ArQule Pleads Tivantinib’s Promise In Liver Cancer After Lung Cancer Blow-up

After a progression-free survival benefit failed to translate into overall survival in a Phase III NSCLC study of ArQule/Daiichi Sankyo’s c-Met inhibitor tivantinib, ArQule is shifting focus to an imminent, targeted second-line Phase III study in high-Met expressing hepatocellular cancer.

With partner Daiichi Sankyo Co. Ltd. still on board, ArQule Inc. is signaling a shift in the primary focus for its c-Met inhibitor tivantinib to liver cancer after the companies announced that the Phase III non-small cell lung cancer study was halted due to lack of efficacy.

After a planned interim analysis, a data monitoring committee recommended stopping the MARQUEE trial early because, while the drug was demonstrating a significant benefit for progression-free survival, it was not going to meet the trial’s primary endpoint of overall survival in the intent-to-treat population, the companies announced Oct. 2.

“My advice to companies is to run a Phase II trial that has an OS endpoint,” ArQule CEO Paolo Pucci said after a progression-free survival benefit for tivantinib failed to translate into overall survival.

NSCLC represented ArQule’s first Phase III attempt for the candidate. During an investor call announcing the news, CEO Paolo Pucci stressed that its second attempt at Phase III, in hepatocellular carcinoma, is “completely unaffected.”

In HCC, a 300-patient Phase III study will test tivantinib as a single agent in second-line therapy specifically targeted at high-Met expressing cancer. The trial should get under way at the end of 2012 or early 2013. In high-Met expressing tumors, tivantinib showed a statistically significant benefit for the primary endpoint of time-to-progression, as well as significant effects for progression-free survival and disease control. The drug also demonstrated a trend toward overall survival in this study.

“On the strength of the signal [in Phase II], my personal confidence in our opportunity to demonstrate eventually, in Phase III, the value of this drug remains intact,” Pucci said during the call.

The companies’ third major focus is colorectal cancer, with a large Phase II study due to report at the end of 2012 or very early in 2013.

Daiichi Still On Board

A small molecule that blocks c-Met, a tyrosine kinase receptor, tivantinib has shown activity in combination with other drugs such as imatinib (Novartis AG’s Gleevec) and erlotinib (Genentech Inc./Astellas Pharma Inc.’s Tarceva).

The double-blind MARQUEE study tested tivantinib with erlotinib against erlotinib/placebo in 1,000 patients with locally advanced or metastatic, non-squamous NSCLC who had received one or two prior therapies. Details about the PFS results were not disclosed.

But while the drug disappointed on efficacy, MARQUEE did deliver positive safety results, as no signals were reported. In September, Kyowa Hakka Kirin, which holds rights to tivantinib in Asian countries per a 2007 deal, suspended the Phase III ATTENTION study of the drug in NSCLC due to a signal for interstitial lung disease, under advice from a safety monitoring committee (Also see "Kyowa Hakko Kirin Suspends Recruitment For ARQ197 Phase III Trials" - Scrip, 6 Sep, 2012.).

Daiichi obtained worldwide commercialization rights to the candidate, excluding Japan, China, South Korea and Taiwan, in 2008. As part of the deal, the company paid $75 million upfront and agreed to split Phase II and Phase III development costs (Also see "ArQule Signs c-Met Inhibitor, Discovery Platform Deals With Daiichi-Sankyo" - Pink Sheet, 13 Nov, 2008.).

During the call, ArQule execs reassured analysts that Daiichi was still on board for future tivantinib development. Execs highlighted a statement from Daiichi in the press release about the MARQUEE termination as reflective of its partner’s continued commitment: “Fighting cancer is a complex process in that therapies work differently in different tumor settings, so we will continue to investigate tivantinib in other tumor types.”

Lung Cancer Sees Frequent Disappointment

During the investor call, ArQule execs said that the Phase III outcome of MARQUEE was unexpected, based on Phase II data that showed a PFS benefit for the drug. FDA has made it very clear that overall survival is the necessary endpoint for NSCLC trials (Also see "FDA’s NSCLC Guidance Stresses Overall Survival Endpoint, Sets PFS Standards" - Pink Sheet, 4 Jul, 2011.).

Though ArQule says it is disappointed by this trial, it intends to continue to analyze the data and see if any knowledge can be extracted from a full analysis. For the MARQUEE post-mortem, the company will look at effects on subgroups, for example – patients were stratified by EGFR and KRAS status – and the impact of subsequent therapies after treatment and progression. The outcome of this analysis could have implications for earlier stage studies of tivantinib in lung cancer; according to clinicaltrials.gov, the company is recruiting for a Phase II second-line trial in combination with erlotinib in KRAS mutation-positive patients.

The difficult-to-treat tumor setting has been the site of many failures, Pucci pointed out. A Biotechnology Industry Organization-sponsored study found that NSCLC trials have the lowest success rate in oncology at 2% (Also see "Cancer Drugs Have The Worst Phase III Track Record, BIO Study Shows" - Pink Sheet, 15 Feb, 2011.).

“There is a long list of second- and third-line trials that delivered a good PFS signal in Phase II that did not translate to OS,” Pucci said.

Pucci believes, consequently, that it’s important to design a Phase II study as closely as possible to plans for Phase III, including randomization and the same endpoint, particularly overall survival. FDA has urged companies to power their Phase II trials sufficiently that the overall survival analysis is meaningful.

Shifting To Targeted Approach In Liver

The path forward for tivantinib may be in higher levels of Met expression.

ArQule’s Phase II study suggests that Met status is associated with prognosis in HCC, execs said during a UBS Global Life Science meeting on Sept. 19, but Met expression represents a relatively new area of research in HCC.

The company acknowledged the possibility that even in NSCLC, tivantinib may perform better in high Met-expressing tumors. About half of NSCLC tumors have high Met expression, yet the MARQUEE protocol didn’t include a preplanned analysis of tumors stratified by Met expression. Regardless, it’s extremely unlikely that the companies will pursue another trial in this subgroup, due to the competitive situation in this tumor type.

The reality is that for this subgroup, the “door of competition is shut,” Pucci commented.

In particular, Pucci noted the development of Roche/Genentech Inc.’s selective c-Met inhibitor onartuzumab (MetMAb). A one-armed monoclonal antibody, onartuzumab blocks hepatocyte growth factor/scatter factor (HGF/SF), the binding partner of Met linked to activating the Met signaling cascade. A companion diagnostic is being developed to identify high Met-expressing tumors.

In a Phase II lung cancer study, onartuzumab was shown to have an effect on high Met-expressing tumors, and Roche began dosing in a Phase III second-line and third-line NSCLC study on Jan. 1 specifically in that subgroup.

This study could establish a new standard of care for high-Met expressing lung cancer, Pucci said.

“At this point in time, we have better opportunities,” he said, highlighting once again potential in hepatocellular cancer, starting with second-line treatment in that indication, as well as colorectal cancer and other trials being run by the National Institutes of Health.