Single-Agent Mosunetuzumab Shows Durable Complete Responses in Patients With Relapsed or Refractory B-Cell Lymphomas: Phase I Dose-Escalation Study

Lihua E Budde, Sarit Assouline, Laurie H Sehn, Stephen J Schuster, Sung-Soo Yoon, Dok Hyun Yoon, Matthew J Matasar, Francesc Bosch, Won Seog Kim, Loretta J Nastoupil, Ian W Flinn, Mazyar Shadman, Catherine Diefenbach, Carol O'Hear, Huang Huang, Antonia Kwan, Chi-Chung Li, Emily C Piccione, Michael C Wei, Shen Yin, Nancy L Bartlett, Lihua E Budde, Sarit Assouline, Laurie H Sehn, Stephen J Schuster, Sung-Soo Yoon, Dok Hyun Yoon, Matthew J Matasar, Francesc Bosch, Won Seog Kim, Loretta J Nastoupil, Ian W Flinn, Mazyar Shadman, Catherine Diefenbach, Carol O'Hear, Huang Huang, Antonia Kwan, Chi-Chung Li, Emily C Piccione, Michael C Wei, Shen Yin, Nancy L Bartlett

Abstract

Purpose: Mosunetuzumab is a bispecific antibody targeting CD20 and CD3 that redirects T cells to engage and eliminate malignant B cells and is being developed for relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHLs).

Methods: This first-in-human trial (ClinicalTrials.gov identifier: NCT02500407) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and established the recommended phase II dose. Data from dose escalation are presented. Single-agent mosunetuzumab was administered intravenously in 3-week cycles, at full dose in cycle 1 day 1 (group A) or with ascending (step-up) doses during cycle 1 on days 1, 8, and 15 (group B), for eight or 17 cycles on the basis of tumor response.

Results: Two hundred thirty patients were enrolled. Doses up to 2.8 mg and 60 mg were assessed in groups A and B, respectively; maximum tolerated dose was not exceeded. In group B (n = 197), common adverse events (≥ 20% of patients) were neutropenia (28.4%), cytokine release syndrome (27.4%), hypophosphatemia (23.4%), fatigue (22.8%), and diarrhea (21.8%). Cytokine release syndrome was mostly low-grade (grade ≥ 3: 1.0%) and mainly confined to cycle 1. Across the doses investigated (group B), best overall response rates were 34.9% and 66.2% in patients with aggressive and indolent B-NHL, respectively, and complete response rates were 19.4% and 48.5%. Among patients with a complete response, the median duration of response was 22.8 months (95% CI, 7.6 to not estimable) and 20.4 (95% CI, 16 to not estimable) in patients with aggressive and indolent B-NHL, respectively.

Conclusion: Mosunetuzumab, administered with step-up dosing, has a manageable safety profile and induces durable complete responses in R/R B-NHL. The expansion stage of the study is ongoing at the dose level of 1/2/60/60/30 mg selected for further study.

Conflict of interest statement

Lihua E. BuddeConsulting or Advisory Role: Roche/Genentech, Kite/Gilead, Novartis, BeiGeneResearch Funding: Merck, Amgen, MustangBio, AstraZenecaPatents, Royalties, Other Intellectual Property: CCR4 CAR T cells for treatment of patients with CCR4-positive cancer. CD33CAR for treatment of patients with CD33+ acute myeloid leukemiaTravel, Accommodations, Expenses: Roche/Genentech, Kite/Gilead, AstraZeneca Sarit AssoulineStock and Other Ownership Interests: Knight PharmaceuticalsHonoraria: Janssen Oncology, Pfizer, AbbVie, Novartis Canada Pharmaceuticals Inc, AstraZeneca, BMSConsulting or Advisory Role: Roche/Genentech, BeiGeneResearch Funding: Roche Canada (Inst), Takeda (Inst), Astex Pharmaceuticals (Inst), BeiGene (Inst), Novartis (Inst)Travel, Accommodations, Expenses: Roche Canada Laurie H. SehnHonoraria: Amgen, Apobiologix, AbbVie, Celgene, Gilead Sciences, Janssen-Ortho, Karyopharm Therapeutics, Kite, a Gilead company, Lundbeck, Merck, Roche/Genentech, Seattle Genetics, Takeda, Teva, TG Therapeutics, AstraZeneca, Acerta Pharma, morphosys, Incyte, Debiopharm Group, Sandoz-Novartis, Verastem, GenmabConsulting or Advisory Role: Celgene, AbbVie, Seattle Genetics, TG Therapeutics, Janssen, Amgen, Roche/Genentech, Gilead Sciences, Lundbeck, Amgen, apobiologix, Karyopharm Therapeutics, Kite, a Gilead company, Merck, Takeda, Teva, TG therapeutics, AstraZeneca, Acerta Pharma, MorphoSys, Incyte, Debiopharm Group, Sandoz-Novartis, Genmab, VerastemResearch Funding: Roche/Genentech (Inst), Teva (Inst) Stephen J. SchusterConsulting or Advisory Role: Celgene, Nordic Nanovector, Novartis, AbbVie, Acerta Pharma/AstraZeneca, Alimera Sciences, BeiGene, Juno Therapeutics, Loxo Oncology, Tessa Therapeutics, Genentech/RocheResearch Funding: Novartis (Inst), Pharmacyclics (Inst), Adaptive Biotechnologies (Inst), Merck (Inst), Genentech/Roche (Inst), Celgene (Inst), Juno Therapeutics (Inst), AbbVie (Inst), Incyte (Inst), TG Therapeutics (Inst), DTRM (Inst)Patents, Royalties, Other Intellectual Property: Patent Combination Therapies of CAR and PD-1 Inhibitors (via University of Pennsylvania with royalties to Novartis) Sung-Soo YoonHonoraria: NovartisConsulting or Advisory Role: Janssen, Takeda, Amgen, Celgene/JazzResearch Funding: Kyowa Kirin, Roche/Genentech, Yuhan Dok Hyun YoonHonoraria: Celltrion, Roche, Janssen, Amgen, Celgene, Samyang, Kirin Pharmaceuticals, TakedaConsulting or Advisory Role: Roche, Janssen, Amgen, Celgene, Green Cross, NovartisResearch Funding: Samyang, Abclone, Roche/Genentech, Janssen Oncology, Amgen, Genmab, Boryung, Eutilex Matthew J. MatasarStock and Other Ownership Interests: MerckHonoraria: Genentech, Roche, Bayer, Pharmacyclics, Seattle Genetics, Takeda, Immunovaccine, ADC Therapeutics, Karyopharm TherapeuticsConsulting or Advisory Role: Genentech, Bayer, Merck, Juno Therapeutics, Roche, Teva, Rocket Medical, Seattle Genetics, Daiichi Sankyo, TakedaResearch Funding: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Rocket Medical, Seattle Genetics, Immunovaccine, IGM Biosciences , IGM BiosciencesTravel, Accommodations, Expenses: Genentech, Roche, Seattle Genetics, Bayer Francesc BoschConsulting or Advisory Role: AstraZeneca, Roche/Genentech, Janssen-Cilag, Lilly, AbbVie, Kite, a Gilead company, BeiGene, NovartisSpeakers' Bureau: AbbVie, Janssen, Roche, AstraZenecaResearch Funding: Janssen, AstraZeneca Loretta J. NastoupilHonoraria: Celgene, Gilead Sciences, Novartis, Bayer, Janssen Oncology, Pfizer, Gamida Cell, TG Therapeutics, Bristol Myers Squibb, ADC Therapeutics, Morphosys, Epizyme, GenmabResearch Funding: TG Therapeutics, Janssen Biotech, Celgene, Genentech/Roche, LAM Therapeutics, Epizyme, Novartis, IgM Biosciences, Caribou Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda Ian W. FlinnConsulting or Advisory Role: AbbVie (Inst), Seattle Genetics (Inst), TG Therapeutics (Inst), Verastem (Inst), Roche (Inst), Gilead Sciences (Inst), Kite, a Gilead company (Inst), Janssen (Inst), BeiGene (Inst), Takeda (Inst), AstraZeneca (Inst), Juno Therapeutics (Inst), Unum Therapeutics (Inst), MorphoSys (Inst), Nurix (Inst), Shanghai Yingli Pharmaceuticals (Inst), Genentech (Inst), Great Point Partners (Inst), Iksuda Therapeutics (Inst), Novartis (Inst), Pharmacyclics (Inst), Century Therapeutics (Inst), Hutchison MediPharma (Inst), SERVIER (Inst), Vincerx Pharma (Inst), Genmab (Inst), InnoCare Pharma (Inst)Research Funding: Acerta Pharma (Inst), Agios (Inst), Calithera Biosciences (Inst), Celgene (Inst), Constellation Pharmaceuticals (Inst), Genentech (Inst), Gilead Sciences (Inst), Incyte (Inst), Infinity Pharmaceuticals (Inst), Janssen (Inst), Karyopharm Therapeutics (Inst), Kite, a Gilead company (Inst), Novartis (Inst), Pharmacyclics (Inst), Portola Pharmaceuticals (Inst), Roche (Inst), TG Therapeutics (Inst), Trillium Therapeutics (Inst), AbbVie (Inst), ArQule (Inst), BeiGene (Inst), Curis (Inst), FORMA Therapeutics (Inst), Forty Seven (Inst), Merck (Inst), Pfizer (Inst), Takeda (Inst), Teva (Inst), Verastem (Inst), AstraZeneca (Inst), Juno Therapeutics (Inst), Unum Therapeutics (Inst), MorphoSys (Inst), Seattle Genetics (Inst), IGM Biosciences (Inst), Loxo (Inst), Rhizen Pharmaceuticals (Inst), Triact Therapeutics (Inst) Mazyar ShadmanConsulting or Advisory Role: AbbVie, Genentech, AstraZeneca, Sound Biologics, Cellectar, Pharmacyclics, BeiGene, Bristol Myers Squibb/Celgene, MorphoSys, Innate Pharma, Kite, a Gilead company, Adaptive Biotechnologies, EpizymeResearch Funding: Pharmacyclics (Inst), Acerta Pharma (Inst), Merck (Inst), TG Therapeutics (Inst), BeiGene (Inst), Celgene (Inst), Genentech (Inst), MustangBio (Inst), AbbVie (Inst), Sunesis Pharmaceuticals (Inst), Bristol Myers Squibb/Celgene Catherine DiefenbachStock and Other Ownership Interests: Gilead SciencesConsulting or Advisory Role: Seattle Genetics, Bayer, Bristol Myers Squibb, Genentech/Roche, Merck, Janssen, Celgene, MorphoSysResearch Funding: Seattle Genetics (Inst), Genentech (Inst), Incyte (Inst), LAM Therapeutics (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Millennium (Inst), Roche/Genentech (Inst), Janssen (Inst), MEI Pharma (Inst), Trillium Therapeutics (Inst), Astex Pharmaceuticals (Inst)Expert Testimony: Jim Harmon Carol O'HearEmployment: Genentech/RocheStock and Other Ownership Interests: Genentech/RochePatents, Royalties, Other Intellectual Property: Antibody bufferingTravel, Accommodations, Expenses: Genentech/Roche Huang HuangEmployment: Roche Canada Antonia KwanEmployment: Genentech/RocheStock and Other Ownership Interests: Roche/Genentech Chi-Chung LiEmployment: Roche/GenentechStock and Other Ownership Interests: Roche/GenentechPatents, Royalties, Other Intellectual Property: Patent applications pertaining to the development and dosing of bispecific antibodies Emily C. PiccioneEmployment: GenentechStock and Other Ownership Interests: Roche/Genentech Michael C. WeiEmployment: Genentech/RocheStock and Other Ownership Interests: RocheTravel, Accommodations, Expenses: Genentech/Roche Shen YinEmployment: GenentechStock and Other Ownership Interests: GenentechTravel, Accommodations, Expenses: Genentech Nancy L. BartlettConsulting or Advisory Role: Seattle Genetics, Roche/Genentech, ADC Therapeutics, BTG, Acerta PharmaResearch Funding: Seattle Genetics (Inst), Kite, a Gilead company (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Celgene (Inst), Immune Design (Inst), Forty Seven (Inst), Janssen (Inst), Pharmacyclics (Inst), Millennium (Inst), ADC Therapeutics (Inst), Autolus (Inst), Roche/Genentech (Inst), Pfizer (Inst), Affimed Therapeutics (Inst)No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
AEs with incidence ≥ 10% or National Cancer Institute-Common Terminology Criteria for AEs grade 5 (group B; safety population): (A) all AEs and (B) AEs related to mosunetuzumab. Clinical cutoff date: January 21, 2020. CRS events were graded and treated on the basis of the criteria published by Lee et al. AEs, adverse events; CRS, cytokine release syndrome.
FIG 2.
FIG 2.
Best percentage change from baseline in the sum of the products of diameters in group B patients (efficacy population) with (A) aNHL (diffuse large B-cell lymphoma, transformed follicular lymphoma, mantle cell lymphoma, Richter's transformation, transformed marginal zone lymphoma, or grade 3b follicular lymphoma) and (B) iNHL (grade 1-3a follicular lymphoma, marginal zone lymphoma, or small lymphocytic lymphoma). (C) Kaplan-Meier curves for duration of response (including complete and partial response) in aNHL and iNHL (group B; patients achieving complete response or partial response). (D) Kaplan-Meier curve for progression-free survival in group B patients with aNHL or iNHL. Clinical data cutoff: January 21, 2020. (A and B) Waterfall plots of the best overall change in the size of tumor target lesions according to the mosunetuzumab doses received. Plots of the best percentage changes in the sum of the products of diameters of target lesions are shown. The columns represent the results from individual patients, color coded according to the step-up doses of mosunetuzumab received. The dashed lines indicate 50% increase or decrease of the baseline SPD. The y-axis increase is truncated at 100%. aNHL, aggressive non-Hodgkin lymphoma; iNHL, indolent non-Hodgkin lymphoma; NE, not estimable; SPD, sum of the products of diameters.
FIG 3.
FIG 3.
Exposure-response relationships of mosunetuzumab for clinical objective response and CRS: (A) for clinical response in group A and B patients with aggressive NHL (n = 137; left: CR; right: OR); (B) for clinical response in group A and B patients with indolent NHL (n = 80; left: CR; right: OR); (C) for occurrence of grade ≥ 2 CRS within the first 42 days of mosunetuzumab (mixed histology; left: group A fixed dosing; right: group B cycle 1 step-up dosing). PK data cutoff: November 12, 2019; clinical data cutoff: January 21, 2020. ROavg (%) represents the calculated CD20 RO% averaged over 0-42 days after cycle 1 day 1 administration of mosunetuzumab. ROmax (%) represents the maximal RO% value over 0-42 days after cycle 1 day 1 administration of mosunetuzumab. AUC represents the area under the serum concentration–time curve averaged over 0-42 days post cycle 1 day 1 administration of mosunetuzumab. Emax represents the maximal effect at infinite drug levels. (A and B) Open circles represent the observed clinical objective response for each patient (0 = nonresponder; 1 = responder), colored by dosing cohort. (C) Blue open circles represent the observed occurrence of grade ≥ 2 CRS event (0 = no event; 1 = event). Exposure-response plots are divided into intervals (dashed green lines) indicating quartiles (for efficacy plots, A and B) or tertiles (for CRS plot, C) of the corresponding exposure metric; blue-filled circles at each interval indicate the observed response rates as indicated by (A and B) the numbers and associated sample sizes or (C) the observed probability of patients having a CRS event of grade ≥ 2 at the median exposure in each of the corresponding interval. Blue lines are the modeled average trend on the basis of logistic regression models; shaded areas represent the 90% CI of the modeled exposure-response relationship. Dashed horizontal lines represent (A) the model estimated maximal CR rate of 36% (90% CI, 26 to 60%) and the maximal ORR of 63% (90% CI, 48 to 83%) in patients with aggressive NHL and (B) the model estimated maximal ORR of 80% (90% CI, 70 to 100%) in patients with indolent NHL. Maximal response rate (Emax) was not estimated in patients with indolent NHL. A trend toward plateau at higher exposure levels was observed in the dose range studied (0.05-60 mg) in patients with aggressive NHL. In patients with indolent NHL, a trend toward plateau at higher exposure levels was observed for objective but not for CR rates in the dose range studied (0.05-13.5 mg). There was no statistically significant relationship between mosunetuzumab ROmax (%) and the occurrence of grade ≥ 2 CRS within the first 42 days of mosunetuzumab although a visual trend of increasing grade ≥ 2 CRS rate with increasing ROmax (%) exists for the fixed dosing group and not the step-up dosing group. AUC, area under the serum concentration-time curve; CR, complete response; CRR, complete response rate; CRS, cytokine release syndrome; NHL, non-Hodgkin lymphoma; OR, objective response; ORR, objective response rate; RO%, receptor occupancy.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8824395/bin/jco-40-481-g001.jpg

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