Double clue dashes ArQule’s lung cancer hopes

The market’s reluctance to attribute significant value to ArQule’s lead project, tivantinib (ARQ 197), which had made the company one of biotech’s underperformers, has turned out to have been justified after all.

Ironically, the safety issue that had halted tivantinib’s first phase III study had no read-across to the second, which has instead been struck down by lack of efficacy, scuppering the project’s prospects in lung cancer. While ArQule has swiftly turned its focus for tivantinib to liver cancer, the market has taken a dim view of the situation; the shares lost 56% of their value yesterday, taking the company’s market cap to below the $147m of gross cash it reported in June.

Tivantinib was the most advanced c-Met kinase inhibitor in development for NSCLC, and was seen as the catalyst that might have turned around ArQule’s fortunes. After the Asia-focused Attention study had to be halted following suspected cases of interstitial lung disease the company stressed that its focus remained on the 988-patient Marquee trial (ArQule fails to stem sell-off on tivantinib safety scare, August 30, 2012).

From bad to worse

But things have taken a turn for the worse with news that Marquee will now also be discontinued, after a planned interim analysis determined that it would likely fail to meet its primary endpoint of improving overall survival.

Interestingly the interim analysis, after over 400 deaths, did find a statistically significant improvement in progression-free survival, mirroring the effect seen in phase II. But the gold standard overall survival benefit remains elusive; the earlier trial hit statistical significance only if adjusted for prognostic factor imbalances that had favoured the control group.

ArQule said it had carried out a safety analysis after Attention was halted, and stressed that no safety concerns had been identified in Marquee. Both phase III studies had tested tivantinib plus Roche’s Tarceva – which is approved in the US for second and third-line use – versus Tarceva and placebo in second-line treatment of non-squamous NSCLC. It seems unlikely that Attention will be resumed any time soon.

ArQule and its partner Daiichi Sankyo say they will turn to other tumour types, with a 300-patient, second-line, single-agent phase III study planned in hepatocellular carcinoma. This cancer type showed a more promising efficacy signal at phase II than NSCLC, including the demonstration of an overall survival benefit in cMet-high patients.

Tough target

Given how tough a nut to crack NSCLC has proved to be it is hardly surprising that other cancers might hold more promise. Nevertheless, lung cancer has seen one recent success, with positive data presented at Esmo from a study of Pfizer’s Xalkori against single-agent chemotherapy.

In the Profile 1007 study in 347 Alk-positive NSCLC patients, Xalkori showed median progression-free survival of 7.7 months versus 3.0 months for pemetrexed or docetaxel chemo (p<0.0001). Although median overall survival has yet to be reached, the data have secured Xalkori’s position as the second-line standard of care for Alk-positive patients.

Xalkori was last year approved for second-line treatment of patients with the Alk gene mutation, which account for roughly 5% of all NSCLC patients, along with a companion diagnostic to determine the Alk gene abnormality.

Meanwhile, for ArQule a potential subgroup approach in lung cancer is a distant prospect, with a phase II study ongoing in 98 KRAS-positive patients. The company would not be drawn on the analysis of Marquee patients’ cMet status, but given that this trial focused on the intent to treat population any positive effects seen will provide little comfort.

Two things working in ArQule’s favour are that it still has in place Daiichi Sankyo as a committed partner, as well as a cash balance that it continues to expect to stand at $121-126m at the end of 2012.

Unfortunately the market now shares even less of its optimism.

To contact the writer of this story email Jacob Plieth in London at [email protected]

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