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Old 11-05-2009, 02:25 PM   #1
Rich66
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Sorafenib (Nexavar)

(multiple targeted, vegf, antiproliferation, synergy with Capecitabine, w/Letrozole, reverses endocrine resistance, maintenance monotherapy in untreated, renal brain mets, primary liver, off-label possible)


ACORN Research Reports Positive Findings of Phase 2b Metastatic Breast Cancer Trial at ASCO



Published Thursday, Jun. 30, 2011


MEMPHIS, Tenn., June 30, 2011 -- /PRNewswire-USNewswire/ -- Accelerated Community Oncology Research Network, Inc., (ACORN), reported positive results of a large double-blind, randomized Phase 2b trial in patients with breast cancer at the American Society of Clinical Oncology (ASCO) 47th annual meeting in Chicago, June 3-7. The study, managed by ACORN Research, evaluated a novel drug regimen for the treatment of locally advanced or metastatic breast cancer. The regimen, Nexavar® (sorafenib) tablets in combination with either Gemcitabine (Gemzar®) or Capecitabine (Xeloda®), found statistically significant improvement in progression-free survival. Forty investigative sites enrolled 160 patients over a three year period.
Lee S. Schwartzberg, MD, FACP, President of ACORN and Chief Medical Officer of The West Clinic in Memphis, Tennessee served as study co-chair. According to Schwartzberg, "This study was conceived as one of a suite of trials collectively evaluating the addition of Nexavar to chemotherapy in different advanced disease settings. The results demonstrate activity for this antiangiogenic agent in patients who had progressed on bevacizumab containing regimens."
The trial was one of two studies sponsored by Onyx Pharmaceuticals with clinical research and site management services provided by ACORN Research. Dr. Edward Stepanski, Chief Operating Officer of ACORN Research stated, "The success of this trial was due to the enthusiasm of the investigative sites and the close cooperation with ACORN staff."
The West Clinic was, along with Memorial Sloan Kettering Cancer Center, a high enrolling site. According to Kurt Tauer, MD, FACP, Chief of Staff and principal investigator for the study at The West Clinic, "This trial was a high priority for the clinic due to the interest in adding biological agents to standard chemotherapy, and we are pleased to see the positive results."




October 22, 2009
ONCOLOGY. Vol. 23 No. 11 Research Reports
Sorafenib Plus Chemotherapy Significantly Prolongs Progression-Free Survival in Advanced Breast Cancer

Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc, announced the full results from their first collaborative group-sponsored randomized, double-blind, placebo-controlled phase II trial showing that sorafenib (Nexavar) tablets in combination with the oral chemotherapeutic agent, capecitabine (Xeloda), significantly extended progression-free survival in patients with advanced breast cancer. The data were presented at the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress in Berlin.
74% Improvement
Jose Baselga, MD, chairman and professor of medicine at Vall d’Hebron Institute of Oncology in Barcelona, scientific chairman of the Spanish Breast Cancer Cooperative Group SOLTI and the principal investigator of this study, reported that patients receiving sorafenib plus capecitabine had a 74% improvement in the time they lived without their disease progressing compared to those who received the chemotherapy alone. The difference in median progression-free survival with sorafenib plus capecitabine vs capecitabine plus placebo was statistically significant, 6.4 vs 4.1 months (hazard ratio = 0.576, P = .0006).
“Onyx and Bayer have built a strong foundation with Nexavar in treating unresectable liver cancer and advanced kidney cancer—both disease areas with a previously unmet treatment need,” said Todd Yancey, md, vice president of clinical development at Onyx. “These new results signify another step in understanding the potential role of Nexavar in breast cancer.”
Breast Cancer Trial Design
The randomized, double-blind, placebo-controlled phase II study evaluated sorafenib in combination with capecitabine in 229 patients with locally advanced or metastatic HER2-negative breast cancer. These patients had received no more than one prior chemotherapy in this setting. The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, time to progression, and safety. Patients were randomized to receive 400 mg of oral sorafenib or matching placebo twice daily, in addition to 1,000 mg/m2 of capecitabine twice daily for 14 days followed by a 7-day rest from capecitabine.
Overall, treatment with sorafenib plus capecitabine was tolerable and resulted in no new side effects. Common grade 3 or 4 treatment-related adverse events included hand-foot skin reaction, diarrhea, dyspnea, neutropenia and mucositis.


3LBA LATE BREAKING ABSTRACT
SOLTI-0701: A double-blind, randomized phase 2b study evaluating the efficacy and safety of sorafenib (SOR) compared to placebo (PL) when administered in combination with capecitabine (CAP) in patients (pts) with locally advanced (adv) or metastatic (met) breast cancer (BC)

J. Baselga1, J.G.M. Segalla2, H. Roch´e3, A. del Giglio4, E.M. Ciruelos5, S. Cabral Filho6, P. Gomez1, A. Lluch7, A. Llombart8, F. Costa9. 1Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 2Funda¸c˜ao Dr. Amaral Carvalho, Hematology and Oncology, Ja´ u, Brazil; 3Institut Claudius Regaud, Medical Oncology, Toulouse, France; 4ABC-CEPHO, Hematology and Oncology, Santo Andr´ e, Brazil; 5Hospital Universitario 12 de Octubre, Medical Oncology, Madrid, Spain; 6Cl´ınica da Santa Casa de Belo Horizonte, Oncology, Belo Horizonte, Brazil; 7 Hospital Cl´ınico Universitario de Valencia, Medical Oncology, Valencia, Spain; 8Hospital Universitario Arnau de Vilanova de Lleida, Oncology, Lleida, Spain; 9IBPC, Clinical Research, S˜ao Paulo, Brazil

Background:
SOR is a potent multi-kinase inhibitor with antiangiogenic and antiproliferative activity approved for use in renal and hepatocellular cancer. To study the potential benefits of SOR in BC, we have conducted a phase 2b trial of SOR in combination with CAP for adv BC.

Methods: SOLTI-0701 was a double-blind, randomised, PL-controlled phase 2b study in pts with locally adv or met BC. Eligibility criteria included HER-2 negative tumours and <2 prior chemo regimens for adv/met BC. Pts with active brain metastasis were excluded. Pts were randomised (1:1) to receive CAP (1000 mg/m2, orally, twice daily [BID], for 14 of every 21 days) with PL or SOR (400 mg orally BID continuously). Randomisation was stratified by visceral vs nonvisceral disease. The primary endpoint was PFS and secondary endpoints included: OS, TTP, RR, response duration, and safety. Disease assessments occurred every 6 wks for the first 24 wks of the study and then every 9 wks thereafter. A sample size of 220 pts was planned to detect the targeted HR of 0.65 (90% power and 1 sided a = 0.14). The study is registered at EudraCT (ID 2007–000290−32).

Results:
Accrual was achieved over 15 mos with 229 pts enrolled (114 CAP+PL, 115 CAP+SOR). Treatment arms were balanced for age (median 55 y), ECOG (status 0, 68%), stage (IV, 91%), visceral (75%), and hormone-positive (73%). Prior chemotherapies: anthracyclines: 89%; taxanes 60%. By investigator assessment, the median PFS of CAP+PL vs CAP+SOR was 4.1 mos vs 6.4 mos; HR 0.576 (95% CI: 0.410, 0.809), P = 0.0006, overall RR was 31% (CAP+PL) vs 38%. OS data are pending.
No treatment-related deaths in the SOR arm and 1 treatment-related death in the PL arm attributed to CAP. Toxicities of Gr 3 or 4 (CAP+PL vs CAP+SOR) included hand-foot skin reaction (HFSR) (13% vs 45%), 4 Presidential session III diarrhoea (5% vs 5%), dyspnoea (4% vs 5%), neutropaenia (3% vs 5%), mucositis (4% vs 1%), and others less frequently. The no. of pts discontinuing treatment due to adverse events in the CAP+PL arm was 9 (8%) and in the CAP+SOR arm was 15 (13.4%). The most common reasons for discontinuation (CAP+PL vs CAP+SOR) include HFSR (2 vs 8) and diarrhoea (3 vs 1).
Conclusions:
In this randomised double-blind phase 2 trial, the oral combination of CAP+SOR demonstrated significant improvement in PFS in pts with locally adv or met BC. The regimen was tolerable and exhibited a clinically manageable toxicity profile. No new or unexpected side effects were observed with this combination. These results represent the first randomised study to demonstrate the efficacy of SOR in the treatment
of adv BC.

Principal investigator of the study, Professor José Baselga told his audience: “This is the first, large, randomized study that demonstrates significant clinical activity of sorafenib in breast cancer when given in combination with chemotherapy. Our results showed that patients who received sorafenib plus capecitabine had a 74% percent improvement in the time they lived without their disease worsening compared to those who received the chemotherapy alone. This is a very positive study and the magnitude of the benefit is such that it suggests that this agent will be an important addition to our therapeutic armory in breast cancer.”


http://www.reuters.com/article/idUKTRE5BB0B520091212

Friday
, December 11, 2009
Nexavar may help breast cancer drugs work longer

By Julie Steenhuysen
CHICAGO (Reuters) - U.S. researchers may have found a way to overcome resistance to hormone-blocking breast cancer drugs, extending the life of treatments that keep the disease in check.
They said the drug Nexavar or sorafenib, made by German drugmaker Bayer and its development partner Onyx Pharmaceuticals, helped re-sensitize breast cancer to treatment with aromatase inhibitors, drugs given to post-menopausal women with hormone-sensitive breast cancers.
"Hormone-receptor positive breast cancers eventually become resistant to hormonal therapy," said Dr. Claudine Isaacs of Georgetown University in Washington, who presented her findings at the American Association for Cancer Research's San Antonio Breast Cancer Symposium.
"There has been a great deal of interest in trying to figure out how we might overcome that resistance or stop the cancer cells from figuring out how to circumvent that hormonal therapy," Isaacs said in a telephone interview.
She said Nexavar, a drug approved for liver and kidney cancer, acts on a lot of cancer-related genes and it also acts to inhibit new blood vessels from forming.
The researchers studied the drug in 35 post-menopausal women with advanced breast cancer resistant to treatment with aromatase inhibitors.
Women in the trial, funded with a grant by Bayer, continued to take the aromatase inhibitor, but they also took Nexavar.
"These women all had disease progression. Twenty-three percent of the women in the study had a clinical benefit from it. It means they either had shrinkage of their tumors or it stayed stable," Isaacs said.
Isaacs said the finding suggests the drug somehow circumvents the mechanism used by the cancer to resist the effects of the aromatase inhibitors.
"It puts the brakes on it so it didn't grow for at least six months," she said.
The treatment was not without side effects. Many women in the study developed a rash called hand-foot syndrome, which causes redness, peeling and some tenderness on the palms of the hands and soles of the feet.
It also caused elevated blood pressure in 11 percent of the women, but Isaacs this could be overcome by putting women on blood pressure drugs before taking Nexavar.
She said the findings were strong enough to inspire the drug companies to start a large, late-stage study to see if it has a significant benefit for women.


Breast Cancer Res Treat. 2010 Jan 7. [Epub ahead of print]
Synergistic activity of letrozole and sorafenib (Nexavar) on breast cancer cells.


FULL TEXT purchase

Bonelli MA, Fumarola C, Alfieri RR, La Monica S, Cavazzoni A, Galetti M, Gatti R, Belletti S, Harris AL, Fox SB, Evans DB, Dowsett M, Martin LA, Bottini A, Generali D, Petronini PG.
Department of Experimental Medicine, University of Parma, Via Volturno, 39, 43100, Parma, Italy.
Estrogens induce breast tumor cell proliferation by directly regulating gene expression via the estrogen receptor (ER) transcriptional activity and by affecting growth factor signaling pathways such as mitogen-activated protein kinase (MAPK) and AKT/mammalian target of rapamycin Complex1 (mTORC1) cascades. In this study we demonstrated the preclinical therapeutic efficacy of combining the aromatase inhibitor letrozole with the multi-kinase inhibitor sorafenib in aromatase-expressing breast cancer cell lines. Treatment with letrozole reduced testosterone-driven cell proliferation, by inhibiting the synthesis of estrogens. Sorafenib inhibited cell proliferation in a concentration-dependent manner; this effect was not dependent on sorafenib-mediated inhibition of Raf1, but involved the down-regulation of mTORC1 and its targets p70S6K and 4E-binding protein 1 (4E-BP1). At concentrations of 5-10 muM the growth-inhibitory effect of sorafenib was associated with the induction of apoptosis, as indicated by release of cytochrome c and Apoptosis-Inducing Factor into the cytosol, activation of caspase-9 and caspase-7, and PARP-1 cleavage. Combination of letrozole and sorafenib produced a synergistic inhibition of cell proliferation associated with an enhanced accumulation of cells in the G(0)/G(1) phase of the cell cycle and with a down-regulation of the cell cycle regulatory proteins c-myc, cyclin D1, and phospho-Rb. In addition, longer experiments (12 weeks) demonstrated that sorafenib may be effective in preventing the acquisition of resistance towards letrozole. Together, these results indicate that combination of letrozole and sorafenib might constitute a promising approach to the treatment of hormone-dependent breast cancer.

PMID: 20054642 [PubMed - as supplied by publisher]


Breast Cancer Res Treat. 2010 Dec 9. [Epub ahead of print]
HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib.

Valabrega G, Capellero S, Cavalloni G, Zaccarello G, Petrelli A, Migliardi G, Milani A, Peraldo-Neia C, Gammaitoni L, Sapino A, Pecchioni C, Moggio A, Giordano S, Aglietta M, Montemurro F.

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Source

Department of Oncological Sciences, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Strada Provinciale 142 km 3.95, 10060, Candiolo, TO, Italy, giorgio.valabrega@unito.it.

Abstract

Trastuzumab has changed the prognosis of HER2 positive breast cancers. Despite this progress, resistance to trastuzumab occurs in most patients. Newer anti-HER2 therapies, like the dual tyrosine-kinase inhibitor (TKI) lapatinib, show significant antitumor activity, indicating that HER2 can be still exploited as a target after trastuzumab failure. However, since a high proportion of patients fail to respond to these alternative strategies, it is possible that cell escape from HER2 targeting may rely on HER2 independent pathways. The knowledge of these pathways deserve to be exploited to develop new therapies. We characterized two human HER2 overexpressing breast cancer cell lines resistant to trastuzumab and lapatinib (T100 and JIMT-1) from a molecular and biological point of view. Indeed, we assessed both in vitro and in vivo the activity of the multitarget inhibitor sorafenib. In both cell lines, the previously proposed mechanisms did not explain resistance to HER2 inhibitors. Notably, silencing HER2 by shRNA did not affect the growth of our cells, suggesting loss of reliance upon HER2. Moreover, we identified alterations in two antiapoptotic proteins Mcl-1 and Survivin which are known to be targets of the multikinase inhibitor sorafenib. Moreover, sorafenib, strongly inhibited the in vitro growth of T100 and JIMT-1 cells, through the downregulation of both Mcl-1 and Survivin. Similar results were obtained in JIMT-1 xenografts subcutaneously injected in NOD SCID mice. We provide preclinical evidence that tumor cells resistant to trastuzumab and lapatinib may rely on HER2 independent pathways that can be efficiently inhibited by sorafenib.

PMID:
21153051




MONOTHERAPY:



Anticancer Drugs. 2009 Aug;20(7):616-24.
Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer.

Bianchi G, Loibl S, Zamagni C, Salvagni S, Raab G, Siena S, Laferriere N, Peña C, Lathia C, Bergamini L, Gianni L.
Fondazione IRCCS Istituto Tumori di Milano, Via Venezian, 1, 20133 Milan, Italy.
This trial was conducted to assess the efficacy and safety of sorafenib in patients with metastatic breast cancer. In this multinational, open-label phase II study, patients with metastatic breast cancer that had progressed after at least one prior chemotherapy regimen were continuously treated with oral sorafenib, 400 mg twice daily. The primary endpoint was overall best response; a secondary endpoint was percentage of patients with stable disease for greater than or equal to 16 weeks. Biomarker analysis were also performed. Of the 56 patients enrolled into the study, 54 were treated with at least one dose of sorafenib. Partial response was observed in one patient (2%) and stable disease in 20 patients (37%); no complete responses were observed. Disease stabilization for greater than or equal to 16 weeks was seen in 12 patients (22%); stabilization for greater than or equal to 6 months in seven patients (13%). The most common drug-related grade 3 adverse events were rash/desquamation (6%), hand-foot skin reaction (4%), and fatigue (4%). Baseline vascular endothelial growth factor levels, levels of soluble epidermal growth factor receptor during treatment and both baseline and changes in soluble human epidermal growth factor receptor 2 levels correlated significantly with clinical outcomes. Although the primary endpoint of overall response rate showed minimal improvement on sorafenib 400 mg twice-daily treatment, the rate of disease stabilization was encouraging in patients treated with one or more lines of chemotherapy. The treatment had a clinically manageable toxicity profile.investigating combinations of sorafenib with chemotherapeutic agents are warranted and ongoing. Further investigation of single-agent sorafenib in this patient population is not recommended; however, studies

PMID: 19739318 [PubMed - indexed for MEDLINE]




J Clin Oncol. 2009 Jan 1;27(1):11-5. Epub 2008 Dec 1.
Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336.

Moreno-Aspitia A, Morton RF, Hillman DW, Lingle WL, Rowland KM Jr, Wiesenfeld M, Flynn PJ, Fitch TR, Perez EA.
Division of Hematology/Oncology, Mayo Clinic and Mayo Foundation, Jacksonville, FL 32224, USA. morenoaspitia.alvaro@mayo.edu
PURPOSE: We conducted a cooperative group phase II study to assess antitumor activity and toxicity of sorafenib in patients with metastatic breast cancer (MBC) who had received prior treatment for their disease. PATIENT AND METHODS: Patients were eligible if they had measurable disease and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. The primary end point of the study was tumor response per Response Evaluation Criteria in Solid Tumors (RECIST). The study was designed in two stages. Sorafenib was administered as 400 mg twice daily on days 1 through 28 of each 4-week cycle. RESULTS: Twenty-three patients were enrolled with a median age of 54 years (range, 37 to 70 years). Twenty-two (96%) had prior anthracycline treatment and 16 (70%) had prior taxane treatment. Patients received sorafenib for a median of two cycles (range, one to 15 cycles) with a median follow-up of 2.4 years (range, 2.2 to 2.6 years). There were no grade 4 toxicities and few grade 3 toxicities. Among the 20 patients eligible for efficacy analysis, no patients experienced a partial response or complete response per RECIST criteria. Thus, the trial stopped at the end of the first stage per study design. Two patients (10%; 90% CI, 1.8% to 28.3%) achieved stable disease lasting longer than 6 months. CONCLUSION: Sorafenib as a single agent, although well tolerated, did not exhibit activity when measured by tumor shrinkage in patients with MBC who had received prior treatment. Further research should focus on combinations with standard therapy and end points more sensitive to effects of targeted agents, such as disease stabilization.

PMID: 19047293 [PubMed - indexed for MEDLINE]




J Neurooncol. 2009 Jan;91(1):47-50. Epub 2008 Aug 19.
Long-lasting successful cerebral response with sorafenib in advanced renal cell carcinoma.

Valcamonico F, Ferrari V, Amoroso V, Rangoni G, Simoncini E, Marpicati P, Vassalli L, Grisanti S, Marini G.
Department of Medical Oncology, Spedali Civili di Brescia, Brescia, Italy. franzval@yahoo.it
We report the case of a 75-year old woman who received sorafenib (Nexavar), Bayer Pharmaceuticals Corporation, West Haven, CT) for a CNS relapse of clear cell renal cell carcinoma. After four months of sorafenib treatment, a brain magnetic resonance imaging showed 95%-volumetric regression of cerebral metastasis. To the best of our knowledge, this is the first almost complete resolution of brain metastases in renal cell carcinoma treated with sorafenib that has been described.

PMID: 18712279 [PubMed - indexed for MEDLINE]




Endocr Pract. 2009 Nov 26:1-19. [Epub ahead of print]
Sustained remission with the kinase inhibitor sorafenib in Stage IV metastatic adrenocortical carcinoma.

Butler C, Butler WM, Rizvi AA.
Division of Oncology, Medical University of South Carolina, Charleston, South Carolina.
Objective: To report our experience with the use of kinase inhibition therapy with sorafenib in a patient with advanced adrenocortical carcinoma.Methods: A 56 year old female presented with rapid development of virilization, cushingoid features, hypertension, weight gain, abdominal distension. An 8 cm left adrenal lesion was found on imaging, removed surgically, and confirmed as adrenal carcinoma on pathology. Postoperative scanning revealed metastases to both lungs and the liver that were confirmed by fine-needle biopsy, thus establishing Stage IV disease.Results: Treatment with the adrenolytic agent mitotane failed to halt disease progression. A trial of sorafenib resulted in regression and eventual resolution of bilateral metastatic lung lesions and reduction in size of hepatic lesion, normalization of androgen hypersecretion, and marked clinical improvement. The radiological and biochemical remission on sorafenib has continued for 28 months.
Conclusion: Adrenocortical carcinoma is a rare endocrine malignancy that carries an extremely poor prognosis when discovered in an advanced stage. Traditional medications seldom afford long-term control. Multiple kinase inhibitors such as sorafenib provide targeted oncologic treatment and may be effective in advanced adrenal cancer. The challenge in ongoing and future studies is to identify patients who would have an increased likelihood of a favorable response to these agents.

PMID: 20061282 [PubMed - as supplied by publisher]




Cancer Chemother Pharmacol. 2008 Apr;61(4):535-48. Epub 2007 Nov 17.
Safety and anti-tumor activity of sorafenib (Nexavar) in combination with other anti-cancer agents: a review of clinical trials.

Takimoto CH, Awada A.
South Texas Accelerated Research Therapeutics (START), 4319 Medical Drive, Suite 205, San Antonio, TX, 78229, USA. takimoto@start.stoh.com
PURPOSE: Sorafenib (Nexavar) is an oral multi-kinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. Sorafenib has demonstrated preclinical and clinical activity against several tumor types, as a monotherapy and in combination with other anti-cancer agents. METHODS: This review summarizes the safety, pharmacokinetics, and anti-tumor activity of sorafenib combined with other targeted agents or cytotoxics from a series of Phase I/II trials in approximately 600 patients with advanced solid tumors. RESULTS: Sorafenib in combination with other agents was generally well tolerated, and most adverse events were mild to moderate in severity. Frequent drug-related toxicities were dermatologic, gastrointestinal, or constitutional. Most trials supported sorafenib 400 mg bid as the recommended dose for combination. Sorafenib generally had little effect on the pharmacokinetics of coadministered agents and vice versa. Preliminary anti-tumor activity was observed; overall disease control rates (partial response plus stable disease) ranged from 33 to 92%. Particularly promising activity was observed in patients with melanoma, hepatocellular carcinoma, and non-small-cell lung cancer receiving sorafenib plus paclitaxel/carboplatin, doxorubicin, and gefitinib, respectively. CONCLUSIONS: Sorafenib demonstrated a good safety profile and encouraging anti-tumor effects when coadministered with other agents in patients with advanced solid tumors.

PMID: 18026728 [PubMed - indexed for MEDLINE]



Oncologist. 2008 Aug;13(8):845-58. Epub 2008 Aug 11.
Selected combination therapy with sorafenib: a review of clinical data and perspectives in advanced solid tumors.

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Dal Lago L, D'Hondt V, Awada A.
Head of the Medical Oncology Clinic, Jules Bordet Institute, Boulevard de Waterloo 121, B-1000 Brussels, Belgium.
The development of targeted therapies has provided new options for the management of patients with advanced solid tumors. There has been particular interest in agents that target the mitogen-activated protein kinase pathway, which controls tumor growth and survival and promotes angiogenesis. Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in renal cell carcinoma, and there is a strong rationale for investigating its use in combination with other agents. In particular, targeting multiple Raf isoforms with sorafenib may help to overcome resistance to other agents, while the ability of sorafenib to induce apoptosis may increase the cytotoxicity of chemotherapeutic agents. Based on positive results in preclinical studies, further investigation in phase I and II studies has shown potential antitumor activity when sorafenib is combined with cytotoxic agents in different solid tumors, including hepatocellular carcinoma and melanoma. Promising results have been reported in phase I and II studies of sorafenib combined with paclitaxel and carboplatin, with oxaliplatin in gastric and colorectal cancer, with docetaxel in breast cancer, with gemcitabine in ovarian cancer, and with capecitabine in different solid tumors. Phase II and III studies are currently investigating the use of sorafenib in combination with different agents in a variety of solid tumors. The primary objective of this review is to summarize the early clinical studies of sorafenib with cytotoxic agents and discuss future perspectives of these combinations in different tumor types.

PMID: 18695262 [PubMed - indexed for MEDLINE]





Expert Opin Drug Saf. 2010 Jan 17. [Epub ahead of print]
Toxicity of sorafenib: clinical and molecular aspects.

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Blanchet B, Billemont B, Barete S, Garrigue H, Cabanes L, Coriat R, Francès C, Knebelmann B, Goldwasser F.
Laboratoire de Pharmacologie-Toxicologie, Service de Pharmacie, GH Cochin-Saint Vincent-de-Paul, 75014 Paris, France + 33 1 58 41 23 13 ; + 33 1 58 41 23 15; benoit.blanchet@cch.aphp.fr.
Importance of the field: Sorafenib is a novel oral bis-aryl urea compound originally developed as an inhibitor of RAF kinase for its anti-proliferative property. Sorafenib also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-1/2/3, Flt-3 and PDGFR-beta. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. Sorafenib has been approved for the treatment of metastatic renal cell carcinoma as well as hepatocellular cancer. Despite its inherent selectivity, sorafenib can cause unusual adverse events whose the management represents a challenge for oncologists. Areas covered in this review: Relevant literature was identified using a Pubmed search of articles published up to June 2009. Search terms included 'sorafenib' and 'toxicity'. Original articles were reviewed and relevant citations from these articles were also considered. What the reader will gain: The clinical aspect of sorafenib-induced adverse events and the molecular basis behind this toxicity are discussed. Finally, recommendations for the management of these adverse events are proposed. Take home message: Although not life-threatening, toxicity of sorafenib can severely impact the physical, psychological and social well-being of patients. The management of this unusual toxicity highlights the particular need of new pluridisciplinarities linking oncologist, cardiologist and dermatologist.

PMID: 20078249 [PubMed - as supplied by publisher]


J Neurosurg. 2009 Sep;111(3):497-503.
Brain magnetic resonance imaging changes after sorafenib and sunitinib chemotherapy in patients with advanced renal cell and breast carcinoma.

Hill KL Jr, Lipson AC, Sheehan JM.
Penn State Milton S. Hershey Medical Center, Department of Neurosurgery, Hershey, Pennsylvania 17033, USA.
OBJECT: The authors report novel imaging findings associated with the treatment of sorafenib (Nexavar) and sunitinib (Sutant), 2 agents used in the treatment of advanced metastatic disease. METHODS: Patients with renal cell and breast carcinoma metastases to the brain were identified from the prospective database at the Penn State Hershey Medical Center and Penn State Cancer Institute. RESULTS: Four patients who received sorafenib or sunitinib after surgical or radiosurgical treatment of their metastases were identified from the database. Clinical and/or radiographic changes consisting of seizures and cognitive or motor changes were described, associated with an increase in peritumoral edema and enhancement. These findings were observed to improve with discontinuation of the medications. CONCLUSIONS: The administration of sorafenib and sunitinib in patients with metastatic breast and renal cell carcinoma may lead to reversible clinical and imaging changes following surgical or radiosurgical treatment of their brain lesions. The authors hypothesize that leakage of the drug across a locally impaired blood-brain barrier contributes to peritumoral edema and inflammation, which may be erroneously interpreted as disease progression.

PMID: 19199506 [PubMed - indexed for MEDLINE]






Drugs. 2009;69(2):223-40. doi: 10.2165/00003495-200969020-00006.
Sorafenib: a review of its use in advanced hepatocellular carcinoma.

Keating GM, Santoro A.
Wolters Kluwer Health mid R: Adis, Auckland, New Zealand.
Sorafenib (Nexavar) is an orally active multikinase inhibitor that is approved in the EU for the treatment of hepatocellular carcinoma. Monotherapy with sorafenib prolongs overall survival and delays the time to progression in patients with advanced hepatocellular carcinoma who are not candidates for potentially curative treatment or transarterial chemoembolization. Sorafenib is generally well tolerated in patients with advanced hepatocellular carcinoma. Thus, sorafenib represents an important advance in the treatment of advanced hepatocellular carcinoma and is the new standard of care for this condition. The bi-aryl urea sorafenib is an oral multikinase inhibitor that inhibits cell surface tyrosine kinase receptors (e.g. vascular endothelial growth factor receptors and platelet-derived growth factor receptor-beta) and downstream intracellular serine/threonine kinases (e.g. Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in tumour cell proliferation and tumour angiogenesis. In vitro, dose-dependent inhibition of cell proliferation and induction of apoptosis was seen with sorafenib in human hepatocellular carcinoma cells lines. Sorafenib demonstrated dose-dependent antitumour activity in a murine xenograft model of human hepatocellular carcinoma. Steady-state plasma concentrations were reached within 7 days in patients with advanced, refractory solid tumours who received twice-daily oral sorafenib. Metabolism of sorafenib occurs primarily in the liver and is mediated via cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase 1A9. In advanced hepatocellular carcinoma, differences in sorafenib pharmacokinetics between Child-Pugh A and B patients were not considered clinically significant. Sorafenib may be associated with drug interactions. For example, sorafenib exposure was reduced by an average 37% with concomitant administration of the CYP3A4 inducer rifampicin (rifampin); sorafenib concentrations may also be decreased by other CYP3A4 inducers. Monotherapy with oral sorafenib 400 mg twice daily prolonged median overall survival and delayed the median time to progression in patients with advanced hepatocellular carcinoma, according to the results of two randomized, double-blind, placebo-controlled, multicentre, phase III trials (the SHARP trial and the Asia-Pacific trial). There was no significant difference between sorafenib and placebo recipients in the median time to symptomatic progression in either trial. The vast majority of patients included in these trials were Child-Pugh A. Combination therapy with sorafenib plus doxorubicin did not delay the median time to progression to a significant extent compared with doxorubicin alone in patients with advanced hepatocellular carcinoma, according to the results of a randomized, double-blind, phase II trial. However, the median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone. Combination therapy with sorafenib plus tegafur/uracil or mitomycin also showed potential in advanced hepatocellular carcinoma, according to the results of noncomparative trials. Monotherapy with oral sorafenib was generally well tolerated in patients with advanced hepatocellular carcinoma, with a manageable adverse effect profile; diarrhoea and hand-foot skin reaction were consistently the most commonly occurring drug-related adverse events in clinical trials. In the SHARP trial, drug-related adverse events of any grade occurring in significantly more sorafenib than placebo recipients included diarrhoea, hand-foot skin reaction, anorexia, alopecia, weight loss, dry skin, abdominal pain, voice changes and 'other' dermatological events. A similar tolerability profile was seen in the Asia-Pacific trial. As expected given the addition of a chemotherapy agent, the adverse event profile in patients with advanced hepatocellular carcinoma who received combination therapy with sorafenib plus doxorubicin differed somewhat to that seen with sorafenib monotherapy in the SHARP trial. In patients receiving sorafenib plus doxorubicin, the most commonly occurring all-cause adverse events (all grades) included fatigue, neutropenia, diarrhoea, elevated bilirubin levels, abdominal pain, hand-foot skin reaction, left ventricular dysfunction, hypertension and febrile neutropenia.

PMID: 19228077 [PubMed - indexed for MEDLINE]



Curr Med Chem. 2008;15(5):422-32.
From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage.

Petrelli A, Giordano S.
Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Str. Provinciale 142, 10060, Candiolo (Torino), Italy. annalisa.petrelli@ircc.it
Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy which acts on all dividing cells generating toxic effects and damage of normal tissues, targeted drugs allow to hit, in a more specific manner, subpopulations of cells directly involved in tumor progression. Molecules controlling cell proliferation and death, such as Tyrosine Kinase Receptors (RTKs) for growth factors, are among the best targets for this type of therapeutic approach. Two classes of compounds targeting RTKs are currently used in clinical practice: monoclonal antibodies and tyrosine kinase inhibitors. The era of targeted therapy began with the approval of Trastuzumab, a monoclonal antibody against HER2, for treatment of metastatic breast cancer, and Imatinib, a small tyrosine kinase inhibitor targeting BCR-Abl, in Chronic Myeloid Leukemia. Despite the initial enthusiasm for the efficacy of these treatments, clinicians had to face soon the problem of relapse, as almost invariably cancer patients developed drug resistance, often due to the activation of alternative RTKs pathways. In this view, the rationale at the basis of targeting drugs is radically shifting. In the past, the main effort was aimed at developing highly specific inhibitors acting on single RTKs. Now, there is a general agreement that molecules interfering simultaneously with multiple RTKs might be more effective than single target agents. With the recent approval by FDA of Sorafenib and Sunitinib--targeting VEGFR, PDGFR, FLT-3 and c-Kit--a different scenario has been emerging, where a new generation of anti-cancer drugs, able to inhibit more than one pathway, would probably play a major role.

PMID: 18288997 [PubMed - indexed for MEDLINE]



The multikinase inhibitor sorafenib induces apoptosis and sensitises endometrial cancer cells to TRAIL by different mechanisms
European Journal of Cancer, 01/25/10
Llobeta D et al. – In the present study, we show that Sorafenib induces apoptosis of both endometrial cancer cell lines and human primary cultures and sensitises these cells to TRAIL and agonistic Fas antibodies (aFas)-induced apoptosis. However, Raf/MEK/ERK inhibition by Sorafenib was not responsible for Sorafenib cell death or TRAIL sensitisation of endometrial cancer cells.
Methods
  • Evaluated the contribution of FLIP and Mcl-1 downregulation in apoptosis triggered by Sorafenib alone or Sorafenib plus TRAIL. Interestingly, cell death caused by Sorafenib was mediated by downregulation of Mcl-1, but not by FLIP
Results
  • Cell death caused by Sorafenib was mediated by downregulation of Mcl-1, but not by FLIP
  • Sorafenib sensitisation of endometrial carcinoma cells to TRAIL- and Fas-induced apoptosis was dependent on FLIP but not on Mcl-1 downregulation



Medicare off label guidelines: LINK


Nexavar Access/financial assistance:

http://www.nexavar-us.com/scripts/pages/en/home/rcc/rcc_reach/index.php

1- 877-322-4448




Link to other financial resources: http://www.liferaftgroup.org/treat_finance.html

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Old 02-02-2010, 10:48 AM   #2
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Re: Sorafenib (Nexavar)

J Hepatol. 2010 Mar 30. [Epub ahead of print]
Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma.

Hsu CH, Shen YC, Lin ZZ, Chen PJ, Shao YY, Ding YH, Hsu C, Cheng AL.
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan.
Abstract

BACKGROUND & AIMS: Sorafenib, a multi-kinase inhibitor with anti-angiogenic activity, was recently approved for the treatment of advanced hepatocellular carcinoma (HCC). Metronomic chemotherapy using tegafur/uracil (4:1molar ratio), an oral fluoropyrimidine, has been shown to enhance the anti-tumor effect of anti-angiogenic agents in preclinical models. This phase II study evaluated the efficacy and safety of combining metronomic tegafur/uracil with sorafenib in patients with advanced HCC. METHODS: Patients with histologically- or cytologically-proven HCC and Child-Pugh class A liver function were treated with sorafenib (400mg twice daily) and tegafur/uracil (125mg/m(2) based on tegafur twice daily) continuously as first-line therapy for metastatic or locally advanced disease that could not be treated by loco-regional therapies. The primary endpoint was progression-free survival (PFS). RESULTS: The study enrolled 53 patients. Thirty-eight patients (72%) were hepatitis B surface antigen-positive. The median PFS was 3.7months (95% C.I., 1.9-5.5) and the median overall survival was 7.4months (95% C.I., 3.4-11.4). According to RECIST criteria, 4 patients (8%) had a partial response and 26 patients (49%) had a stable disease. Major grade 3/4 toxicities included fatigue (15%), abnormal liver function (13%), elevated serum lipase (10%) hand-foot skin reaction (HFSR) (9%), and bleeding (8%). HFSR was the major adverse event resulting in dose reduction (19%) or treatment delay (21%). CONCLUSIONS: Metronomic chemotherapy with tegafur/uracil can be safely combined with sorafenib and shows preliminary activity to improve the efficacy of sorafenib in advanced HCC patients. Copyright © 2010. Published by Elsevier B.V.

PMID: 20416968 [PubMed - as supplied by publisher]




Oncol Rep. 2010 Oct;24(4):1049-58.
Sorafenib enhances the in vitro anti-endothelial effects of low dose (metronomic) chemotherapy.

Murray A, Little SJ, Stanley P, Maraveyas A, Cawkwell L.
Cancer Biology Proteomics Group, Postgraduate Medical Institute, University of Hull, Hull, UK.



Abstract

Angiogenesis inhibitors may enhance the effects of low dose (metronomic) chemotherapy. However, there is a wide range of novel angiogenesis inhibitors which must be tested in combinations with oral chemotherapy agents to assess the anti-endothelial and anti-cancer effects. This preliminary testing is most suited to high throughput in vitro models, rather than clinical trials. We aimed to establish an in vitro model and test the anti-endothelial and anti-cancer effects of the multi-kinase inhibitor sorafenib when used as a single agent and in combination with oral chemotherapy agents used at low concentrations. Micro-vascular endothelial cells and 3 cancer cell lines were utilised and an extended treatment strategy (96 h) was employed in order to mimic a continuous low dose anti-angiogenic chemotherapy regimen. Sorafenib significantly enhanced the anti-endothelial effect of low dose etoposide, paclitaxel and temozolomide. Sorafenib also significantly enhanced the anti-cancer effect of low dose etoposide, paclitaxel and temozolomide in SK-MEL-2 melanoma cells, producing an additive effect on inhibition of cell growth in all cases. These combinations appear to be the most promising for in vivo pre-clinical studies, with a view to testing in melanoma patients as a continuous dosing strategy, due to the in vitro additive inhibitory effect on growth seen in both endothelial and cancer cells.

PMID: 20811688 [PubMed - in process]









Br J Cancer. 2010 Jan 5. [Epub ahead of print]
Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity.

Lee JM, Sarosy GA, Annunziata CM, Azad N, Minasian L, Kotz H, Squires J, Houston N, Kohn EC.
Medical Ovarian Cancer Team, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.


Background: We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing.
Methods: Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed.
Results: Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation >/=4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months.
Conclusion: Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.British Journal of Cancer advance online publication, 5 January 2010; doi:10.1038/sj.bjc.6605514 www.bjcancer.com.

PMID: 20051952 [PubMed - as supplied by publisher]



Oncologist. 2010;15(1):85-92. Epub 2010 Jan 5.
Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib.

Vincenzi B, Santini D, Russo A, Addeo R, Giuliani F, Montella L, Rizzo S, Venditti O, Frezza AM, Caraglia M, Colucci G, Del Prete S, Tonini G.
Correspondence: Antonio Russo, M.D., Ph.D., Department of Surgical and Oncological Sciences, Section of Medical Oncology; Universit* di Palermo, Palermo, Italy, Via del Vespro 127, 90127 Palermo, Italy. Telephone: 39-091-6552500; Fax: 39-091-6554529; e-mail: lab-oncobiologia@usa.net


TEXT here



Introduction. Sorafenib is an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases and has led to a longer median overall survival (OS) time and time to progression (TTP) in patients with advanced hepatocellular carcinoma (HCC). This study was conducted to assess the link between the antitumor efficacy of sorafenib and its early cutaneous side effects in advanced HCC patients. Materials and Methods. All patients received 800 mg daily of sorafenib until progression or unacceptable toxicities. We retrospectively analyzed the incidence of rash and hand-foot skin reactions (HFSR) during the first month of treatment, comparing tumor control (partial response plus stable disease) and TTP. Results. Sixty-five HCC patients treated with sorafenib were included in this analysis: 47 (73.3%) received sorafenib after failure of some local treatment, whereas 18 (27.7%) received it as first-line treatment. Twenty-nine patients developed at least grade 1 skin toxicity (rash, 13; HFSR, 16). In patients who developed skin toxicity, the tumor control rate was 48.3%, versus 19.4% in patients without cutaneous side effects. The median TTP was 8.1 months in the group of patients with skin toxicity versus 4.0 months in those without skin toxicity. This difference was also statistically significant on multivariate analysis. A borderline statistically significant difference was also observed in terms of OS in patients with early skin toxicity. Conclusions. Skin toxicity should be closely monitored in HCC patients treated with sorafenib in relation to its potential role as a surrogate marker of efficacy.

PMID: 20051477 [PubMed - in process]




Oncol Rep. 2010 Oct;24(4):1049-58.
Sorafenib enhances the in vitro anti-endothelial effects of low dose (metronomic) chemotherapy.

Murray A, Little SJ, Stanley P, Maraveyas A, Cawkwell L.
Cancer Biology Proteomics Group, Postgraduate Medical Institute, University of Hull, Hull, UK.


$ TEXT

Abstract

Angiogenesis inhibitors may enhance the effects of low dose (metronomic) chemotherapy. However, there is a wide range of novel angiogenesis inhibitors which must be tested in combinations with oral chemotherapy agents to assess the anti-endothelial and anti-cancer effects. This preliminary testing is most suited to high throughput in vitro models, rather than clinical trials. We aimed to establish an in vitro model and test the anti-endothelial and anti-cancer effects of the multi-kinase inhibitor sorafenib when used as a single agent and in combination with oral chemotherapy agents used at low concentrations. Micro-vascular endothelial cells and 3 cancer cell lines were utilised and an extended treatment strategy (96 h) was employed in order to mimic a continuous low dose anti-angiogenic chemotherapy regimen. Sorafenib significantly enhanced the anti-endothelial effect of low dose etoposide, paclitaxel and temozolomide. Sorafenib also significantly enhanced the anti-cancer effect of low dose etoposide, paclitaxel and temozolomide in SK-MEL-2 melanoma cells, producing an additive effect on inhibition of cell growth in all cases. These combinations appear to be the most promising for in vivo pre-clinical studies, with a view to testing in melanoma patients as a continuous dosing strategy, due to the in vitro additive inhibitory effect on growth seen in both endothelial and cancer cells.

PMID: 20811688 [PubMed - in process]
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Old 07-19-2010, 12:40 PM   #3
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Antitumor and Antimicrovascular Effects of Nexavar

Antitumor and antimicrovascular effects of Nexavar (sorafenib) in fresh human tumor culture in comparison with other putative tyrosine kinase inhibitors (TKIs).

Sub-category:
Tyrosine Kinase Inhibitors

Category:
Developmental Therapeutics - Experimental Therapeutics

Meeting:
2010 ASCO Annual Meeting

Session Type and Session Title:
Abstract published in conjunction with the meeting.

Abstract No:
e13617

Citation:
J Clin Oncol 28, 2010 (suppl; abstr e13617)

Author(s):
L. M. Weisenthal; Weisenthal Cancer Group, Huntington Beach, CA

Abstract:

Background: Nexavar is postulated to be a clinical anti-angiogenic agent. Yet preliminary clinical evidence suggests it may not be cross resistant with other anti-angigenic agensts, including Sutent (sunitinib) (Tamaskar, et al. J Urology 179:81,2008). An alternative hypothesis is that Nexavar has direct antitumor cell effects. In order to determine whether antivascular or antitumor cell effects were more important, we measured both antivascular and antitumor cell effects of Nexavar in short term cultures of fresh human tumor biopsies and compared these activities with those of other putative tyrosine kinase inhibitors.

Methods: We used methods described in the following publication: Weisenthal, et al. Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood. J Intern Med 264: 275-287, 2008. doi: 10.1111/j.1365-2796.2008.01955.x

Results: Utilizing methods described in Table 1 of the above publication, we determined the relative antivascular activity vs antitumor cell activity of tyrosine kinase inhibitors and other agents. Expressed as a ratio of antivascular activity divided by antitumor cell activity, the rank order (greatest to least relative antivascular activity) was as follows: pazopanib > bevacizumab > dasatinib > sunitinib > erlotinib > lapatinib > gefitinib > imatinib > sorafenib > cisplatin. Antivascular activity of Nexavar was minimal. We also determined correlation coefficients for antitumor cell activity of these agents (comparing activity of two agents at a time in the same specimen datasets; size of comparison tyrosine kinase inhibitor datasets ranging from 11 to 587, median of 247 direct activity comparisons between pairs of agents. Correlation coefficients are as follows: doxorubicin/epirubicin 0.88, cisplatin/carboplatin 0.86, paclitaxel/docetaxel 0.64, cisplatin/oxaliplatin 0.48, cisplatin/5FU 0.35, gefitinib/erlotinib 0.61, erlotinib/imatinib 0.51, erlotinib/lapatinib 0.46, erlotinib/dasatinib 0.41, erlotinib/sunitinib 0.28, sunitinib/imatinib 0.51, soraf/dasatinib 0.19, soraf/gefitinib 0.17, soraf/pazopanib 0.10, soraf/sunitinib 0.01, soraf/lapatinib 0.00, soraf/imatinib -0.01.

Conclusions: Nexavar has minimal antivascular activity in short term cultures of fresh human tumors, in comparison with other tyrosine kinase inhibitors and has virtually non-cross resistant antitumor cell activity.
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Old 07-19-2010, 12:43 PM   #4
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Antitumor and Antimicrovascular Effects of Nexavar, Tykerb and Avastin

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
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Old 12-17-2010, 12:12 AM   #5
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Re: Sorafenib (Nexavar)

The eighty extra days is for the group in the study, not the "individual" patients treated in the real world. One person may live two days, another two-hundred additional days. What may work in some patients, may not work in other patients.

What's good for the group may not be good for the individual, affirms that in the tactic of using "fresh" biopsied cells to predict which cancer treatments will work best for the individual patient, this "smart" drug has to get inside the cells in order to "target" anything.

If the "targeted" drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, it just isn't going to work. Each of these new "targeted" drugs are not for everybody. Even when the disease is the same type, different patients' tumors respond differently to the same agent.

If a drug works extremely well for a certain percentage of cancer patients, identify which ones. If one drug or another is working for some people (not average populations) then obviously there are others out there who would also benefit.

Upgrading clinical therapy by using drug sensitivity assays measuring "cell death" of three dimensional microclusters of live "fresh" tumor cells, can improve the situation by allowing more drugs to be considered. The more drug types there are in the selective arsenal, the more likely the system is to prove beneficial.

Drug sensitivity tests support the idea that a marginal benefit in terms of overall survival is observed in cancer patients with normal prognoses, but there are marked survival benefits for cancer patients with poor prognoses.

What is needed is to sort out what's the best profile in terms of which patients benefit from this drug or any other drug. Can they be combined? What's the proper way to work with these new drugs?

Every cancer patient should have his/her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Having some foreknowledge of a given agent's expected result before its administration would benefit the individual patient.
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