On December 12, 2024 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:HCM; HKEX:13) reported that the Center for Drug Evaluation of China’s National Medical Products Administration ("NMPA") has granted Breakthrough Therapy Designation ("BTD") to the combination of ORPATHYS (savolitinib) and TAGRISSO (osimertinib) for the treatment of patients with locally advanced or metastatic epidermal growth factor receptor ("EGFR") mutation-positive non-small cell lung cancer ("NSCLC") with MET amplification after disease progression on EGFR inhibitor therapy (Press release, HUTCHMED, DEC 12, 2024, View Source [SID1234649073]). ORPATHYS is an oral, potent and highly selective MET tyrosine kinase inhibitor ("TKI"). TAGRISSO is a third-generation, irreversible EGFR TKI.

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This treatment combination is being evaluated in China in the ongoing multi-center, open-label, randomized, controlled, Phase III SACHI trial. The study is investigating the efficacy and safety of a combination of ORPATHYS and TAGRISSO compared to platinum-based doublet-chemotherapy (pemetrexed plus cisplatin or carboplatin), the standard-of-care treatment option, in patients with locally advanced or metastatic NSCLC with MET amplification after failure of EGFR inhibitor therapy. The primary endpoint of the study is progression-free survival ("PFS") as assessed by investigators. Other endpoints include PFS assessed by an independent review committee, overall survival (OS), objective response rate (ORR), duration of response (DoR), disease control rate (DCR), time to response (TTR), and safety (NCT05015608).

NMPA grants BTD to new drugs that treat life-threatening diseases or serious conditions for which there are no effective treatment options, and where clinical evidence demonstrates significant advantages over existing therapies. Drug candidates with BTD may be considered for conditional approval and priority review when submitting an NDA. This indicates that the development and review of the therapy for this disease indication may be expedited, to address patients’ unmet needs more quickly.

About NSCLC and MET aberrations

Lung cancer is the leading cause of cancer death, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.2 The majority of NSCLC patients (approximately 75%) are diagnosed with advanced disease, and approximately 10-15% of NSCLC patients in the US and Europe and 30-40% of patients in Asia have EGFR-mutated ("EGFRm") NSCLC.3,4,5,6

MET is a tyrosine kinase receptor that has an essential role in normal cell development.7 MET overexpression and/or amplification can lead to tumor growth and the metastatic progression of cancer cells, and is one of the mechanisms of acquired resistance to EGFR TKI for metastatic EGFR-mutated NSCLC.7,8 Approximately 2-3% of NSCLC patients have tumors with MET exon 14 skipping alterations, a targetable mutation in the MET gene.9 MET aberration is a major mechanism for acquired resistance to both first/second-generation EGFR TKIs as well as third-generation EGFR TKIs like osimertinib. Among patients who experience disease progression post-osimertinib treatment, approximately 15-50% present with MET aberration.10,11,12,13,14 The prevalence of MET aberration depends on the sample type, detection method and assay thresholds used.15

About ORPATHYS and TAGRISSO Combination Development in EGFR mutation-positive NSCLC

The combination of ORPATHYS and TAGRISSO has been studied extensively in patients with EGFR mutation-positive NSCLC, including the TATTON (NCT02143466) and SAVANNAH (NCT03778229) studies. The encouraging results from these studies led to the initiation of three Phase III trials with this combination: SACHI (NCT05015608) and SANOVO (NCT05009836) were initiated in China in 2021, and the global, pivotal Phase III SAFFRON (NCT05261399) study started enrollment in 2022. In comparison to other treatment options, this combination treatment is chemotherapy-free, biomarker-specific and orally administered, aiming for a balanced efficacy, safety and quality-of-life profile for lung cancer patients.

SAVANNAH is a global Phase II study in patients who have progressed following osimertinib due to MET amplification or overexpression, and recruitment completed earlier in 2024. The evaluation of savolitinib in combination with osimertinib was designated as a Fast Track development program by the US Food and Drug Administration (FDA) in 2023.

SAFFRON is a multi-center, randomized, controlled, open-label, global Phase III trial in patients with EGFR mutation-positive NSCLC with MET overexpression and/or amplification after disease progression on osimertinib.

SACHI is a multi-center, randomized, controlled, open-label, China Phase III trial in patients with EGFR mutation-positive NSCLC with MET amplification after disease progression on any EGFR inhibitor therapy, including third-generation EGFR-TKIs such as osimertinib.

SANOVO is a multi-center, randomized, controlled, blinded, China Phase III trial in treatment-naïve patients with EGFR mutation-positive NSCLC with MET-positive tumors.

About ORPATHYS Approval in China

ORPATHYS was granted conditional approval in China for the treatment of patients with locally advanced or metastatic NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. ORPATHYS is the first selective MET inhibitor approved in China. It has been included in the National Reimbursement Drug List of China (NRDL) since March 2023. A supplementary NDA is under review which, if approved, could expand this indication to include treatment-naïve adult patients in China. More than a third of the world’s lung cancer patients are in China and, among those with NSCLC globally, approximately 2-3% have tumors with MET exon 14 skipping alterations.

About ORPATHYS (savolitinib)

ORPATHYS is an oral, potent and highly selective MET TKI that has demonstrated clinical activity in advanced solid tumors. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression.

ORPATHYS is marketed in China and is currently under clinical development for multiple tumor types, including lung, kidney and gastric cancers, as a single treatment and in combination with other medicines.

In 2011, AstraZeneca and HUTCHMED entered a global licensing and collaboration agreement to jointly develop and commercialize ORPATHYS. Joint development of ORPATHYS in China is led by HUTCHMED, while AstraZeneca leads development outside of China. HUTCHMED is responsible for the marketing authorization, manufacturing and supply of ORPATHYS in China. AstraZeneca is responsible for the commercialization of ORPATHYS in China and worldwide. Sales of ORPATHYS are recognized by AstraZeneca.

About TAGRISSO

TAGRISSO (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system (CNS) metastases. TAGRISSO (40mg and 80mg once-daily oral tablets) has been used to treat nearly 800,000 patients across its indications worldwide and AstraZeneca continues to explore TAGRISSO as a treatment for patients across multiple stages of EGFRm NSCLC.

There is an extensive body of evidence supporting the use of TAGRISSO as standard of care in EGFRm NSCLC. TAGRISSO improved patient outcomes in early-stage disease in the ADAURA Phase III trial, locally advanced disease in the LAURA Phase III trial, late-stage disease in the FLAURA Phase III trial, and with chemotherapy in the FLAURA2 Phase III trial.