Targeted therapy medicines work on specific cancer cell characteristics that affect how the cells behave. For example, Avastin (chemical name: bevacizumab) blocks VEGF (vascular endothelial growth factor), a protein cancer cells make to grow new blood vessels (called angiogenesis). By blocking the VEGF protein, Avastin disrupts the growth of new cancer blood vessels and starves the cancer of nutrients it needs to grow.
Several small studies on targeted therapies are reviewed here. These findings were reported at the 2009 San Antonio Breast Cancer Symposium.
Nexavar studies: Nexavar (chemical name: sorafenib) is a targeted therapy medicine that blocks the actions of proteins that make cancers grow and spread. Nexavar is approved by the U.S. Food and Drug Administration (FDA) to treat advanced-stage liver and kidney cancer, and doctors wondered if it could treat advanced-stage breast cancer. Results were mixed.
Nexavar in combination with the chemotherapy medicine paclitaxel (brand names: Taxol and Abraxane) didn't seem to offer any benefits for women diagnosed with locally advanced-stage or metastatic breast cancer compared to paclitaxel alone. The length of time a woman lived without the cancer growing (progression-free survival) was longer in women who got Nexavar and paclitaxel (6.9 months) compared to women who got only paclitaxel (5.6 months). Still, this difference wasn't statistically significant, which means the difference could have been due to chance and not because of the Nexavar.
Compared to women who got paclitaxel alone, women who got both Nexavar and paclitaxel:
Still, side effects -- some of them serious -- were more common in women who got Nexavar and paclitaxel compared to women who got paclitaxel alone (55% compared to only 7%).
Nexavar combined with the chemotherapy medicine Xeloda (chemical name: capecitabine) offered longer progression-free survival compared to Xeloda alone (6.4 months compared to 4.1 months).
When the combination of Nexavar and Xeloda or Xeloda alone was used as the first treatment for advanced-stage breast cancer, the difference in progression-free survival was larger: 7.4 months for women who got the combination compared to 4.1 months for women who got Xeloda alone.
Sutent studies: Sutent (chemical name: sunitinib) is a targeted therapy medicine that blocks the actions of other proteins that make cancers grow and spread. Sutent is approved by the FDA to treat certain advanced-stage kidney and intestinal cancers. So doctors wondered if it could treat advanced-stage breast cancer. Results suggest that Sutent doesn't work on breast cancer.
In women diagnosed with advanced-stage breast cancer, Sutent had shorter progression-free survival compared to Xeloda (2.8 months compared to 4.2 months). The study was stopped early when the researchers found that Sutent wasn't as effective as Xeloda.
Motesanib studies: motesanib is a targeted therapy being studied as a treatment for a number of cancers, including breast cancer.
Women diagnosed with metastatic breast cancer were given one of three treatments:
There was no real difference in the number of women who responded to the Avastin combination compared to the motesanib combination:
But both were better than paclitaxel alone:
There also was no difference in progression-free survival between the treatments. Serious side effect were more common in women who got motesanib than women who got Avastin or paclitaxel alone.
While these results may seem disappointing, it's clear that doctors are working hard to find more effective breast cancer treatments and better ways to use available medicines. Finding better ways to treat breast cancer is usually the result of many small steps that add up to bigger strides toward better care.
SAN ANTONIO (MedPage Today) -- Progression-free survival (PFS) in advanced breast cancer failed to improve when the angiogenesis inhibitor sorafenib (Nexavar) was combined with paclitaxel chemotherapy, data from a multinational trial showed.
The hazard ratio for PFS was reduced by about 20% with the combination, compared, with paclitaxel alone, but the difference did not meet statistical significance.
The cytotoxic-targeted therapy combination did improve major secondary endpoints: time to progression, overall response rate, and median duration of response, William Gradishar, MD, said at the San Antonio Breast Cancer Symposium.
The negative study was part of a mixed-bag of results with targeted therapies in patients with HER2-negative breast cancer.
A second study paring sorafenib and capecitabine (Xeloda) showed an improvement in PFS compared with capecitabine alone. Sunitinib (Sutent) was inferior to capecitabine in a comparison of single-agent therapies. The investigational tyrosine kinase inhibitor motesanib failed to improve on results achieved with bevacizumab (Avastin) when added to paclitaxel.
Gradishar presented findings from a randomized, phase II trial involving patients with locally advanced or metastatic breast cancer.
Patients were randomized to paclitaxel 90 mg/m2 weekly for three of four weeks plus placebo, or the same dose of paclitaxel plus sorafenib 400 mg BID. The primary endpoint was PFS. Secondary endpoints included time to progression, overall response rate, and duration of response.
Investigators in the U.S., India, and Brazil enrolled 237 patients, who were followed at eight-week intervals for the first 24 weeks and then every 12 weeks thereafter. About 70% of the patients were from India.
Median PFS in the sorafenib arm was 6.9 months, compared with 5.6 months in the placebo group. The difference translated into a 21% reduction in the hazard ratio for sorafenib (95% CI 0.56-1.11, P=0.0857).
Median time to progression favored the sorafenib arm (8.1 versus 5.6 months) and represented a 33% reduction in the hazard for progression (HR 0.674, P=0.0171). The sorafenib-paclitaxel combination also resulted in a higher response rate (68% versus 54%, P=0.0234) and a longer median duration of response (5.6 months versus 3.7 months, P=0.0079).
Substantially more patients in the sorafenib arm had adverse events (55% versus 7%), and grade 3 events (30% versus 3%). No patient in either arm had a grade 4 adverse event. Principal differences between the sorafenib and placebo groups were diarrhea, vomiting, stomatitis, and asthenia.
Spanish oncologist Jose Baselga, MD, reported that the pairing of sorafenib and capecitabine improved median PFS to 6.4 months, compared with 4.1 months for capecitabine alone (HR 0.576, P=0.0006). The trial involved 229 patients with locally advanced or metastatic disease who were randomized to capecitabine with or without sorafenib.
The combination demonstrated a greater advantage when used as first-line therapy, said Baselga, of Vall d'Hebron University Hospital in Barcelona.
Patients treated with sorafenib and capecitabine had a median PFS of 7.4 months, versus 4.1 months in the placebo group (HR 0.498, P=0.0032). When used as second-line therapy, the combination still demonstrated a statistically significant advantage over capecitabine and placebo (5.7 versus 4.1 months, HR 0.65, P=0.0339).
"Subgroup analyses confirmed the robustness of the progression-free survival benefit," said Baselga. "Sorafenib plus capecitabine was favored across all prespecified and exploratory subgroup analyses."
In the evaluation of single-agent therapy for advanced breast cancer, sunitinib resulted in a median PFS of 2.8 months versus 4.2 months with capecitabine, as reported by Carlos Barrios, MD, of PUCRS School of Medicine in Porto Alegre, Brazil.
The trial was terminated prematurely after enrollment of 482 of 700 patients, when an interim analysis showed the trial was unlikely to meet the prespecified endpoint of a 33% improvement in PFS with sunitinib.
The placebo-controlled study of motesanib and bevacizumab, paired with paclitaxel, showed no significant difference in the primary endpoint of overall response rate.
Bevacizumab plus paclitaxel resulted in a response rate of 52%, compared with 50% for the motesanib-paclitaxel arm and 41% for placebo-paclitaxel. said John Mackey, MD, of the Cross Cancer Institute in Edmonton, Alberta.
The trial involved 282 patients enrolled by investigators in 12 countries. Overall response was the primary endpoint.
PFS, a secondary endpoint, was not a statistically significant difference between the motesanib and bevacizumab arms. The median PFS was 11.50 months with bevacizumab, 9.49 months with motesanib, and 9.0 months with placebo.
Motesanib was associated with an increased incidence of grade 3-4 gastrointestinal toxicities, hepatobiliary toxicities, and neutropenia.
The studies reported by Gradishar and Baselga were supported by Onyx Pharmaceuticals and Bayer HealthCare. The study reported by Barrios was supported by Pfizer. The study reported by Mackey was supported by Amgen.
Gradishar disclosed relationships Onyx/Bayer, GlaxoSmithKline, BMSO, Abraxis, AVentis, Genomic Health, and Novartis. Baselga disclosed relationships with Exelixis, Novartis, Merck, Roche, and GlaxoSmithKline. Barrios disclosed relationships with Pfizer and Novartis. Mackey disclosed relationships with Amgen and Roche.
Primary source: San Antonio Breast Cancer Symposium Source reference: Gradishar WJ et al. "A double-blind, randomized, placebo-controlled, phase IIb study evaluating the efficacy and safety of sorafenib in combination with paclitaxel as first-line therapy in patients with locally recurrent or metastatic breast cancer" SABCS 2009; Abstract 44.Additional source: San Antonio Breast Cancer SymposiumSource reference: Baselga J et al. "SOLTI-0701: A multinational double-blind, randomized, phase 2b study evaluating the efficacy and safety of sorafenib compared with placebo when administered in combination with capecitabine in patients with locally advanced or metastatic breast cancer" SABCS 2009; Abstract 45.Additional source: Barrios C et al. "Phase III randomized trial of sunitinib vs capecitabine in patients with previously treated HER2-negative advanced breast cancer" SABCS 2009; Abstract 46. Mackey J et al. "CIRG-TORI 010: 10-month analhysis of a randomized phase II trial of motexanib plus weekly paclitaxel as first-line therapy in HER2-negative metastatic breast cancer" SABCS 2009; Abstract 47. Source reference: Barrios C et al. "Phase III randomized trial of sunitinib vs capecitabine in patients with previously treated HER2-negative advanced breast cancer" SABCS 2009; Abstract 46. Mackey J et al. "CIRG-TORI 010: 10-month analhysis of a randomized phase II trial of motexanib plus weekly paclitaxel as first-line therapy in HER2-negative metastatic breast cancer" SABCS 2009; Abstract 47.
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