CLEOPATRA Reveals New Treatment Option for HER2+ Breast Cancer Patients

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Addition of pertuzumab to traztuzumab + docetaxel added almost 16 months to overall survival.
Addition of pertuzumab to traztuzumab + docetaxel added almost 16 months to overall survival.

In a long-term follow-up of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) enrolled in the CLEOPATRA study, the addition of pertuzumab to traztuzumab plus docetaxel added almost 16 months to overall survival (OS) compared with women who did not receive pertuzumab.

With a median 50 months of patient follow-up, the median OS with pertuzumab is 56.5 months versus 40.8 months without (hazard ratio [HR]=0.68; P=0.0002).1

These results represent an additional 20 months of follow-up after a previous publication2 according to lead author Sandra M. Swain, MD, of the MedStar Washington Hospital Center in Washington, DC, and “the survival improvement is unprecedented among studies of metastatic breast cancer.”

The current analysis looks at all randomly assigned patients without adjustment for crossover once the study was unblinded: in other words, those originally assigned to receive traztuzumab and docetaxel plus placebo were counted as placebo patients, even if they later crossed over to treatment with pertuzumab. Thus, “this is a very conservative final analysis of survival,” said Dr. Swain, as crossover patients likely obtained some benefit from receiving pertuzumab later in treatment.

The CLEOPATRA study group had previously reported that the pertuzumab regimen was associated with significant extensions of progression-free survival (PFS) and OS in earlier follow-up (Table). In those reports, PFS was approximately 30% longer with pertuzumab than with placebo.2,3

Importantly, the survival benefit was seen across all patient subgroups, and the extension of PFS seen in earlier studies was maintained in long-term follow-up.1

Table. Overall Survival: Results Over Time in CLEOPATRA
Median Follow-Up Hazard Ratio (HR): Pertuzumab vs. Placebo
19 months3 0.64 (0.47–0.88) NS*
30 months3 0.66 (0.52–0.84) P=0.0008
50 months3 0.68 (0.56–0.84) P=0.0002
Results expressed as HR (95% CI).

*Interim analysis did not cross O'Brien-Fleming stopping boundary threshold and is not significant and considered exploratory.

The overall and cardiac safety profiles seen in earlier studies of pertuzumab were unchanged in long-term follow-up in CLEOPATRA.1 Higher incidences of diarrhea, rash, febrile neutropenia, mucosal inflammation, pruritis, and dry skin were seen with pertuzumab therapy. There were no adverse cardiac effects associated with pertuzumab.2,3

CLEOPATRA, a multinational, double-blind, and placebo-controlled phase 3 trial, enrolled women with HER2-positive MBC who did not receive previous biologic therapy or chemotherapy for metastatic disease. The primary endpoint of the study was PFS after random assignment to pertuzumab or placebo added to traztuzumab plus docetaxel. The intent-to-treat population included 806 women with a median age at study entry of 54 years.3

“We should consider this combination as the standard of care for our patients,” said Javier Cortés, MD, PhD, another study author and Director of the Breast Cancer Program at Vall D'Hebron Institute of Oncology in Barcelona, Spain. 

With these results, “I can see no reason to justify use of trastuzumab without pertuzumab,” he added. Although further research into resistance mechanisms and to identify patients who could forego chemotherapy remains to be done, Dr. Swain sees this combination as a significant step forward in therapy. “This is the kind of survival improvement for which we have worked,” she said. “[These results] will be incredibly meaningful to patients and their families.”


  1. Swain S, Kim S, Cortes J, et al. Final overall survival (OS) analysis from the CLEOPATRA study of first-line (1L) pertuzumab (Ptz), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC). European Society for Medical Oncology (ESMO) 2014 Congress. Abstract 350O.
  2. Swain SM, Kim S-B, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14(6):461-471.
  3. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119.

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