ESMO 2014: CLEOPATRA Study Shows ‘Unprecedented’ Survival With Dual HER2 Blockade in Metastatic Breast Cancer


Key Points

  • In the final overall survival analysis of the international phase III CLEOPATRA trial, median overall survival was improved by almost 16 months with the addition of pertuzumab to trastzumab plus docetaxel in HER2-positive breast cancer.
  • Median overall survival was 56.5 months with the combination vs 40.8 months with placebo.
  • The combination did not increase the risk for cardiac events.

In the final overall survival analysis of the phase III CLEOPATRA trial, patients with HER2-positive metastatic breast cancer patients lived 15.7 months longer if they received pertuzumab (Perjeta) in addition to trastuzumab (Herceptin) and docetaxel, investigators reported at the ESMO 2014 Congress in Madrid, Spain (Abstract 350O_PR).

“The 56.5 months of median overall survival is unprecedented in this indication, and confirms the pertuzumab regimen as the first-line standard of care in HER2-positive metastatic disease,” said Sandra Swain, MD, of Medstar Washington Hospital Center in Washington, DC, who reported the findings at a press briefing and at the ESMO Presidential Symposium.


CLEOPATRA, which enrolled 808 patients from 204 centers in 25 countries, evaluated the benefit of dual HER2 blockade in previously untreated metastatic breast cancer. Pertuzumab and trastuzumab bind to different sites on the HER2 receptor.

Patients were randomly assigned to trastuzumab and docetaxel plus either pertuzumab or placebo. They received pertuzumab or placebo at an 840-mg intravenous loading dose followed by 420 mg for subsequent infusions every 3 weeks plus trastuzumab at a loading dose of 8 mg/kg followed by 6 mg/kg for subsequent infusions and docetaxel 75 mg/m2 intravenously every 3 weeks for at least six cycles (median of eight). Treatment with the anti-HER2 agents continued until progression or unmanageable toxicity. 

A previous analysis performed in May 2012 showed that the addition of pertuzumab increased progression-free survival significantly, to 18.5 months from 12.4 months with placebo. While a strong trend toward an overall survival benefit was observed, median overall survival had not been reached in the experimental arm.

The final survival analysis reported at ESMO, performed after 385 deaths and at a median follow-up of 50 months, showed median overall survival to be 56.5 months in the pertuzumab arm vs 40.8 months in the placebo arm (hazard ratio [HR] = .68; P = .0002). Dr. Swain, who is a Past President of ASCO, deemed this outcome “phenomenal” and said it had never been observed with other metastatic breast cancer regimens.

A 6.3-month increase in progression-free survival was also sustained (HR = 0.68, P < .0001). In June 8, 2012, the U.S. Food and Drug Administration approved pertuzumab for use in combination with trastuzumab and docetaxel in this setting, based on the initial progression-free survival results. Dr. Swain commented at an ESMO press briefing that the similarity between the hazard ratios for progression-free and overall survival suggest that, at least for this placebo-controlled trial, “progression-free survival is a good surrogate for overall survival.”

Safety, including a lack of cardiac toxicity, was also confirmed in the updated analysis. Symptomatic left-ventricular dysfunction as well as declines in left-ventricular ejection fraction were rare and were similar between the arms.

Dual HER2 Blockade for All Patients

Luca Gianni, MD, the formal discussant of the study at the Presidential Symposium, said that CLEOPATRA sets a new paradigm for the treatment of HER2-positive metastatic breast cancer “because of the almost 5 years of median overall survival and because patients gain a dramatic improvement of more than 1 year over the best possible treatment so far.” Dr. Gianni is Director of Medical Oncology at the Istituto Nazionale dei Tumori, in Milano, Italy. 

Dr. Swain maintained that, based on a consistent benefit across subgroups, almost all women with HER2-positive metastatic breast cancer should be considered candidates for the pertuzumab/trastuzumab/docetaxel regimen.

Co-investigator Javier Cortés, MD, of Vall d’Hebron Institute of Oncology in Barcelona, Spain, agreed. “I can see no reason to justify the use of trastuzumab without pertuzumab,” he said.

For full disclosures of the study authors, view the study abstract at

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.