Frontline T-DM1 Results Disappointing in Phase III MARIANNE Trial

Sandra Horning, MD

Two HER2-targeting regimens anchored by T-DM1 (ado-trastuzumab emtansine; Kadcyla) failed to outperform the standard strategy in women with previously untreated advanced HER2-positive breast cancer in the MARIANNE trial, dealing a blow to efforts to move the drug into frontline settings.

Topline results from the phase III trial indicate that neither T-DM1—containing arm significantly improved progression-free survival (PFS) compared with a cohort who received trastuzumab (Herceptin) plus chemotherapy, according to Genentech, the drug developer. The company, which did not release any details, said full results would be presented at a future medical meeting.

“In this study, we had hoped to show improvement in progression-free survival without the use of traditional chemotherapy in the first-line treatment of patients with advanced HER2-positive breast cancer,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a statement “While MARIANNE didn’t achieve this result, we will continue to study these medicines, as well as investigational treatments for other types of breast cancer, with the goal of improving outcomes for patients.”

T-DM1 is an antibody-drug conjugate that links the monoclonal antibody trastuzumab with the microtubule inhibitor DM1, a maytansine derivative, to deliver both the anti-HER2 agent and chemotherapy directly to the cancer cells.

The agent is approved in second-line settings, but researchers had been hoping the MARIANNE trial would provide support for moving T-DM1 forward in the treatment timeline.

Promising data from an earlier randomized phase II trial indicated that patients with HER2-positive metastatic or recurrent locally advanced breast cancer who received T-DM1 achieved a median PFS of 14.2 months versus 9.2 months for participants treated with trastuzumab/docetaxel (HR = 0.59; 95% CI, 0.36-0.97).¹

In the MARIANNE trial, researchers sought to randomized 1095 women to T-DM1 plus or minus pertuzumab (Perjeta) compared with trastuzumab plus either docetaxel or paclitaxel.

T-DM1 was administered at 3.6 mg/kg IV every 3 weeks, and pertuzumab was given with an 840-mg dose IV on day 1 of cycle 1 followed by 420 mg every 3 weeks in subsequent cycles.¹

In the chemotherapy-containing arm, trastuzumab was administered at 8 mg/kg IV on cycle 1 followed by 6 mg/kg every 3 weeks when given with docetaxel, or at 4 mg/kg IV on day 1 of cycle 1 followed by 2 mg/kg weekly starting on day 8 of cycle 1 when given with paclitaxel. Docetaxel was dosed at 75 mg/m² or 100 mg/m² IV every 3 weeks for a minimum of 6 cycles, while paclitaxel was given at 80 mg/m² intravenously weekly for a minimum of 18 weeks.

The primary endpoints of the study were PFS and the incidence of adverse events, while secondary endpoints included overall survival, response rates, and duration of response.

The study showed “similar” PFS rates in all three arms, thus meeting its noninferiority goals, Genentech said. However, the PFS in the T-DM1 arms did not meet the superiority threshold, the company said.

The FDA has approved T-DM1 as a single agent for the treatment of patients with HER2-positive metastatic breast cancer who have previously received trastuzumab and a taxane separately or in combination and who have either received prior therapy for metastatic disease or who have experienced a recurrence during or within 6 months after adjuvant therapy.

Pertuzumab is indicated in combination with trastuzumab and docetaxel for patients with HER2-positive metastatic breast cancer who have not been previously treated for metastatic disease and as neoadjuvant treatment for patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer.

References

1. Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2—positive metastatic breast cancer. J Clin Oncol. 2013;31(9):1157-1163.
2. NIH Clinical Trial Registry. www.ClinicalTrials.gov website. Identifier: NCT01120184.