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

— Follows important findings from the TATTON¹ study of the combination in EGFR inhibitor refractory lung cancer patients whose tumors harbor aberrations of MET —

HONG KONG and FLORHAM PARK, N.J., Nov. 24, 2021 (GLOBE NEWSWIRE) -- HUTCHMED (China) Limited (“HUTCHMED”) (Nasdaq/AIM:HCM; HKEX:13) and AstraZeneca Pharmaceuticals LP (“AstraZeneca”) (LSE/STO/Nasdaq:AZN) have initiated SACHI, a China Phase III study of ORPATHYS^® (savolitinib), an oral, potent, and highly selective MET tyrosine kinase inhibitor (“TKI”), in combination with AstraZeneca’s third-generation, irreversible epidermal growth factor receptor (“EGFR”) TKI, TAGRISSO^® (osimertinib). The first patient received their first dose on November 22, 2021.

The Phase III trial is a multi-center, open-label, randomized, controlled study in patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer (“NSCLC”) with MET amplification after disease progression on EGFR inhibitor therapy. The study will evaluate the efficacy and safety of ORPATHYS^® in combination with TAGRISSO^®, compared to platinum-based doublet-chemotherapy (pemetrexed plus cisplatin or carboplatin), the standard-of-care treatment option in this setting. The primary endpoint of the study is median progression free survival (“PFS”) as assessed by investigators. 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. Additional details may be found at clinicaltrials.gov, using identifier NCT05015608.

About NSCLC, EGFR and MET Aberrations

Lung cancer is the leading cause of cancer death among men and women, accounting for about one-fifth of all cancer deaths.² More than a third of the world’s lung cancer patients are in China.³ Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.⁴ The majority of NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis.^5,6 For patients with resectable tumors, the majority of patients eventually develop recurrence despite complete tumor resection and adjuvant chemotherapy.⁷

Approximately 10-25% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFR-mutated NSCLC.^8,9,10 These patients are particularly sensitive to treatment with an EGFR TKI which blocks the cell-signaling pathways that drive the growth of tumor cells.¹¹

MET is a tyrosine kinase receptor.¹² Aberration of MET (amplification or overexpression) is present in both treatment naïve patients as well as being one of the primary mechanisms of acquired resistance to EGFR TKIs for metastatic EGFR-mutated NSCLC.^13,14

About Savolitinib (ORPATHYS^® in China)

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) or gene amplification.

Savolitinib is marketed in China under the brand name ORPATHYS^® 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 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, following its discovery and initial development by HUTCHMED, AstraZeneca and HUTCHMED entered a global licensing agreement to jointly develop and commercialize savolitinib. Joint development in China is led by HUTCHMED, while AstraZeneca leads development outside of China. HUTCHMED is responsible for the marketing authorization, manufacturing and supply of savolitinib in China. AstraZeneca is responsible for the commercialization of savolitinib in China and worldwide. Sales of savolitinib are recognized by AstraZeneca.

Savolitinib development in NSCLC

Phase II study of savolitinib monotherapy in MET Exon 14 skipping alteration NSCLC (NCT02897479) – In June 2021, savolitinib was granted drug registration conditional approval by the National Medical Products Administration of China (NMPA) for MET Exon 14 skipping alteration NSCLC. The approval was based on the results of a Phase II study in China; results of this study were published in The Lancet Respiratory Medicine¹⁵. At a median follow up of 17.6 months, savolitinib demonstrated an ORR of 42.9% (95% confidence interval [CI] 31.1-55.3) and median PFS of 6.8 months (95% CI 4.2-9.6) in the overall trial population. DCR in the overall trial population was 82.9% (95% CI 72.0-90.8). The safety and tolerability profile of savolitinib was consistent with previous trials, and no new safety signals were identified. Continued approval is contingent upon the successful completion of a confirmatory trial in this patient population (NCT04923945).

TATTON Phase Ib/II expansion studies of savolitinib in combination with TAGRISSO^® in patients who have progressed following EGFR TKI treatment due to MET amplification (NCT02143466) – This global exploratory study in over 220 EGFR mutation positive NSCLC patients with MET amplified tumors following progression after treatment with any EGFR TKI. Results were published in Lancet Oncology¹⁶ and final analysis was presented at the World Conference on Lung Cancer¹. Three cohorts with patients treated following progression on first- or second-generation EGFR TKI demonstrated an ORR of 64.7-66.7% and a median PFS of 9.0-11.1 months. The cohort of patients treated following progression on a third-generation EGFR TKI demonstrated an ORR of 33.3% (95% CI 22.4-45.7), with a median PFS of 5.5 months (95% CI 4.1-7.7). The combination demonstrated encouraging anti-tumor activity and an acceptable risk-benefit profile.

SAVANNAH Phase II study of savolitinib in combination with TAGRISSO^® in patients who have progressed following TAGRISSO® due to MET amplification or overexpression (NCT03778229) – This is a single-arm, open-label, global study in epidermal growth factor receptor (“EGFR”) mutation positive NSCLC patients with MET amplified/overexpressed tumors following progression after treatment with TAGRISSO^®, an EGFR TKI owned by AstraZeneca.

SACHI Phase III study of savolitinib in combination with TAGRISSO^® in patients who have progressed following EGFR TKI treatment due to MET amplification (NCT05015608) – This is a randomized, open-label study in China in EGFR mutation positive NSCLC patients with MET amplified tumors following progression after treatment with any EGFR TKI.

SANOVO Phase III study of savolitinib in combination with TAGRISSO^® in treatment-naïve patients with EGFR mutant positive NSCLC with MET overexpression (NCT05009836) – This is a randomized, blinded study in China in untreated, unresectable or metastatic patients with EGFR mutation positive NSCLC with MET positive tumors.

Savolitinib development in kidney cancer

SAVOIR randomized, controlled study of savolitinib monotherapy in MET-driven papillary renal cell carcinoma (“RCC”) (NCT03091192) – In May 2020, data from 60 patients in this global study of savolitinib monotherapy compared with sunitinib monotherapy in MET-driven papillary RCC was presented at the ASCO 2020 Program and published simultaneously in JAMA Oncology¹⁷. Savolitinib demonstrated encouraging activity, including an ORR of 27% versus 7% for sunitinib, with no savolitinib responding patients experiencing disease progression at data cut-off, and an encouraging OS hazard ratio of 0.51 (95% CI: 0.21–1.17; p=0.110) with median not reached at data cut-off.

CALYPSO Phase I/II study of savolitinib in combination with IMFINZI^® PD-L1 inhibitor in RCC (NCT02819596) – The CALYPSO study is an investigator initiated open-label Phase I/II study of savolitinib in combination with IMFINZI^®, a PD-L1 antibody owned by AstraZeneca. The study is evaluating the safety and efficacy of the savolitinib/IMFINZI^® combination in patients with papillary RCC and clear cell RCC. An analysis of 41 patients enrolled in the papillary RCC cohort of in this study was presented at the 2021 ASCO Annual Meeting¹⁸, showing a confirmed response rate in 8 out of the 14 MET-driven patients, or 57%, with a median DoR of 9.4 months, median PFS of 10.5 months and median OS of 27.4 months. No new safety signals were seen.

SAMETA Phase III study in combination with IMFINZI^® PD-L1 inhibitor in MET-driven, unresectable and locally advanced or metastatic papillary RCC (NCT05043090) – Based on the encouraging results of the SAVOIR and CALYPSO studies, we have initiated SAMETA, a global Phase III, open-label, randomized, controlled study of savolitinib plus IMFINZI^® versus sunitinib monotherapy versus IMFINZI^® monotherapy in patients with MET-driven, unresectable and locally advanced or metastatic papillary RCC.

Savolitinib development in gastric cancer

Phase II study of savolitinibmonotherapy in advanced or metastatic MET amplified gastric cancer (“GC”) or adenocarcinoma of the gastroesophageal junction (“GEJ”) (NCT04923932) – This is an open-label, two-cohort, multi-center study to evaluate the efficacy, safety and pharmacokinetics (PK) of savolitinib in locally advanced or metastatic GC or GEJ patients whose disease progressed after at least one line of standard therapy.

This trial follows multiple Phase II studies that have been conducted in Asia to study savolitinib in MET-driven GC patients, including VIKTORY.¹⁹ VIKTORY is an investigator-initiated Phase II umbrella study in GC in South Korea in which a total of 715 patients were successfully sequenced into molecular-driven patient groups, including those with MET amplified GC. Patients whose tumors harbor MET amplification were treated with savolitinib monotherapy, reporting an ORR of 50% (10/20, 95% CI: 28.0, 71.9).

Savolitinib development in other cancer indications

Savolitinib opportunities are also continuing to be explored in multiple other MET-driven tumor settings via investigator-initiated studies including colorectal cancer.

About TAGRISSO^®

TAGRISSO^® (osimertinib) is a third-generation, irreversible EGFR TKI with clinical activity against central nervous system metastases. TAGRISSO^® (40mg and 80mg once-daily oral tablets) has been used to treat more than 485,000 patients across indications worldwide and AstraZeneca continues to explore TAGRISSO^® as a treatment for patients across multiple stages of EGFR-mutated NSCLC.

In Phase III trials, TAGRISSO^® is being tested in the neoadjuvant resectable setting (NeoADAURA), in the Stage III locally advanced unresectable setting (LAURA) and, in combination with chemotherapy, in the Stage III locally advanced or Stage IV metastatic settings (FLAURA2). AstraZeneca is also researching ways to address tumor mechanisms of resistance through the SACHI and SANOVO Phase III trials, as well as the SAVANNAH and ORCHARD Phase II trials, which test TAGRISSO^® given concomitantly with savolitinib, (ORPATHYS^® in China), as well as other potential new medicines.

About HUTCHMED

HUTCHMED (Nasdaq/AIM:HCM; HKEX:13) is an innovative, commercial-stage, biopharmaceutical company. It is committed to the discovery and global development and commercialization of targeted therapies and immunotherapies for the treatment of cancer and immunological diseases. It has more than 4,500 personnel across all its companies, at the center of which is a team of over 1,400 in oncology/immunology. Since inception it has advanced eleven cancer drug candidates from in-house discovery into clinical studies around the world, with its first three oncology drugs now approved and marketed. For more information, please visit: www.hutch-med.com or follow us on LinkedIn.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect HUTCHMED’s current expectations regarding future events, including its expectations regarding the therapeutic potential of savolitinib for the treatment of patients with NSCLC, the further clinical development of savolitinib in this and other indications, its expectations as to whether clinical studies of savolitinib would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding the sufficiency of its data to support New Drug Application approval of savolitinib for the treatment of patients with NSCLC in China, its potential to gain expeditious approvals for savolitinib in other jurisdictions such as E.U. or Japan, the safety profile of savolitinib the potential for savolitinib to become a new standard of care for NSCLC patients, its ability to implement and complete its further clinical development plans for savolitinib its potential commercial launch in the U.S., E.U., Japan, China and other jurisdictions, the timing of these events, and the impact of the COVID-19 pandemic on general economic, regulatory and political conditions. In addition, as certain studies rely on the use of TAGRISSO^® and IMFINZI^® as combination therapeutics with savolitinib, such risks and uncertainties include assumptions regarding the safety, efficacy, supply and continued regulatory approval of TAGRISSO^® and IMFINZI^®. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see HUTCHMED’s filings with the U.S. Securities and Exchange Commission, on AIM and with The Stock Exchange of Hong Kong Limited. HUTCHMED undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise.

CONTACTS

¹ Han JY, et al. Osimertinib + savolitinib in patients with EGFRm MET-amplified/overexpressed NSCLC: Phase Ib TATTON Parts B and D final analysis. WCLC January 2021 #FP14.03. doi: 10.1016/j.jtho.2021.01.146.
² World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Available at gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed June 2021.
³ World Health Organization. International Agency for Research on Cancer. Globocan China Fact Sheet 2020. Available at gco.iarc.fr/today/data/factsheets/populations/160-china-fact-sheets.pdf. Accessed June 2021.
⁴ LUNGevity Foundation. Types of Lung Cancer. Available at lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer. Accessed June 2021.
⁵ Cagle PT, Allen TC, Olsen RJ. Lung Cancer Biomarkers: Present Status and Future Developments. Arch Pathol Lab Med. 2013;137(9):1191-1198. doi: 10.5858/arpa.2013-0319-CR.
⁶ Le Chevalier T, et al. Adjuvant Chemotherapy for Resectable Non-Small Cell Lung Cancer: Where is it Going? Ann Oncol. 2010;21:vii196-vii198. doi: 10.1093/annonc/mdq376.
⁷ Pignon J, et al. Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552-3559. doi: 10.1200/jco.2007.13.9030.
⁸ Zhang YL, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985-78993. doi: 10.18632/oncotarget.12587.
⁹ Keedy V.L., et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients with Advanced Non-Small Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol. 2011:29;2121-27. doi: 10.1200/JCO.2010.31.8923.
¹⁰ Ellison G, et al. EGFR Mutation Testing in Lung Cancer: a Review of Available Methods and Their Use for Analysis of Tumour Tissue and Cytology Samples. J Clin Pathol. 2013:66;79-89. doi: 10.1136/jclinpath-2012-201194.
¹¹ Cross DA, et al. AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer. Cancer Discov. 2014;4(9):1046-1061. doi: 10.1158/2159-8290.CD-14-0337.
¹² Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Ther Adv Med Oncol 2011; 3(1 Suppl):S7-S19. doi: 10.1177/1758834011422556.
¹³ Ramalingham SS, et al. Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study. Ann Oncol. 2018; 29, SUPPLEMENT 8, VIII740. doi: 10.1093/annonc/mdy424.063.
¹⁴ Sterlacci W, et al. MET overexpression and gene amplification: prevalence, clinico-pathological characteristics and prognostic significance in a large cohort of patients with surgically resected NSCLC. Virchows Arch. 2017;471(1):49-55. doi:10.1007/s00428-017-2131-1.
¹⁵ Lu S, et al. Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study. Lancet Respir Med. 2021 Jun 21:S2213-2600(21)00084-9. doi: 10.1016/S2213-2600(21)00084-9.
¹⁶ Sequist LV, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study. Lancet Oncol. 2020;21(3):373-386. doi:10.1016/S1470-2045(19)30785-5.
¹⁷ Choueiri TK, et al. Efficacy of Savolitinib vs Sunitinib in Patients With MET-Driven Papillary Renal Cell Carcinoma: The SAVOIR Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Aug 1;6(8):1247-1255. doi: 10.1001/jamaoncol.2020.2218.
¹⁸ Suarez C, et al. Clinical activity of durvalumab and savolitinib in MET-driven, metastatic papillary renal cancer. J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4511-4511. doi: 10.1200/JCO.2021.39.15_suppl.4511.
¹⁹ Lee J, et al. Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial. Cancer Discov. 2019;9(10):1388-1405. doi: 10.1158/2159-8290.CD-19-0442.