HUTCHMED and AstraZeneca Launch Phase III SACHI Trial of ORPATHYS® and TAGRISSO® Combination Therapy in China for EGFR-Mutant, MET-Amplified NSCLC Patients Post-EGFR Inhibitor Failure

On November 24, 2021, HUTCHMED and AstraZeneca announced the initiation of a Phase 3 clinical trial in China. The trial will be conducted in lung cancer patients with EGFR and MET mutations or abnormalities who have relapsed after treatment with EGFR inhibitors. It aims to evaluate the efficacy and safety of the highly selective and potent oral mesenchymal-epithelial transition factor (MET) tyrosine kinase inhibitor (TKI) Orpathys (savolitinib), in combination with AstraZeneca's third-generation irreversible epidermal growth factor receptor (EGFR) TKI Tagrisso (osimertinib). The first patient was dosed on November 22, 2021.

Lung cancer accounts for approximately one-fifth of all cancer-related deaths. The number of lung cancer patients in China accounts for more than one-third of the global total. Lung cancer is typically divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with 80-85% being NSCLC. Among Asian NSCLC patients, about 30-40% have EGFR mutations, and these patients are particularly sensitive to EGFR-TKI treatment. As an irreversible third-generation EGFR-TKI, Tagrisso can simultaneously inhibit both EGFR-sensitizing mutations and the EGFR-T790M resistance mutation, while demonstrating clinical efficacy against central nervous system metastases. This inhibitor blocks the signaling pathways that drive tumor cell growth.

In China, Tagrisso was first approved in March 2017 for second-line treatment of patients with advanced NSCLC who have EGFR T790M mutation-positive, and was approved in October 2019 for first-line treatment of patients with EGFR mutation-positive advanced NSCLC. Currently, Tagrisso has been approved for marketing in more than 80 countries and regions worldwide.

MET is a receptor tyrosine kinase. MET amplification or overexpression can occur not only in untreated NSCLC patients but also serves as one of the primary mechanisms of acquired resistance to EGFR-TKI treatment in EGFR-mutant metastatic NSCLC patients. Orpathys is a potent, highly selective oral MET-TKI that has demonstrated positive clinical activity in advanced solid tumors. Orpathys can block abnormal activation of the MET receptor tyrosine kinase signaling pathway caused by mutations (such as exon 14 skipping mutations or other point mutations) or gene amplification.

AstraZeneca's Drug Approved in China for Treatment of NSCLC Patients with MET Exon 14 Skipping MutationsVolitinib has been approved for marketing in China for the treatment of patients with non-small cell lung cancer (NSCLC) who have MET exon 14 skipping mutations and whose disease has progressed after systemic therapy or who are unable to receive chemotherapy. Currently, volitinib is being developed as a monotherapy or in combination with other drugs for the treatment of various tumor types, including lung cancer, renal cancer, and gastric cancer.

This open-label, randomized controlled, multi-center Phase III clinical trial will be conducted in patients with locally advanced or metastatic NSCLC who have progressed following treatment with EGFR inhibitors, and who have EGFR mutations accompanied by MET amplification. The trial will evaluate the efficacy and safety of Tagrisso in combination with Orpathys versus platinum-based doublet chemotherapy (current standard of care). The primary endpoint is investigator-assessed median progression-free survival (PFS). Other endpoints include median PFS assessed by an independent review committee, median overall survival (OS), objective response rate (ORR), duration of response (DoR), disease control rate (DCR), time to response (TTR), and safety.

References:

[1] HUTCHMED and AstraZeneca Initiate SACHI Phase III Trial of ORPATHYS® and TAGRISSO® Combination in Certain Lung Cancer Patients in China After Progression on EGFR Inhibitor Therapy. Retrieved November 23, from https://www.globenewswire.com/news-release/2021/11/24/2340238/0/en/HUTCHMED-and-AstraZeneca-Initiate-SACHI-Phase-III-Trial-of-ORPATHYS-and-TAGRISSO-Combination-in-Certain-Lung-Cancer-Patients-in-China-After-Progression-on-EGFR-Inhibitor-Therapy.html

[2] HUTCHMED and AstraZeneca Initiate SACHI China Phase III Clinical Trial of ORPATHYS® (Volitinib) and TAGRISSO® (Osimertinib) Combination Therapy for Certain Lung Cancer Patients with Disease Progression After EGFR Inhibitor Treatment. Retrieved November 24, 2021, from https://www.hutch-med.com/sc/sachi-phase-iii-trial-initiated/

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