Clinical Overview of Sorafenib in Breast Cancer

Alvaro Moreno-Aspitia

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

Sorafenib in Combination with Standard Chemotherapy in Advanced Breast Cancer

An international effort was launched to evaluate the effects of sorafenib in combination with standard endocrine and chemotherapy regimens for breast cancer. 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 breast cancer or MBC.^[56] The primary end point in these trials is progression-free survival (PFS); secondary end points include safety, overall survival (OS), duration of response, TTP and objective response rate. Two of these studies have already been completed and recently presented – the NU 07B1 and the SOLTI-0701 trials.

The NU 07B1 trial, comparing the efficacy and safety of sorafenib in combination with paclitaxel as a first-line regimen for patients with MBC, was recently presented at the 2009 San Antonio Breast Cancer Symposium (SABCS).^[57] Patients were randomized 1:1 (stratified by visceral vs nonvisceral metastatic disease) to sorafenib (400 mg orally twice daily, continuously) or placebo in combination with paclitaxel (intravenous 90 mg/m² weekly, 3 weeks on/1 week off).^[57] The primary end point was PFS. Secondary end points included OS, TTP, overall response rate (ORR) and safety. A total of 119 patients were randomized to the paclitaxel/sorafenib treatment arm and 118 patients to the paclitaxel/placebo group. This was an international trial with 170 patients enrolled from India, 52 patients from the USA and 15 patients from Brazil. Treatment groups were balanced for age (mean: 51.9 years), Eastern Cooperative Oncology Group performance 0 (45%) and 1 (53%), stage IV disease (85%), visceral metastatic disease (75%) and previous non-metastatic chemotherapy (58%). This trial demonstrated the following results for paclitaxel/sorafenib versus paclitaxel/placebo: median PFS was 6.9 versus 5.6 months (hazard ratio [HR]: 0.788; 95% CI: 0.558–1.112; one-sided log rank: p = 0.0857), median TTP was 8.1 versus 5.6 months (HR: 0.674; 95% CI: 0.465–0.975; one-sided log rank: p = 0.0171), median duration of response was 5.6 versus 3.7 months (p = 0.0079) and objective response rates were 67 versus 54%, respectively (one-sided Cochran–Mantel–Haenszel: p = 0.0234). OS data are pending. Toxicity evaluation demonstrated that 23 patients (19%) in the paclitaxel/sorafenib arm discontinued therapy due to AEs versus five patients (4%) in the paclitaxel/placebo arm. Grade 3/4 toxicities (paclitaxel/sorafenib vs paclitaxel/placebo) included hand–foot skin reaction (30 vs 3%), asthenia (7 vs 3%), peripheral neuropathy (6 vs 7%), neutropenia (13 vs 7%) and anemia (11 vs 6%). Treatment-related deaths occurred in two patients (malaria and liver dysfunction), both of whom were in the paclitaxel/sorafenib arm. The conclusion of the authors of this trial was that the study demonstrated a trend favoring paclitaxel/sorafenib versus paclitaxel/placebo with regards to the primary end point of PFS, with significant improvements in TTP and ORR without observing unexpected new toxicities. There were a higher number of deaths in the sorafenib arm, mostly of patients enrolled in India, but these deaths were partially attributed to unusual causes (e.g., TB, malaria or meningitis) and were considered by the authors to be unrelated to the treatment regimen. These deaths may have skewed the PFS results, as TTP, which does not include deaths, showed a 3-month difference in favor of the sorafenib/paclitaxel combination.

The SOLTI-0701 trial, a multinational, double-blind, randomized, placebo-controlled Phase IIb study evaluating sorafenib-plus-capecitabine versus capecitabine-plus-placebo in 229 patients with locally advanced breast cancer or MBC, was initially presented at the 2009 European Cancer Organisation and 34th European Society and Medical Oncology Multidisciplinary Congress and recently updated at the 2009 SABCS.^[58] Eligibility criteria included HER-2-negative tumors, lack of active brain metastasis and fewer than two prior chemotherapy regimens for advanced breast cancer or MBC. Patients were randomized (1:1) to receive capecitabine (1000 mg/m², orally, twice daily, for 14 out of every 21 days) with placebo (n = 112) or sorafenib (400 mg orally twice daily, continuously; n = 112). The primary end point was PFS and secondary end points included OS, TTP, ORR, response duration, safety and quality of life. Approximately 50% of patients in this trial were receiving treatment as first-line therapy and 30% of the patients had triple negative (estrogen-,progesterone- and HER-2-negative) MBC. This trial demonstrated that patients in the capecitabine-plus-sorafenib group had a statistically significant improvement in the median PFS (6.4 vs 4.1 months; HR: 0.576; p = 0.0006) and TTP (6.8 vs 4.2 months; HR: 0.562; p = 0.0005) in comparison with capecitabine-plus-placebo. The ORRs were 38 versus 31% (p = 0.122) favoring the capecitabine-plus-sorafenib combination. The benefits of the combination was also observed across all prespecified and exploratory subgroup analyses, including both first (HR: 0.498; p = 0.0022) and second (HR: 0.652; p = 0.0339) lines of MBC. Toxicity evaluation demonstrated a higher incidence of grade 3 hand–foot skin reaction/syndrome (45 vs 13%) in the capecitabine/sorafenib group, but similar rates of grade 3 diarrhea, asthenia, fatigue, dyspnea and neutropenia among both arms. A total of 15% of patients in the capecitabine-plus-sorafenib arm discontinued treatment owing to a treatment-related event versus only 7% in the capecitabine-plus-placebo arm. However, there were more patients in the capecitabine-plus-placebo arm (66%) who discontinued therapy due to progression of disease versus only 45% in the capecitabine-plus-sorafenib arm. The encouraging results of this trial are to be confirmed in a global Phase III registration study, which is expected to initiate sometime in 2010.

The other two randomized Phase IIb trials of the TIES program include a trial comparing sorafenib (400 mg twice daily) plus gemcitabine (1000 mg/m² on days 1 and 8 every 21 days) or capecitabine (1000 mg/m²/twice daily for 14 of 21 days), versus gemcitabine or capecitabine-plus-placebo in patients who have progressed during or after bevacizumab therapy. The last trial compares sorafenib (400 mg twice daily) plus docetaxel (75 mg/m² every 3 weeks) or letrozole (2.5 mg daily) versus docetaxel or letrozole-plus-placebo as first-line therapy for patients with locally advanced breast cancer or MBC. We expect to see the results of these two trials within the next 24 months.

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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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