FRESCO-2: A global phase 3 study of the efficacy and safety of fruquintinib in patients (pts) with metastatic colorectal cancer (mCRC)

Arvind Dasari, James Yao, Alberto Sobrero, Takayuki Yoshino, William Schelman, Shivani Nanda, Caly Chien, Su-Fen Pu, Marek Kania, Josep Tabernero, Cathy Eng

Background: Pts with mCRC have limited treatment options following progression on standard therapies.  Current standard of care (SOC) after pts progress on trifluridine/tipiracil (TAS-102) or regorafenib is re-challenge with previous systemic treatments, enrollment in a clinical trial, or best supportive care (BSC).  Fruquintinib (Elunate) is a novel, highly selective, vascular endothelial growth factor (VEGF) receptor (VEGFR)-1, -2, and -3 tyrosine kinase inhibitor (TKI) (Cancer Biol Ther 2014;15:1635-1645).  Fruquintinib is approved in China to treat pts with mCRC who received or are intolerant to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-epidermal growth factor receptor (EGFR) therapy.  Approval was based on results of the phase 3 FRESCO study (2013-013-00CH1; NCT02314819; JAMA 2018;319:2486-2496), in which fruquintinib 5 mg daily (QD), 3 weeks on, 1 week off (3 on/1 off), significantly improved overall survival (OS) in pts with mCRC in the 3rd-line+ setting when compared to placebo (median OS 9.3 months [mo] versus 6.6 mo; hazard ratio [HR] 0.65; p <.001).  Progression-free survival (PFS) was also superior (median PFS 3.7 mo versus 1.8 mo; HR 0.26; p <.001).  The toxicities of fruquintinib were consistent with those of other VEGF TKIs and were manageable.  At the time FRESCO was conducted in China, SOC for pts with mCRC differed from that in the US, EU, and Japan.  We describe here a global phase 3 study (FRESCO-2; 2019-013-GLOB1; NCT04322539) being conducted to investigate fruquintinib’s efficacy and safety in pts with refractory mCRC and a treatment profile representative of the global SOC.

Methods: FRESCO-2 is a randomized, double-blind, placebo-controlled study to compare fruquintinib + BSC to placebo + BSC.  Key inclusion criteria are progression on or intolerance to treatment with TAS-102 and/or regorafenib; previous treatment with standard approved therapies including chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-EGFR therapy.  Prior therapy with immune checkpoint or BRAF inhibitors is required for pts with corresponding tumor alterations.  Pts (~522) will be randomized 2:1 to receive either fruquintinib 5 mg orally (PO) QD + BSC or placebo 5 mg PO QD + BSC, with a 3 on/1 off schedule.  Randomization will be stratified by prior therapy, RAS status, and duration of metastatic disease.  The primary endpoint is OS; secondary endpoints include PFS, disease control rate, objective response rate, duration of response, and safety.  Final OS analyses will be performed when 364 OS events are observed; futility analysis will be conducted with 1/3 (121) OS events.  If enrichment of post-regorafenib pts occurs, enrollment to that strata will be capped at approximately 262.  FRESCO-2 will be activated in the US, EU, and Japan; global enrollment is anticipated over 13 mo.

Hong Kong, Shanghai, & Florham Park, NJ: Thursday, January 14, 2021: Hutchison China MediTech Limited (“Chi-Med”) (Nasdaq/AIM: HCM) today announces that the final analysis of savolitinib in Phase Ib TATTON study Parts B and D will be presented at the upcoming virtual 2020 World Conference on Lung Cancer (WCLC 2020), taking place on January 28-31, 2021, virtually.

Further details of the featured poster presentation are as follows:

About Savolitinib

Savolitinib is an oral, potent, and highly selective small molecule inhibitor of MET, a receptor tyrosine kinase which has been shown to function abnormally in many types of solid tumors promoting tumor growth, angiogenesis, and metastasis.  Savolitinib has been studied in over 1,000 patients to date.  In clinical studies, it has shown promising clinical efficacy in patients with MET gene alterations in multiple tumor types with an acceptable safety profile.

In 2011, Chi-Med entered into a global licensing and joint development and commercialization agreement with AstraZeneca PLC (LSE/STO/NYSE: AZN) for savolitinib.  Savolitinib’s global development plan includes non-small cell lung cancer (“NSCLC”) and kidney cancer, and additional MET-driven tumors are being explored.

Savolitinib development in NSCLC:

Phase II in MET Exon 14 alteration NSCLC (NCT02897479) – In May 2020, data from an ongoing open-label, Phase II registration study was presented as part of the American Society of Clinical Oncology 2020 Virtual Scientific Program (“ASCO 2020”).  In patients with MET Exon 14 skipping alteration NSCLC in the efficacy evaluable population, savolitinib demonstrated a 49.2% objective response rate (“ORR”), a 93.4% disease control rate (DCR) and a 9.6 months interim duration of response (“DoR”).  36% of patients in the study have pulmonary sarcomatoid carcinoma (PSC), an aggressive subtype of NSCLC.  Data were not yet mature for DoR, progression-free survival (PFS) or overall survival (“OS”).  Clinical data indicated an acceptable safety profile, with a low adverse event (AE) related discontinuations rate of 14.3%.  This data supported the China new drug application (“NDA”) acceptance in May 2020.

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

Savolitinib development in kidney cancer:

MET-driven papillary renal cell carcinoma (“RCC”) (NCT03091192) – In May 2020, data from 60 patients in the SAVOIR global study of savolitinib monotherapy compared with sunitinib monotherapy in MET-driven papillary RCC was presented at ASCO 2020.  Savolitinib demonstrated encouraging activity, including an ORR of 27% versus 7% for sunitinib, with no savolitinib responding patients with 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 II 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.

Based on these data, AstraZeneca and Chi-Med are actively evaluating the opportunity to progress clinical work in papillary RCC for savolitinib.

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 gastric cancer and colorectal cancer.

About Chi-Med

Chi-Med (Nasdaq/AIM: HCM) is an innovative biopharmaceutical company committed, over the past twenty years, to the discovery and global development of targeted therapies and immunotherapies for the treatment of cancer and immunological diseases.  It has a portfolio of nine cancer drug candidates currently in clinical studies around the world and extensive commercial infrastructure in its home market of China. For more information, please visit: www.chi-med.com.

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 Chi-Med’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 NDA 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 the U.S., 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 of savolitinib in 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 Chi-Med’s filings with the U.S. Securities and Exchange Commission and on AIM. Chi-Med 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.

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Hong Kong, Shanghai, San Diego & Florham Park, NJ: Monday, January 11, 2021: Hutchison China MediTech Limited (“Chi-Med”) (Nasdaq/AIM: HCM) and Inmagene Biopharmaceuticals (“Inmagene”) today announce a strategic partnership to further develop four novel preclinical drug candidates discovered by Chi-Med for the potential treatment of multiple immunological diseases. Funded by Inmagene, the companies will work together to move the drug candidates towards investigational new drug (“IND”) submission. If successful, Inmagene will then move the drug candidates through global clinical development.

Under the terms of the agreement, Chi-Med grants Inmagene exclusive options to four drug candidates solely for the treatment of immunological diseases. Should Inmagene exercise the option, it will have the right to further develop, manufacture and commercialize that specific drug candidate worldwide, with Chi-Med retaining first right to co-commercialization in mainland China. For each of the drug candidates, Chi-Med will be entitled to development milestones of up to US$95 million and up to US$135 million in commercial milestones, as well as up to double-digit royalties upon commercialization.

Christian Hogg, Chief Executive Officer of Chi-Med, said, “This partnership will enable Inmagene to investigate the immunological disease applications of these four drug candidates, discovered by our in-house discovery organization. We believe that these four candidates have scope in multiple immunological diseases and we are pleased to see these opportunities investigated further by Inmagene.”

Jonathan Wang, Chairman and Chief Executive Officer of Inmagene, added, “We are delighted to partner with Chi-Med, one of China’s flagship biopharmaceutical companies with a proven track record and excellent reputation for innovation. Focused on immunology-related therapeutic areas, Inmagene is ideally positioned to unlock the global potential of these important Chi-Med immunology innovations.”

About Chi-Med

Chi-Med (Nasdaq/AIM: HCM) is an innovative biopharmaceutical company committed, over the past twenty years, to the discovery and global development of targeted therapies and immunotherapies for the treatment of cancer and immunological diseases.  It has a portfolio of nine cancer drug candidates currently in clinical studies around the world and extensive commercial infrastructure in its home market of China. For more information, please visit: www.chi-med.com.

About Inmagene Biopharmaceuticals

Inmagene, with wholly owned subsidiaries in Shanghai, San Diego, and Hangzhou, is one of the leading companies in immunology drug development in China. It is building a strong pipeline of over ten compounds, among which IMG-020 is about to enter global clinical trials in multiple indications for registration. For additional information about Inmagene Biopharmaceuticals, please visit www.inmagenebio.com.

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 Chi-Med’s current expectations regarding future events, including its expectations for the further preclinical and clinical development of certain drug candidates in partnership with Inmagene, Chi-Med’s and Inmagene’s roles and responsibilities in the partnership, and the potential benefits of such drug candidates for the treatment of autoimmune diseases.  Forward-looking statements involve risks and uncertainties.  Such risks and uncertainties include, among other things, the ability of Chi-Med and Inmagene to develop and receive regulatory approvals for their partnered drug candidates; the risk that the potential benefits of such drug candidates do not materialize or do not outweigh the costs; the preclinical and clinical results for such drug candidates, which may not support further development or marketing approval; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials and marketing approval; Inmagene’s ability to obtain funding to complete the development and commercialization as planned; and the impact of the COVID-19 pandemic on general economic, regulatory and political conditions.  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 Chi-Med’s filings with the U.S. Securities and Exchange Commission and on AIM.  Chi-Med 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.

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