TDM-1 results reported @ ASCO annual mtg 2012 now in New England Journal of Medicine

[Lani]

EMILIA study-- good media coverage/ publicity may help sway FDA


N Engl J Med. 2012 Oct 1. [Epub ahead of print]
Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer.
Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; the EMILIA Study Group.
Source

From Sunnybrook Odette Cancer Centre, Toronto (S.V.); Mount Vernon Cancer Centre, Northwood, United Kingdom (D.M.); San Raffaele Hospital, Milan (L.G.); Dana-Farber Cancer Institute (I.E.K.) and Massachusetts General Hospital (J.B.) - both in Boston; Medical Office Hematology, Aschaffenburg, Germany (M.W.); University of Miami Sylvester Comprehensive Cancer Center, Miami (M.P.); Seoul National University College of Medicine, Seoul, South Korea (D.-Y.O.); Institut Curie, Paris (V.D.); Genentech, South San Francisco, CA (E.G., L.F., M.W.L., S.O.); and Duke University Medical Center, Durham, NC (K.B.).
Abstract

Background Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. Methods We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. Results Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. Conclusions T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166 .).

PMID:
23020162

[jellybean]

Actually, this article (and the full article seems to be available for free) updates the ASCO data, and includes the significant point that T-DM1 improves overall survival over Tykerb and Xeloda by almost 6 months. Very impressive! Genentech says it anticipates approval of T-DM1 by the end of February 2013. The updated data was presented at the ESMO conference.

[phil]

We can only hope . Un-fortunately this FDA, with its " politicized " , and distorted " scientific " attitude will probably wait until after the Election , and release appr. late on a Friday , to hide. That's their pattern. Its sad that every researcher listed on that NEJM article knew how good this drug was in 2010, and expected accelerated approval. When it didn't happen, they were SILENT ! They would have been retaliated against by This FDA.
Its going to take Public Shaming. We at Our Her2Cancer Struggle are doing our part . Google our latest Protest video at " Protesting This FDA : Still Delaying The Miracle Cancer Drug, Herceptin T DM-1 ". Our version , not the 5 second attention span media's version. A retired pol told us we need to tone down our language , " They don't talk like that in Washington ". yeah , and nothing gets done either. We speak the truth, we know it's not personal , its very impersonal. We are not part of the DC Inner Circle Elite . We stand by every word in the video, This FDA is an Embarassment in the War on Cancer, stumbling and bumbling with this wonderful drug , and The DC Elite is un-interested , and in lock-step protecting them ... Costing Lives Every Month !! History will look back and say , " Who Spoke Up ? "

[Hopeful]

this article (and the full article seems to be available for free)

I posted it in the Articles Forum yesterday:

http://her2support.org/vbulletin/sho...eferrerid=1173

Hopeful

[Lani]

Thanks Hopeful--Wanted to title it "first reported @ ASCO" but too verbose for title line.

Wonderful about the link--usually NEJM is usually not open for all so very happy you could provide the link(I am notoriously terribly with "linkage"!

[Hopeful]

Lani, my pleasure. Thanks for keeping us all in the loop on so many issues.

Hopeful

[schoonder]

Phil,
Wouldn't it be wonderful if FDA took a close look at 1st-line mBC phase II data, where median PFS 14.2 months vs. SOC 9.2 months, reduced probability of disease progression or death by 41 percent , with much improved tolerability profile.

To apologize and even more so compensate for T-DM1's UNNECESSARY three year delay of 2nd line mBC Her2+ approval, by Feb 2013 as latest, approve this agent for ALL mBC Her2+ settings with caviat that Marianne phase III and Th3resa trials continue their runs to successful completion.
Sufficient data from these two ongoing trials is already available to justify world of benefits that can be realized by providing for an early release of T-DM1. It's time for that government agency to become more pro-active.

[phil]

yeah , wouldn't it be wonderful, but This FDA needs outside, more objective supervision at this point, Under the new boss , Dr. Hamburg , there's been chaos over there since the beginning, 2009 : FDA workers complaining about having " managers " instead of scientists in charge screwing up, approving defective medical devices. 2010 : thier insensitive denying of avastin to TNBCERS, and taking their anger at Gen's appeal of avastins revoking out on T DM-1. 2011 - FDA spies on its own employees , 2012 : grants only conditional appr to pertuzumab, denying it to Late Stage IV , again disrespecting the pts who are the BACKBONE of ALL RESEARCH ! So, I am pessimistic about This FDA , but the Negative Publicity will turn the tide ...

[StephN]

Does the term "thrombocytopenia" mean the same as "hard on platelets?"

[Lani]

No, it ("thrombocytopenia") means you don't have enough of them (thrombocytes, AKA platelets) ie, they are in short supply

I used to complain/joke that I had a severe case of "caninopenia" (badly in need of a visit from a sweet dog!)

When reading the literature, remember that XXXpenia is the opposite of xxxosis

eg thrombocytopenia(too few platelets) vs thrombocytosis (too many platelets)...but , in my opinion, there can never be " caninosis"--too many dogs!

Hope this helps you remember the difference!

Lani

[schoonder]

Phil,
It looks like problem of FDA being unable to keep up with timely approval process of drugs is becoming more and more apparent.

Implementation of ideas spelled out in this excerpt:

"To improve drug evaluation, the group says the FDA needs to more frequently pursue accelerated approvals, paired with post-approval studies to evaluate drugs addressing unmet needs; it suggests the agency create a new pathway for approving drugs shown to be safe and effective for a specific subgroup of patients; and, the FDA should explore approaches for adaptive approvals, it says, a framework for iteratively expanding the market for a drug as new evidence about its risks and benefits becomes available."

are great starters in getting much improved drugs out in more timely fashion to patients in need.

http://www.burrillreport.com/article...approvals.html

[Ellie F]

Hi all
If you think the FDA is bad then NICE ( or nasty) here in England is terrible! The bean counters still won't fund lapatinib and I suspect T-DM1 and pertuzumab will have a big struggle also. This is such a shame for all those that need it and causes huge frustration for our breast oncologists who effectively have their hands tied.
Ellie

[phil]

You will just have to have a Big Protest for Stage IV Rights over there in Europe ! T DM-1 is just too good to be kept undr wraps .
As far as the PCAST article, that will take years . I heard that This FDA just gave Dr. Pazdur an award ! Not for his " work " on T DM-1 ! But it shows the mindset of Dr. Hamburg over there . An outside Investigation is the only way to make change now ! Negative Publicity !

[karen z]

Thanks so much for posting.
K

[Rolepaul]

Roche has been granted a priority review of its Herceptin successor, known as T-DM1. The action date for this review by the U.S. FDA is February 26th, 2013. A spokesperson for Roche has expressed their belief that this priority review increases the likelihood of a market release in early 2013.

This would hopefully mean that a lot more women would get treated. The company is very hopeful.

['lizbeth]

Are the only trials for TDM1 for metastatic breast cancer? Would TDM1 likely be effective for primary breast cancer?

[schoonder]

Roche plans in 2013 to start three t-dm1 trials in early stage her2+ BC, they are:

As single-agent therapy for patients with residual invasive disease following preoperative (neoadjuvant) systemic treatment.

Used in combination with chemotherapy and pertuzumab in the adjuvant setting.
Used in combination with chemotherapy and pertuzumab in the neoadjuvant setting.



http://investor.immunogen.com/common...VU3S1&mobileid=#

[phil]

So, if This FDA approves T DM-1 for Stage IV , will it take another 7 YEARS to approve it for first or second - line tx. ? Wow ! Imagine if , back in 2006, when L. was dx. Stage IV, but w/ only ONE liver tumor, nothing else visible outside the breast /nodes , FISH scale of 6, it could have been blasted then ? Think of all the Pts in the same situation now ...

['lizbeth]

Phil,

I have to agree another 5 to 7 years to get TDM1 approved for primary breast cancer seems unreasonable. The entire system does not favor the patient. I once argued with a fellow cancer patient who was an attorney - and lost. Seems that cancer patients and survivors should expect to be sacrificed so that the FDA can do a proper approval process.

At least I am not the only one who sees the irony in this. Are we not the ones who are supposed to be saved instead of sacrificed?

[ElaineM]

I was chatting with the senior oncologist in my doctor's office. He said based upon the Emila trial results he thinks there will be an announcement at San Antonio the beginning of December. He thinks T DM1 will be fast tracked through the FDA after that. He is going to San Antonio and will give me an update after that. The Genetech drug reps are in the T DM1 training session this week. He said that doesn't happen until a drug is close to being approved. Keep your fingers crossed everyone !!