▎WuXi AppTec Content Team Report

On April 9, GEN HOUSE announced its collaboration with AstraZeneca（AstraZeneca）Establish clinical research collaboration, both parties will exploreSHP2 InhibitorGH21 in combination with Osimertinib MesylateNon-Small Cell Lung Cancer (NSCLC)Clinical efficacy.It was reported that this study is an open-label, multi-center, Phase 1b/2 study aimed at evaluating the combination therapy inwith epidermal growth factor receptor (EGFR) Mutation in Advanced NSCLCSafety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral Administration in Patients, the first patient has completed the initial dosing recently.

SHP2Has received widespread attention in recent years, itsLocated downstream of most receptor tyrosine kinases (RTKs), mediating critical signaling pathways for cell growth and survival; also situated downstream of immune checkpoints such as PD1 and BTLA, mediating tumor immune escape signals.GH21 is a small-molecule inhibitor targeting SHP2, effective against variousSHP2Point mutation is effective.According to the introduction in the GEN HOUSE press release,Studies in vivo and in vitro have shown that GH21 has low off-target risk, high oral bioavailability, and a wide safety margin, making it a small-molecule anti-tumor drug with significant development potential. Non-clinical studies have indicated that GH21, as a single agent or in combination with other anti-tumor drugs, is effective against various solid tumors.Currently, GH21 is undergoing clinical research in both China and the United States.Demonstrated good PK and safety in clinical studies, with efficacy signals observed even in the low-dose group.

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) that has brought significant clinical benefits to patients with NSCLC. However, with long-term use, resistance issues have gradually emerged, and the mechanisms of resistance have become more complex, involving secondary...EGFRMutation such asC797SMultiple mechanisms such as mutations, bypass RTK activation like MET amplification, and transformations into small cell lung cancer, squamous cell carcinoma, and sarcoma. Therefore, effective treatment strategies for resistance to third-generation EGFR-TKI are still urgently needed.

Studies show that the combination of SHP2 inhibitors with Osimertinib has the potential to enhance clinical benefits for patients.In preclinical studies, the combination of GH21 and osimertinibEGFR C797SMutation/METThe efficacy demonstrated in amplification and other models provides new possibilities for future clinical treatments.

[1] GEN HOUSE collaborates with AstraZeneca to evaluate the clinical efficacy of GH21 combined with Osimertinib in treating non-small cell lung cancer patients. Retrieved Apr 9 , 2024, from https://mp.weixin.qq.com/s/ulyfdwbqzQuLuxltA1mEyw