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Thread: Avastin (bevacizumab) Fails in Advanced, HR-Positive Breast Cancer?

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    Default Avastin (bevacizumab) Fails in Advanced, HR-Positive Breast Cancer?

    All women in the BEATRICE trial with triple negative early breast cancer received chemotherapy. One half were also given Avastin (bevacizumab). There was no difference in outcome with or without Avastin.

    According to Dr. Silvana Martino, though there was much excitement with this drug when it was first available and initial preliminary results were positive, two studies further confirm that in breast cancer Avastin adds little benefit yet adds toxicity.

    Avastin (bevacizumab) has failed to show substantial efficacy in yet another breast cancer setting, according to a Spanish–German study presented here at the 35th Annual San Antonio Breast Cancer Symposium (SABCS).

    This time, bevacizumab was added to either letrozole (Femara, Novartis) or fulvestrant (Faslodex, AstraZeneca) as first-line treatment for advanced hormone receptor (HR)-positive breast cancer. But the combination therapy failed to demonstrate a statistically significant increase in progression-free survival compared with endocrine monotherapy, according to Miguel Martin, MD, who presented the results on behalf of investigators from the Letrozole/Fulvestrant and Avastin (LEA) trial.

    Dr. Martin is from the Instituto de Investigacion Gregorio Marañón in Madrid, Spain, and is a member of the Spanish Group for Breast Cancer Research (GEICAM). The study was cosponsored by the German Breast Group.

    The first efficacy results from the study show that progression-free survival was better with the combination of bevacizumab plus endocrine therapy than with endocrine monotherapy (18.4 vs 13.8 months; P = .14). This translated into a nonsignificant hazard ratio of 0.83 (95% confidence interval, 0.65 - 1.06). There were 131 progression-free survival events in the combination group and 117 in the monotherapy group over the 4-year study period.

    The difference in progression-free survival of 4.6 months resulted in a 17% reduction in time to progression, which fell short of the goal of a 31% reduction, said Dr. Martin.

    Adding bevacizumab to endocrine therapy did not improve median overall survival, which was 41 months for the 191 women receiving combination therapy and 42 months for the 189 women receiving monotherapy (P = .469).

    However, the addition of bevacizumab to endocrine therapy resulted in significantly more hematologic and nonhematologic adverse events.

    The trial was designed to test the hypothesis that antivascular endothelial growth-factor (VEGF) treatment can delay resistance to endocrine therapy in patients with HR-positive advanced breast cancer, Dr. Martin said.

    He explained the origin of the hypothesis. Preclinical and retrospective clinical data have suggested that high VEGF levels in tumor tissue from breast cancer are associated with a decreased response to endocrine therapy. Furthermore, early clinical data suggest that the downregulation of VEGF can overcome resistance to hormonal therapy and improve efficacy.

    Neither trial of bevacizumab presented here at SABCS showed statistically significant benefits in new settings. The absence of a robust positive effect in the LEA trial and the BEATRICE trial (of women with triple-negative disease) had one expert doubting the efficacy of angiogenesis inhibition in breast cancer.

    "It makes me wonder if there is a role for angiogenesis inhibitors like bevacizumab in breast cancer," Kent Osborne, MD, from the Baylor College of Medicine in Houston, Texas, told Medscape Medical News. He is one of the codirectors of the symposium.

    The collective data on bevacizumab suggest that the drug will have a "very limited role, if any" in breast cancer, he told reporters at a meeting press conference.

    More Toxicity With Bevacizumab

    Participants in the LEA trial were postmenopausal and had histologically confirmed inoperable locally advanced or metastatic breast cancer. The women had estrogen- and/or progesterone-positive cancers that were also HER2-negative.

    About half of both groups had received previous adjuvant endocrine therapy, and about half had received previous chemotherapy. A small minority of women had locally advanced disease (about 3%); most had metastatic disease (about 80%). About 15% had advanced disease that was not precisely determined. About two thirds of the women had multiple metastatic sites.

    In the LEA trial, about 90% of the women received letrozole 2.5 mg/day and about 10% received intramuscular fulvestrant 250 mg every 28 days. The dose of bevacizumab was 15 mg/kg every 3 weeks.

    In terms of hematologic toxicities (all grades), there was more neutropenia (11.2% vs 5.7%; P = .061) in the combination group than in the monotherapy group, more leukopenia (24.6% vs 11.4%; P = .001), and more thrombocytopenia (19.3% vs 9.1%; P = .006).

    In terms of nonhematologic toxicities (all grades), there was more fatigue (50.5% vs 29%; P < .001) in the combination group than in the monotherapy group, more hypertension (59% vs 15.9%; P < .001), more hemorrhage (18.6% vs 1.7%; P < .001), more elevated liver enzymes (46.5% vs 28%; P < .001), and more proteinuria (30.3% vs 2.8%; P < .001).

    Financial and drug support were provided by Roche Spain and Germany. Dr. Martin reports being a consultant for Amgen, Roche, Bayer, Novartis, GSK, and Sanofi. Dr. Osborne reports being a consultant/advisor for Genentech, Novartis, and AstraZeneca.

    35th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S1-7. Presented December 5, 2012.

    Citation: Bevacizumab Fails in Advanced, HR-Positive Breast Cancer. Medscape. Dec 11, 2012
    Gregory D. Pawelski

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    Distinguished Community Member gpawelski's Avatar
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    Default Does BEATRICE Spell the End of Avastin (bevacizumab) in Breast Cancer?

    Direct anti-tumor and anti-vascular effects were studied of Tykerb, Nexavar and Avastin in fresh biopsy specimens of breast cancer and presented at the American Society of Clinical Oncology Breast Cancer Symposium on September 5, 2008.

    While the other clinically-available 'nib' drugs have been shown to have anti-vascular activity, anti-vascular activity of Tykerb has not been previously reported.

    Angiogenesis studies are limited by the clinical relevance of laboratory model systems. They don't do "real world" studies under "real world" conditions. Patient outcomes need to be reported in real-time, so patients and cancer physicians can learn immediately if and how patients are benefiting from new drug therapies.

    Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood can identify the activity of both single drugs and combinations of drugs at the level of individual patients with individual cancers. It works by measuring drug effects (real-time) upon endothelial cells which make up blood vessels.

    Drugs like Avastin had striking anti-microvascular effects but minimal anti-tumor effects. Tarceva and Gleevec had mixed antitumor and anti-microvascular effects. Anti-microvascular effects of Tarceva and Iressa were equal to those of Sutent and Nexavar. Anti-microvascular additivity was observed between Avastin and other drugs on an individual basis.

    Conclusions of the study had shown that Tykerb has antivascular activity superior to that of Nexavar. Avastin + Tykerb may be the first clinically-exploitable antivascular drug combination. High dose, intermittent 'bolus' schedules of Tykerb to coincide with Avastin administration may be clinically advantageous, even in HER2-negative tumors.

    The system utilized for the study was a functional profiling assay, which may be used to individualize antivascular therapy. It can be adapted for simple, inexpensive and sensitive/specific detection of tissue and circulating microvascular cells in a variety of neoplastic and non-neoplastic conditions, for drug development, and individualized cancer treatment.

    It can accurately sort drugs into categories of above average probability of providing clinical benefit on one hand and below average probability of providing clinical benefit on the other hand, based both on tumor response and patient survival.

    http://www.weisenthal.org/Weisenthal_ASCO.pdf
    http://onlinelibrary.wiley.com/doi/1...8.01955.x/full
    Gregory D. Pawelski

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    Distinguished Community Member gpawelski's Avatar
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    Default BEATRICE: Adjuvant chemotherapy/Avastin (Bevacizumab)

    The first presentation of the BEATRICE trial, evaluating adjuvant Avastin with a physician’s choice taxane- and/or anthracycline-based regimen in patients with triple-negative disease, was at the annual San Antonio Breast Cancer Symposium (SABCS). Given the diminished recent role of Avastin in the metastatic setting and the well-publicized failure of the adjuvant trial in colorectal cancer, these negative results were not too surprising.

    Interestingly, Dr. Norman Wolmark is still frustrated that the signal of an impressive reduction in recurrence observed when Avastin was on board in the NSABP-C-08 colon cancer trial has not been further pursued. BEATRICE, like C-08, used one year of Avastin, and Wolmark continues to believe that more benefit would be seen with a greater duration of treatment, although this is not likely to be studied.

    Primary Results of BEATRICE, a Randomized Phase III Trial Evaluating Adjuvant Bevacizumab-Containing Therapy in Triple-Negative Breast Cancer

    Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, Steger G, Suter T, Toi M, Parmar M, Bubuteishvili-Pacaud L, Henschel V, Laeufle R, Bell R. University of Edinburgh and Cancer Services, NHS Lothian, Edinburgh, United Kingdom; University of Leeds, United Kingdom; Sunnybrook Health Sciences Center and University of Toronto, Toronto, ON, Canada; Klinikum Offenbach, Offenbach, Germany; Cross Center Institute, Edmonton, Canada; University Hospital Jean Minjoz, Besançon, France; Medical University of Vienna, Austria; Bern University Hospital, Inselspital, Switzerland; Kyoto University, Kyoto, Japan; MRC Clinical Trials Unit, London, United Kingdom; F. Hoffmann-La Roche Ltd, Basel, Switzerland; F Hoffmann-La Roche Ltd, Basel, Switzerland; F. Hoffmann-La Roche Ltd., Basel, Switzerland; Andrew Love Cancer Centre, Geelong, Australia; National Cancer Center, Singapore, Singapore

    Background:

    Bevacizumab (BEV), an anti-VEGF antibody, significantly enhanced progression-free survival in metastatic breast cancer (BC) (E2100, AVADO, RIBBON-1, RIBBON-2) and pathologic complete response rates in the neoadjuvant setting (GeparQuinto, NSABP B-40) when combined with chemotherapy (CT). The dependence of micro-metastases on angiogenesis [Holmgren 1995] suggests that patients might benefit from anti-angiogenic strategies applied in the adjuvant setting. The BEATRICE trial was designed to test this hypothesis in patients with triple-negative BC, who have a poor prognosis and lack targeted options for treatment.

    Methods:

    In this open-label randomized multinational phase III trial, patients with centrally confirmed triple-negative operable primary invasive BC (pT1a-pT3) were randomized 1:1 after definitive surgery to receive ≥4 cycles of either CT alone or the same CT + 1 year of BEV 5 mg/kg/wk equivalent. CT was anthracycline [anth] and/or taxane-based. Patients were stratified by nodal status (0 vs 1-3 vs ≥4 involved nodes), CT backbone (anth vs anth + taxane vs taxane), hormone receptor status (negative vs low), and surgery (breast-conserving vs mastectomy). The primary objective is to compare invasive disease-free survival (IDFS) [Hudis 2007] with adjuvant CT ± 1 year of BEV. Secondary outcome measures are overall survival (OS), breast cancer-free interval, disease-free survival (DFS), distant DFS, and safety (NCI CTCAE v3.0). The sample size was calculated to provide 80% power for a HR=0.75 at α=0.05 assuming 5-year IDFS of 72.0% with CT vs 78.2% with CT + BEV with 388 events. BEATRICE also includes evaluation of potential predictive and prognostic biomarkers.

    Results:

    Between Dec 2007 and Mar 2010, 2591 patients were randomized. At data cut-off (Feb 29, 2012), median follow-up was 32 months.

    http://www.abstracts2view.com/sabcs1...u=SABCS12L_754
    http://www.researchtopractice.com/si...wnloadable.pdf
    Gregory D. Pawelski

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    Distinguished Community Member gpawelski's Avatar
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    Default Avastin Misses Mark Again in Breast Cancer?

    The addition of bevacizumab (Avastin) to standard adjuvant therapy for HER2-positive breast cancer failed to improve invasive disease-free survival (iDFS) in a randomized clinical trial.

    Patients treated with chemotherapy plus trastuzumab (Herceptin) had 92% iDFS with or without the bevacizumab. Subgroup analysis did not identify any group of patients that benefited from the addition of the angiogenesis inhibitor.

    Added to negative outcomes in several other studies, the results could spell the end of clinical investigation of anti-angiogenesis inhibitors in breast cancer, Dennis Slamon, MD, PhD, of the University of California Los Angeles, said here at the San Antonio Breast Cancer Symposium.

    "All these anti-angiogenic strategies have really not impacted survival in breast cancer," said Slamon. "There may still be something there if we were able to find the right markers, but, so far, they have all come out negative for any impressive survival advantage.

    "The challenge in terms of the safety issues is that if you're not getting a lot of benefit and you're adding safety concerns, you have to wonder whether it's going to be worthwhile pursuing that much further. Unless there is a new drug or new strategy to define the subgroup, I think this is not going anywhere."

    Slamon reported findings from the multicenter BETH trial (Bevacizumab and Trastuzumab in HER2-Positive Breast Cancer). The study involved 3,500 patients with early-stage HER2-positive, node-positive breast cancer or high-risk node-negative disease.

    Patients received either non-anthracycline or anthracycline-containing chemotherapy and trastuzumab and were randomized to bevacizumab or no additional therapy. The primary endpoint was iDFS, and secondary endpoints included DFS, overall survival, recurrence-free interval, distant recurrence-free interval, and toxicity.

    The patients had a median age of 51, almost half were node negative, half had tumors ≤2 cm, and 59% were hormone-receptor positive.

    When the trial ended after a median follow-up of 33 months, it had not met the primary endpoint. Overall survival was 96% to 97% in both treatment groups. Analysis of iDFS according to chemotherapy regimen showed no difference between groups.

    The addition of bevacizumab increased the toxicity burden. Patients treated with bevacizumab had a 27% incidence of grade 3/4 adverse events of interest, as compared with 8% in patients who did not receive the angiogenesis inhibitor.

    The bevacizumab group had significantly higher rates of hypertension (19% versus 4%, P<0.0001), bleeding (2% versus <1%, P<0.0001), heart failure (2.1% versus <1%, P=0.021), proteinuria (21 cases versus 1, P<0.0001), and gastrointestinal perforation (11 cases versus 1, P<0.031).

    Slamon showed results from previous studies to emphasize the progress in breast cancer survival. With surgery alone, long-term DFS was 26%. The introduction of adjuvant therapy increased DFS to 32%, and anthracyline-based therapy added another 4%.

    With the introduction of the taxanes, DFS increased to 62%, and then to 67% with dose-dense therapy and 84% with the introduction of targeted therapy. The BETH trial demonstrated iDFS of 92% in both groups.

    "We have very little room at the top to think about new strategies for those patients who are not getting the benefit that we had hoped they would with targeted therapy," said Slamon.

    The results leave little doubt that angiogenesis inhibitors do not have a role in breast cancer -- HER2-positive disease in this case, said Jennifer Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston.

    "This study asked a question that has been ongoing for several years: Whether anti-angiogenesis -- and specifically bevacizumab in this case -- is going to add anything to the current treatment strategies," said Litton, who was not involved in the study. "I feel that Dr. Slamon and his group have definitively answered this in the HER2 question. Bevacizumab adds really significant toxicity and no benefit."

    The BETH trial was sponsored by the National Surgical Adjuvant Breast and Bowel Project, the Cancer International Research Group, Hoffmann-LaRoche, and Genentech.

    Slamon reported no relevant disclosures.

    Source: San Antonio Breast Cancer Symposium

    Reference: Slamon D, et al "BETH: A randomized phase III study evaluating adjuvant bevacizumab added to trastuzumab/chemotherapy for treatment of HER2+ early breast cancer" SABCS 2013; Abstract S1-03.

    Citation: "Avastin Misses Mark Again in Breast Cancer" MedPage Today December 11, 2013

    Tykerb enhances the antivascular activity of Avastin

    http://cancerfocus.org/forum/showthread.php?t=3152
    Gregory D. Pawelski

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