Senior Director Novartis Cambridge, Massachusetts, United States
Disclosure(s):
Jaeyeon Kim: No relevant disclosure to display
Objectives: 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 continuously every day at 200 mg BID and different doses of TNO155 was dosed intermittently or continuously.
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 received JDQ443 and TNO155 combination therapy. Together with PK-neutropenia model, the tumor kinetic model was used to identify 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 regrowth 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 validated preclinically through targeted experiments in various cell models. Analysis of clinical data showed even though the better tumor response was observed for patients with higher dose/exposure of TNO155 in patients received the combination therapy of JDQ443 and TNO155, it was not tolerable beyond 20mg BID TNO155 with 2 weeks on and 1 week off regimen. The tumor kinetic model in patients indicated that the pulsed dosing of TNO155 at a higher dose (i.e., 30 mg BID dosed 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.
Conclusions: Based on the results of this MID3 approach (model-informed drug discovery & development), a pulsed dosing of TNO155 at a higher dose was recommended for Phase 2 study for the JDQ443+TNO155 combination. 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.
Citations: [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.
.jpg "Jaeyeon Kim, PhD (he/him/his) photo")