Perez Surprised by Frontline T-DM1 Flop

“Edith

Edith A. Perez, MD

Researchers will dissect topline results from the MARIANNE trial in the coming weeks in an effort to understand why T-DM1 (ado-trastuzumab emtansine; Kadcyla) failed to triumph as a first-line treatment in the metastatic setting for patients with advanced HER2-positive breast cancer despite the promise of earlier findings, according to lead investigator Edith A. Perez, MD.

Perez said in an interview withTargeted Oncologythat she was “very surprised” to learn last week that regimens containing T-DM1 with or without pertuzumab (Perjeta) did not show superiority over standard trastuzumab (Herceptin) plus chemotherapy. Genentech, which is developing the drug, announced broad results gathered from nearly 300 sites in approximately 40 countries.

“In our laboratory models, it was clear that the combination was better, and we have done a randomized phase II trial which really provided some important data showing that T-DM1 was better than the combination of trastuzumab with docetaxel,” said Perez.

Perez said researchers would examine how patients treated in the control arm fared, particularly participants in this cohort who had received prior trastuzumab as part of adjuvant therapy.

“I’m very happy there is a commitment from all of us, including the company, to study the data very carefully,” said Perez, adding that the investigative team would seek to present detailed findings at the 2015 American Society of Clinical Oncology Annual Meeting in May.

Meanwhile, the phase III MARIANNE trial results reverberated in stock market trading for both Roche Holding AG, whose member companies include Genentech, and ImmunoGen, which developed the linker technology used in the antibody-drug conjugate T-DM1 and receives royalties from sales of the drug.

Roche, which markets all three of the anti-HER2 study drugs, saw its stock drop approximately 6% in trading on Friday amid the perception that the trial results would hamper the expansion of clinical uses for both T-DM1 and pertuzumab. ImmunoGen saw its stock plunge $44% to close at $6.11 Friday.

Rationale for Frontline T-DM1

Although trastuzumab in combination with taxane-based chemotherapy has significantly improved outcomes for women with HER2-positive metastatic breast cancer, researchers have been searching for more effective therapies with fewer toxicities. T-DM1, which links the monoclonal antibody trastuzumab with a chemotherapy agent, is approved as a single agent for patients with HER2-positive metastatic breast cancer who have progressed after receiving trastuzumab/chemotherapy treatment for advanced disease.

Perez served as the principal investigator for a phase II study in which 137 patients with metastatic or recurrent locally advanced HER2-positive breast cancer were randomized to receive either T-DM1 or trastuzumab plus docetaxel.¹In explaining the rationale for that study, investigators particularly noted that severe myelosuppression frequently occurs in patients who have received docetaxel.

The study, which helped lay the groundwork for the MARIANNE trial, found that patients who received T-DM1 achieved a median progression-free survival (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 addition, patients who received T-DM1 experienced fewer grade ≥3 adverse events (AEs) than those who were given the trastuzumab combination (46.4% vs 90.9%, respectively). For hematologic malignancies grade ≥3, the incidence was lower in the T-DM1 arm compared with the trastuzumab regimen for neutropenia (5.8% vs 62.1%), leukopenia (0 vs 24.2%), and febrile neutropenia (0 vs 13.6%).

In the three-arm MARIANNE trial, researchers sought to randomize 1095 women to T-DM1 plus or minus pertuzumab compared with trastuzumab plus either docetaxel or paclitaxel. 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.

Topline results indicate that neither T-DM1 regimen produced PFS findings that were significantly superior to the trastuzumab arm, although the novel therapeutic approaches did result in PFS rates similar to the standard arm, according to Genentech. Specific findings were not released.

Perez declined to comment specifically about the AE profile of the MARIANNE trial arms, but said that investigators would be looking at the benefit/side effect equation.

“T-DM1 is an excellent drug in the portfolio of therapies for patients with HER2-positive metastatic breast cancer,” said Perez. “It’s still there. Whether T-DM1 will substitute for trastuzumab and chemotherapy, I think it will require [us] to look at the data in detail to try to figure out the benefit ratio. Now we know there’s noninferiority, so there are other issues we’ll have to look at in detail.”

In order to move HER2-targeting therapies forward in the metastatic setting, Perez said researchers must focus on three key areas: an understanding of the intricacies of the MARIANNE trial results; a plan for translational or correlative studies as a result of these findings; and a continued effort to develop HER2-targeting agents, particularly monoclonal antibodies that can enhance the patient’s immune system.

Reference

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.