T-DM1 Offers Similar PFS, More Tolerable in Advanced HER2-Positive Breast Cancer

The antibody-drug conjugate trastuzumab emtansine (T-DM1) showed non-inferior-but not superior-efficacy to trastuzumab plus a taxane in women with advanced HER2-positive breast cancer, according to a phase III trial. T-DM1 alone and in combination with pertuzumab showed similar results.

“As with trastuzumab, T-DM1 inhibits HER2 signaling, activates antibody-dependent cellular cytotoxicity, and inhibits HER2 shedding,” wrote study authors led by Edith A. Perez, MD, of Genentech, in South San Francisco. “T-DM1 has demonstrated superior efficacy and improved tolerability compared with the previous standard of care in two phase III trials in patients with previously treated HER2-positive advanced breast cancer.”

The MARIANNE trial compared T-DM1 with trastuzumab/taxane and with T-DM1 plus pertuzumab. It included 1,095 patients randomized to one of three arms: 365 patients were considered the control group and received trastuzumab plus taxane; 367 received T-DM1; and 363 received T-DM1 plus pertuzumab. The results were published online ahead of print in the Journal of Clinical Oncology.

Both T-DM1 arms showed non-inferiority with regard to progression-free survival (PFS) compared with the control group, though not superiority. The hazard ratio (HR) for T-DM1 alone vs trastuzumab/taxane was 0.91 (97.5% CI, 0.73–1.13; P = .31). The same was true when pertuzumab was added to T-DM1, with an HR of 0.69 (97.5% CI, 0.69–1.08; P = .14).

The median PFS was 13.7 months in the control group, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab. There was no difference with regard to PFS between the two T-DM1 groups (HR, 0.91; 97.5% CI, 0.73–1.13). The median overall survival had not yet been reached in any of the three groups, and survival curves were overlapping for all three arms.

The objective response rate was 67.9% in control patients, compared with 59.7% with T-DM1 alone and 64.2% with T-DM1 plus pertuzumab. In those patients who did achieve a response, the median duration of response was 12.5 months with trastuzumab/taxane, 20.7 months with T-DM1 alone, and 21.2 months with the addition of pertuzumab.

There were more grade 3 or higher adverse events in control patients (54.1%) than in either of the T-DM1 arms (45.4% and 46.2%, respectively). In control patients, the most common such adverse events included neutropenia (19.8%), febrile neutropenia (6.5%), and diarrhea (4.2%). In the TDM-1 alone group, they included increased aspartate aminotransferase (6.6%), thrombocytopenia (6.4%), and anemia (4.7%), while in the pertuzumab patients they included thrombocytopenia (7.9%), anemia (6.0%), and increased alanine aminotransferase (5.2%). Only grade 3 diarrhea was increased with pertuzumab in comparison to T-DM1 alone.

“On the basis of the improved tolerability and noninferior PFS observed with T-DM1, it may provide an alternate treatment option to trastuzumab plus taxane in patients with HER2-positive metastatic breast cancer,” the authors concluded.