Record-Breaking Survival in HER2 Metastatic Breast Cancer

Sandra Swain, MD

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Final results of the CLEOPATRA trial show that dual HER2 blockade with the combination of pertuzumab and trastuzumab plus chemotherapy extended overall survival (OS) by almost 16 months compared with trastuzu­mab plus chemotherapy in patients with HER2-positive metastatic breast cancer. This should become the new standard of care for metastatic HER2-positive disease, according to investigators.

“The final results of CLEOPATRA show that the addition of pertuzumab to standard therapy [trastuz­­u­mab plus docetaxel] significantly improved overall survival by 15.7 months. I am so pleased to present these results. The 56.5-month median overall survival is unprecedented for this indication. This study confirms the pertuzumab/trastuzumab regimen as standard of care for first-line therapy in patients with HER2-positive metastatic breast cancer,” stated lead investigator Sandra Swain, MD, MedStar Washington Hospital Center, Washington, DC.

These findings confirm interim results reported 2 years ago, she said. “Two monoclonal antibodies that bind at different sites of the HER2 receptor, used together, not sequentially, extended survival,” she told listeners at the 2014 ESMO Congress.

CLEOPATRA enrolled 808 patients with centrally confirmed HER2-positive metastatic breast cancer from 204 centers in 25 countries. Patients were randomized to treatment with placebo + trastuzumab + docetaxel versus pertuzumab + trastuzumab + docetaxel. Docetaxel was given for at least 6 cycles (median number, 8) and both monoclonal antibodies were given until disease progression.

The final OS analysis was presented after a median follow-up of 50 months. “This is 20 months longer than the last interim analysis,” Swain noted.
Median OS was 56.5 months for the dual combination arm versus 40.8 months for those treated with trastuzumab + docetaxel, representing a highly statistically significant 32% increase in the risk of survival (P=.0002).

“This change of 15.7 months [favoring dual HER2 blockade] has changed things for HER2-positive patients. I have never seen a survival benefit of this magnitude in metastatic HER2-positive breast cancer,” she said.

The OS improvement was in the context of a 6.3-month improvement in progression-free survival (PFS) reported in the updated final analysis. “PFS was significantly improved in the interim analyses [6.1-month improvement] and in the final analysis. This shows that in this blinded study, PFS was a good surrogate for OS,” Swain continued.

There was concern that the combination of 2 monoclonal antibodies would lead to additional toxicities. In this study, rash, mucositis, and diarrhea were increased in the pertuzumab-containing arm compared with trastuzumab + docetaxel.

There was no increase in cardiac toxicities with dual HER2 blockade. Asymptomatic declines in left ventricular ejection fraction were actually less with the combination (6.1% vs 7.4%), and symptomatic left ventricular dysfunction was reported in 1.5% and 1.8%, respectively. These decreases in heart function were reversible in 88% of patients in the combination arm, she said.

“The median overall survival data presented by Dr Swain here at ESMO 2014 with pertuzumab and trastuzumab–based therapy in patients with HER2-positive metastatic breast cancer is remarkable. This is one of the biggest steps toward making this disease a chronic condition in the near future,” said Javier Cortés, MD, director of the Breast Cancer Program at Vall d’Hebron Institute of Oncology in Barcelona, Spain. Cortés was a coauthor of the CLEOPATRA report.

“We should consider this as standard of care for our patients. I can see no reason to justify the use of trastuzumab without pertuzumab,” he added.

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