Background: Richter's transformation (RT) is characterized by the development of chronic lymphocytic leukemia to an aggressive lymphoma, most commonly CD20+ large B-cell lymphoma. RT remains an unmet medical need with a poor prognosis and no standard of care. Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. In a Phase I/II study (NCT02500407), fixed-duration mosunetuzumab monotherapy demonstrated notable efficacy and a manageable safety profile in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (Bartlett et al. Blood Advances 2023). We report the efficacy and safety of mosunetuzumab monotherapy in patients with R/R RT after a median follow-up of 8.7 (range: 1-37) months.
Methods: Eligible patients with R/R RT and ≥1 prior therapies were enrolled. Patients with lymphocyte counts of ≥5000/µL were excluded. Mosunetuzumab was administered intravenously in 21-day cycles with step-up dosing in Cycle (C) 1 (C1 Day [D] 1, 1mg; C1D8, 2mg; C1D15/C2D1, 60mg; C3D1 and onwards, 30mg). Hospitalization for treatment was not required. Patients achieving a complete response (CR) by C8 completed treatment without additional cycles; patients with a partial response (PR) or stable disease received a total of 17 cycles. The primary endpoints were safety and tolerability. Efficacy was a secondary endpoint and was assessed according to Cheson 2007 criteria. Cytokine release syndrome (CRS) events were graded using the American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019).
Results: Twenty patients with R/R RT were enrolled. Median age was 70 (range: 49-87) years, 95.0% of patients had Ann Arbor stage III/IV disease, and 70.0% had an International Prognostic Index score of ≥3. Median number of prior therapies was 2.5 (range: 1-10), 65.0% of patients had ≥2 prior therapies, and 45.0% had received prior treatment with a Bruton tyrosine kinase inhibitor. Overall, 80.0% of patients were refractory to their last therapy. Investigator-assessed overall response and CR rates were 40.0% and 20.0%, respectively. Of four patients with a CR, two had a CR ongoing for ≥20 months at data cut-off (duration of CR [DOCR] at data cut-off: 21.2 months [patient had disease progression at a later timepoint] and 34.2 months), and the other two patients had received a subsequent stem-cell transplant (DOCR with mosunetuzumab: 0.1 and 4.2 months) ( Figure). The four patients with a PR had individual durations of response of: 1.7, 2.1, 2.3, and 2.8 months. The most common adverse event (AE) was CRS (65.0%), and events were predominantly Grade (Gr) 1 (20.0%) or Gr 2 (40.0%); a Gr 3 event was reported after C1D15 in one patient (5.0%). CRS was primarily associated with treatment administration during C1 (C1D1, 15.0%; C1D15, 50.0%); a Gr 1 CRS event was reported in one patient (5.0%) during C2. Of the 14 patients with CRS, six (42.9%) received tocilizumab, three (21.4%) received low-flow oxygen, one (7.1%) received a single pressor, and four (28.6%) received steroids; of the patients who received steroids, two (14.3%) received both tocilizumab and steroids. One patient was admitted to the intensive care unit for the management of Gr 3 CRS. The median duration of CRS was 3 (range: 1‒9) days. All CRS events resolved. Neurologic AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and considered treatment-related, occurred in two patients (Gr 1 ICANS and Gr 2 lethargy, each n=1); both events resolved. ICANS occurred one day after a Gr 2 CRS event. No Gr 5 (fatal) AEs, or AEs leading to treatment discontinuation were reported. AEs of special interest included infections (35.0%), neutropenia (15.0%), thrombocytopenia (20.0%), and tumor flare events (10.0%).
Conclusions: In patients with R/R RT, fixed-duration mosunetuzumab monotherapy demonstrates activity with durable responses and a manageable safety profile in a limited sample size of 20 patients. Treatment with mosunetuzumab warrants further study in this patient population with a high unmet medical need.
OffLabel Disclosure:
Cheah:F. Hoffmann-La Roche Ltd, Janssen, Gilead, AstraZeneca, Lilly, TG therapeutics, Beigene, Novartis, Menarini, Daizai, Abbvie, Genmab. BMS: Honoraria; BMS, F. Hoffmann-La Roche Ltd, Abbvie; MSD, Lilly: Research Funding; F. Hoffmann-La Roche Ltd, Janssen, Gilead, AstraZeneca, Lilly, TG therapeutics, Beigene, Novartis, Menarini, Daizai, Abbvie, Genmab. BMS: Consultancy. Assouline:AbbVie: Honoraria; Novartis Canada: Research Funding; BeiGene: Consultancy; Roche-Genentech: Honoraria; AstraZeneca: Honoraria; Janssen: Honoraria; Ipsen: Consultancy; Gilead: Honoraria; Palladin: Honoraria. Baker:F. Hoffmann-La Roche Ltd, CSL Behring: Consultancy; Takeda, Bristol Myers Squibb, Boehringer Ingelheim,: Research Funding; Bayer, AstraZeneca: Speakers Bureau. Bartlett:ADC Therapeutics, Foresight Diagnostics, Kite, F. Hoffmann-La Roche Ltd / Genentech, Inc., Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics, Autolus, BMS/Celgene, Forty Seven, Gilead/Kite Pharma, Janssen, Merck, Millennium, Pharmacyclics, F. Hoffmann-La Roche Ltd / Genentech, Inc., Seattle Genetics: Research Funding; Washington University School of Medicine: Current Employment. El-Sharkawi:Abbvie, ASTEX, AstraZeneca, BeiGene, Janssen, Kyowa Kiirin: Consultancy; Abbvie, AstraZeneca, BeiGene; Gilead, Janssen, Lily, Novartis, F. Hoffman-La Roche, Takeda: Honoraria; Abbvie: Speakers Bureau; Royal Marsden NHS Foundation trust: Current Employment. Giri:Royal Adelaide Hospital: Current Employment. Ku:Clinical Haematologist St Vincent's Hospital, Melbourne: Current Employment; Antengene, Genor BioPharma, F. Hoffmann-La Roche Ltd: Consultancy. Schuster:Janssen Research & Development: Research Funding; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding; Nordic Nanovector: Other: Scientific Advisory Committee; Genentech: Consultancy; Acerta: Consultancy. Matasar:Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Other: Stipends; ADC Therapeutics: Consultancy, Honoraria, Other: Stipend; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celegene: Honoraria, Other: Stipends; BMS: Honoraria, Other: Stipend; Janssen: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria; Bayer: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria, Other: Stipend; Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Honoraria, Other: Stipends; Pharmacyclics: Honoraria, Research Funding; Merck: Current equity holder in private company; Juno: Consultancy; Regeneron: Honoraria, Other: Stipends; Seagen: Honoraria, Other: stipends; Takeda: Consultancy, Honoraria; Teva: Consultancy; Immunovaccine Technologies: Research Funding. Radford:ADC Therapeutics, Takeda: Speakers Bureau; ADC Therapeutics, Takeda, Sobi: Honoraria; Takeda: Research Funding; AstraZeneca: Divested equity in a private or publicly-traded company in the past 24 months; GlaxoSmithKline: Current equity holder in publicly-traded company; ADC Therapeutics, Takeda, Sobi: Consultancy. Wei:Genentech, Inc.: Current Employment; F. Hoffman-La Roche Ltd: Current equity holder in publicly-traded company; F. Hoffman-La Roche Ltd: Patents & Royalties. Yin:F. Hoffmann-La Roche Ltd / Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. To:Genentech, Inc.: Current Employment. Huang:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Kwan:F. Hoffmann-La Roche Ltd / Genentch, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Budde:Merck: Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Roche: Consultancy; Amgen: Research Funding; Novartis, Gilead, F. Hoffmann-La Roche Ltd, BeiGene, Genentech, Inc.: Consultancy; MustangBio: Research Funding.
Mosunetuzumab (Lunsumio) is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy.
