SHANGHAI – Hutchison China Meditech Ltd. (Chi-Med) is a biopharma unwilling to leave any stone unturned with its c-Met inhibitor, savolitinib. The Nasdaq-listed, China-based company has 11 clinical trials in 17 different indications for savolitinib. That list includes a global study (referred to as TATTON) being led by Hutchison's partner, Astrazeneca plc, for savolitinib as a first-line treatment in non-small-cell lung cancer (NSCLC) patients.

The two companies are now expanding their study to include a global phase II trial of savolitinib in combination with Tagrisso (osimertinib) or Iressa (gefitinib) in 25 EGFR-mutant lung cancer patients – hopefully giving a second chance at treatment for patients that failed EGFR tyrosine kinase inhibitors (TKIs) such as Iressa, Tarceva (erlotinib, Roche Holding AG) or Gilotrif (afatinib, Boehringer Ingelheim GmbH).

According to analyst Thomas Schrader, of Stifels, the phase II trial of savolitinib with Tagrisso could help to define the standard of care in NSCLC.

Rationale for the expanded study is based on the strong results that came from a 12-patient trial of savolitinib in combination with Tagrisso or Iressa in c-Met-amplified NSCLC. The data showed an overall response rate (ORR) of 55 percent. Expectations are that the expanded trial, this time in 25 c-Met-positive patients, will garner an even higher response rate given savolitinib's effectiveness at hitting the c-Met target.

"We believe that savolitinib, either as a monotherapy in first-line NSCLC or in proprietary combinations with Astrazeneca's Iressa and Tagrisso in second- and third-line NSCLC, will address the key genetic drivers of cancer cell proliferation in these very difficult to treat NSCLC patients," said Christian Hogg, Chi-Med's CEO. "We are hopeful about proceeding into phase III in 2017 based on future data from this study."

Chi-Med will receive a $10 million milestone payment from Astrazeneca for commencing the expanded phase II second-line trial.

If lung cancer is a game of whack-a-mole, then Chi-Med and Astrazeneca are hoping they have the most effective mallets in savolitinib and Tagrisso.

Savolitinib, discovered by Chi-Med and partnered with Astrazeneca in 2011, has shown effectiveness against aberrant c-Met signaling tumors but without the toxicity of off-target multikinase inhibitors such as Pfizer Inc.'s Xalkori (crizotinib), said Hogg. "What you tend to find with multikinase inhibitors is you get a response, but it is not a durable response," he explained. "You leave the door open; you don't cover the target fully 24 hours a day. Our view is that when a highly selective c-Met enters [the market] it is going to perform better than a multikinase inhibitor."

Furthermore, due to its chemical formulation, savolitinib looks to have solved the kidney toxicity caused by poor solubility that plagued other c-Met programs, such as Eli Lilly and Co.'s SGX-523, Janssen Pharmaceutica NV's JNJ-38877605 and Pfizer's PF-04217903. Although there is one c-Met contender still standing that has the same 2-quinolinone structure as the others: INC-280, from Novartis AG and Incyte Corp.

A Numbers game

There are 1.7 million new cases of NSCLC annually worldwide, according to Frost & Sullivan. Of those, China had 623,000 new cases in 2015, or about one-third.

But as a first-line treatment, savolitinib may only be effective in about 4 percent to 5 percent of patients that have MET-driven NSCLC. MET-driven NSCLC includes MET exon-14 mutations (3 percent to 4 percent) and c-Met gene amplification (1 percent to 2 percent). While the MET-driven patient population is relatively small (68,000 to 85,000 patients) for first-line treatment, there are no approved c-Met TKIs for that group.

The market potential for second-line treatment in the EGFR-mutant, TKI-resistant, lung cancer patients with c-Met amplification is numerically more substantial. The EGFR mutation form of NSCLC is comparatively more common, estimated to be 10 percent to 15 percent in Europe, and 30 percent to 40 percent in Asia.

While that group of patients is particularly sensitive to treatment with available EGFR TKIs – those tumors almost always return – many develop resistance to treatment with median progression-free periods of about nine months. In those cases a second-line treatment is needed to tackle the resistance.

There are two main resistance pathways: the T790M mutation covers about half the cases, while one-fifth stems from c-Met gene amplification. That is where Tagrisso –approved in record time by the FDA for patients with the EGFR T790M mutation last year - and savolitinib come in. Combined, they can reach 70 percent of the second-line patient population. (See BioWorld Today, Nov. 16, 2015, and Dec. 21, 2015.)

"For more than two-thirds of patients that fail on Iressa you have a solution for them; that is a big deal," said Hogg.

"Savolitinib has enormous potential in the second-line setting in combination with the Tagrisso," he added. "In the first-line setting, it has potential, too, but it is 4 percent or 5 percent of the patients as opposed to 15 percent to 20 percent of the patients.

"Tagrisso is also being studied as a front-line EGFR treatment and has published data showing PFS of close to 20 months vs. Iressa's nine months," said Hogg. "The conventional wisdom is that Tagrisso will move to the front-line setting for EGFR mutation-positive NSCLC patients.

"Astrazeneca is a great partner to be with," said Hogg. "First of all, they have Iressa and, secondly, they have Tagrisso, which I think will ultimately [will make] obsolete first-generation EGFR tyrosine kinase inhibitors, at least in the developed world."

In other markets such as China, where Iressa went off-patent in April, there will be greater competition from low-cost generics makers.

Savolitinib is also being studied in the world's largest papillary renal cell carcinoma (PRCC) trial to date, with patient enrollment completed last year. Chi-Med has scheduled to publish the study data at the European Society for Medical Oncology meeting in Copenhagen, to be held October. The study will include findings from the molecular profiling of 109 PRCC patients to provide a better understanding of the drivers of the disease along with the proportion that are MET driven. (See BioWorld Today, Oct. 21, 2015.)

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