Abstract CT022: Divarasib plus migoprotafib combination treatment in patients with <i>KRAS G12C</i>-positive non-small cell lung cancer (NSCLC)
Bibliographic record
Abstract
Abstract Introduction: Divarasib (GDC-6036), an oral, highly potent, and selective next-generation KRAS G12C inhibitor (KRAS G12Ci), has shown encouraging clinical activity and tolerability as a single agent in patients with KRAS G12C-positive NSCLC. In pre-clinical models, SHP2 inhibition increases KRAS-GDP occupancy and enhances the antitumor activity of KRAS G12C inhibitors. Here, we report clinical safety and activity of combination divarasib and migoprotafib (GDC-1971; SHP2 inhibitor) in patients with NSCLC. Methods: As part of an ongoing phase I study (NCT04449874), patients received divarasib 200 mg or 400 mg daily in combination with oral migoprotafib 20, 40, or 60 mg daily, until intolerable toxicity or disease progression. Safety (NCI-CTCAE v5), pharmacokinetics, and preliminary antitumor activity (RECIST v1.1) were assessed. Circulating tumor DNA (ctDNA) analyses were performed at Cycle 1 Day 1 and Cycle 3 Day 1. Results: As of April 1, 2024, a total of 74 patients with NSCLC received combination divarasib and migoprotafib; 48 patients had no prior KRAS G12Ci exposure. Median lines of prior systemic therapy was 2 (range 0-7) and median time on study treatment was 7.2 months (range 0.3-26.0). Overall, 70 (94.6%) patients experienced at least one treatment-related adverse event (TRAE); the most common TRAEs (≥15%) were diarrhea, nausea, vomiting, peripheral edema, increased blood creatine phosphokinase, fatigue, increased amylase, increased aspartate aminotransferase and increased alanine aminotransferase. Grade 3-4 TRAEs occurred in 32 (43.2%) patients, including diarrhea in 11 (14.9%) patients, increased ALT in 4 (5.4%) patients, and pneumonitis, thrombocytopenia, and neutropenia in 3 (4.1%) patients each. There were no Grade 5 TRAEs. TRAEs led to divarasib dose reduction in 23 (31.1%) patients and migoprotafib dose reduction in 32 (43.2%) patients. Divarasib discontinuation due to TRAEs occurred in 2 (2.7%) patients; migoprotafib discontinuations due to TRAEs occurred in 5 (6.8%) patients. The pharmacokinetic profiles of both divarasib and migoprotafib in combination were similar to their respective single-agent profiles. Among the 48 patients who had no prior KRAS G12Ci exposure (all of whom had measurable disease at baseline), the confirmed ORR was 43.8% and the median PFS was 15.2 months (CI 95% 8.4-not estimated). A decline in ctDNA level was observed at Cycle 3 Day 1 upon divarasib plus migoprotafib treatment, similar to single-agent divarasib treatment. Updated data will be presented for patients both with and without prior KRAS G12Ci exposure. Conclusion: Divarasib in combination with migoprotafib demonstrated an acceptable safety profile and preliminary clinical activity in patients with KRAS G12C-positive NSCLC. Citation Format: Jia Luo, Adrian Sacher, Armando Santoro, Luis Paz-Ares, Sanjeev Deva, Hans Prennen, Maria de Miguel, Rafal Dziadziuszko, Scott A. Laurie, Manish R. Patel, Elena Garralda, Gianluca Del Conte, Loes Latten Jansen, Jayesh Desai, Rita De Cassia Costamilan, Patricia LoRusso, Ben Markman, Salvatore Siena, Pierre Freres, Marloes Van Dongen, Eugenio Fernandez, Andres Cervantes, Josiane Mourão Dias, Sergio Azevedo, Kathryn Arbour, Ruth Perets, Se Hyun Kim, Rasha Cosman, Victor Moreno, Matthew G. Krebs, Yoonha Choi, Sandhya Mandlekar, Mark T. Lin, Zhen Shi, Kenneth K. Yau, Julie Chang, Stephanie Royer-Joo, Tomi Jun, Neekesh V. Dharia, Jennifer L. Schutzman, Myung-Ju Ahn. Divarasib plus migoprotafib combination treatment in patients with KRAS G12C-positive non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT022.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".