On October 16, 2024 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:​HCM; HKEX:​13) reported positive high-level results from the SAVANNAH Phase II trial that showed TAGRISSO (osimertinib) plus ORPATHYS (savolitinib) demonstrated a high, clinically meaningful and durable objective response rate ("ORR") for patients with epidermal growth factor receptor-mutated ("EGFRm") non-small cell lung cancer ("NSCLC") with high levels of MET overexpression and/or amplification, defined as IHC90+ and/or FISH10+, whose disease progressed on treatment with TAGRISSO (Press release, HUTCHMED, OCT 16, 2024, View Source [SID1234647228]). These data will be presented at a forthcoming medical meeting and shared with global regulatory authorities. In 2023, TAGRISSO plus ORPATHYS received Fast Track designation from the US Food and Drug Administration (FDA) in this setting.

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ORPATHYS is an oral, potent, and highly selective MET tyrosine kinase inhibitor ("TKI") being jointly developed by AstraZeneca and HUTCHMED and commercialized by AstraZeneca. It is approved in China for the treatment of patients with NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy.

While EGFR-targeted therapy can provide a substantial survival benefit to patients with EGFRm NSCLC, most will eventually develop resistance to their treatment, with MET being a common resistance biomarker.1 Among patients screened for enrollment in SAVANNAH, an estimated 62% had tumors with MET overexpression and/or amplification, and approximately 34% met the defined high MET level cut-off upon clinical progression.

Myung-Ju Ahn, MD, PhD, Professor of Hemato-Oncology at the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, and principal investigator in the SAVANNAH Phase II trial, said: "Osimertinib can provide patients with EGFR-mutated lung cancer unprecedented survival and has transformed the treatment landscape, but patients can develop resistance due to genes like MET – a common resistance biomarker. These results show that adding savolitinib, a selective MET-inhibitor, while continuing osimertinib treatment helped to deliver a meaningful response among patients whose disease progressed, providing a potential new treatment option following standard-of-care osimertinib."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "These positive SAVANNAH results show the benefit of a targeted treatment approach in EGFR-mutated lung cancer patients who experience MET-driven resistance. The improved response rates from ORPATHYS added to TAGRISSO, which is the backbone EGFR-mutated lung cancer therapy, reinforce the importance of identifying MET aberration and validate our combination strategy to address resistance while allowing continued TAGRISSO treatment."

Weiguo Su, Chief Executive Officer and Chief Scientific Officer, HUTCHMED, said: "Previous results from the SAVANNAH Phase II trial provided a novel biomarker approach for identifying patients with MET overexpression and/or amplification who are most likely to benefit from a MET-directed therapy, an existing unmet need. These new, positive results affirm our selective, patient-centric approach, which could allow us to deliver the first biomarker-driven targeted therapy combination option in this setting."

The safety and tolerability of TAGRISSO plus ORPATHYS was consistent with the known safety profiles of the combination and each treatment alone. No new safety signals were identified.

In August 2022, initial positive ORR results from the SAVANNAH trial were presented at the International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer (WCLC).

The global SAFFRON Phase III trial sponsored by AstraZeneca will further assess the TAGRISSO plus ORPATHYS combination versus platinum-based doublet chemotherapy in patients with EGFRm, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC following TAGRISSO. Patients are being prospectively selected using the high MET level cut-off identified in SAVANNAH.

About NSCLC and MET aberrations

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.2,3 Lung cancer is broadly split into NSCLC and small cell lung cancer.4 Each year there are an estimated 2.4 million people diagnosed with lung cancer globally, with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.2,4,5 Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC. 6,7,8

MET is a tyrosine kinase receptor that has an essential role in normal cell development. MET overexpression and/or amplification can lead to tumor growth and the metastatic progression of cancer cells, and is the primary mechanism of acquired resistance to EGFR TKIs for metastatic EGFRm NSCLC. Among patients who experience disease progression post-osimertinib treatment, approximately 15-50% present with MET aberration. 9,10,11,12,13 The prevalence of MET depends on the sample type, detection method and assay cut-off used.14

About SAVANNAH

SAVANNAH is an ongoing global, randomised, Phase II trial sponsored by AstraZeneca studying the efficacy of ORPATHYS added to TAGRISSO in patients with EGFRm, locally advanced or metastatic NSCLC with MET overexpression and/or amplification who progressed following treatment with TAGRISSO. Based on the original single-arm trial design, patients were treated with ORPATHYS 300 or 600 mg once-daily (QD) or 300 mg twice-daily, in combination with oral TAGRISSO 80 mg QD. In 2022, a registrational component was added to the trial that compared ORPATHYS 300 mg twice-daily and TAGRISSO 80 mg QD to ORPATHYS 300 mg twice-daily and placebo.

The trial enrolled over 360 patients in more than 80 centers globally, including in North America, Europe, South America and Asia. The primary endpoint is ORR and key secondary endpoints include progression-free survival and duration of response.

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.

About ORPATHYS

ORPATHYS (savolitinib) 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.

It is approved in China for the treatment of patients with NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. It is the first selective MET inhibitor approved in China and the first in the National Reimbursement Drug List of China (NRDL).

It 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 addition to SAVANNAH and SAFFRON, in China the combination of savolitinib and osimertinib in lung cancer is also being studied in the SACHI and SANOVO Phase III trials.