LEKSHMI DHARMARAJAN1, Jaeyeon Kim4, Andreas Weiss1, Carmine Fedele2, Eshita Khera2, Xiaoming Cui3, Jeffrey D Kearns2, Peter McCormack5
1Biomedical Research, Novartis Pharma AG, 2Biomedical Research, Novartis Pharmaceuticals Corporation, 3Biomedical Research, Novartis Pharmaceuticals Corporation, 4Development, Novartis Pharmaceuticals Corporation, 5Development, Novartis Pharma AG
Background Combining drugs at optimal dosing regimens remains vital for improving treatment options for patients in oncology. Here we share a case study of dose-regimen optimization of JDQ443, a KRAS G12C inhibitor with TNO155, a SHP2 inhibitor. The potential benefit of combining them was demonstrated preclinically [1] and this combination was also tested in the CJDQ443A12101 clinical study in patients with advanced KRAS-G12C mutations [2]. In the trial, JDQ443 was administered orally every day at 200 mg BID and different doses of TNO155 were administered intermittently or continuously. Objectives 1.Determine the optimal dosing regimen for JDQ443+TNO155 based on preclinical data and validate model predictions preclinically 2.Evaluate if emerging clinical data supported the predictions from the preclinical data modelling and propose dosing regimens to inform clinical trial design. Methods In this study, we used preclinical and clinical PK and tumor growth kinetic modeling to determine the optimal dosing regimen for TNO155 and JDQ443 combination therapy. Tumor-bearing mice received single or combined doses of JDQ443 and TNO155, either continuously or intermittently. We modeled data from these experiments and performed simulations to suggest alternative regimens for follow-up experiments. The clinical PK-tumor kinetic models were developed to describe tumor size changes in patients who received JDQ443 and TNO155 combination therapy. Together with PK-neutropenia model, the tumor kinetic model was used to identify an optimal dosing regimen of TNO155 and to inform a new clinical study to validate the model prediction. Results The preclinical PK and tumor growth kinetic model predicted that intermittent dosing of TNO155 (e.g., 2 days ON/3 days OFF in tumor-bearing mice) risks tumor re-growth during the OFF phase, even with continuous dosing of JDQ443. The model predicted that low doses of TNO155 administered continuously or intermittently could be replaced by a higher pulsed dose of TNO155 (e.g., every 2 days) when combined with JDQ443. These findings were confirmed through targeted preclinical experiments in various cell models. Analysis of clinical data showed that despite a better tumor response for patients with higher dose/exposure of TNO155 in patients receiving the combination of JDQ443 and TNO155, the regimen was not tolerable beyond 20 mg BID TNO155 on a ‘2 week on and 1 week off’ schedule. The tumor kinetic model in patients indicated that the pulsed dosing of TNO155 at a higher dose (i.e., 30 mg BID dosing on Days 1 and 2) could result in improved tumor activity as compared to the intermittent dosing of TNO155 at lower dose (i.e., 10 mg BID for 2 weeks ON/1 week OFF) without exacerbating safety response (e.g., neutropenia). Furthermore, these analyses suggested that doses of TNO155 could be increased in the clinic in a pulsed dosing regimen to better achieve the target preclinical thresholds necessary for activity across both sensitive and less-sensitive cell models. Conclusion Based on the results of this MID3 (model-informed drug discovery & development) approach, a pulsed dosing of TNO155 at a higher dose was recommended for the JDQ443+TNO155 Phase 2 combination study. This work highlights the importance of targeted experiments and modelling via a cross departmental collaboration between research teams and early clinical teams to successfully integrate the totality of data (preclinical and clinical) to optimize dosing schedules for the patient.
1. Weiss, Andreas, et al. “Discovery, preclinical characterization, and early clinical activity of JDQ443, a structurally novel, potent, and selective covalent oral inhibitor of KRASG12C.” Cancer Discovery 12.6 (2022): 1500-1517. 2. Negrao, M. V., et al. “MA06. 03 KontRASt-01: preliminary safety and efficacy of JDQ443+ TNO155 in patients with advanced, KRAS G12C-mutated solid tumors.” Journal of Thoracic Oncology 18.11 (2023): S117-S118.
Reference: PAGE 33 (2025) Abstr 11404 [www.page-meeting.org/?abstract=11404]
Poster: Drug/Disease Modelling - Oncology