Missed Phase II endpoint but promising signs for tivantinib in colorectal cancer
This article was originally published in Scrip
ArQule's lead product candidate tivantinib (ARQ 197) has hit another bump on its road to market, this time in the colorectal cancer setting where it has missed the primary endpoint in a Phase II international trial.
But while the results for the oral small molecule c-Met receptor tyrosine kinase inhibitor missed statistical significance, the US firm and its ex-Asia global partner Daiichi Sankyo stressed they remained committed to conducting further work in the indication based on promising signals from the study.
News flow for tivantinib has not been positive over the past few months, with Asian licensee Kyowa Hakko Kirin dropping it for non-small cell lung cancer (NSCLC) last year following cases of interstitial lung disease in the Asian Phase III ATTENTION study (scripintelligence.com, 30 October 2012).
Tivantinib had previously failed in the 1,000-patient international Phase III MARQUEE trial in NSCLC, missing significance against its overall survival primary endpoint (scripintelligence.com, 3 October 2012).
ArQule has partnered the molecule globally with Daiichi Sankyo for co-development and co-commercialization outside Japan, China, South Korea and Taiwan, for which it has been licensed exclusively to Kyowa Kirin.
In the new topline results from the 122-patient Phase II colorectal cancer trial conducted at sites mainly in the US and also Russia and Western Europe, tivantinib 360mg twice daily was added to combination therapy with irinotecan and cetuximab (Erbitux), in patients with unresectable refractory or relapsed KRAS wild-type disease that had progressed following first-line therapy.
While the trial missed statistical significance for its primary endpoint of progression-free survival (PFS), at 8.3 months this figure in the tivantinib arm was nevertheless an improvement over the 7.3 months for irinotecan and cetuximab plus placebo (HR=0.85, 95% CI: 0.55, 1.33).
"Somewhat to our surprise, the control arm also performed quite well [in PFS terms] as well," ArQule CEO Paolo Pucci noted at a conference call. In a statement, the two firms observed that both PFS figures "were longer than expected compared to previously published historical norms." Mr Pucci also told the call that the trial recruited fewer than the 150 patients under the original statistical power plan.
The 45% objective response rate (the secondary endpoint) was also improved in the tivantinib group compared with the 33% in the control arm, but again failed to reach statistical significance.
While the irinotecan and cetuximab combination was the standard of care at the time the trial was designed in 2009, standard first-line and later therapy for colorectal cancer has evolved in the meantime, the CEO observed. The study, which also did not stratify for Met status, predates a reliable test for Met status that is now available, he added.
Adverse events were generally similar across the two groups, and while increased neutropenia was observed in the tivantinib group, this did not lead to any treatment discontinuations.
Mr Pucci said the partners plan to present additional data, including mature overall survival findings and other subset analyses, at a future medical meeting, and stressed the firms will continue discussions on how best to progress the clinical development of tivantinib in the colorectal setting. There are around 140,000 new cases of colorectal cancer annually in the US.
"We are encouraged by these results, but more work is needed to understand the possibilities for tivantinib in colorectal cancer and to discuss with investigators how best tivantinib can add value," Mr Pucci told the conference call. An assessment of the regional trends in the trial and the other post-study analyses are expected to be available for presentation by mid-year.
Abnormally activated c-Met in malignant cells is involved in a variety of processes including cell growth, survival, angiogenesis and metastasis, and targeting of the pathway is expected to give tivantinib activity across a broad range of oncology indications.
Despite the NSCLC setback, Kyowa Kirin is continuing with a Phase II study in Japan and South Korea in patients with previously treated advanced/recurrent gastric cancer, while ArQule/Daiichi Sankyo have secured a special protocol assessment from the US FDA for Met-high inoperable hepatocellular carcinoma.