Firstline Kadcyla Results Disappointing in HER2-Positive Metastatic Breast Cancer Trial

Two HER2-targeting regimens anchored by Kadcyla (T-DM1) failed to outperform the standard strategy of Herceptin (trastuzumab) plus chemotherapy in women newly diagnosed with advanced HER2-positive breast cancer. Kadcyla, also known as ado-trastuzumab emtansine, is currently approved for second-line treatment for patients with metastatic HER2-positive breast cancer who progress on Herceptin and taxane chemotherapy.

In the MARIANNE trial, 1095 women were given either Kadcyla alone or in combination with Perjeta (pertuzumab) compared with Herceptin plus either docetaxel or paclitaxel. Kadcyla is an antibody-drug conjugate that links Herceptin with the microtubule inhibitor DM1 to deliver both the anti-HER2 agent and chemotherapy directly to the cancer cells. Perjeta is another HER2-targeted therapy, which is approved in combination with Herceptin and docetaxel for patients not previously treated for metastatic disease and as neoadjuvant treatment for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer.

Researchers had been hoping the results of the phase 3 trial would provide support for moving Kadcyla forward in the treatment timeline. Instead, topline results from the trial indicate that neither Kadcyla-containing arm significantly improved progression-free survival (PFS) compared with the patient group who received the standard treatment. Full results will most likely 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, 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.”

Promising data from an earlier randomized phase 2 trial indicated that patients with HER2-positive metastatic or recurrent locally advanced breast cancer who received Kadcyla achieved a median PFS of 14.2 months versus 9.2 months for participants treated with Herceptin and docetaxel.

The primary endpoints of MARIANNE 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 groups, thus meeting its noninferiority goals. However, the PFS in the Kadcyla arms did not meet the superiority threshold, according to a statement released by the drug’s maker, Genentech. Side effects reported in the two Kadcyla arms were consistent with previous studies of Kadcyla and Perjeta.