128: Food & Formulation Effect of a Novel Src Homology Region 2 Domain−containing Protein Tyrosine Phosphatase 2 (SHP2) Allosteric Inhibitor in Combination With Pembrolizumab

Statement of Purpose, Innovation or Hypothesis: SAR442720 (also known as RMC-4630) is a potent, selective, and orally bioavailable Src Homology region 2 domain−containing protein tyrosine phosphatase 2 (SHP2) allosteric inhibitor. SHP2 is a positive regulator of RAS activation and is also involved in T-cells signaling. SHP2 binds immune-inhibitory receptors, including PD-1, and inhibits signaling from activating immunoreceptors such as T cell receptor (TCR) (Pardoll, 2012). The objective of this study was to evaluate the effect of food on the pharmacokinetics of SAR442720 tablet and to assess the relative bioavailability of SAR442720 tablet formulation (test) compared to the SAR442720 capsule formulation (reference) when dosed in combination with pembrolizumab in participants with advanced solid tumors.

Description of Methods & Materials: Approximately 12 participants were enrolled in this part of the study in which SAR442720 was administered orally at the previously determined RP2D in combination with pembrolizumab. The first treatment cycle was for 21 days in which participants were administered SAR442720 tablet formulation (test) and starting from C2D1, SAR442720 capsule formulation (reference) until the end of treatment. A validated LC MS/MS assay (LLOQ 1.00 ng/mL) and validated ELISA assay (LLOQ 30.0 ng/mL) was utilized for SAR442720 and pembrolizumab analysis respectively. PK parameters for SAR442720 were calculated using Non-compartmental Analysis. Food effect was assessed using a linear mixed effects model with fed state taken as a fixed effect (fed versus fasting) and patient as random variable. Formulation effect was assessed using a linear mixed effects model with formulation as a fixed effect (tablet versus capsule) and patient as random variable.

Data & Results: The observed data demonstrated that presence of food slightly delayed absorption with Tmax from 2.02 hours in fasted state to 3.75 hours in fed state and slightly reduced the maximum concentration (C_max) from 828 ng/mL in fasted state to 637 ng/mL in fed state. This delay decreased the rate and the extent of SAR442720 absorption leading to a fed/fasted geometric mean ratio (90% CI) of 0.78 (0.68 to 0.89) for C_max and 0.90 (0.69 to 1.17) for AUC_last respectively. For the formulation effect the tablet formulation demonstrated slightly faster absorption (T_max) 2.02 hours when compared to capsule formulation which was 3.6 hours and slightly increased C_max to 828 ng/mL from 658 ng/mL for capsules. Therefore, the change of the oral formulation of SAR442720 under fasted conditions, from capsules (reference) to tablets (test) resulted in a slight increase in the absorption which is translated to a more marked effect on C_max than on AUC_last: tablet/capsule geometric mean ratio (90% CI) was 1.31 (1.08 to 1.61) for C_max and 1.08 (0.82 to 1.42) for AUC_last.

Interpretation, Conclusion or Significance: Considering the extent of observed food effect, it can be concluded that the presence of food had a negligible effect on SAR442720 exposure, therefore it can be administered with or without food. Similarly, from a formulation bridging perspective, the observed changes in SAR442720 exposure with tablet instead of capsule administration is not considered clinically meaningful.

Disclosures: KJ, DS, SM, YZ, OY and GA are employees of and hold stock in Sanofi. ZW and XW are employees of and hold stock in Revolution Medicines.

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Additional Information/Authors: This study was sponsored by Sanofi.