior therapies.