Phase III MARIANNE Trial Results

Phase III MARIANNE Trial Results

T-DM1 treatment resulted in noninferior, but not superior, progression-free survival (PFS) compared with trastuzumab plus a taxane (HT) in patients with locally advanced or metastatic HER2-positive breast cancer. Furthermore, the addition of pertuzumab to T-DM1 provided no efficacy benefit, based on results of the randomized, phase III MARIANNE trial (Abstract 507). Paul Anthony Ellis, MD, FRACP, of Guy’s Hospital and the Sarah Cannon Research Institute, United Kingdom, presented the results of the large, multinational trial on Monday, June 1, during the Breast Cancer—HER2/ER Oral Abstract Session.

Prof. Paul Anthony Ellis

T-DM1 consists of trastuzumab linked to the cytotoxic agent DM1. Pertuzumab is a monoclonal antibody targeting HER2/HER3 dimerization. Early reports that suggested a benefit with a combination of the two agents led to the design of the MARIANNE trial.

“Neither T-DM1 nor T-DM1 plus pertuzumab proved to be superior to the old standard of care, taxane plus trastuzumab,” Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, said in her discussion. She called the MARIANNE trial “a very important study for our field, with far-reaching implications.”

The MARIANNE trial randomly assigned 1,095 patients with progressed or recurrent locally advanced or previously untreated metastatic HER2-positive breast cancer to receive T-DM1 plus pertuzumab (363 patients), T-DM1 plus placebo (367 patients), or HT (docetaxel or paclitaxel; 365 patients). At the time the trial was initiated, the control arm represented the standard of care for this patient population.

After a median follow-up of 35 months, both T-DM1–containing regimens showed noninferior PFS, but not superiority, over HT. The median PFS was 15.2 months in the T-DM1 plus pertuzumab arm (hazard ratio [HR] 0.87, 95% CI [0.69, 1.08]; p = 0.14), 14.1 months with T-DM1 alone (HR 0.91, 95% CI [0.73, 1.13]; p = 0.31) compared with 13.7 months with HT. The overall survival data were not yet reached.

The objective response rate was 64.2%, 59.7%, and 67.9% among the T-DM1 plus pertuzumab, T-DM1 alone, and HT arms, respectively. However, the median duration of response was 21.2 months (95% CI [15.8, 29.3]) in the T-DM1 plus pembrolizumab arm, 20.7 months (95% CI [14.8, 25.0]) in the T-DM1 alone arm, and 12.5 months (95% CI [10.5, 16.6]) in the HT arm.

“MARIANNE was a valiant trial,” Dr. Modi said, “but THP [taxane, trastuzumab, and pertuzumab] remains our first-line standard care, with T-DM1 a preferred second-line option.”

The trial did show a benefit with T-DM1 over the control regimen in regards to toxicity and health-related quality of life outcomes. Rates of grade 3/4 neutropenia, febrile neutropenia, and diarrhea were lower in the T-DM1–containing arms. “It would be very informative to reassess these toxicities based on the taxane delivered,” said Dr. Modi, “knowing that weekly paclitaxel has a very low febrile neutropenia rate and may be the preferred partner.”

Rates of alopecia were also substantially lower with T-DM1, as were health-related quality of life outcomes as assessed by patient-reported physical and functional well-being. The median time to a five-point or more decrease from baseline in the Health-Related Quality of Life score ranged from 7.7 months with T-DM1 and 9.0 months with T-DM1 plus pertuzumab to 3.6 months with HT.

Dr. Modi noted that the role of pertuzumab in adjuvant breast cancer therapy is being further evaluated in the randomized, phase III APHINITY trial, which is evaluating the addition of pertuzumab to the current standard of care chemotherapy and trastuzumab in patients with centrally-confirmed HER2-positive early-stage breast cancer.

Based on the available evidence, Dr. Modi concluded that, “for the time being, THP remains our preferred first-line therapy for HER2-positive metastatic breast cancer, and our treatment guidelines for 2015 remain unchanged.”

Watch the session: Visit the ASCO Virtual Meeting website.