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ArQule Tumbles on Survival Miss in Lung Cancer Study

By Catherine Shaffer
Staff Writer

Shares of ArQule Inc., of Woburn, Mass., plummeted 56.3 percent Tuesday following news that an independent data safety monitoring committee had terminated its Phase III MARQUEE trial of ARQ 197 in nonsquamous non-small-cell lung cancer (NSCLC).

There was a statistically significant improvement in progression-free survival, but it didn't extend to overall survival.

"Unfortunately the trend in overall survival that we observed in Phase II did not materialize in Phase III," said ArQule CEO Paolo Pucci in a press conference Tuesday.

ArQule's stock (NASDAQ:ARQL) fell $2.18 to close at $2.81.

MARQUEE was designed to compare tivantinib (ARQ 197) in combination with Tarceva (erlotinib, Astellas Pharma Inc. and Roche AG) to placebo plus erlotinib in previously treated patients with metastatic or locally advanced nonsquamous NSCLC.

The randomized, double-blind trial recruited about 1,000 patients at more than 200 clinical sites worldwide. The trial's primary endpoint was overall survival in the overall intent-to-treat (ITT) population.

Progression-free survival in the ITT population was a secondary endpoint, as well as overall survival in the subgroup wild-type for epidermal growth factor receptor and safety.

The trial termination led Pucci to rue the design of the company's Phase II, which had progression-free survival as its endpoint.

"My advice to anybody planning for a Phase III trial for non-small-cell lung cancer is to execute the Phase II that has the same endpoint that one intends to execute in Phase III," he said.

The silver lining in ArQule's otherwise dreary cloud was that there were no unexpected safety findings. Concerns about interstitial lung disease (ILD) had halted enrollment in the company's Phase III ATTENTION trial of the drug in NSCLC. (See BioWorld Today, Aug. 30, 2012.)

An independent safety review committee terminated that program, which was being carried out by ArQule's Asian territories partner, Kyowa Hakko Kirin Co. Ltd.

"We were waiting for a 'clean' safety signal from the MARQUEE study to lift the overhang created by the partial halt from the ATTENTION study," wrote analyst Adnan Butt, of RBC Capital Markets. "We had estimated a detailed analysis of ILD cases (number and magnitude not disclosed) could be available around Nov./Dec. 2012. The decision to begin enrollment would have been a positive but is now questionable, in our view."

ArQule plans to forge ahead, gathering as much data as possible from the failed trial.

"Though we are disappointed by this trial, we are going to collect the results of the events that we will have available. We will analyze them to see if there is any knowledge that we can extract from a pooled analysis," Pucci said.

ArQule is partnered with Daiichi Sankyo in a two-deal package in 2008. Daiichi paid $60 million in cash for rights to tivantinib in cancer.

Under that agreement, the two companies have equally shared costs of Phase II and Phase III studies, with ArQule's shares of Phase III costs payable solely from milestone and royalty payments by Daiichi. (See BioWorld Today, Nov. 11, 2008.)

Pucci said the trial termination would have no long- or short-term financial implications for the company. "We remain in a strong financial position," he said.

The main financial consequence, Pucci explained, is that it will take longer to repay its share of the development costs to Daiichi Sankyo without future revenues from the drug in that indication.

ArQule is still pursuing tivantinib in hepatocellular carcinoma. In June, it reported that second-line patients receiving tivantinib as monotherapy attained median overall survival of 7.2 months vs. 3.8 months for those on placebo, and median time to progression of 2.9 months vs. 1.5 months for placebo.

According to Pucci, if tivantinib is approved for hepatocellular carcinoma, ArQule will still be able to pay its obligations, just more slowly.

"That debt we are incurring will not be repaid as quickly as it would be if we had two indications," Pucci said.

A third indication, colorectal cancer, could put the company back on its rapid repayment schedule.

ArQule began a Phase I/II program in February 2010 to evaluate tivantinib in combination with irinotecan and Erbitux in patients with metastatic colorectal cancer who are wild-type for the KRAS gene.

"There is no altering of our year-end cash balance, no altering current projections," Pucci said.