Lapatinib Flops, Solidifying Standard Treatment of HER2-Positive MBC

Giuseppe Curigliano, MD, PhD

Giuseppe Curigliano, MD, PhD

First-line treatment with lapatinib (Tykerb) and a taxane failed to improve progression-free survival (PFS) versus trastuzumab (Herceptin) plus a taxane in patients with HER2-positive metastatic breast cancer, according to final results from the phase III MA.31 trial. The results were recently published in theJournal of Clinical Oncology.

At the final analysis, PFS was 9.0 months in the lapatinib arm versus 11.3 months in the trastuzumab arm (HR = 1.37; 95% CI, 1.13-1.65;P= .001). These data, along with results from phase III CLEOPATRA and MARIANNE trials, add further clarity to the frontline treatment of HER2-positive disease.

The phase III CLEOPATRA study showed a dramatic overall survival (OS) benefit of nearly 16 months for pertuzumab (Perjeta) when combined with trastuzumab 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 ESMO Congress in Madrid, Spain, are practice-changing, according to Giuseppe Curigliano, MD, PhD.

“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 III MARIANNE trial of untreated patients with HER2-positive disease showed no PFS benefit with a regimen anchored by T-DM1 (ado-trastuzumab emtansine; Kadcyla) compared with standard therapy (trastuzumab plus chemotherapy).

MA.31 was the first head-to-head analysis of lapatinib and trastuzumab in this setting. In the trial, 537 patients with confirmed HER2-positive disease were randomized 1:1 to receive lapatinib in combination with a taxane followed by lapatinib or trastuzumab in combination with a taxane followed by trastuzumab. Taxane therapy was defined as paclitaxel once per week or 75 mg/m²of docetaxel (lower than the approved single-agent dose) once every 3 weeks. In total, 82% of patients did not receive adjuvant anti-HER2 therapy.

After a median follow-up of 21.5 months, more patients receiving lapatinib discontinued treatment (70.4%) than those who received trastuzumab (63.4%).

In addition to inferior PFS with lapatinib in both the interim analysis (HR = 1.33; 95% CI, 1.06-1.67;P= .01) and final analysis (HR = 1.37; 95% CI, 1.13-1.65;P= .001), the agent was also associated with worse OS compared with trastuzumab (stratified HR =1.47; 95% CI, 1.03-2.09;P= .03).

Toxicity was also worse in the lapatinib arm in MA.31—treatment discontinuations were more common with the agent (15%) versus trastuzumab (8%).

Authors on the study noted that the incidence of CNS metastases was 6% to 8% lower among patients treated with lapatinib. This difference was not significant, however, because of the “low rate of CNS scans at [disease progression] despite being mandated by the protocol, low frequency of CNS events, size of the study, or [disease progression] in other sites.”

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

A remarkable aspect of the CLEOPATRA data was the lack of increased toxicity, according to Mark D. Pegram, MD, who participated in a panel discussion on practical considerations in breast cancer.

“A little bit more myelosuppression, a little bit more GI toxicity, and a little skin dryness but that was it,” said Pegram, who is a professor of Medicine at Stanford University Medical Center.

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.

Gelmon KA, Boyle FM, Kaufman B, et al. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2—positive advanced breast cancer: Final results of NCIC CTG MA.31 [published online March 16, 2015].J Clin Oncol.doi: 10.1200/JCO.2014.56.9590.