Lorenza Rimassa, MD
Tivantinib has demonstrated statistically significant improvements in time to progression (TTP) and overall survival (OS) versus placebo among patients with unresectable hepatocellular carcinoma (HCC) in a phase II trial, particularly those with high MET expression levels.
The trial was designed to explore the impact of MET levels as a biomarker in patients with HCC, and to lay the groundwork for further evaluation of tivantinib as a single-agent, second-line option in the difficult-to-treat tumor type, according to researchers. As it stands now, sorafenib (Nexavar) is the only FDA-approved systemic therapy for HCC.
The orally administered tivantinib disrupts MET signaling, which has been implicated in several tumor types, lead investigator Lorenza Rimassa, MD, said during an oral presentation of the trial results at ASCO 2012. She said the findings are the first randomized data showing an OS advantage for a MET inhibitor as a single agent in this HCC population.
“MET is a clear prognostic factor,” said Rimassa, who is deputy director of the Medical Oncology Unit at Humanitas Cancer Center in Milan, Italy. “We have to confirm this result in a larger study, but I think that MET expression analysis should be done in all clinical trials, at least in second-line hepatocellular carcinoma.”“MET is a clear prognostic factor,” said Rimassa, who is deputy director of the Medical Oncology Unit at Humanitas Cancer Center in Milan, Italy. “We have to confirm this result in a larger study, but I think that MET expression analysis should be done in all clinical trials, at least in second-line hepatocellular carcinoma.”
In the trial, 107 patients were randomized 2:1 to receive tivantinib at 360 mg twice daily (n = 38) or 240 mg twice daily (n = 33), versus placebo (n = 36). Participants had experienced disease progression after first-line treatment or were unable to tolerate the first-line therapy, which was sorafenib for all but four of the patients.
Overall, the 71 patients treated with tivantinib achieved a median 6.9 weeks TTP—the primary endpoint—compared with 6.0 weeks for the placebo group (hazard ratio [HR] = 0.64; P
= .04). Median progression-free survival (PFS) was 1.7 months for the tivantinib group versus 1.5 months for the placebo arm (HR = 0.67; P
= .06). Overall survival did not reach statistical significance, said Rimassa.
The benefit for tivantinib was far greater among the 37 patients whose tumors tested positive for higher levels of MET expression. MET high was defined as ≥50% of tumor cells with moderate or strong (2+ or 3+) staining intensity as evaluated with immunohistochemistry assay.
“The most compelling finding of this trial is the advantage in overall survival experienced by MET-high patients treated with tivantinib,” said Rimassa.
In MET-high patients, median OS was 7.2 months in the tivantinib arm compared with 3.8 months in the placebo group (HR = 0.38; P
= .01). Additionally, in the MET-high subgroup, median TTP was 11.7 weeks in the tivantinib arm versus 6.1 weeks in the placebo group (HR = 0.43; P
= .03). The median PFS was 2.4 months on tivantinib and 1.5 months on placebo (HR = 0.45; P
Rimassa said the dosage for patients in the first group was adjusted from 360 mg twice daily to 240 mg twice daily after patients experienced a higher-than-expected incidence (21%) of ≥grade 3 neutropenia. She said the incidence of hematologic incidents decreased after the dosage was lowered, and that the overall safety profile for tivantinib was manageable.
Jordan Berlin, MD, the discussant at the oral session, said patients with high MET expression levels appeared to derive all the benefit from tivantinib. Berlin, who is co-director of the GI Oncology Program at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, agreed that tivantinib merits further study.
At the same time, however, Berlin said he “strongly recommended” that tivantinib be explored further before a full-blown phase III trial is launched because of the relatively small number of MET-high patients to whom the data apply. “We have been fooled by subset analyses because they are subset analyses,” said Berlin. “They are hypothesis-driving, not trial-driving.”
Investigators are digesting the trial results and designing a phase III trial, according to RuiRong Yuan, MD, PhD, executive medical director for Medical Research and therapeutic area head in Oncology for Daiichi Sankyo, Inc. The company has partnered with ArQule, Inc, to develop the drug in the United States, Europe, South America, and elsewhere.
She commented in an interview that there is a “clear, unmet medical need” for patients with HCC who fail first-line treatment. “The prognosis is really grave,” she said.