new article by Genentech authors--herceptin TM1 works equivanlently2 herceptin AND
 

active vs. lapatinib resistant tumors

ie, adding on the strong "poison", the maytansine derivative, to the herceptin did not change its pharmacokinetics (how long it lasts, how it is distributed, etc) nor how it worked ie, same as herceptin without the addition of the maytansine derivative, but it also worked against those tumor cell lines which had developed resistance to lapatinib

Interesting conclusion and discussion of future hopes--see info at end


Breast Cancer Res Treat. 2010 Aug 21. [Epub ahead of print]
Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer.
Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX.

Research Oncology, Genentech, Inc., 1 DNA Way, Mailstop 72, South San Francisco, CA, 94080, USA.
Abstract
Trastuzumab (Herceptin((R))) is currently used as a treatment for patients whose breast tumors overexpress HER2/ErbB2. Trastuzumab-DM1 (T-DM1, trastuzumab emtansine) is designed to combine the clinical benefits of trastuzumab with a potent microtubule-disrupting drug, DM1 (a maytansine derivative). Currently T-DM1 is being tested in multiple clinical trials. The mechanisms of action for trastuzumab include inhibition of PI3K/AKT signaling pathway, inhibition of HER-2 shedding and Fcgamma receptor mediated engagement of immune cells, which may result in antibody-dependent cellular cytotoxicity (ADCC). Here we report that T-DM1 retains the mechanisms of action of unconjugated trastuzumab and is active against lapatinib resistant cell lines and tumors.

PMID: 20730488



In the present report, we address whether chemical modification of trastuzumab affects its known mechanisms of action. The anti-signaling properties of trastuzumab are primarily the consequence of antibody recognition of HER2 on the surface of breast cancer cells. Our studies confirm that T-DM1 binding to HER2 is not affected by the derivatization with MCC-DM1. As expected, once bound to HER2, T-DM1 blocks HER2 shedding. Perhaps more importantly, T-DM1 also downregulates PI3K-AKT signaling due to the fact that, like trastuzumab [11], it effectively disrupts the constitutive HER2–HER3 complex. Activation of immune effector function requires binding of the antibody’s Fc region to Fcγ receptors. Antibody-dependent cytotoxicity assays (ADCC) performed with peripheral blood mononuclear cells obtained from health volunteers verified that T-DM1 maintains full trastuzumab activity.

Most novel anticancer agents are initially tested in model systems that are refractory to standard of care therapies. To date our preclinical focus with T-DM1 has examined tumor models that are refractory to trastuzumab. Our clinical studies have also selected patients whose tumors have progressed through Herceptin® and in many cases Tykerb® (lapatinib). In the current report we demonstrate that T-DM1 efficiently inhibits growth of cells and tumors that are insensitive to lapatinib and have hyperactivated PI3K signaling due to activating mutations in p110α. Because the T-DM1 preclinical and clinical data are promising, we are now designing and executing clinical trials that will examine T-DM1’s activity in patients who may not have received previous HER2 directed therapies. The data presented in this report suggest that T-DM1 maintains all of the known mechanisms of action of trastuzumab. As a result of these findings, we are optimistic that T-DM1 can be moved into earlier lines of therapy for the treatment of HER2 positive cancer.

Conflict of interest
All authors are employees of Genentech, Inc.

Re: new article by Genentech authors--herceptin TM1 works equivanlently2 herceptin
 

bumping this up as it is relevant and supports info Chrisy and others have provided to the thread on what can be done to let FDA know TDM-1 approval obstruction is harmful to the health of those her2+ breast cancer patients running out of options--it adds that both adjuvant and neoadjuvant trials are being designed and begun and the rationale for these

Seems the improved efficacy over herceptin (without changing its pharmacokinetics) and its ability to work when herceptin and/or tykerb no longer do not are truly motivating them to proceed despite this setback

Re: new article by Genentech authors--herceptin TM1 works equivanlently2 herceptin
 

A physician's comment re T-DM1 RTF

"Wow, said a physician who was hearing the news. She developed HER2 breast cancer herself and tested positive for BRCA, which means she has inherited the breast cancer gene. As a matter of fact, her 28 year-old daughter tested also positive for the gene. She has not developed metastasis or any other tumor recurrence, but she is concerned. Commenting on the FDA letter explanation to its decision, the physician/patient said, “trying to figure out what the FDA meant by exhausting all available treatment choices approved for metastatic breast cancer, the question that keeps crossing my mind is: Haven’t those patients received prior Herceptin (trastuzumab), capecitabine, anthracycline, taxane and lapatinib. How much more drugs must they receive? You know what? The drugs would be exhausted when Genentech uses them all, but definitely the patients who would receive them will.” We asked the doctor/patient whether there are existing data on these drugs that were not used in T-DM1 trials, her answer was, “Of course the data exist and have been published, yet, why do we need them? Oncologists know that most non-specific treatments have not helped most HER2 breast cancer even in its early stages, let alone their recurrences. I wonder why should we withdraw the big hope that HER2 metastatic patients hung on since they heard about TDM-1 results – hope that has tremendously increased since these patients learned about the filing for early approval of the promising drug. Most these patients might not be around on the delayed day of the approval.”
http://seekingalpha.com/article/2230...s?source=yahoo

Re: new article by Genentech authors--herceptin TM1 works equivanlently2 herceptin
 

The article link is to a stock commentary on immunogen. The comment at the very end if the article:
TDM1 is formidable

I agree!