(S-034) Pharmacometric analysis of pharmacokinetics, safety, and efficacy data of migoprotafib in combination with divarasib for KRAS G12C-positive non-small cell lung cancer.

Vidya Ramakrishnan – Genentech, Inc.; Julia Suchomel – Genentech, Inc.; Tomi Jun – Genentech, Inc.; Jennifer Eng-Wong – Genentech, Inc.; Sarita Dubey – Genentech, Inc.; Mark Lin – Genentech, Inc.; Neekesh Dharia – Genentech, Inc.; Jennifer Schutzman – Genentech, Inc.; Michael Chick – Genentech, Inc.; Michelle Deng – Genentech, Inc.; Sandhya Mandlekar – Genentech, Inc.; Nastya Kassir – Genentech, Inc.

Objectives: Migoprotafib is a potent and highly selective Src homology-2 domain–containing phosphatase 2 (SHP2) inhibitor and divarasib is a covalent KRAS G12C inhibitor. The combination of migoprotafib and divarasib is currently being tested in the phase 1 study, NCT04449874, evaluating safety (per NCI-CTCAE v.5), pharmacokinetics (PK), and preliminary anti-tumor activity (per RECIST v1.1) in patients with KRAS G12C-positive non-small cell lung cancer (NSCLC) [1,2]. Migoprotafib was also previously evaluated as a single-agent in patients with advanced solid tumors in the first-in-human study [3], NCT04252339, at doses ranging from 10 to 150 mg QD. This work utilized population PK, exposure-safety (ES), and exposure-response (ER) modeling of migoprotafib alone and with divarasib to assess the potential benefit of the combination therapy over single-agent divarasib treatment in KRAS G12C-positive NSCLC.

Methods: Patients received oral migoprotafib (20, 40, or 60 mg daily [QD]) in combination with oral divarasib (200 mg or 400 mg daily [QD]) until intolerable toxicity or disease progression. Migoprotafib PK concentrations, across all solid tumors, were used to develop a population PK model using data from both the single-agent and the combination studies with migoprotafib, which allowed the estimation of steady-state exposure metrics for subsequent ES and ER analyses of data from the single-agent migoprotafib and the migoprotafib and divarasib combination study.

Results: Consistent with model predictions, migoprotafib exposures were comparable as a single agent or in combination with divarasib, suggesting a lack of PK interaction for migoprotafib. The most common treatment-related adverse events in the combination cohort were gastrointestinal events (diarrhea, nausea, and vomiting). The probability of Grade ≥3 diarrhea was higher in the combination setting than in the single-agent divarasib treatment of patients with NSCLC. While ES analysis showed no statistically significant correlation between Grade ≥3 diarrhea and migoprotafib dose or exposure (single-agent and in combination), a positive trend was observed. This suggested that 20 mg QD migoprotafib contributes to an improved gastrointestinal tolerability profile than 40 or 60 mg QD migoprotafib in combination with 400 mg QD divarasib. No responses were observed in the single-agent migoprotafib study, reflecting its limited single-agent activity, with ER analysis showing no correlation between migoprotafib exposures and response. In combination with divarasib in KRAS G12C-positive NSCLC, ER analysis showed no correlation between migoprotafib dose or exposure and the probability of disease control (defined as stable disease, partial response, or complete response). Per the ER analysis reported here, the overall contribution of increasing migoprotafib dose/exposure in the combination with divarasib, in comparison to single-agent divarasib at 400 mg QD, was unlikely to contribute to improvement in disease control.

Conclusions: ES and ER analyses did not reveal a clear exposure-safety (Grade ≥3 diarrhea) or exposure-efficacy (disease control) relationship for migoprotafib in combination with divarasib in patients with NSCLC.

Citations:

References:
1. Sacher A. et al. Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. N Engl J Med 23 Aug 2023; 389 (8): 710–721.
2. Luo J et al. Divarasib plus migoprotafib combination treatment in patients with KRAS G12C-positive non-small cell lung cancer (NSCLC). To be presented at the AACR Annual Meeting 2025; April 25-30, 2025; Chicago, IL.
3. Melissa L. et al. First Results of Migoprotafib, a Potent and Highly Selective Src Homology-2 Domain–Containing Phosphatase 2 Inhibitor in Patients with Advanced Solid Tumors. Mol Cancer Ther 1 March 2025; 24 (3): 384–391.

Keywords: Migoprotafib, divarasib, KRAS G12C-positive NSCLC