Kannan Thiagarajan: No financial relationships to disclose
Background: Antibody-drug conjugates (ADCs) are a class of therapeutics that combine the specificity of targeting tumor-associated antigens (TAAs) with the potency of a highly cytotoxic payload, delivered via a chemical linker. However, the clinical and radiographic benefits of ADC monotherapy are often limited by the development of treatment-related adverse events (AE)and resistance mechanisms. Combining ADCs with immune checkpoint inhibitors has shown success in indications, such as urothelial cancer, and remains an active area of research. The use of cytotoxic agents like platinum, fluorouracil, and topotecan in combination regimens such as FOLFOX and FOLFOXIRI has been a frontline treatment strategy for cancers like gastric, pancreatic, and colorectal cancer. More recently, researchers have been exploring ADC combinations with chemotherapy or other ADCs, making this an emerging and actively investigated approach. Key Scientific Questions: The primary objective of this work is to develop a platform quantitative systems pharmacology (QSP) model describing the ADC distribution into tissues, plasma and tumor and, to understand the drivers of haematological safety and efficacy in solid tumor indications. Using the platform model, we have demonstrated how either 2 ADCs can be combined or an ADC can be combined with chemotherapy. For this current effort, we focus on recommending appropriate dosing regimen for the combination from available clinical data, while also proposing strategies to hamper down treatment related AEs.
Methods: We have utilized a previously published QSP ADC model and added physiological complexity to the structure, which comprehensively captures drug dynamics at both cellular and systemic levels by incorporating drug as well as antigen related properties. In addition to ADC mediated tumor cell killing, the model also describes the by-stander effect. Moreover, we have incorporated a haematological AE module capturing neutrophil, platelet dynamics. The model was calibrated to enfortumab vedotin (EV), Sacituzumab govitecan (SG) and available carboplatin monotherapy.
Results: Model reasonably captures the monotherapy clinical readouts of the 3 monotherapies [1-3] and the combination of two ADCs (EV + SG) was validated against the Double Antibody Drug Conjugate (DAD) trial. Model was capable of not only capturing the clinical PK, efficacy but also the incidence rates of Grade >= 3 neutropenia and thrombocytopenia published in the literature. Different strategies such as combination of ADC with carboplatin, combining 2 ADCs were explored using the platform model.
Conclusions: Strategy of combining ADC with either chemotherapy or another ADC might overcome resistance of both modalities and mitigate the antigen heterogeneity. Induction of immunogenic cell death caused by the ADC combinatorics should result in immune response, yielding in a deeper and durable response. In-silico trials offer a cheap, but comprehensive option to play out different scenarios that cannot be tested in the clinic.
Citations: [1] O'Donnell PH, Milowsky MI, Petrylak DP, Hoimes CJ, Flaig TW, Mar N, Moon HH, Friedlander TW, McKay RR, Bilen MA, Srinivas S, Burgess EF, Ramamurthy C, George S, Geynisman DM, Bracarda S, Borchiellini D, Geoffrois L, Maroto Rey JP, Ferrario C, Carret AS, Yu Y, Guseva M, Homet Moreno B, Rosenberg JE. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2023 Sep 1;41(25):4107-4117. doi: 10.1200/JCO.22.02887. Epub 2023 Jun 27. PMID: 37369081; PMCID: PMC10852367. [2] Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. doi: 10.1056/NEJMoa2312117. PMID: 38446675. [3] McGregor BA, Sonpavde GP, Kwak L, Regan MM, Gao X, Hvidsten H, Mantia CM, Wei XX, Berchuck JE, Berg SA, Ravi PK, Michaelson MD, Choueiri TK, Bellmunt J. The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma. Ann Oncol. 2024 Jan;35(1):91-97. doi: 10.1016/j.annonc.2023.09.3114. Epub 2023 Oct 21. PMID: 37871703.
