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Old 06-03-2012, 04:38 PM   #1
Lani
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Scarlet Pimpernel (or Waldo) logs in from ASCO-- TDM-1 presentation extremely strong

(stronger than it sounds in this press release) hope it helps get FDA approval soon:


Antibody Drug Conjugate T-DM1 Improves PFS in HER2-Positive Breast Cancer

Trastuzumab emtansine (T-DM1, Genentech) extended progression-free survival (PFS) by 3.2 months in women with HER2-positive locally advanced or metastatic breast cancer, according to data from a phase III trial presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting.

In a press briefing, lead study author Kimberly L. Blackwell, MD, professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University in Durham, North Carolina, said that T-DM1 is part of a new class of targeted therapies known as “antibody drug conjugates” that link antibodies with cytotoxic treatments.

T-DM1 combines the monoclonal antibody trastuzumab (Herceptin, Genentech) with the cytotoxic drug emtansine (DM1) using an MCC stable linker. By combining the treatments, T-DM1 both disrupts HER2 signaling and transports the cytotoxic agent DM1 directly into tumor cells.

In the phase III EMILIA trial, Blackwell et al randomized 978 patients with HER2-positive breast cancer 1:1 to either T-DM1 or standard therapy with the FDA-approved “XL” doublet (capecitabine [Xeloda, Genentech] and lapatinib [Tykerb, GlaxoSmithKline]). All of the accrued patients had been previously treated with trastuzumab and a taxane.

T-DM1 was administered at a dose of 3.6 mg/kg once every 3 weeks. The XL regimen was also given on a 3-week cycle, with 1000 mg/m2 of capecitabine being administered twice a day on days 1-14, along with daily treatment with 1250 mg of lapatinib. Patients received treatment until disease progression or unmanageable toxicity, at which point patients were not allowed to cross over. The primary endpoints were PFS, overall survival (OS), and safety.

The trial met its PFS endpoint, with T-DM1 delaying disease progression for a median of 9.6 months, as compared with 6.4 months with XL (hazard ratio [HR] = 0.650; 95% CI, 0.549–0.771; P <.0001).

With OS, the study approached, but did not meet, its primary endpoint. The 2-year OS for patients receiving T-DM1 was 65.4% versus 47.5% in the control arm (HR = 0.621; 95% CI, 0.475-0.813; P = .0005). These data did not meet a predetermined statistical goal for OS.


At the press conference, Blackwell explained that the targeted P value for statistical significance in OS was set “very high because of the coprimary endpoints [PFS and OS],” and that there is still “an apparent survival benefit in T-DM1 over the control arm.” A final OS analysis will be forthcoming, Blackwell added.

The safety data revealed that T-DM1 was better tolerated than XL, with fewer treatment-related toxicities and discontinuations. Grade ≥3 adverse events occurred in 57.0% of the XL arm, as compared with 40.8% of the T-DM1 group. Dose reductions were necessary in 53.4%, 27.3%, and 16.3% of patients receiving capecitabine, lapatinib, and T-DM1, respectively.

The most common grade ≥3 adverse events in the T-DM1 arm included thrombocytopenia (12.9%) and elevations in the liver enzymes aspartate transaminase (4.3%) and alanine transaminase (2.9%). Blackwell said that these side effects were manageable through interruptions in treatment.

Based on EMILIA’s efficacy and safety results, Blackwell said she considers the trial to be a success, but that she is uncertain how regulatory agencies will interpret the data.

“From a clinician’s standpoint and from a patient’s standpoint this is definitely a positive study. It’s continuing to be discussed as to whether or not meeting one of the efficacy endpoints, PFS, being extremely close on the second efficacy endpoint, OS, and having a really good safety profile is a positive study in the eyes of the regulatory agencies,” Blackwell said.

“The regulatory discussions are ongoing,” she added. “I will say that both the US and European regulatory authorities have been very considerate in their willingness to [discuss] the data.”

In the meantime, Blackwell said a manuscript of the EMILIA data is being prepared and will soon be submitted for publication in a peer-reviewed journal.

Beyond T-DM1, Blackwell envisions further breakthroughs with antibody drug conjugates in cancer care. “I think it’s the first of many antibody drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system with an antibody.”

Blackwell KL, Miles D, Gianni L, et al. Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) vs capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. J Clin Oncol. 2012;30(suppl; abstr LBA1).
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Old 06-03-2012, 05:43 PM   #2
Lani
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Re: Scarlet Pimpernel (or Waldo) logs in from ASCO-- TDM-1 presentation extremely str

another news story


June 3, 2012 (Chicago, Illinois) — The investigational agent trastuzumab emtansine (T-DM1) can improve progression-free survival in some women with metastatic breast cancer.

According to study results presented at the plenary session here at the 2012 Annual Meeting of the American Society of Clinical Oncology®, T-DM1 (Roche/Genentech), compared with standard therapy using capecitabine (Xeloda) and lapatinib (Tykerb), significantly improved progression-free survival in women with HER2-positive locally advanced or metastatic breast cancer who had previously been treated with a taxane and trastuzumab.

Median progression-free survival was longer in patients treated with T-DM1 than in those treated with the standard therapy (9.6 vs 6.4 months). This difference reached statistical significance.

Median overall survival for patients treated with T-DM1 was not reached, but median overall survival for those treated with standard therapy was 23.3 months (hazard ratio [HR], 0.621; P = .0005).

"What we have shown is that T-DM1 significantly improves progression-free survival, compared with capecitabine and lapatinib, and there is a strong trend favoring overall survival," said senior author Sunil Verma, MD, chair of breast medical oncology at the Sunnybrook Odette Cancer Centre and assistant professor at the University of Toronto, in Ontario, Canada.

In an interview, Dr. Verma pointed out that "incredible strides" have been made in the treatment of HER2-positive breast cancer using trastuzumab and lapatinib, but that they have to be used with chemotherapy to see the benefit. "The idea with this compound is really precision chemotherapy and to deliver the chemotherapy right to the targeted cells," he explained.

"This is a treatment option for patients with metastatic HER2-positive breast cancer that truly changes what we can offer for them. It should be one of the standards of care available to them," Dr. Verma told Medscape Medical News.

T-DM1 is an antibody–drug conjugate consisting of the antibody trastuzumab (Herceptin) and linked to the cytotoxin mertansine (DM1). It incorporates the antitumor activities of trastuzumab and the HER2-targeted delivery of DM1.

We've taught an old friend a new trick.
"We've taught an old friend a new trick — we're using [trastuzumab] as a delivery vehicle," said Andrew D. Seidman, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City who was not involved with the trial.

This is a very exciting time; other agents are also currently in trials, Dr. Seidman told Medscape Medical News.

It has yet to be determined how some of these agents should best be combined, he continued. For example, pertuzumab, which is currently being developed by Genentech, and T-DM1 are being examined together in the MARIANNE trial, which is a first-line study in HER2-positive breast cancer. "They recently completed accrual, so we are going to be hearing more big stories," he said.

"What I'm hearing from the EMILIA trial is that 1 drug...outperforms 2 drugs in terms of cancer progression," Dr. Seidman explained. "This can translate to a survival benefit."

Study Details

The EMILIA trial is a randomized phase 3 international study that compared T-DM1 with capecitabine and lapatinib. It is currently the only approved combination for trastuzumab-refractory HER2-positive metastatic breast cancer.

Dr. Verma and colleagues enrolled 991 patients with confirmed HER2-positive metastatic breast cancer (positive for immunohistochemistry [IHC] 3+ and/or fluorescent in situ hybridization [FISH]) who had been previously treated with trastuzumab and a taxane. The primary end points were progression-free survival, overall survival, and safety.

A total of 978 patients in the cohort received treatment. The median durations of follow-up were 12.9 months in the T-DM1 group and 12.4 months in the standard-therapy group. The baseline demographics, previous therapy, and disease characteristics were balanced between the 2 groups.

Outcomes

Measures T-DMI Standard Therapy
Overall Survival at 1 Year, % 84.7 77.0
Overall Survival at 2 Years, % 65.4 47.5
Objective Response Rate, Months (95% CI) 43.6 (38.6–48.6) 30.8 (26.3–35.7)
Duration of Response in Patients
With Overall Response, Months 12.6 6.5
Adverse Events of Grade 3 or Higher, % 40.8 57.0

The most common adverse events of grade 3 or higher with T-DM1, compared with standard therapy, were thrombocytopenia (12.9% vs 0.2%), increased aspartate aminotransferase (4.3% vs 0.8%), and increased alanine aminotransferase (2.9% vs 1.4%). Patients treated with capecitabine and lapatinib experienced more diarrhea (20.7% vs 1.6%), palmar plantar erythrodysesthesia (16.4% vs 0.0%), and vomiting (4.5% vs 0.8%) than those treated with T-DM1.

Dose reductions were more common with standard therapy (53.4% for capecitabine and 27.3% for lapatinib.

2012 Annual Meeting of the American Society of Clinical Oncology® (ASCO): Abstract LBA1. Presented June 3, 2012.
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Old 06-03-2012, 05:47 PM   #3
Laurel
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Re: Scarlet Pimpernel (or Waldo) logs in from ASCO-- TDM-1 presentation extremely str

They were sure trumpeting it as the next best thing since sliced bread for breast cancer on the news all day today, but with no mention of its being for Her2 positive BC. Fingers crossed it get approval!
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Laurel


Dx'd w/multifocal DCIS/IDS 3/08
7mm invasive component
Partial mast. 5/08
Stage 1b, ER 80%, PR 90%, HER-2 6.9 on FISH
0/5 nodes
4 AC, 4 TH finished 9/08
Herceptin every 3 weeks. Finished 7/09
Tamoxifen 10/08. Switched to Femara 8/09
Bilat SPM w/reconstruction 10/08
Clinical Trial w/Clondronate 12/08
Stopped Clondronate--too hard on my gizzard!
Switched back to Tamoxifen due to tendon pain from Femara

15 Years NED
I think I just might hang around awhile....

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Old 06-03-2012, 05:59 PM   #4
7andcounting
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Re: Scarlet Pimpernel (or Waldo) logs in from ASCO-- TDM-1 presentation extremely str

Please oh please will the FDA have some mercy on us ladies and let this get approved. Are they even listening? I can only wish that someone high up would move heaven and earth and get this thing moving so we can get this soon and not have to wait. We need it now! Atleast I sure do!
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