Novel Agent Trastuzumab-DM1 Shows Efficacy in Metastatic Breast Cancer

Becky McCall

October 09, 2010

October 9, 2010 (Milan, Italy) (UPDATED October 12, 2010) — Results of the first-ever phase 2 study of an anti-Her2 antibody-drug conjugate, trastuzumab-DM1 (T-DM1), as first-line therapy in patients with Her2-positive metastatic breast cancer, confirm good efficacy and lower toxicity than standard therapy.

These findings were presented by principal investigator Edith Perez, MD, from the Mayo Clinic, Jacksonville, Florida, here at the 35th European Society for Medical Oncology Congress.

This is the first randomized phase 2 study on efficacy and safety of T-DM1 in this population. T-DM1 was compared with trastuzumab (Herceptin; Genentech/Roche) plus docetaxel (Taxotere; Sanofi-Aventis) in patients with Her2-positive metastatic breast cancer who had not received prior chemotherapy for metastatic disease.

"So far our results are really very encouraging," Dr. Perez told Medscape Medical News. "T-DM1 provides efficacy with lower toxicity in patients with Her2-positive metastatic breast cancer. The results are early, but the response data are solid, and we want to follow-up with progression-free survival.

"It's not only the response rate which is indeed numerically much higher, but it is the lower toxicity of this drug compared to traditional chemotherapies and Herceptin," she added.

T-DM1 is the first of a novel class of antitumor therapy known as antibody–drug conjugates. It consists of 2 existing cancer drugs bound together so that both are delivered to the cancer cells. Trastuzumab is a monoclonal antibody, which targets cells that overproduce the protein HER2, whereas DM1 is a chemotherapy agent that targets microtubules.

"This coupling means that chemotherapy is not found free floating but is delivered inside the tumor cells per se," explained Dr. Perez. "With T-DM1, we target delivery far better by coupling chemotherapy with Herceptin."

Thus, when trastuzumab binds to the Her2 protein in the cell, the whole trastuzamab-DM1 molecule is internalized and the chemotherapy is released inside the cell — where it is supposed to be — not in the blood, circulating, causing adverse effects, she pointed out.

Response Rates Similar

In this ongoing phase 2 trial, 67 women received T-DM1 (3.6 mg/kg intravenously every 3 weeks), and 70 received treatment with trastuzumab (6 mg/kg intravenously; 8 mg/kg in cycle 1) plus docetaxel (75 or 100 mg/m2 intravenously on day 1 every 3 weeks). Patients remained on treatment until disease progression or unacceptable toxicity.

Progression-free survival and safety were primary endpoints, whereas secondary endpoints included overall response rate, clinical benefit rate, and overall survival.

After a median of 6 months' follow-up, the percentage of patients in the T-DM1 group who showed objective response (complete or partial response based on RECIST 1.0) was 48% (95% confidence interval [CI], 35.4% - 60.3%) compared with 41% (95% CI, 30.2% - 53.8%) in patients in the trastuzumab-plus-docetaxel group.

The percentage of patients showing clinical benefit (objective response or maintained stable disease for at least 6 months from treatment start) was similar between the 2 groups: 55.2% (95% CI, 43.1% - 67.2%) in the T-DM1 group and 57.1% (95% CI, 44.8% - 68.9%) in the comparator group.

Dr. Perez explained that they wanted to determine whether T-DM1 delays overall progression of breast cancer. "We can shrink tumors, but now we want to know for how long we can shrink these tumors, as compared to older standard treatments," she said. "We have very mature data related to response in this study, but it will take another year to consolidate our data regarding progression-free survival."

Toxicity Lower in Experimental Group

Most notably, rates of clinically relevant adverse events (grade > 3) were significantly lower in the T-DM1 group (37.3%) compared with the rate in patients given trastuzumab plus docetaxel (75.0%).

The most common adverse events of any grade were alopecia (1.5% vs 66.2%), neutropenia (7.5% vs 57.4%), and diarrhea (10.4% vs 45.6%) for T-DM1 and trastuzumab plus docetaxel, respectively.

"Even if the response had been the same with this level of lower toxicity, then it is something to pay attention to. We want to both improve response in our patients but also to improve their lives," said Dr. Perez.

Replace Systemic Chemotherapy?

Jose Baselga, MD, chief of hematology and oncology, Massachusetts General Hospital, Boston, commented that T-DM1 was a wonderful addition to the treatment of Her2-positive disease. "The concept is very appealing. A very important cytotoxic agent is linked to trastuzumab, and clinical trials have shown a very high response rate with minimal toxicity," he said.

"Why is it that the response rate is so good in patients who have received so many therapies previously, as if they were patients treated first-line?" he questioned, adding that in his opinion, the answer to that question lies in the biology.

"Her2 tumors are extremely sensitive, and they continue to respond to second-line plus treatments," he said. "We shouldn't give up on treating this disease."

In conclusion, he speculated that in the future, this might replace systemic chemotherapy in Her2-positive breast cancer. "It is provocative data. If T-DM1 is even equal to trastuzumab plus chemotherapy, then that is a big win because we have highly efficacious therapy, which is nontoxic.

"I think this is phenomenal," he added.

Progression-free survival, 1-year overall survival rates, mature overall response rates, and duration of response data are expected in 2011. A phase 3 trial, called MARIANNE, has now begun that assesses trastuzumab plus taxane vs T-DM1, with a third option of T-DM1 plus pertuzumab.

Genentech supported the study. L. Dirix, J. Kocsis, L. Gianni, J. Lu, J. Vinholes, and S. Hurwitz received research/contract funding from Roche/Genentech covering costs associated with the conduct of this study. V. Ng, C. Linehan, and S. Agresta are employees and stockholders of Roche. All other authors have disclosed no relevant financial relationships. Dr. Perez does not own any stock in Genentech or Roche. Genentech and Roche supply research support for the breast cancer program at the Mayo Clinic. Dr. Baselga has disclosed no relevant financial relationships.

35th European Society for Medical Oncology Congress: Abstract LBA3. Presented October 11, 2010.

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