NEW YORK (Reuters Health) - Regorafenib improves survival in patients with advanced hepatocellular carcinoma (HCC) who progress during sorafenib treatment, researchers report.
Based on the findings, Bayer, which markets the drug as Stivarga, recently submitted a supplemental new drug application to the U.S. Food and Drug Administration for the oral multikinase inhibitor's use as second-line treatment for patients with unresectable HCC.
For the Phase 3 trial, Dr. Jordi Bruix of the University of Barcelona, Spain, and the multicenter RESORCE investigators recruited adults with HCC and Child-Pugh class A liver function whose disease progressed despite treatment with sorafenib (at least 400 mg/daily over the previous month).
As reported online December 5 in The Lancet, 567 of 573 recruited patients (88% male, average age 63) participated in the trial: 374 received regorafenib and 193 received placebo.
Among patients receiving regorafenib, 309 (83%) discontinued treatment compared with 183 (95%) of those receiving placebo. The most common reason for discontinuation was disease progression in 226 patients (60%) in the regorafenib group and 162 patients (84%) in the placebo group.
The mean daily dose of regorafenib was 144.1 mg. Median treatment duration was 3.6 months and mean treatment duration, 5.9 months.
The mean daily dose of placebo was 157.4 mg. Median treatment duration was 1.9 months and mean treatment duration was 3.3 months.
Excluding treatment delays or interruptions, close to half of the regorafenib group (184 patients, or 49%) received the full protocol dose of 160 mg/day with no reductions.
On February 29, 2016, the cutoff date for the final analysis, after a median follow-up of 7.0 months, 373 (65%) of the study participants had died: 233 (61%) in the regorafenib group and 140 (72%) in the placebo group.
Median overall survival was 10.6 months with regorafenib and 7.8 months with placebo (HR 0.63).
Adverse events were reported in all regorafenib recipients and 93% of placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (15% of patients on regorafenib compared with 5% on placebo), hand-foot skin reaction (13% versus 1%), fatigue (9% versus 5%) and diarrhea (3% versus none).
There were 88 deaths, including 50 in the regorafenib group (13%) - with seven deaths (2%) attributed to the drug - and 28 in the placebo group (20%), with two deaths (1%) attributed to the placebo .
Regorafenib should become the standard second-line treatment for patients with hepatocellular carcinoma who progress under sorafenib treatment, Dr. Bruix told Reuters Health by email.
He added, "Benefits are observed in all subgroups of patients for all study end-points - time to progression, progression-free survival and overall survival."
Taken together, Dr. Bruix concluded, "these (findings) are good news for patients and also for the field of liver cancer, where several failures have taken place after the success of sorafenib 10 years ago."
Dr. Anton Bilchik, chief of medicine and of gastrointestinal research at John Wayne Cancer Institute at Providence Saint John's Health Center in Santa Monica, California, told Reuters Health, "This landmark study . . . is the first . . . to demonstrate that a new anti-angiogenesis drug had a significant survival benefit in those patients who progressed on sorafenib."
"Although the overall survival benefit compared to placebo was only two months, this study opens the door for the development of many more therapeutic agents and provides a better understanding of cancer pathways in this deadly disease," he said by email.
Nevertheless, "many unanswered questions" remain, he said, and need further study. These include: (1) Only patients with good liver function were included in the study. What about other patients?; (2) Could the two drugs have a synergistic effect if used together?; (3) Could these drugs be used after surgical resection or transplantation to reduce recurrence?; and (4) How will we able to afford or justify the cost of these very expensive drugs for only a limited survival benefit?
The study was funded by Bayer. Two coauthors are Bayer employees. Dr. Bruix and 13 coauthors have received funding from Bayer and other companies.
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