CD19 Expression by IHC Alone Is Not a Predictor of Response to Loncastuximab Tesirine: Results from the LOTIS-2 Clinical Trial and Quantitative Systems Pharmacology Modeling

Introduction: CD19 is a clinically-validated target for the treatment of B-cell malignancies, and several CD19-targeted therapies have received approval, including chimeric antigen receptor T-cell (CAR-T) therapy, antibody-drug conjugates (ADCs), monoclonal antibodies, and bispecific agents. However, the optimal sequencing of these treatments has not yet been clarified. Loncastuximab tesirine (loncastuximab tesirine-lypl; Lonca) is an ADC comprising an anti-CD19 antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin, indicated for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥2 systemic treatments. Prior CAR-T therapy does not preclude a response to Lonca, and responses were also observed in patients who received CAR-T therapy post-Lonca. The present analysis was performed to determine the contribution of CD19 expression to responses in patients treated with Lonca.

Methods: CD19 expression determined by immunohistochemistry (IHC) was evaluated in a cohort of patients enrolled in the LOTIS-2 clinical trial (NCT03589469) with available tissue samples obtained after their last anti-cancer systemic therapy and prior to Lonca. IHC was performed using the LE-CD19 antibody (DAKO), and expression was analyzed using the BenchMark ULTRA platform (Ventana). CD19 expression was assessed by semiquantitative scoring of both the percentage of positive tumor cells and the H-Score (semiquantitative assessment of the percentage of CD19 positive cells and staining intensity). Quantitative Systems Pharmacology (QSP) modeling was used to predict response to Lonca and to test hypotheses regarding patient-specific covariates.

Results: The cohort included patients with any prior systemic therapies (n = 59), including patients who received CAR-T as the last therapy prior to biopsy (n = 9). Responses to Lonca were seen in patients across all levels of CD19 expression, including patients with extremely low or no detectable CD19 expression at baseline and extremely low H-Scores. On the basis of the QSP modeling, patients are anticipated to achieve disease response to Lonca with CD19 tumor cell-surface densities as low as 1,000 molecules/cell (Figure 2).

Conclusions: Response to Lonca was observed in R/R DLBCL patients with very low CD19 tumor expression as measured by IHC. QSP modeling predicts that CD19 expression level by IHC is not predictive of response to Lonca, whereas the addition of CD19 surface density improves the response prediction. Patients responded to Lonca with estimated tumor cell surface densities as low as 1,000 molecules/cell, normally below the level of IHC detection. Our findings indicate that Lonca is an effective treatment option for patients with R/R DLBCL following ≥ 2 lines of treatment, even in patients expected to have a low level of CD19 expression. These results serve as a basis for future studies addressing sequencing of CD19-targeted agents.

Funding: ADC Therapeutics SA; medical writing: CiTRUS Health Group.

Caimi:Genentech: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Hamadani:Incyte Corporation: Consultancy; Gamida Cell: Consultancy; Kite: Consultancy; Genmab: Consultancy; SeaGen: Consultancy; MorphoSys: Consultancy; Legend Biotech: Consultancy; Novartis: Consultancy; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; Kadmon: Consultancy; Omeros: Consultancy; Abbvie: Consultancy; Takeda: Research Funding; Spectrum Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Sanofi Genzyme: Speakers Bureau; AstraZeneca: Speakers Bureau; BioGene: Speakers Bureau; Medical University of Wisconsin: Current Employment. Carlo-Stella:Bristol Myers Squibb: Honoraria; Scenic Biotech: Other: Consultancy/Advisory; Novartis: Honoraria; Incyte: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; Merck Sharp & Dohme: Honoraria; ADC Therapeutics: Honoraria, Other: Consultancy/Advisory, Research Funding; Karyopharm Therapeutics: Other: Consultancy/Advisory; Takeda: Honoraria; Sanofi: Other: Consultancy/Advisory, Research Funding; Roche: Other: Consultancy/Advisory, Research Funding; Celgene/Bristol Myers Squibb: Other: Consultancy/Advisory. Nickaeen:Metrum Research Group: Current Employment. Jordie:Metrum Research Group: Current Employment. Utsey:Metrum Research Group: Current Employment. Knab:Metrum Research Group: Current Employment. Zammarchi:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Pantano:ADC Therapeutics SA: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company; Pembrolizumab: Ended employment in the past 24 months; Novartis: Current equity holder in publicly-traded company, Other: Spouse works at Novartis; Alcon: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Organon: Current equity holder in publicly-traded company. Havenith:Genmab: Patents & Royalties: Patent with Genmab; ADC Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Wang:ADC Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Boni:ADC Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company.