Adding sorafenib, an anti-cancer oral medicine, to Hycamtin (topotecan) chemotherapy slows the time to disease progression or death in women with platinum-resistant ovarian cancer, a Phase 2 trial shows.
The trial showed that the combo therapy prolonged median progression-free survival almost seven months, compared to Hycamtin alone.
The study, “Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial,” was published in the journal The Lancet Oncology.
Sorafenib (produced by Bayer under the brand name Nexavar) is a U.S. Food and Drug Administration (FDA)-approved oral treatment for liver, kidney, and thyroid cancer. The compound is an antiangiogenic agent, one that inhibits blood vessels’ growth, reducing blood flow to the tumor and blocking tumor cell proliferation.
Similarly to other classes of antiangiogenic agents, once-daily sorafenib showed anti-tumor activity in preclinical models of ovarian cancer. However, to date, clinical trials testing the therapy revealed only a moderate efficacy, either alone or in combination with chemotherapy.
Novartis‘ Hycamtin is a chemotherapy approved in the United States and Europe for advanced ovarian cancer. Its efficacy was seen to parallel other chemotherapies, including paclitaxel or pegylated liposomal doxorubicin (PLD), for platinum-resistant ovarian cancer; and a conventional 5-day treatment was proven as effective as a weekly schedule.
Based on such knowledge, researchers conducted the TRIAS Phase 2 study (NCT01047891) to assess the safety and efficacy of a combo treatment with 5-day Hycamtin plus oral sorafenib, followed by sorafenib alone as a maintenance therapy, in women who failed to respond or whose cancer returned after platinum chemotherapy.
The trial was a placebo-controlled double-blind study conducted at 20 sites in Germany.
The study included 172 women with ovarian, peritoneal, or fallopian tube cancers whose tumors failed to respond or came back after up to three prior lines of therapy, including platinum-containing medicines.
Patients were randomly assigned to receive 5-day intravenous infusions of Hycamtin followed by either oral sorafenib 400 mg (83 patients) or placebo (89 patients) twice daily on days 6–15, repeated every 21 days for six cycles. Researchers choose this type of scheduling to reduce toxicity caused by combining sorafenib with chemotherapy.
Such an induction regimen was followed by daily maintenance with sorafenib alone or a placebo for up to one year in patients without progression.
Hycamtin treatment was disclosed to all participants ,while investigators and patients were blinded for sorafenib or placebo.
More than half of the patients in the sorafenib group (57%) and in the placebo group (53%) completed the six chemotherapy cycles, while the rest discontinued treatment, primarily due to patient request or toxicity (sorafenib group) and disease progression (placebo group).
After completing chemotherapy, 42% of patients in the sorafenib group and 38% in the placebo group received maintenance therapy for a median 1.6 and 1.4 months, respectively.
Combo therapy with Hycamtin and sorafenib significantly prolonged progression-free survival, or the time between the first treatment cycle and disease progression or death. On this regimen, the median progression-free survival was 6.7 months; with placebo, 4.4 months.
Overall survival was also improved with the combo therapy. Median survival extended from 10.1 months in the placebo group to 17.1 months in the combination treatment.
Even patients who were receiving the third or fourth line of treatment seemed to derive an overall survival benefit, researchers said.
In addition, the percentage of patients who saw their tumor shrink, or objective response, was significantly higher for those on sorafenib (35%) than on placebo (18%).
The frequency of serious adverse events was similar with sorafenib (59%) and placebo (51%). The most common were abdominal pain, shortness of breath, ileus (lack of movement in the bowel), thrombocytopenia (low platelet count), neutropenia, and leukopenia (low white blood cell count).
However, compared with placebo, the combo therapy was associated with increased incidences of severe hand-foot skin reaction (13% vs. 0%) and moderate hair loss (29% vs. 13%), but did not seem to negatively affect patient-reported quality of life.
Adverse events resulted in the death of four patients (5%) in the sorafenib group and seven (8%) in the placebo group.
Overall, these findings “support the pivotal role of antiangiogenic strategies for ovarian cancer and perhaps strengthen the rationale for assessing maintenance approaches in platinum-resistant ovarian cancer,” the researchers said.