Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster III
Hematology Disease Topics & Pathways:
Combination therapy, Lymphomas, Non-Hodgkin lymphoma, Drug development, Diseases, Treatment Considerations, Lymphoid Malignancies
Englumafusp alfa demonstrated no single-agent activity in preclinical studies. However, when combined with glofitamab, which provides the necessary signal 1, in vitro assays with lymphoma cell lines showed a bell-shaped dose-response relationship. This was further confirmed in an in vivo dose-finding efficacy study using humanized mice lymphoma xenografts, indicating an efficacious dose range in vivo where complete tumor response and CD8+ T-cell expansion were observed in combination with glofitamab.
To cover the entire dose/exposure-response (DER) of englumafusp alfa in the clinic, multiple doses were explored during dose escalation. Here, we report an integrated analysis of the totality of data that supported dose selection for further evaluation.
Methods: As of the data cutoff (February 12, 2024), 122 patients were included in the pharmacokinetic (PK) analysis (48 [39%] female, median [range] body weight of 79 [45-169] kg) and 99 patients in the PD analysis, with doses ranging from 0.36 mg to 75 mg. Histologies included 80% aggressive NHL (69 with diffuse large B-cell lymphoma) and 20% indolent NHL (24 with follicular lymphoma and 1 with marginal zone lymphoma). Preclinical and clinical data (efficacy, safety, PK, PKPD, biomarkers) were integrated to characterize the DER relationship. PD analysis of peripheral blood was performed by flow cytometry and plasma cytokines were measured by ELLA. Population PK (PopPK) modeling, logistic regression modeling, and graphical exploration were used to assess englumafusp alfa PK properties, correlation between probability of response and exposure, and relationships between exposure and safety events and PD. Englumafusp alfa average concentrations at steady-state (Cav,ss) and risk of exposure overlap among patients were compared across the different doses tested in dose escalation.
Results: The clinical PK was typical of large molecule constructs with target-mediated drug disposition, dose-dependent elimination, and body weight statistically influencing clearance and volume parameters.
The combination of englumafusp alfa and glofitamab was well tolerated, with no additive or synergistic safety signals and no dose-related toxicity across the tested dose levels. Efficacy was observed at all dose levels with no clear relationship to englumafusp alfa exposure (Hutchings et al, submitted to ASH 2024).
A PD response in line with the expected mode of action (MoA) of 4-1BB costimulators (Korfi et al, ASH 2023) showed a trend towards an inverse bell-shaped relationship between MoA-related PD markers including terminally differentiated and potentially exhausted peripheral PD1+ CD8+ effector memory T cells re-expressing CD45RA (Temra) and soluble CD25, with optimal effect at intermediate doses.
Given the absence of DER relationships pointing to a single dose, an optimal dose range was identified based on the totality of preclinical and clinical data. Two doses with distinct exposures, which maximize the number of patients with englumafusp alfa steady-state exposure (Cav,ss) within the in vivo efficacious dose range and optimal PD response range, were selected for further dose optimization in the next study phase.
Conclusion: This study demonstrates the utility of integrating totality of evidence (safety, efficacy, PK, PK/PD, biomarkers and non-clinical) with quantitative in silico approaches to identify the optimal dose range of englumafusp alfa, a bispecific antibody with no single-agent activity, to maximize benefit/risk when combined with glofitamab.
Acknowledgments: This study was sponsored by F. Hoffmann-La Roche Ltd. We thank the patients who participated in this trial, their families, and caregivers, as well as Kat Reyskens and Jean Christophe Genin for their contributions.
Disclosures: Jamois: Roche: Current Employment, Current equity holder in publicly-traded company. Korfi: Roche: Current Employment, Current equity holder in publicly-traded company. Herter: Roche Glycart AG: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Wilson: Roche: Current Employment, Current equity holder in publicly-traded company. Krishnan: Roche: Current Employment, Current equity holder in publicly-traded company. Wasmer: Roche: Current Employment, Current equity holder in publicly-traded company. Prieto: Roche: Current Employment, Current equity holder in publicly-traded company. Hinton: Roche: Current Employment, Current equity holder in publicly-traded company. Driessen: Roche: Current Employment; Anjarium Biosciences AG: Ended employment in the past 24 months. Kazantzidis: Roche: Current Employment, Current equity holder in publicly-traded company. Sahin: Roche: Current Employment, Current equity holder in publicly-traded company. Tagawa: Roche: Current Employment. Dimier: Roche: Current Employment, Current equity holder in publicly-traded company. Lechner: Roche: Current Employment, Current equity holder in publicly-traded company.
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