Combination Targeted Therapy With Sorafenib & Bevacizumab Shows Antitumor Activity

The results from a recent Phase I solid tumor clinical trial indicate that combination targeted therapy with sorafenib and bevacizumab produces anti-tumor activity (and enhanced toxicity) with respect to 43% of the ovarian cancer patients enrolled in that trial. Sorafenib (Nexavar®) inhibits the Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab (Avastin®) is a monoclonal antibody targeted against VEGF.

Dr. Elise Kohn, Principal Trial Investigator, NCI Center for Cancer Research

Dr. Elise Kohn, Principal Trial Investigator, NCI Center for Cancer Research

The results from a recent Phase I solid tumor clinical trial indicate that combination targeted therapy with sorafenib and bevacizumab produces antitumor activity (and enhanced toxicity) with respect to 43% of the ovarian cancer patients enrolled in that trial. Sorafenib (Nexavar®) inhibits the Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab (Avastin®) is a monoclonal antibody targeted against VEGF. The trial is sponsored by the National Cancer Institute (NCI) and Elise Kohn is the principal trial investigator.

The patients enrolled in the trial had advanced solid tumors, with Eastern Cooperative Oncology Group performance status of 0 to 1. A phase I dose-escalation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level (DL1)) or 10 mg/kg (dose level (DL2)) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD).

Thirty-nine patients were treated under the trial protocol. DL1 was the MTD and was administered to 27 patients. Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22+ months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization ≥ 4 months (median, 6 months; range, 4 to 22+ months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/orally at a median of four cycles (range, one to 12 cycles).

The trial investigators concluded that combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The trial investigators also noted that the rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.

Source: Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity; Azad NS et. al., J Clin Oncol. 2008 Aug 1;26(22):3709-14.

Additional Information:

6 thoughts on “Combination Targeted Therapy With Sorafenib & Bevacizumab Shows Antitumor Activity

  1. Larry,

    As always, thank you for the comment. Your explanation of the potential use of lapatinib as an anti-angiogenesis therapy is interesting, as well as the combination use of drugs within that class. It is my understanding that the general thinking or rationale underlying the use of anti-angiogenesis drugs against ovarian cancer is at least twofold. First, VEGF pathways are strongly associated with the development of malignant ascites, malignant pleural effusions, and carcinomatosis. Second, both VEGF receptor(s) and VEGF ligand(s) can be over-expressed in ovarian cancer.

    Good luck in D.C. with your presentation at the 2008 ASCO Breast Cancer Symposium. Also, we are going to post a tribute to Judah Folkman, M.D. shortly. The medical research community lost an icon in January with Dr. Folkman’s death.

    Best, Paul

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  2. Paul says: In the studies that I have read, HER2 is not often significantly overexpressed with respect to ovarian cancer.

    Paul discusses the role of HER1 and HER2 in promoting cell proliferation; however these receptors also play a role in the growth and survival of new blood vessels, upon which the growth and survival of the tumor depends.

    1: Semin Oncol. 2001 Oct;28(5 Suppl 16):27-32.
    The role of HER2 in angiogenesis.
    Kumar R, Yarmand-Bagheri R.

    Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

    Recent studies have established that growth factors and their receptors play an essential role in regulating the proliferation of epithelial cells. For example, the human epidermal growth factor receptor 2 (HER2), is overexpressed in several human malignancies including breast, ovarian, and colon cancers. Tumor cells must use the process of vascularization (angiogenesis) for growth and metastasis. Overexpression of HER2 in human tumor cells is closely associated with increased angiogenesis and expression of vascular endothelial growth factor (VEGF). Indeed, when the VEGF pathway is inhibited, tumor growth is suppressed. Cancer cell invasiveness can be promoted, even in the absence of HER2 overexpression, by transregulation of HER2 by heregulins that bind to HER3 and HER4. Thus, potential upregulation of VEGF in cancer epithelial cells likely supports angiogenesis, sustaining and promoting survival and metastasis of tumor cells. Copyright 2001 by W.B. Saunders Company.

    The “featured study” of this discussion thread was a broad Phase I trial, in which the clinical activity of combined bevacizumab and sorafenib was not impressive. On subset analysis, there was an ostensibly impressive response rate in ovarian cancer; however, this was not significantly better than has been reported for bevacizumab alone (my earlier point).

    What we’ll be reporting at the ASCO Breast symposium September 5, is that lapatinib has much greater antivascular activity than does sorafenib, both alone and, much more dramatically and importantly, in combination with bevacizumab, even in tumors which do not overexpress Her2.

    I think that the next great frontier in cancer chemotherapy will be combinations of antivascular drugs. I view bevacizumab as being analogous to AZT in HIV/AIDS. It is a single agent which produces some responses and slowing of disease progression, albeit with rather limited improvement in long term survival. The great leap forward in treament of HIV/AIDS came with combination therapy. Likewise, in the mouse tumor studies of Judah Volkmann,single agent antivascular therapy produced only limited results, but combination treatment produced cures.

    The problem has been the lack of a practical system for testing antivascular drug activity in human tumors. We have just reported the invention of such a system.

    http://www3.interscience.wiley.com/journal/121373448/abstract?CRETRY=1&SRETRY=0

    Using this system, we have found that lapatinib often adds strikingly to the antivascular (not direct antitumor) effects of bevacizumab and that this enhanced antivascular activity is much greater in the case of lapatinib than in the case of sorafenib. This is what we are reporting at the upcoming ASCO breast symposium.

    When the “nib” drugs are given as agents to enhance antivascular activity, I think they should be given on a high dose, intermittent “pulse” schedule and not on a continuous, daily dosing schedule (e.g. Milton DT et al Cancer 2006;107:1034–41). In the Milton study, high dose erlotinib was administered weekly, with no increased toxicity over daily dosing. It is probable that administering the “nib” drugs in “pulse” doses every two weeks (in the way that bevacizumab is administered) would be less toxic, less expensive, and more effective, from the standpoint of destroying the tumor vasculature.

    We are initiating a very unique clinical trial, in which combinations of “targeted” agents will be individualized for patients with advanced cancer (including ovarian cancer), based on the results of our various assays for direct antitumor and antivascular drug activity. What makes the study unique is that the results of the trial will be reported, in real time, on an ongoing basis on our web site; so that both results and toxicities will be 100% transparent, in real time, to whomever wishes to follow the progress of the study. This study will launch as soon as we receive IRB approval (the informed consent document is now up to 12 pages) — hopefully within one month. Details of this clinical trial are shown at: http://weisenthalcancer.com/Study%20Pages/TrialHome.htm

    – Larry Weisenthal http://weisenthal.org

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  3. Larry,

    Thank you for the comment. I want to provide our readers with the citation for the preliminary trial of bevacizumab (Avastin)& erlotinib (Tarceva)that you reference in your comment.

    The citation is “Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer: a trial of the Chicago, PMH, and California Phase II Consortia;” Nimeiri HS et. al; Gynecol Oncol. 2008 Jul;110(1):49-55. Epub 2008 Apr 18 (” …RESULTS: Between July and October 2005, 13 patients were enrolled. There were two major objective responses, one complete response of 16+ month duration and one partial response of 11 month duration, for a response rate of 15% (95% CI 1.9% to 45.4%). Seven patients had a best response of stable disease. The most common grade 3 or 4 toxicities included anemia (n=1), nausea (n=2), vomiting (n=1), hypertension (n=1), diarrhea (n=2). One patient with an ileostomy was removed from the study secondary to grade 3 diarrhea. Two patients had fatal gastrointestinal perforations. CONCLUSION: There was no strong suggestion that this combination was superior to single agent bevacizumab, and the rate of gastrointestinal perforation was of concern. The study was therefore stopped. Identification of risk factors for gastrointestinal perforation will be of importance for the use of bevacizumab in the treatment of ovarian cancer.”)

    A small Phase Ib clinical trial recently reported a 52% response rate with the use of docetaxel (Taxotere), carboplatin, and erlotinib (Tarceva) against ovarian cancer. See “A phase Ib trial of docetaxel, carboplatin and erlotinib in ovarian, fallopian tube and primary peritoneal cancers;” Vasey PA et. al.; Br J Cancer. 2008 Jun 3;98(11):1774-80. Epub 2008 May 27. (52% response rate (CR + PR)).

    My PubMed search based upon the keywords “lapatinib” and “ovarian cancer” only produced seven medical abstracts and none of them included test results with respect to ovarian cancer patients. However, there are several ovarian cancer/solid tumor clinical trials in place that are testing erlotinib (Tarceva) and lapatinib (Tykerb).

    For our readers, we should point out that both lapatinib (Tykerb) and erlotinib (Tarceva) act upon the “Epidermal Growth Factor Receptor” (EGFR) family of receptors (which consists of HER1/EGFR, HER2, HER3, HER4). Specifically, erlotinib acts upon the intracellular portion of the HER1 receptor, while lapatinib acts upon the intracellular portion of the HER2 receptor. The EGFR family of receptors control, among other things, cell proliferation. We should also point out that as a technical matter, a cancer tumor (obtained from biopsy or surgery) can be tested for what is known as EGFR/HER1 overexpression and HER2 overexpression. This state of overexpression can lead to accelerated/abnormal cell proliferation. Both drugs act to reduce that overexpression. Both drugs are small molecule drugs which means, among other things, that they have good tumor penetrating ability and can pass through the human “blood-brain barrier” (BBB), thereby creating the potential for use against brain metastases. Both drugs are taken orally.

    In the studies that I have read, HER2 is not often significantly overexpressed with respect to ovarian cancer (i.e., positive overexpression determined by “FISH” pathology testing), with the possible exception of ovarian clear cell carcinoma (see references by clicking on the “Types of Ovarian Cancer” tab located at the top of the homepage). The same may be true with EGFR/HER1. It may be true that there is a subgroup of ovarian cancer patients that may benefit from these drugs if overexpression testing was common. Unfortunately, the vast majority of ovarian cancer tumor biopsies/samples are not tested for estrogen positivity, EGFR positivity, HER2 positivity, and PTEN53 mutation.

    Finally, I believe that care must be taken with respect to the determination of underlying cause associated with bowel perforations produced by anti-vascular drug use, because the condition of the patient at the time of drug administration may dramatically influence the severity of this side effect(i.e., a patient having tried 4 or 5 prior chemotherapy lines of treatment versus a patient who has tried only two lines of treatment, or the existence of bowel metastases).

    I thank you for the your observation and associated citations.

    Best, Paul

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  4. The response rate (6/13) was not significantly different than that reported for bevacizumab alone (7/22, P2=0.48; J Clin Oncol 26: 2008 (May 20 suppl; abstr 16528). Toxicity was greater. Sorafenib is hyped in medical advertisements as an antivascular drug. We’ll be reporting at the ASCO Breast Symposium on Sept 5 that the antivascular activity of sorafenib is negligible in comparison of that of erlotinib and lapatinib, two agents for which claims of antivascular activity are (1) more modest, in the case of erlotinib and (2) currently non-existent (in the case of lapatinib). In a preliminary trial of bevacizumab/erlotinib, there were bowel perforations (a purely antivascular toxicity) in 2/13 patients, as opposed to 2/49 with bevacizumab alone. Bowel perforation was not mentioned above as a toxicity in the 13 patients with bevacizumab/sorafenib, which provides soft support for our findings. – Larry Weisenthal; http://weisenthal.org

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  5. Mike,

    In response to your questions regarding the eligibility criteria with respect to the Phase I solid tumor clinical trial involving the use of sorafenib & bevacizumab, the trial protocol(recently hyperlinked within the post)provides the following entry criteria:

    — Histologically confirmed solid tumor malignancy

    * Metastatic, refractory, or unresectable disease
    * No known standard curative therapies exist or are no longer effective

    — At least 1 lesion amenable to biopsy (applicable to part 2 of the trial only)

    — No squamous cell carcinoma of the lung

    — No history of any type of primary lung cancer with hemoptysis

    — No active brain metastases

    As you know, many patients tend to enter Phase I solid tumor trials after prior “standard of care” treatments (and sometimes prior ovarian cancer clinical trial treatment(s)) are unsuccessful. To obtain detailed disease characteristics (i.e., look behind the “metastatic, refractory, or unresectable disease” entry criteria) of the 13 ovarian cancer patients enrolled in the study, you can review the full text copy of the Journal of Clinical Oncology study results or contact the principal National Cancer Institute (NCI) trial investigator (Elise Kohn, MD (Tel: 301-402-2726)).

    As you know, NCI sponsored this trial, and NCI is part of the National Institutes of Health (NIH). It is my understanding that NIH-supported Phase III clinical trials require data and safety monitoring through a Data and Safety Monitoring Board (DSMB). The DSMB is an independent committee made up of statisticians, physicians, and patient advocates. The DSMB ensures that the risks of trial participation are as small as possible, makes sure the data is complete, and stops a trial if safety concerns arise or when the trial objectives are met.

    Because this trial was conducted as a “Phase I clinical trial,” the objectivity that you are searching for would, I believe, come from the “Institutional Review Board” (IRB). An IRB functions as both a clinical trials clearinghouse and monitor — in other words, it must give approval before any clinical trial can begin, and then keep close tabs on the progress of the research. Most institutions that carry out clinical trials have their own IRBs; in fact, there are roughly 3,000 of them in the U.S. In selected cases, a small research institution might arrange for their research to be reviewed by another IRB, rather than setting up their own.

    While the specific make-up of an IRB varies from place to place, it always includes people who are qualified to evaluate new and ongoing clinical trials on the basis of scientific, legal, and ethical merit. Federal regulations require that an IRB include at least five people of diverse occupations and backgrounds; for instance, an IRB could not be made up of five physicians or five nurses. At least one member must have primarily scientific interests, and another member must have primarily non-scientific interests. In addition, one member must be an institution outsider, not connected by a job or relatives to the institution. To meet these requirements, IRBs usually are made up of a mix of medical specialists, ethicists, and patient advocates.

    RECIST (Response Evaluation Criteria In Solid Tumors) is a set of published rules that define when cancer patients improve (“respond”), stay the same (“stable”), or worsen (“progression”) during treatments. The criteria were published in February, 2000 by an international collaboration including the European Organization for Research and Treatment of Cancer (EORTC), National Cancer Institute (NCI) of the United States, and the National Cancer Institute of Canada Clinical Trials Group. Today, the majority of clinical trials evaluating cancer treatments for objective response in solid tumors are using RECIST. Cancer trials today are increasingly complex, involving dozens or even hundreds of investigators from centers around the world. While the RECIST rules are highly dependent upon measurement of tumor size, different clinicians may vary greatly in their methods for performing these measurements. Certain situations may make consistently following the rules even more challenging, such as when two tumors start to merge into one. When many investigators vary in how they follow RECIST as a trial endpoint, the study results may be placed in jeopardy by significant levels of variability.

    In this trial, tumor vascularity is evaluated by Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) and Positron-Emission Tomography (PET). Others can learn more about these technologies under the homepage tab entitled, “Radiology and Radiation Therapy.” As you know, these technologies are excellent for imaging tumors, especially DCE-MRI. I assume (although I have not verified) that RECIST criteria was applied to the tumor imaging results. But, RECIST criteria is recommended but not mandatory for NCI sponsored trials. See “Imaging Response Criteria,” NCI Cancer Imaging Program (http://imaging.cancer.gov/clinicaltrials/imaging/). Anyone who takes the time to review the complex issues that arise when evaluating tumor response under RECIST, knows that proper, consistent application of the criteria by trial investigators is difficult at best. See e.g., “RECIST Questions & Answers,” European Organization For Research and Treatment of Cancer (http://www.eortc.be/Recist/Default.htm).

    I hope this information is helpful. Best, Paul

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  6. Paul, another great post. I had a question or two.

    What was the eligibility criteria? Were these patients refractory to other therapies? That would make the results much more persuasive, since refractory patients are notoriously difficult to treat. Also, I would like to know if the responses they saw were evaluated by the investigators, or by an independent review committee. Investigators understandably tend to overestimate responses. Also, there are standardized criteria for responses, known as RECIST criteria (there are probably others), and it would be interesting to see how objectively these investigators evaluated response.

    Regards,
    Mike from Interactmd.com

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