(P 116) QUANTITATIVE SYSTEMS PHARMACOLOGY MODELING OF MIPASETAMAB UZOPTERINE INTEGRATES KNOWLEDGE AND DEFINES DOSING STRATEGY FOR PATIENTS WITH SARCOMA

Objective: AXL overexpression is linked to high metastatic potential and chemotherapy resistance, which induces poor overall survival in some solid tumors, notably sarcoma and non-small cell lung cancer.1-3 ADCT-601 (mipasetamab uzoptirine; Mipa) is an antibody-drug conjugate (ADC) comprising a humanized anti-AXL antibody conjugated to a potent chemotherapeutic agent, SG3199 (pyrrolobenzodiazepine dimer cytotoxin), via a cleavable linker.4 Mipa demonstrated antitumor activity in preclinical mouse xenograft models of sarcoma, adenoid cystic carcinoma, and pancreatic cancer and clinical activity in patients with solid tumor in phase 1 trials.4-6 The goal was to develop a model predicting the biodistribution and antitumor effect of Mipa for virtual patients with sarcoma following various dosing regimens.

Methods: A novel physiologically based pharmacokinetics (PK) quantitative systems pharmacology (QSP) model was developed to describe the effect of Mipa on sarcoma. The construct incorporated multiple literature-based model elements,7 including physiologic tissue distribution and interstitial compartment disposition of IgG-1 based ADC, ADC uptake, payload release, and cell killing of the tumor cells. Preclinical in vitro and mouse xenograft data and clinical PK data were leveraged to parameterize this QSP model capable of recapitulating PK across doses (Figure 1) and of representing virtual sarcoma populations such that the population reflected the characteristics of patients enrolled in the ADCT-601-102 trial (NCT05389462). Influential model parameters could then be interrogated, and patient-specific hypotheses could be tested.

Results: In virtual patients, the antitumor effect of Mipa predicted by the model appeared most sensitive to parameters of tumor doubling time (20–40 days), surface AXL molecules expressed per cell (100–100,000),8 tumor perfusion (20–30 L/h/L), and AXL+ fraction (10%–100%).4 Tumors that were predicted to progress were those with low surface AXL expression and short doubling time. A regimen of induction followed by a maintenance dose, or a fractionated dosing interval approach, appeared to be efficacious and resilient with respect to tumors of varying composition/heterogeneity. Continuous treatment with 11 mg every 3 weeks was associated with antitumor effect (> ~20% reduction) for homogeneous tumors but less so for a heterogeneous phenotype (Figure 2).

Conclusion: A novel integrated QSP model with tumor dynamics was developed using literature and in-house preclinical and clinical data. Simulations were used to quantify the impact of disease characteristics, such as disease phenotypes and AXL expression patterns on antitumor responses, and to predict efficacy of alternate dosing regimens in virtual patients with sarcoma.

References:
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5. Tolcher AW, et al. A phase I, open-label, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of ADCT-601 in patients with advanced solid tumours. Presented at: European Society for Medical Oncology Congress, Sep 1, 2019, Barcelona, Spain (Poster #468P).
6. Van Tine BA, et al. Phase 1b Trial Mipasetamab Uzoptirine (ADCT-601-102) Dose-Escalation in Patients With Advanced Bone and Soft Tissue Sarcomas. Presented at: American Association for Cancer Research Annual Meeting 2024. Apr 5-10, 2024, San Diego, CA (Poster #CT059).
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