Event – Lilly faces tricky opt-in decision on fruquintinib

A big pharma’s opt-in decision to take up global rights after a phase III trial success in a large cancer indication would normally be a no-brainer, especially when it already holds marketing rights in a key territory.

However, Lilly will find itself in a quandary as it considers whether to pick up the global, ex-China rights to Hutchinson Chi-Med’s VEGF-R inhibitor fruquintinib over the next six weeks. This is because Chi-Med’s asset, which Lilly is already set to market in China, will undoubtedly compete with its own VEGF-R inhibitor Cyramza elsewhere.

Pulling the trigger

Chi-Med confirmed yesterday that the first of three triggering events specified under the 2013 option deal occurred when it provided a clinical data package on Fresco, the phase III fruquintinib trial in third-line colorectal cancer (CRC). In early March Fresco met all of its endpoints, and the company hopes to present full data as a late-breaking oral presentation at Asco.

Chi-Med plans to file a Chinese NDA mid-year, and will support Lilly in marketing the product in China. The group expects a Chinese data package also to support registrations in around 100 mostly developing nations, but of course additional data will be required for US or EU filings.

It is pressing ahead with a US phase I bridging study to allow a fast move into phase III, subject to an opt-in. Lilly currently funds 70% of development costs in China and, if it takes up its option, will fund 100% of ex-China R&D.

The US group has three opportunities to exercise its opt-in for global development of fruquintinib, although the cost escalates each time. The second will come next year after the outcome of a phase III trial in third-line, non-squamous NSCLC, and the third will presumably come on readout of a phase III study in China in second-line gastric cancer that Chi-Med just started.

To gain US approval in CRC Lilly would likely have to conduct a pivotal study comparing fruquintinib versus Bayer’s Stivarga, which has shown a 1.4-month median OS advantage in third-line CRC, with a hazard ratio of 0.77 and p value of 0.0102. In other indications, such as gastric cancer, fruquintinib might have to be compared head to head against Cyramza itself.

More sceptical biotech observers might suspect that Lilly will either stall or exercise the option now but put fruquintinib on a slow development track, which Chi-Med clearly wants to avoid. On the other hand Lilly might want to have two different VEGF approaches in house: Cyramza is a monoclonal antibody, while fruquintinib is an oral small molecule.

Fruqu Lilly

Chi-Med's chief executive, Christian Hogg, said at an R&D day in London yesterday that Lilly had two months from receiving the data to render a decision; if the option is exercised there is a four-month window in which a global development plan must be agreed upon. “We are not going to accept anything short of a full development plan … and the example is what Cyramza received,” he stated.

This would represent quite some investment as Lilly has sponsored 11 phase III trials with its product; four have so far been successful, and supported approvals in advanced gastric and gastro-esophageal junction cancers, NSCLC and CRC; five studies have yet to read out, and two have failed.

It would be frustrating for Chi-Med if Lilly delays its opt-in decision or if agreement could not be reached on global development. Chi-Med would then have to rely on the deal's best-endeavours clauses, but this would be risky since it clearly wants Lilly to remain its China partner. Competition looms in the shape of Jiangsu HengRui, the largest domestic company, which has a phase III trial with famitinib in third-line CRC, with results due imminently.

Whatever the decision of this first option trigger, it seems likely to be important for both Cyramza and fruquintinib.