Chi-Med and AstraZeneca announced an amendment (the Amendment) to the 2011 global licensing, co-development, and commercialisation agreement (the 2011 Agreement) regarding savolitinib. Based on data from multiple phase I/II studies, savolitinib has shown early clinical benefit as a highly selective c-Met inhibitor in a number of cancers.

As a consequence, savolitinib’s global development plan now covers multiple c-Met-driven solid tumor indications including non-small cell lung cancer (NSCLC), kidney, gastric and colorectal cancers.

Chi-Med and AstraZeneca have agreed to the amendment in order to accelerate savolitinib’s global development and increase Chi-Med’s participation in the programme. The amendment provides that Chi-Med will contribute up to $50 million, spread primarily over three years, to the joint development costs of the global pivotal phase III study in c-Met-driven PRCC. Subject to approval in the PRCC indication, Chi-Med will receive a 5 percentage point increase in the global  excluding China) tiered royalty rate payable on savolitinib sales across all indications. All other provisions of the 2011 agreement will remain unchanged.

Final results from savolitinib’s recently completed open-label global PRCC phase II study (NCT02127710) will be presented at an upcoming scientific meeting. Chi-Med and AstraZeneca have now agreed to proceed to phase III.

The global phase III trial of savolitinib will be the first pivotal study conducted in c-Met-driven PRCC, a rare histological subtype of renal cell carcinoma (RCC) that is associated with alterations in the c-Met gene (e.g. mutations, amplifications, and/or chromosomal changes). Currently, available RCC therapies have demonstrated only modest benefit in PRCC and there are no therapies specifically approved for the  treatment of c-Met-driven PRCC. Ongoing interactions with health authorities will determine the final design of the global pivotal phase III trial, and its initiation will be aligned with availability of a companion diagnostic for c-Met-driven PRCC. The PRCC phase III companion diagnostic platform will be largely similar for other indications such as NSCLC and gastric cancer.

AstraZeneca is also continuing to lead the development of savolitinib in other c-Met-driven types of cancer. Most notably, a phase II expansion of the ongoing TATTON trial to evaluate savolitinib in epidermal growth factor receptor (EGFR) mutant NSCLC patients has been initiated. This trial is a single-arm global Phase II study of savolitinib in combination with Tagrisso (osimertinib) in advanced NSCLC patients who have developed resistance to approved EGFR tyrosine kinase inhibitors. The Phase II expansion was initiated following early data from the TATTON study.

Susan Galbraith, senior vice president, Head of Oncology, Innovative Medicines and Early Development, AstraZeneca, said, “The accelerated development of savolitinib in RCC and NSCLC reflects our ongoing commitment to deliver world-class medicines to patients with limited treatment options. We are pleased to be building on our established collaboration with Chi-Med, as this reinforces our enterprise leadership approach to drug development.”

Christian Hogg, chief executive officer of Chi-Med, said, “Bringing savolitinib to a global launch in multiple areas of unmet medical need is our very clear focus. We believe that savolitinib has the potential to become the first approved therapy in kidney cancer in a molecularly selected patient population, as well as in multiple c-Met-driven lung and gastrointestinal tract cancers. As we enter a period where  pivotal trials in multiple indications are close at hand, we are now happy to take on a small minority of the investment in order to help accelerate development while increasing our share in the long-term economic value of savolitinib.”

Savolitinib is a potential global first-in-class inhibitor of c-Met (also known as mesenchymal epithelial transition factor) receptor tyrosine kinase, an enzyme which has been shown to function abnormally in many types of solid tumors. It was developed as a potent and highly selective oral inhibitor specifically designed to address issues observed in the clinic with first-generation c-Met inhibitors, including renal toxicity.

Worldwide, about 366,000 new patients are diagnosed with kidney cancer annually, and the total market for kidney cancer treatments is expected to reach $4.5 billion in 2020, according to Frost & Sullivan. RCC accounts for approximately 80-85% of kidney cancer and has several histological sub-types with different genetic and biochemical characteristics. Among these histologic variants of RCC, clear cell RCC (ccRCC) is the most common, accounting for 75-80% of RCC.

PRCC is the most common of the non-clear cell renal carcinomas accounting for 10-15% of RCC. The proportion of PRCC patients whose tumors are c-Met-driven has historically been estimated at 40-70%. In the largest study to date, presented at the annual meeting of the American Association for Cancer Research 2014, analysis of 220 frozen tumor samples catalogued in the French RCC Network indicated that 55-60% of PRCC patients showed gains in Chromosome 7 (i.e. c-Met amplification).

The biology and molecular characteristics of PRCC are different from those of ccRCC. This results in significantly worse prognosis and treatment outcomes for patients with PRCC when compared to patients with ccRCC. Highlighting the unmet need is the fact that, although there are several drugs approved for use in RCC (the latest being approved in April 2016), these approvals were generally on the basis of studies conducted with a preponderance of ccRCC patients. The need for different agents and more specific data tailored to the PRCC disease setting has been identified as a critical gap in the care of these patients.

Australia phase I Study – A phase I dose escalation study in a range of tumor types demonstrated the clinical activity and safety profile of savolitinib 600mg once-daily, with a confirmed partial response observed at an early point in the study in a patient with c-Met-driven PRCC. In total, confirmed partial responses were observed in 3/8 (38%) PRCC patients, all of whom harbored c-Met-driven disease, and durations of response were approximately 10-37 months (ongoing). Phase I safety data (n=33) reported that the most common Grade 3 or 4 events included fatigue (9%), dysphonia (hoarseness) (6%), peripheral edema (6%) and headache (3%). Based on these phase I findings, which were reported at the American Society of Clinical Oncology annual meeting in 2014, AstraZeneca and Chi-Med agreed to proceed with a global phase II study in PRCC.

Global Phase II Study – The global open-label single arm phase II study of savolitinib in patients with locally advanced or metastatic PRCC was initiated in May 2014, reaching a total of 22 clinical centers in the U.S., Canada, UK, and Spain, and completing enrollment of 109 PRCC patients in October 2015. This phase II study is the largest prospective clinical study ever conducted in PRCC. The primary objective of the study is to assess the anti-tumor activity of savolitinib in patients with PRCC, with secondary assessment objectives including median Progression Free Survival, duration of response, safety and tolerability, and pharmacokinetics and pharmacodynamics. Importantly, tumor samples from each patient were concurrently subjected to molecular analysis to determine c-Met status in order to better understand the relationship between c-Met aberration and clinical outcome. The results of the phase II study will be presented at an upcoming scientific meeting.

The savolitinib c-Met-driven PRCC pivotal phase III study will be the first molecularly selected trial in RCC. The molecular analysis of each patient in the PRCC Phase II study has provided an understanding of the biomarker and selection criteria needed to identify PRCC patients most likely to benefit from treatment with savolitinib. AstraZeneca and Foundation Medicine, Inc. (Nasdaq: FMI) have an agreement to develop companion diagnostic assays to facilitate personalized medicine in oncology by identifying patients most likely to benefit from novel targeted therapies, including savolitinib. The companion diagnostic assays assess multiple cancer-related genes as well as classes of genomic alterations, and are being developed in parallel with the clinical development of savolitinib as part of a coordinated regulatory strategy. The PRCC phase III companion diagnostic platform will be largely similar for other indications such as NSCLC and gastric cancer.