T-DM1: A BETTER HERCEPTIN?

SAN ANTONIO -- A novel form of trastuzumab (Herceptin) with a chemotherapy-like conjugate attached appears to substantially improve outcomes in heavily-pretreated metastatic breast cancer, researchers said.

Median progression-free survival was 7.3 months (range 0.0 to 11.7) with single agent trastuzumab-DM1 (T-DM1) in a Phase II study reported here at the San Antonio Breast Cancer Symposium.

The objective response rate was 32.7% in women whose tumors had progressed after treatment with an anthracycline, taxane, capecitabine (Xeloda), trastuzumab, and lapatinib (Tykerb), including two HER2-targeted agents in the metastatic setting.

Moreover, the investigational agent was well tolerated, with no dose-limiting cardiotoxicity, according to Ian Krop, MD, PhD, of the Dana-Farber Cancer Center in Boston, and colleagues.

A response this good didn't even seem possible in a setting where women had received an average of seven prior agents, José Baselga, MD, of the Vall d'Hebron University Hospital in Barcelona, Spain, commented at the poster discussion session he moderated.

The new molecule consists of the trastuzumab monoclonal antibody, chemically fused to a cytotoxin: a potent microtubule inhibitor called maytansine that's derived from a sea sponge.

"It is supposed to pack the antibody, which targets the pathway, and the chemotherapy, which targets the cancer cell, hopefully as a smart missile that will target the cancer cell with minimal toxicity," explained Mothaffar Rimawi, MD, of Baylor College of Medicine in Houston, who wasn't involved in the study.

The agent is being developed by Genentech in partnership with ImmunoGen as a possible "replacement" for Genentech's trastuzumab, which comes off patent in 2015.

"Many people feel the data is worth bringing to the FDA, even though it is only Phase II, because these patients have no other options," Knop said standing at his poster.

The companies have given no specifics on filing but hinted in an investigator conference call that "clearly there is potential for filing and approval over the next 12 months for T-DM1." The drug is going into Phase III study for first-line treatment around May 2010.

Regardless, the early results presented here at SABCS generated a buzz at the meeting.

"It is just remarkable in Phase II activity against HER2-positive breast cancer that's resistant to trastuzumab and lapatinib," commented targeted therapy pioneer Mark Pegram, MD, of the University of Miami.

The study included 110 women assigned to open-label treatment with single agent trastuzumab-DM1 (3.6 mg/kg intravenously every three weeks).

Objective response rate as judged by an independent review board -- the primary endpoint -- was 32.7%, all partial responses. The duration ranged from 1.2 to 8.4 months.

Clinical benefit rate -- stable disease or complete or partial response maintained for at least 28 days -- was 44.5% as judged by the same outside experts.

For the 83.5% of patients confirmed to have HER2-positive disease, the objective response rate was even better (39.5%), as was the clinical benefit rate (52.6%).

The researchers reported no new safety signals with the drug, with observed toxicities called "acceptable and manageable."

Overall, 22.7% of patients had a serious adverse event -- most