Anubhav Prakash 1, Rahul Sing 1, Indrakanty Surya Shashank 1, Neelima Patnaikuni 1, Kannan Thiagarajan 1, Rukmini Kumar 1
1 Vantage Research Inc (Lewes, USA)
Introduction & Objectives:
Antibody Drug Conjugates (ADCs) have shown reasonable success in several cancer indications in the last decade. However, the therapeutic benefits of ADC monotherapy are often limited by treatment-related adverse events (AE) and resistance mechanisms. More recently, researchers have been exploring ADC combinations with chemotherapy or other ADCs, making this an actively investigated approach. Mitigating the associated toxicities in this approach with non-traditional approaches such as prophylactics, are worth investigating. The objective of the present work is to assess the role of prophylactic agents in improving the efficacy outcome by utilizing a quantitative systems pharmacology (QSP) model.
Methods:
We utilized a previously published QSP ADC model to evaluate the benefit of prophylactics (G-CSF) in the alleviation of cytotoxic induced neutropenia. The model has by-stander effect, neutrophil & leucocyte dynamics. And PK module that accounts for distribution of ADC & payload in the central, peripheral and tumor compartment. The model has thus been enhanced to simulate the following clinical outcomes of interest: ORR, PFS, OS and % patients experiencing Grade >= 3 neutropenia. This model was calibrated to Sacituzumab Govitecan (SG) & Enfortumab Vedotin (EV) monotherapies in metastatic urothelial cancer (mUC). In order to evaluate the best trial design for combination, we incorporated the effect of a small n (n=23) academic trial with prophylactic G-CSF use in combo ADC. Then we simulated a prospective trial of SG+EV combo with 2 trial arms , one with G-CSF as a prophylactic and another with randomized rescue treatment when patients reach Gr >= 3 neutropenia.
Results:
The model reasonably captured the clinical PKs, readouts (ORR, PFS) and incident rates (of Grade>=3 neutropenia and leukopenia) of the ADC monotherapies. Two arms of combination therapy (EV +SG) are simulated, with the trial arm receiving prophylactic G-CSF and the control arm not receiving it. The simulated ORR and incident rates from the virtual trial arm are validated against the DAD trial using a bootstrapped approach for our VPop. Simulations show ~2.3x improvement in median time on trial (75 vs 175 days) and ~2.7x reduction in neutropenia incidence (36 vs. 96%) without & with prophylactic G-CSF.
Conclusions:
This simulation study incorporates learning from a small n trial and establishes patient benefits that were suggested by the trial. The simulations in Virtual population indicate that patients in the arm with prophylactics have greater PFS, better patient retention, fewer incidence of hematological AEs, fewer dropouts and derive greater benefit from the combo ADCs. Such theoretical research can be cost-effective for clinicians and drug developers to visualize outcomes of non-traditional strategies and promote greater testing and adoption of these strategies.
References:
1. The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma. McGregor, B.A. et al. Annals of Oncology, Volume 35, Issue 1, 91 – 97.
2. Evolution of the systems pharmacokinetics-pharmacodynamics for antibody drug conjugates to characterize tumor heterogeneity and In vivo bystander effect. Singh A P et al. J Pharmacol Exp Ther. 374 (1), 2020, pp. 184 -199
3. Population Pharmacokinetics of Sacituzumab Govitecan in Patients with Metastatic Triple-Negative Breast Cancer and Other Solid Tumors. Sathe AG et al. Clin Pharmacokinet. 2024 May;63(5):669-681.
4. TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes. Loriot, Y. et al. Annals of Oncology, Volume 35, Issue 4, 392 – 401
5. EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4–Positive Solid Tumors, Including Metastatic Urothelial Carcinoma. Jonathan Rosenberg et al. Journal of clinical oncology, Volume 38, Number 10, 1041-1049.
6. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin ineligible patients with previously untreated Locally Advanced or Metastatic Urothelial Cancer. O’Donnell P H et al. J. Clin. Oncol., 41 (25), 2023, pp. 4107–4117.
Reference: PAGE 34 (2026) Abstr 11911 [www.page-meeting.org/?abstract=11911]
Poster: Drug/Disease Modelling - Oncology