A novel form of trastuzumab (Herceptin) with chemotherapy attached appears to improve progression-free survival (PFS) in advanced HER2-positive breast cancer with a hint of survival benefit as well, a pivotal clinical trial showed.

Progression-free survival (PFS) rose by a relative 35% and absolute 3.2 months with the agent, dubbed trastuzumab emtansine or T-DM1, compared with standard chemotherapy (P<0.0001), Kimberly Blackwell, MD, of Duke University Medical Center, and colleagues reported in an interim analysis of the EMILIA trial.

Overall survival odds improved 38%, but didn’t reach the high bar set for statistical significance (P=0.0005 versus the trial stopping threshold of P=0.0003), the group reported here at the American Society for Clinical Oncology meeting.

“I think this will offer a very important therapeutic option for patients with HER2-positive metastatic breast cancer,” Blackwell told reporters at an ASCO press conference. “I think it’s the first of many antibody-drug conjugates to follow that will link a potent anti-cancer agent to a targeted delivery system with an antibody.”

T-DM1 uses trastuzumab to guide the cytotoxic agent emtansine, which is too potent to give systemically, according to Blackwell, inside cancer cells using the HER2 receptor as a target.

The trial included 991 women with locally advanced or metastatic HER2-positive breast cancer and disease progression on, or within 6 months of, adjuvant treatment with a taxane and conventional trastuzumab. They were randomized to open-label treatment with:

  T-DM1 at 3.6 mg/kg intravenously every 3 weeks
  Capecitabine (Xeloda) at 1,000 mg/m2 orally twice daily for days one to 14 in a 3-week cycle and lapatinib (Tykerb) at 1,250 mg orally once daily

After a median follow-up of over 12 months, median PFS reached 9.6 months with the novel trastuzumab drug compared with 6.4 months in the control chemotherapy group for a stratified hazard ratio of 0.65 (95% confidence interval 0.55 to 0.77).

Overall survival rates were 85% with T-DM1 versus 77% in the capecitabine and lapatinib group at 1 year, and 65% versus 48%, respectively, at 2 years.

Survival topped out at a median 23.3 months in the chemotherapy group, which Blackwell called “quite good,” but had not yet reached a median with the novel agent.

Serious adverse events were less common with T-DM1 than with capecitabine and lapatinib (41% versus 57%).

The most common grade 3 or higher events with the novel agent were thrombocytopenia (13% versus less than 1%) and elevated liver enzymes (4% versus less than 1% aspartate aminotransferase and 3% versus 1% alanine transaminase).

Drugmaker Genentech is preparing to go to the FDA with just the phase II and interim phase III data to seek approval for T-DM1, Blackwell noted.

However, without significant overall survival benefit, there’s some question of whether the FDA would give the drug a green light based on prolonged PFS alone.

Since the debacle in which bevacizumab’s (Avastin) accelerated approval was revoked in metastatic breast cancer over lack of overall survival advantage, and minimal PFS benefit in subsequent trials, the agency has given signs that PFS is no longer a sufficient outcome on its own.

Primary source: American Society of Clinical Oncology

Source reference: Blackwell KL, et al “Primary results from EMILIA, a phase 3 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” ASCO 2012; Abstract LBA1.