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Old 10-17-2012, 09:17 AM   #1
Debbie L.
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T-DM1: Adjuvant or neoadjuvant use

Hi all. I'd like to ask for your opinion and thoughts about the design of adjuvant and neoadjuvant trials of T-DM1. I've been asked by NBCC to talk a bit about the advocate perspective on this, in a pre-meeting Project LEAD session at SABCS this year.

NBCC's concern is that it looks like adjuvant/neoadjuvant trials of T-DM1 will look at adding T-DM1 to standard-of-care -- in other words, administering WITH a systemic chemo agent. Most of the metastatic trials have not done this. In addition, of course, to efficacy in controlling/stopping HER2+ cancer, the most hopeful benefit of T-DM1 looks to be the lower toxicities. For example, fewer or no reports of nausea, hair loss, neuropathies, etc. If the adjuvant trials do not have a T-DM1-only arm (or at least a T-DM1 without systemic chemo arm), we'll miss the opportunity to know the answer to this important question.

The broader trial design issue that this illustrates is that it is typical, in adjuvant/neoadjuvant trials, to add new drugs INTO older regimens, rather than taking the opportunity to reduce toxicities and overtreatment by trialing less-toxic but possibly equally-effective treatments on their own. An example of this is the question of Herceptin alone (with an endocrine tx when appropriate) for both very small HER+ tumors and for those at high risk of harm from a combination chemo/Herceptin tx. It seems like everyone wants to know the answer to this question but no one is willing to do a trial to find the answer(s).

Thanks in advance for any help you can provide. I would like to have a slide with comments from patients and advocates, representing all perspectives. So although I do have an opinion and will include that in what I say, I want to include everyone's opinion in order to get the most-balanced perspective.

Debbie Laxague
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Old 10-17-2012, 10:11 AM   #2
schoonder
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Re: T-DM1: Adjuvant or neoadjuvant use

The only evaluation in this setting that's presently going on, labeled:

"A Multicenter, Multinational Phase II Study to Assess the Clinical Safety and Feasibility of T-DM1 Sequentially With Anthracycline-Based Chemotherapy, As Adjuvant or Neoadjuvant Therapy for Patients With Early Stage HER2-Positive Breast Cancer"
is indeed a single-arm open-label study. It's to assess the safety, feasibility and efficacy of trastuzumab emtansine (T-DM1) AFTER COMPLETION of anthracycline-based adjuvant/neoadjuvant chemotherapy in patients with early HER2-positive breast cancer. Patients will receive T-DM1 3.6 mg/kg intravenously on Day 1 of each 3-week cycle, for up to 17 cycles.
Link points to trial specifics including participating centers, some of which already have completed their assigned task.

http://clinicaltrials.gov/archive/NC..._08_15/changes
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Old 10-17-2012, 11:47 AM   #3
chrisy
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Re: T-DM1: Adjuvant or neoadjuvant use

Would love to be a fly on the wall in that session! Glad that you will be participating.

This study design seems to be aimed more at discovering if TDM1 is more effective than "plain vanilla" herceptin, particularly in the adjuvant setting. I fear this misses a big point - which you mention - and that is can TDM1 replace the more toxic chemo therapies. The trial design does not answer that question.

I was on TDM1 as single agent for 3 years, and I can tell you (now that I've had to go back to rougher chemos), it is a HUGE deal. People seem to disregard QOL as a worthy goal, but especially in the mets setting it is the difference between being in your life or sitting on the sidelines suffering. I was able to continue being a fully productive member of society and to be fully IN MY LIFE. With stage IV disease that is EVERYTHING. But even as adjuvant or neoadjuvant therapy, it's inexcusable to not seriously look at less toxic options. Why should we expect women to give up 6 months, or a year of their lives to get back the rest of them?

I think the strategy of adding to vs replacing therapies stems from wanting to make sure people get at least standard of care treatment. It may be more challenging to recruit into trials with TDM1 as a single agent in the adjuvant setting especially, many people want to do the most aggressive thing to prevent a recurrence. But I think there have been studies looking at say, lapatinib and herceptin without chemo, at least as neoadjuvant.

Anyway, if I were ever able to say anything in a concise fashion, it would be this:
We need to be able to answer the question can the use of harsh chemos be forgone in at least some cases. In my view, TDM1 is a great opportunity to explore this option and we should not squander that opportunity.
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Chris in Scotts Valley
June 2002 extensive hi grade DCIS (pre-cancer-stage 0, clean sentinal node) Mastectomy/implant - no chemo, rads. "cured?"
9/2004 Diag: Stage IV extensive liver mets (!) ER/PR- Her2+++
10/04-3/05 Weekly Taxol/Carboplatin/Herceptin , complete response!
04/05 - 4/07 Herception every 3 wks, Continue NED
04/07 - recurrence to liver - 2 spots, starting tykerb/avastin trial
06/07 8/07 10/07 Scans show stable, continue on Tykerb/Avastin
01/08 Progression in liver
02/08 Begin (TDM1) trial
08/08 NED! It's Working! Continue on TDM1
02/09 Continue NED
02/10 Continue NED. 5/10 9/10 Scans NED 10/10 Scans NED
12/10 Scans not clear....4/11 Scans suggest progression 6/11 progression confirmed in liver
07/11 - 11/11 Herceptin/Xeloda -not working:(
12/11 Begin MM302 Phase I trial - bust:(
03/12 3rd times the charm? AKT trial

5/12 Scan shows reduction! 7/12 More reduction!!!!
8/12 Whoops...progression...trying for Perjeta/Herceptin (plus some more nasty chemo!)
9/12 Start Perjeta/Herceptin, chemo on hold due to infection/wound in leg, added on cycle 2 &3
11/12 Poops! progression in liver, Stop Perjeta/Taxo/Herc
11/12 Navelbine/Herce[ptin - try for a 3 cycles, no go.
2/13 Gemzar/Carbo/Herceptin - no go.
3/13 TACE procedure
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Old 10-17-2012, 06:48 PM   #4
Cellomomof5
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Re: T-DM1: Adjuvant or neoadjuvant use

Debbie,
I was in the Phase II trial that Schoonder mentioned in her reply, completing the T-DM1 last March. Part of the reason I chose this trial over ACT + herceptin was that the Phase II trial required Adriamycin, but made Taxol optional. As a musician, I was particularly concerned about developing neuropathy, and my doctor (Eric Winer at Dana Farber) felt that with T-DM1, I could comfortably skip the Taxol altogether, and avoid that particular set of toxicities.

With the recent findings about the differing responses between two different subgroups of HER2 patients: (one of which doesn't seem to respond to Herceptin,) I am very glad that I did at least receive Adriamycin before starting a year of T-DM1. If I turn out to be part of that HER2 group that doesn't respond to herceptin, I at least want to know that I had some standard-of-care chemo as "backup."

One point I'd like to mention - I began T-DM1 exactly three weeks after my last adriamycin cycle. I had not recovered from the side effects of Adriamycin, and had a rather nasty start with T-DM1 as a result, garnering seriously high liver function counts, and a very low white count. My T-DM1 dose ended up getting reduced for a couple of cycles, but was then re-escalated to the original dose when I bounced back to normal within a few weeks. My understanding was that it was not unusual for patients in this trial to have a rough start right after adriamycin and need a few weeks to recover and adjust.

Sounds like an interesting debate!

I'm happy to be helpful in any way I can.

-Karen
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Age 49
  • 1/24: dx IDC in right breast
  • 2/16: lumpectomy, axillary node removal
  • path: Stage 3 grade 3 IDC, ER+, PR+, Her2+++, 5/13 nodes
  • 3/10: began 4x AC
  • 5/12: began 17x T-DM1
  • 8/1: 6 weeks rads
  • 9/20: started Tamoxifen
  • 4/12: Last T-DM1 infusion!!!!
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Old 10-17-2012, 07:06 PM   #5
Barbara H.
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Re: T-DM1: Adjuvant or neoadjuvant use

I also prefer to have treatment with the least amount of side effects as long as it is effective.
I was on the TDM-1 trial from 2007 to 2009. it was still working but I developed lung inflammation.
Since then I have been on Herceptin/Tykerb.
TDM-1 did work for me and I continue to be NED with Herceptin/Tykerb. Unfortunately this combo is not approved, but with some effort I was able to convince my insurance to cover it.
Barbara H.
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