Exposure-Response Analyses Indicate a Promising Benefit/Risk Profile of Mosunetuzumab in Relapsed and Refractory Non-Hodgkin Lymphoma

Autor: Natalie Dimier, Ian W. Flinn, Antonia Kwan, Lihua E. Budde, Hong Wang, Sung-Soo Yoon, Cindy Zhang, Chi-Chung Li, Shen Yin, Joanne I. Adamkewicz, Genevive Hernandez, Brendan Bender, Carol O'Hear, Sue-Zen Lim, Zao Li, Michael C. Wei, Laura Sun, Chunze Li, Laurie H. Sehn
Rok vydání: 2019
Předmět:
Zdroj: Blood. 134:1285-1285
ISSN: 1528-0020
0006-4971
Popis: Introduction: Mosunetuzumab (M; RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Clinical data from GO29781 (NCT02500407), a Phase I/Ib study in relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) pts, indicate that M has promising efficacy and safety (Budde et al. ASH 2018; Bartlett et al. ASCO 2019). We report the characterization of exposure-response (E-R) relationships for safety and efficacy to inform clinical dose/regimen finding. Methods: DATA: Data from Group A (0.05 to 2.8mg q3w dosing) and Group B (0.4/1/2.8 to 1/2/27mg Cycle 1 Day 1/8/15 step-up dosing, followed by q3w dosing) were analyzed. E-R for safety was assessed in 142 evaluable pts by dosing Group. E-R for efficacy was assessed in 130 evaluable pts by aggressive (a) (n=83, primarily DLBCL and transformed FL) and indolent (i) (n=47, primarily FL) NHL histologies. PHARMACOKINETIC (PK) ENDPOINTS: Pt-specific PK exposure metrics, including AUC and Cmax, were derived using a preliminary two-compartment population PK model with time-dependent clearance. Due to the presence of residual rituximab (R) at baseline from prior treatments, an additional exposure metric of average CD20 receptor occupancy (RO%) of M was derived based on the serum PK and binding affinity (KD) of both agents to assess the impact of target binding competition over time. E-R ANALYSES: Objective response rate (ORR), complete response rate (CRR), and adverse event (AE) rates, including cytokine release syndrome (CRS) and neurological AEs (NAE), were summarized by exposure-tertiles and the E-R relationships modeled by logistic regression (linear or Emax models). Response rates and E-R were further assessed in subgroups by RO% tertiles and baseline factors, such as the number of prior lines of therapy, refractory status, lactate dehydrogenase level, and tumor burden, and modeled by multivariate logistic regression. Results: R was present at modest levels at baseline in aNHL pts (median, 3 µg/ml, 33% of pts below quantitation limit [BQL] of 0.5µg/ml) but minimally in iNHL pts (median, Conclusions: E-R analyses indicate promising therapeutic benefit/risk of M in R/R NHL pts. Step-up dosing mitigated CRS-related toxicities, resulting in a broad therapeutic window of M that enables further dose escalation to maximize efficacy. The lack of E-R for safety was contrasted by a steep E-R for efficacy whereby higher M exposures overcome target binding competition in pts with residual R. Our analyses provide useful guidance for the dosing strategy of CD20-targeting T-cell bispecifics. Disclosures Li: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Bender:Genentech, Inc.: Employment, Equity Ownership. Yin:Genentech, Inc: Employment, Equity Ownership. Li:Pro Unlimited - Genentech, Inc. contractor: Employment; F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Zhang:Genentech, Inc., SSF: Employment. Hernandez:Genentech, Inc.: Employment, Equity Ownership. Kwan:Genentech, Inc: Employment, Equity Ownership. Sun:Harpoon Therapeutics: Employment, Equity Ownership; F. Hoffmann-La Roche Ltd / Genentech, Inc.: Employment. Adamkewicz:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Wang:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Dimier:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Lim:Genentech, Inc.: Employment. O'Hear:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Sehn:Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Apobiologix: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Lundbeck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Flinn:AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding. Yoon:Novartis: Consultancy, Honoraria; Janssen: Consultancy; Kyowa Hako Kirin: Research Funding; Amgen: Consultancy, Honoraria; Yuhan Pharma: Research Funding; Genentech, Inc.: Research Funding; MSD: Consultancy. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Li:Genentech, Inc. / F. Hoffmann-La Roche Ltd: Employment. Wei:Genentech, Inc./F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. OffLabel Disclosure: Mosunetuzumab (RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.
Databáze: OpenAIRE
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