Hutchison China MediTech Limited (Chi-Med) has initiated a phase II study of a combination therapy using fruquintinib and Iressa in the first-line setting for patients with advanced or metastatic non-small cell lung cancer (NSCLC) in China. Fruquintinib is a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFR). The first drug dose was administered on January 9, 2017.

This phase II combination therapy study is a multi-center, single-arm, open-label study. The objectives are to evaluate the safety and tolerability as well as preliminary efficacy of the combination therapy in the first-line setting for advanced or metastatic non-squamous NSCLC patients with epidermal growth factor receptor (EGFR) activating mutations. Treatment will be continued until disease progression or intolerable toxicity occurs.

At an advanced stage, tumours secrete large amounts of vascular endothelial growth factors (VEGF), which are protein ligandsthat stimulate formation of excessive vasculature (angiogenesis) around the tumour in order to provide greater blood flow, oxygen, and nutrients to the tumour.  VEGF and VEGFR play a pivotal role in tumour-related angiogenesis. Inhibition of the VEGF/VEGFR pathway represents an important therapeutic strategy in blocking the development of new blood vessels essential for tumors to grow and invade.

Every year, it is estimated that approximately 1.7 million new patients around the world are diagnosed with NSCLC, according to Frost & Sullivan.  Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-quarter of all cancer deaths (American Cancer Society), and more than breast, prostate and colorectal cancers combined.

NSCLC patients with EGFR activating mutations, which are an estimated 10-15% of NSCLC patients in the United States and Europe and 30-40% of NSCLC patients in Asia, are particularly sensitive to treatment with currently available EGFR-TKIs.  However, tumours almost always develop resistance to treatment leading to disease progression.  Combining therapies that inhibit different signalling pathways has the potential to be more effective than inhibition of a single pathway and to overcome tumour resistance.

Fruquintinib (HMPL-013) is a highly selective small molecule drug candidate that has been shown to inhibit VEGFR 24 hours a day via an oral dose without known off-target toxicities.  It is currently under the joint development in China by Chi-Med and its partner Eli Lilly and Company.  Two late-stage, pivotal Phase III registration studies are ongoing in colorectal cancer (FRESCO) and lung cancer (FALUCA).  In addition, fruquintinib is also in clinical development for gastric cancer.

Colorectal: The FRESCO trial is a randomized, double-blind, placebo-controlled, multi-center, Phase III pivotal trial in patients with locally advanced or metastatic colorectal cancer who have failed at least two prior systemic antineoplastic therapies, including fluoropyrimidine, oxaliplatin and irinotecan.  Enrollment was completed in May 2016.  416 patients were randomized at a 2:1 ratio to receive either: 5 mg of fruquintinib orally once per day, on a three-weeks-on / one-week-off cycle, plus best supportive care (“BSC”); or placebo plus BSC.  The primary endpoint is overall survival (“OS”), with secondary endpoints including progression free survival (“PFS”), objective response rate, disease control rate and duration of response.  

Lung: The FALUCA trial is a randomized, double-blind, placebo-controlled, multi-center, Phase III registration study targeted at treating patients with advanced non-squamous NSCLC, who have failed two lines of systemic chemotherapy.  Enrollment began in December 2015.  Patients are randomized at a 2:1 ratio to receive either: 5 mg of fruquintinib orally once per day, on a three-weeks-on / one-week-off cycle, plus BSC; or placebo plus BSC . The primary endpoint is OS, with secondary endpoints including PFS, ORR, DCR and duration of response.  Chi-Med plans to enroll approximately 520 patients in about 45 centers across China.

Gastric: Chi-Med completed a phase Ib dose finding study of fruquintinib in combination with paclitaxel, which established a combination regimen that was well tolerated.  

Iressa (gefitinib) is a targeted monotherapy developed by AstraZeneca for the treatment of patients with advanced or metastatic EGFR activating mutation positive NSCLC.  Iressa® acts by inhibiting the tyrosine kinase enzyme in the EGFR, thus blocking the transmission of signals involved in the growth and spread of tumours.  Iressa is approved in 91 countries worldwide.

Chi-Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products.