Clinical Overview of Sorafenib in Breast Cancer

Future Perspective

Preclinical studies with sorafenib in different solid tumors have been demonstrated to be an effective way to target the Ras/Raf/MEK/ERK signaling pathway as well as the VEGF pathway, enabling the simultaneous blockade of tumor cell proliferation and angiogenesis as well as increasing tumor apoptosis. However, clinical trials using targeted agents alone in breast cancer have been disappointing except for single-agent trastuzumab in HER-2-positive breast cancer. It has become very clear in recent years that these agents work synergistically with standard chemotherapy, but by themselves they are weak inducers of malignant cell death, because the mechanisms of survival on these tumors turn on too many different aberrant pathways, which are unable to be blocked by a single agent, or we are using these agents in too broad a population of cancer patients without correctly selecting the patients whose tumors may express the target that the novel drug is intended to inhibit. At least in the setting of anti-VEGF agents and based on current knowledge, we can conclude that these drugs work best when in combination with standard therapies, as demonstrated in the E2100 trial of bevacizumab and paclitaxel^[19] and the recently presented trials of sorafenib in combination with capecitabine and paclitaxel in advanced breast cancer.^[57–58] If the large E5103 trial^[113] demonstrates clinical benefits of anti-VEGF therapy (bevacizumab) in the adjuvant setting of breast cancer, we could envision a clinical trial where sorafenib is incorporated as part of the adjuvant regimen. Such a pilot study of adjuvant doxorubicin and cyclophosphamide followed by paclitaxel-plus-sorafenib has already been tested in a Phase II study of 45 patients with node-positive or high-risk node-negative breast cancer.^[63] The primary end point of this multicenter community-based study was to assess the safety of this combination regimen. Treatment consisted of doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²), every 3 weeks × 4 cycles, followed by paclitaxel (175 mg/m² every 3 weeks × 4 cycles or 80 mg/m² intravenously weekly × 12 cycles), combined with sorafenib 400 mg orally twice daily. Sorafenib was held during radiation therapy and resumed once this treatment modality was completed. Sorafenib was continued for a total of 12 months and in combination with adjuvant hormonal therapy (where indicated). Evaluation of cardiac function occurred after doxorubicin and cyclophosphamide, paclitaxel and every 3 months during sorafenib therapy. Of the 45 patients, 80% had node-positive disease and the other 20% had high-risk node-negative disease (tumor size >2 cm; hormone receptor negative; grade 2–3; or age <35 years). The median follow-up was 6 months (range: 4–12 months). Safety evaluation demonstrated that the combination of sorafenib and paclitaxel led to 19 patients (42%) having to discontinue sorafenib before completing paclitaxel (mean time on sorafenib: 3.7 weeks; <1 week in 18% of all patients). Nine of these 19 patients (47%) stopped sorafenib owing to symptoms, although this early withdrawal rate did not appear to be due to severe toxicity (grade 3/4), aside from rash and hand–foot skin reaction/syndrome. Multiple factors appear to account for this early withdrawal, including grade 1/2 toxicity, patient or physician decision and difficulty with treatment compliance. Grade 3/4 nonhematologic toxicity during sorafenib therapy in more than 5% of patients included arthralgias/myalgias, neuropathy, pain and pulmonary symptoms (8% each) and rash (11%). Grade 3/4 hematologic toxicity during sorafenib treatment was limited to neutropenia in 11% of patients. There were no sorafenib-related deaths. The conclusion of the authors was that sequencing sorafenib treatment after paclitaxel may be more feasible than concurrent administration with chemotherapy in the adjuvant setting.

As previously noted, the combination of sorafenib and capecitabine led to a significant HR of 0.57 for PFS (p = 0.0006) as first- or second-line therapy for patients with MBC, which is even more relevant if we consider that bevacizumab did not improve PFS when combined with capecitabine in pretreated (second- or third-line) MBC patients,^[64] albeit an improvement of PFS that was noted when used as second-line chemotherapy in the RIBBON-2 trial (7.2 vs 5.1 months; HR: 0.78 [0.64–0.93]; p = 0.00072).^[65] These encouraging results noted on a Phase II study need to be confirmed in a larger randomized Phase III trial. Such a trial is expected to commence sometime this year. This combination of capecitabine/sorafenib could become the first all oral regimen approved for the treatment of advanced previously treated breast cancer. However, although tyrosine kinase inhibitors such as sorafenib can potentially interrupt multiple pathways, by doing so, they lose the specificity that monoclonal antibodies offer and increase the possibility for greater toxicity. Thus, for this regimen of capecitabine and sorafenib to appeal to the treating physician and, most importantly, our patients, we must overcome the increased toxicity of this combination, especially hand–foot skin reaction/syndrome. This may be achieved by using a somewhat lower dose of sorafenib or a different dose and schedule. If we are able to obtain prospective data indicating that these agents reach their targets and result in downregulation of their functions leading to loss of the malignant process, we may realize that the maximum tolerated dose may not be appropriate with these drugs, as we are likely to be able to modulate the intended target at lower doses, which would also be more tolerable. A potential modification of this regimen would be using capecitabine on alternate weeks (1 week on then 1 week off in every 28-day cycle) in accordance with the schedule based on the Norton–Simon mathematical model proposed by the Memorial Sloan Kettering Cancer Center.^[66] This schedule appears to be better tolerated than the approved one. If we were able to achieve a good control of the AEs of hand–foot skin reaction/syndrome and diarrhea, we could conceive a trial with the combination of capecitabine, sorafenib and lapatinib for patients with metastatic HER-2-positive breast cancer. In the meantime, we await the results of the ongoing trials of sorafenib in combination with other standard chemotherapy for MBC to assess their efficacy and tolerability.

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

Cite this: Clinical Overview of Sorafenib in Breast Cancer - Medscape - May 01, 2010.