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Old 02-26-2010, 01:10 AM   #1
Lani
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Thumbs up Results of phase II trial of pertuzumab+herceptin in Stage IV patients who progressed

on herceptin

OPEN ACCESS: Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy
[Journal of Clinical Oncology]
Purpose: Pertuzumab, a human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibody, potently inhibits HER2 dimerization and HER-mediated signaling pathways. Pertuzumab and the approved HER2-targeted monoclonal antibody trastuzumab have complementary mechanisms of action and result in enhanced antitumor activity when combined. This phase II trial assessed the efficacy and safety profile of the combination in patients with HER2-positive breast cancer whose disease had progressed during prior trastuzumab-based therapy.
Patients and Methods: This was a multicenter, open-label, single-arm, Simon two-stage study. Patients with advanced HER2-positive breast cancer in whom disease progression had occurred during prior trastuzumab-based therapy received trastuzumab weekly (4 mg/kg loading dose, then 2 mg/kg every week) or every 3 weeks (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) and pertuzumab every 3 weeks (840 mg loading dose, then 420 mg every 3 weeks). Treatment continued until disease progression or excessive toxicity.
Results: All 66 patients were assessable for efficacy and safety. The objective response rate was 24.2%, and the clinical benefit rate was 50%. Five patients (7.6%) experienced a complete response, 11 patients (16.7%) experienced a partial response, and 17 patients (25.8%) experienced stable disease of ≥ 6 months. Median progression-free survival was 5.5 months. Overall, the combination of pertuzumab and trastuzumab was well tolerated, and adverse events were mild to moderate. Cardiac dysfunction was minimal, and no patients withdrew as a result of cardiac-related adverse events.
Conclusion: The combination of pertuzumab and trastuzumab is active and well tolerated in patients with metastatic HER2-positive breast cancer who had experienced progression during prior trastuzumab therapy.
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Old 02-26-2010, 07:12 AM   #2
schoonder
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Re: Results of phase II trial of pertuzumab+herceptin in Stage IV patients who progre

Recently Roche indicated that starting around July they will conduct a 3-arm (trastuzumab-taxotere, T-DM1 and T-DM1-pertuzumab) phase III trial 1st line MBC.
A patient partaking in the T-DM1 arm of the phase II had the following to say:

"Before you can understand how good this recent scan is, you have to understand how bad the last one was. I haven't put too much detail up about what my liver and bones looked like when we began treatment, only that the cancer had spread there. In fact, I didn't really know myself exactly how things looked until I picked up my original scan report last Friday in preparation to understand the new results. In retrospect, I'm glad I didn't know the details until I was fairly comfortable that good progress was being made. My doctor was wise to be vague with me.

Before treatment, the cancer was quite widespread and intensely active. Besides the breast, which was basically one solid tumor, I had numerous affected lymph nodes, several of which had measurable tumors in the neighborhood of 2.5 centimeters, and at least eight measurable tumors in the liver. The largest of these was 2.4 by 1.7 centimeters. Cancer virtually covered my bones from neck to knee and, again, was intensely active. In fact, it was so active that the radiologist who reviewed the scan believed that I must be on bone marrow stimulating medication in order to create that kind of metabolic activity. I was not, nor had I ever been.

Last week's scan shows a completely different picture. When examined for actively growing cancer, the breast and liver are noted as "resolved" while the skeleton and lymph nodes are "mild" or "interval reduced". The liver tumors, although still numerous, are now all "subcentimeter". The lymph node tumors are slightly reduced. The sclerotic lesions on the skeleton are unchanged. (Which means they are no longer growing, so this is great news.) I am not sure how bones heal themselves from cancerous lesions, so I will have to ask my doctor more about that. But either way, bone damage is more inconvenient than life-threatening. The liver was, by far, our greatest concern and it is responding beautifully.

Perhaps most significant is that I have made this kind of progress against this nasty, aggressive cancer in just 9 weeks. Only three treatments. There are many people who are on chemo for years without ever hearing news this good. The hope is that I will continue to respond to this drug for many months to come, and there is every reason to believe that I will continue along this path, although, admittedly, I still have a way to go.

In my eyes, my biggest danger right now is hope. When first diagnosed, I never imagined a cure was possible. I never could have entertained the idea of receiving a NED scan someday. (No Evidence of Disease.) Now I want that, am hoping for it, will be disappointed if I don't get it. I prefer, from a self-preservation standpoint, to be less hopeful, but here I am. Full of hope, reassured that prayer really does work, and completely grateful for the medical care I am receiving."

Let's hope that the pertuzumab-DM1 combination can deliver even better responses.
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Old 03-12-2010, 08:23 PM   #3
schoonder
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Re: Results of phase II trial of pertuzumab+herceptin in Stage IV patients who progre

"Let's hope that the pertuzumab & T-DM1 combination can deliver even better responses."

At the upcoming AACR meeting Genentech will discuss early data on this subject matter.

Abstract Number: 5607

Presentation Title: Dual targeting of HER2: Enhanced antitumor efficacy of trastuzumab-DM1 combined with pertuzumab

Presentation Time: Wednesday, Apr 21, 2010, 8:00 AM -11:00 AM

Location: Exhibit Hall A-C, Poster Section 30

Poster Section: 30

Poster Board Number: 28

Author Block: Carter T. Fields, Lisa M. Crocker, Mark X. Sliwkowski, Gail D. Lewis Phillips. Genentech, Inc., South San Francisco, CA

Abstract Body: The EGFR family of transmembrane receptors consists of HER1 (ErbB1/EGFR), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). These receptors are often dysregulated in human solid tumors. For example, amplification and overexpression of HER2 occur in approximately 20 percent of human breast cancers and are predictive of poor clinical outcome. A principal means by which these receptors exert their growth-stimulatory effect is through homo- and hetero-dimerization which can occur in either a ligand-dependent or -independent manner and subsequently promotes receptor tyrosine kinase activity, leading to autophosphorylation and activation of downstream signal transduction pathways.
The humanized HER2 antibody, trastuzumab (Herceptin®), is approved for use in adjuvant and metastatic HER2-positive breast cancer and has shown significant clinical benefit. Trastuzumab-DM1 (T-DM1, TMAb-mcc-DM1, trastuzumab emtansine) is an antibody-cytotoxic drug conjugate composed of the maytansine derivative DM1 directly coupled, through a thioether SMCC linker, to trastuzumab. We previously reported the potent in vitro and in vivo efficacy of T-DM1 in trastuzumab-sensitive and -refractory breast tumor models. Both trastuzumab and T-DM1 bind domain IV of the HER2 extracellular domain (ECD) and inhibit HER2 function in a ligand-independent manner. T-DM1 provides additional efficacy through selective delivery of the cytotoxic agent DM1 to HER2-overexpressing cancer cells. Pertuzumab is a humanized HER2 antibody that binds domain II of the HER2 ECD and thereby inhibits ligand-induced activation of HER2 by blocking dimerization of HER2 with other HER family members. Pertuzumab in combination with trastuzumab has shown impressive preclinical as well as clinical activity in HER2-positive breast cancer.
The purpose of our studies was to evaluate the in vitro and in vivo efficacy of T-DM1 combined with pertuzumab. Our in vitro results show that combination treatment resulted in synergistic inhibition of cell proliferation in human breast and lung cancer cells that over-express HER2. Drug combination effects were analyzed by the Chou and Talalay method for determining combination index values. Similarly, we observed enhanced in vivo efficacy when administering T-DM1 in combination with pertuzumab, as compared with either agent alone, in breast and lung cancer xenograft models. Treatment of cells with T-DM1 combined with pertuzumab also resulted in a synergistic increase in apoptosis as measured by increased activity of the apoptotic enzymes, caspases 3 and 7, and increased levels of the apoptotic population in cell cycle experiments. Together, these studies support the hypothesis that T-DM1 in combination with pertuzumab for HER2-amplified cancer may offer an additional therapeutic approach for patients whose disease progresses on trastuzumab and lapatinib-based therapy.
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Old 03-13-2010, 09:58 PM   #4
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Re: Results of phase II trial of pertuzumab+herceptin in Stage IV patients who progre

Dear Lani,
Both T-DM1 and PERTUZUMAB are large mollecules, which do not cross the brain blood barrier. We all know that cancer is opportunistic; it is my opinion that until another drug that does cross the brain blood barrier is added to the above combo or even just T-DM1 alone, one is just playing "russian roulet" with their brain...! There seem to be an also an issue of "severe liver enzimes elevation", and other desease progressions, other severe metastases, etc. All we have to do is think of "Irene" from Tampa, and "Vickyh".....[as just two that I have noted].
In my case, I have done well with T-DM1 alone, [not NED], healing all over and stable in bone areas, my tumor markers had dropped to 27. Novertheless PERTUZUMAB was added to my protocol [I was told "you will be droped from the Study if you refuse to add PERTUZUMAB to the T-DM1 !...] Pertuzumab was added, and it nearly distroyed me, a total disaster.....within a month I developed brain metastases....Now, after a series of Cyberknife treatments I am scrambling to find something new to keep me alive.....Is it not time to start a discussion on PERTUZUMAB combination with T-DM1 tragic results, as well as good results/if any? Not just the "fabulous" results in other PERTUZUMAB subtrials such as the above?
You appear very informed, in all facets of breast cancer, studies, studies results, etc. How about you starting a true and honest discussions on the above drugs combo. Angela
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Old 03-14-2010, 02:38 AM   #5
Lani
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Join Date: Mar 2006
Posts: 4,778
Re: Results of phase II trial of pertuzumab+herceptin in Stage IV patients who progre

I am currently travelling, but have taken your request to heart. I am hoping to

(but not sure I can) attend both the AACR annual meeting and the ASCO annual

meeting and will try to talk with poster presenters as possible. Drug

companies are usually very tight lipped about problems, but the young

researchers who present posters are often much more communicative.

Drug companies are required to do post-marketing surveillance to follow the

number of people with side effects AFTER the drug is approved. During the

Trials phase they know any adverse news will negatively affect their stock

price and it seems there are few interval reports. I don't know what the

rules/laws are on reporting adverse effects in trials. I will see if I can find out during one of these meetings.
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Old 03-14-2010, 04:05 AM   #6
Ellie F
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Re: Results of phase II trial of pertuzumab+herceptin in Stage IV patients who progre

Angela
I am so sorry this has happened to you. There is a lot of excitement around T-DM1 and getting into trials.I am also mindful of the relationship with herceptin and brain mets. I hope Lani manages to get some info about the valid concerns you have raised but mostly I hope you find another treatment that works well for you.
Please let us know.
Ellie
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Old 03-14-2010, 08:08 AM   #7
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Re: Results of phase II trial of pertuzumab+herceptin in Stage IV patients who progre

This is the first I've heard of the brain-blood barrier mentioned. My wife is on Herceptin-Taxotere, just completed her 3rd treatment. With all the good things I've heard about Herceptin and showed to my wife I think I'll let this one slide for a while before I tell her. I did a search and this is one of the articles I found.
http://clincancerres.aacrjournals.or...9/15/5435.full
__________________
Wifes Dx:
Found tumor 11-09
Biopsy 11-09 positive: IDC Stage 4 grade 3 Her2 +, 3 nodes of 16 positive.
Surgery 12-09
CT scan: liver mets
MRI of Head: clean
Bone scan: clean
1st treatment: 1-28-10
Taxotere & Herceptin every 21 days
6 rounds of Taxotere
Herceptin every 21 days (on going)
Liver mets...GONE!
CT scans,bone scans & MRI's NED
NED to date
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