Tykerb Falls Short Versus Herceptin, Adding Clarity to Frontline HER2-Positive Metastatic Breast Cancer Strategy

First-line treatment with Tykerb and a taxane failed to improve progression-free survival versus Herceptin plus a taxane in patients with HER2-positive metastatic breast cancer.
BY Andrew J. Roth
PUBLISHED March 23, 2015
First-line treatment with Tykerb (lapatinib) and a taxane failed to improve progression-free survival (PFS) versus Herceptin (trastuzumab) plus a taxane in patients with HER2-positive metastatic breast cancer. Final results from the phase 3 MA.31 trial were recently published in the Journal of Clinical Oncology.

At the final analysis, PFS was 9 months in the Tykerb arm versus 11.3 months in the Herceptin arm. These data, along with results from phase 3 CLEOPATRA and MARIANNE trials, add further clarity to the frontline treatment of HER2-positive disease.

The phase 3 CLEOPATRA study showed a dramatic overall survival (OS) benefit of nearly 16 months for Perjeta (pertuzumab) when combined with Herceptin and chemotherapy versus trastuzumab and chemotherapy alone in previously untreated patients with HER2-positive metastatic disease. The study also showed no new safety concerns or added cardiac toxicity.

Data from CLEOPATRA, which were presented at the 2014 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain, are practice-changing, according to Giuseppe Curigliano.

“We now have a new standard of care for patients with metastatic HER2-positive breast cancer,” Curigliano, director, Division of Experimental Therapeutics, Istituto Europeo di Oncologia (IEO), Milan, Italy, said in a statement during ESMO in late September. “This is dual targeting with pertuzumab and trastuzumab plus chemotherapy, which was docetaxel in the trial.”

Conversely, the phase 3 MARIANNE trial of untreated patients with HER2-positive disease showed no PFS benefit with a regimen anchored by Kadcyla (T-DM1, ado-trastuzumab emtansine) compared with standard therapy (Herceptin plus chemotherapy).

MA.31 was the first head-to-head analysis of Tykerb and Herceptin in this setting. In the trial, 537 patients with confirmed HER2-positive disease were randomized 1:1 to receive Tykerb in combination with a taxane followed by Tykerb or Herceptin in combination with a taxane followed by Herceptin. Taxane therapy was defined as paclitaxel once per week or 75 mg/m2 of docetaxel (lower than the approved single-agent dose) once every three  weeks. In total, 82 percent of patients did not receive adjuvant anti-HER2 therapy.

In addition to inferior PFS with Tykerb in both the interim analysis and final analysis, the agent was also associated with worse OS compared with Herceptin. Toxicity was also worse in the Tykerb arm in MA.31—treatment discontinuations were more common with the agent (15 percent) versus Herceptin (8 percent).

Incidences of diarrhea and rash were both higher among patients receiving Tykerb compared with those receiving Herceptin. In the combination phase of the trial, grade 3/4 rash occurred in 8 percent and 0 percent of patients in the Tykerb and Herceptin arms, respectively.

Results from MA.31 further clarify the best frontline treatment regimen for patients with HER2-positive metastatic breast cancer. For Curigliano, it is definitively dual-HER2 blockade.

“In the future, in any country of the world, when you have a patient with metastatic breast cancer that is HER2-positive, the proposal for treatment should include dual targeting with pertuzumab and trastuzumab plus chemotherapy,” Curigliano said.
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