Clinical Overview of Sorafenib in Breast Cancer

Alvaro Moreno-Aspitia

Future Oncol. 2010;6(5):655-663.

Sorafenib as Single Agent in Advanced Breast Cancer

The North Central Cancer Treatment Group (NCCTG) conducted a multicenter Phase II trial (N0336) of single-agent sorafenib in 23 patients previously exposed to anthracycline and taxanes.^[49] The primary end point of the study was tumor response, as assessed by the Response Evaluation Criteria In Solid Tumors (RECIST). The study was designed in two stages, and it was temporarily closed after accrual to the first stage of the trial to ascertain whether there was sufficient activity to open enrollment to the second stage of the trial. The analysis was conducted 6 months after the last eligible patient was enrolled. Patients were eligible if they had fewer than two prior chemotherapy regimens in the metastatic setting. A total of 23 patients were enrolled in the first stage of the trial, but three patients were found to be ineligible for efficacy analysis because they had undergone at least two cycles of chemotherapy for MBC. However, all patients were included in the tolerability and toxicity analysis. Sorafenib was administered as 400 mg twice daily on days 1–28 of each 4-week cycle. The median age of patients was 54 years (range: 37–70 years). A total of 22 (96%) patients had prior anthracycline treatment and 16 (70%) had prior taxane treatment. Patients received sorafenib for a median of two cycles (range: 1–15 cycles) with a median follow-up of 2.4 years (range: 2.2–2.6 years). Among the 20 patients eligible for efficacy analysis, no patients experienced a partial response or complete response per RECIST. Thus, the trial stopped at the end of the first stage in accordance with the study design. Two patients (10%; 90% CI: 1.8–28.3%) achieved stable disease lasting longer than 6 months. Overall, treatment was well tolerated and there were no grade 4 toxicities and few grade 3 toxicities. The authors concluded that sorafenib as a single agent, although well tolerated, did not exhibit significant activity, but further research was encouraged focusing on combinations with standard therapy and using end points more sensitive to the effects of targeted agents, such as disease stabilization or clinical benefit rate (CBR).

The second Phase II multicenter trial of single-agent sorafenib in MBC was conducted in Europe by Bianchi et al..^[50] Sorafenib was also administered at 400 mg twice a day continuously. The study was initially planned as a Simon two-stage design similar to the NCCTG study. However, based on subsequent data from the advanced renal cell carcinoma trials that demonstrated sorafenib to lead to stabilization of disease more than tumor shrinkage, the study was conducted as a single-stage design and accrued 56 patients. Of these 56 patients, two were deemed ineligible and the other 54 patients received at least one dose of sorafenib. The primary end point was overall best response and secondary end point was percentage of patients with stable disease for at least 16 weeks. Biomarker analyses (plasma levels of VEGF and soluble EGF receptor [sEGFR] and soluble HER-2 [sHER-2] were also performed. In this trial, no patient achieved a complete response, but one patient achieved a partial response (2%). Stabilization of disease was observed in 20 (38%) patients for at least 8 weeks and in 12 (23%) patients for at least 16 weeks. Median time-to-progression (TTP) was 58 days (95% CI: 52–112 days). Sorafenib had manageable toxicity and the most common drug-related grade 3 AEs were rash/desquamation (6%), hand–foot skin reaction (4%) and fatigue (4%). Baseline VEGF levels and levels of sEGFR during treatment and both baseline and changes in sHER-2 levels correlated significantly with clinical outcomes. The authors reached similar conclusions to those from the previous trial: further investigation of single-agent sorafenib in this patient population was not recommended, but studies investigating combinations of sorafenib with chemotherapeutic agents were indeed warranted.

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Abstract and Introduction
Sorafenib as Single Agent in Advanced Breast Cancer
Sorafenib in Combination with Standard Chemotherapy in Advanced Breast Cancer
Sorafenib Plus Endocrine Therapy
Sorafenib in Combination with other Agents
Future Perspective
References
Sidebar

Sidebar

Executive Summary

General Overview

Sorafenib is an oral tyrosine kinase inhibitor able to inhibit VEGF receptors 1, 2 and 3, PDGF receptors α and β, RET, Flt3, c-KIT and the RAF kinase and MAPK pathways.
Over 10,000 patients have been treated with sorafenib as single agent or in combination regimens.
Sorafenib is US FDA approved for the treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma.
The recommended single-agent dose is 400 mg orally twice a day, at least 1 h before or 2 h after eating.
Drug-related adverse events include hand–foot syndrome, diarrhea, fatigue, hypertension, pain and rash.
Concurrent use with docetaxel, doxorubicin or irinotecan increases the exposure to these chemotherapy drugs.
Concurrent use with carbamazepine, phenobarbital and phenytoin decreases sorafenib concentrations. Similar effects are observed with dexamethasone and St John's wort.
Monitor international normalized ratio regularly for patients taking concomitant warfarin.
No dose adjustment is necessary for patients with mild-to-moderate renal or hepatic impairment.

Sorafenib in Breast Cancer

Sorafenib as a single agent, although well tolerated, does not exhibit significant activity in the treatment of metastatic breast cancer (MBC).
Sorafenib, in combination with capecitabine, had a statistically significant improvement in the median progression-free survival and time-to-progression in comparison with capecitabine/placebo for patients with MBC.
Sorafenib-plus-capecitabine is associated with a high incidence of grade 3 hand–foot syndrome/skin reaction (45%).
Sorafenib-plus-paclitaxel demonstrated a statistically significant improvement in the median time-to-progression, duration of response and objective response rate in comparison with paclitaxel/placebo for patients with MBC. Improvement of progression-free survival also favored the two-drug combination.
Sorafenib-plus-paclitaxel is also associated with a high incidence of grade 3 hand–foot syndrome/skin reaction (30%).
Sorafenib might help overcome resistance to the aromatase inhibitors in patients with hormone receptor-positive MBC who have developed resistance to one of these agents.

The Trials to Investigate the Effects of Sorafenib in Breast Cancer program

The Trials to Investigate the Effects of Sorafenib in Breast Cancer (TIES) program includes four Phase IIb randomized, double-blind, placebo-controlled trials to evaluate the efficacy and tolerability of sorafenib in patients with HER-2 negative locally advanced or MBC:
- Trial 1: the SOLTI-0701, a multinational study comparing sorafenib-plus-capecitabine versus capecitabine-plus-placebo in previously treated patients with MBC.
- Trial 2: the NU 07B1, a multinational trial comparing sorafenib-plus-paclitaxel versus paclitaxel-plus-placebo as a first-line regimen in MBC.
- Trial 3: An American trial comparing sorafenib plus gemcitabine or capecitabine versus gemcitabine or capecitabine plus placebo in MBC patients who have progressed during or after bevacizumab therapy.
- Trial 4: A multinational European trial comparing sorafenib-plus-docetaxel or -letrozole versus docetaxel- or letrozole-plus-placebo as first-line therapy in patients with MBC.

Future Perspective

Potential trials may include sorafenib, capecitabine and lapatinib for HER-2-positive MBC and the use of sorafenib as an anti-angiogenic agent in the adjuvant setting of early-stage breast cancer.

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