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Baselga J, et al. "Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer". The New England Journal of Medicine. 2012. 366(2):109-119.
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Clinical Question

In patients with HER2-positive metastatic breast cancer, does the addition of pertuzumab to front-line therapy with trastuzumab and docetaxel improve progression-free survival?

Bottom Line

Pertuzumab significantly improves progression-free survival among patients with HER2-positive metastatic breast cancer, when added to trastuzumab and docetaxel.

Major Points

HER2 gene amplification and protein overexpression yields an aggressive clinical phenotype in breast cancer. The HERA trial demonstrated a survival benefit of adjuvant anti-HER2 therapy with the monoclonal antibody trastuzumab, resulting the drug's FDA approval in 1998. Efforts to target the HER2 protein continue. Pertuzumab is a monoclonal antibody against HER2 with a different binding site than trastuzumab. While trastuzumab blocks HER2 homodimerization, pertuzumab prevents heterodimerization between HER2 and other effector molecules. The 2012 CLEOPATRA study sought to determine whether theoretical synergy may result in clinical benefit when the two drugs were administered in combination to patients with HER2-positive breast cancer.

In CLEOPATRA, 808 patients with HER2-positive metastatic breast cancer were randomized to trastuzumab plus docetaxel, or pertuzumab plus trastuzumab plus docetaxel. Docetaxel was given for 6 cycles, while trastuzumab and either pertuzumab or placebo were continued until disease progression or intolerance. Progression-free survival (PFS), the study's primary endpoint, was prolonged in the pertuzumab group compared to the control group (18.5 versus 12.4 months; HR 0.62). Objective responses were more common in the pertuzumab group compared to control (80.2% versus 69.3%), and the majority of responders had partial responses. An interim analysis of overall survival showed numerically higher survival in the pertuzumab group which did not reach statistical significance. Toxicity was greater in the pertuzumab group, including adverse events of interest such as left ventricular systolic dysfunction (8.3% versus 4.4%). The authors conclude that use of multiple anti-HER2 agents with complementary mechanisms of action may facilitate optimum HER2 inhibition among patients with HER2-positive cancer, and that pertuzumab plus trastuzumab should be studied in patients with earlier stages of disease.

Long-term follow-up of CLEOPATRA has since been published.[1] In this final analysis, median follow-up was nearly 100 months. Median PFS confirmed the conclusions of the initial analysis. Median overall survival was prolonged in the pertuzumab group compared to control (57.1 versus 40.8 months; HR 0.69), and landmark analyses of overall survival all favored pertuzumab. At the 8-year landmark survival analysis, survival was 37% in the pertuzumab group and 23% in control. Long-term toxicity including cardiac toxicity was no different between groups; in particular, grade ≥3 LV dysfunction occurred in 8-9% of patients, and LV ejection fraction decline by ≥10% points from baseline occurred in 7% of patients within each group.

Similar findings supporting the use of dual HER2-targeting agents have been seen in the TRYPHAENA study in the neoadjuvant setting.[2][3] However, in the adjuvant setting, ALTTO showed no improvement in disease-free survival with dual HER2 inhibition (trastuzumab plus lapatinib) compared to trastuzumab monotherapy.[4]

The optimal cytotoxic agent to pair with HER2-directed therapy has not been defined. In the PERUSE study (2019), patients with locally recurrent or metastatic HER2-positive breast cancer received trastuzumab plus pertuzumab with either docetaxel, paclitaxel, or nab-paclitaxel, with similar PFS between taxanes.[5]


NCCN Breast Cancer Guidelines (version 2.2023, adapted) First-line systemic therapy for recurrent unresectable or stage IV (M1) disease:

  • Pertuzumab, trastuzumab, and docetaxel (Category 1, preferred)
  • Pertuzumab, trastuzumab, and paclitaxel (preferred)


  • Multicenter, double-blind, randomized, controlled trial
  • N=808 patients with HER2-positive metastatic breast cancer
    • Pertuzumab plus trastuzumab/docetaxel (n=402)
    • Placebo plus trastuzumab/docetaxel (n=406)
  • Setting: Multiple centers in the US, France, Spain, Russia, South Korea, and elsewhere
  • Enrollment: 2008-2010
  • Mean follow-up: 49.5 months (intervention), 50.6 months (control)
  • Analysis: Intention-to-treat
  • Primary outcome: Progression-free survival


Inclusion Criteria

  • Age ≥18 years
  • Metastatic, unresectable, or locally recurrent HER2-positive breast cancer
  • Measurable or nonmeasurable disease
  • ECOG 0-1
  • LVEF ≥50%

Exclusion Criteria

  • CNS metastases
  • Cumulative exposure to 360 mg/mm² doxorubicin per BSA
  • ≥2 hormonal treatments for metastatic disease
  • Received non-hormonal chemotherapy (other than adjuvant or neoadjuvant chemotherapy)

Baseline Characteristics

No significant differences between groups.

  • Age: 54, ECOG 0 (65%), with visceral disease (78%)
  • HER2 status 3+ (89%), FISH+ (95%)
  • ER or PR+ (48%)
  • Asia 31%, Europe 38%, North America 16.7%, South America 14%
  • Type of neo/adjuvant therapy: Anthracycline 39%, Hormone 25%, Taxane 23%, Trastuzumab 11%


  • Randomized to pertuzumab or placebo, in combination with trastuzumab and docetaxel
    • Randomization was stratified according to continent and prior treatment status (yes/no)
  • Docetaxel was given for 6 cycles
  • Trastuzumab and pertuzumab (or placebo) were given until progression or intolerance
    • Progression was defined by RECIST v1.0 criteria at an independent review facility


Comparisons are pertuzumab vs. placebo.

Primary Outcomes

Progression-free survival
18.7 vs. 12.4 months (HR 0.68; 95% CI 0.58-0.80; P<0.001)

Secondary Outcomes

Overall survival
41.8% vs. 54.4% (HR 0.68; 95% CI 0.56-0.84; P<0.001)
Median Survival: 56.5 months vs. 40.8 months (P<0.05)
1-year survival: 94.4% vs. 89.0%
2-year survival: 80.5% vs. 69.7% (P<0.05)
3-year survival: 68.2% vs. 54.3% (P<0.05)
4-year survival: 57.6% vs. 45.4% (P<0.05)

Subgroup Analysis

No significant interaction was identified for age, ER or PR status, region, race, previous treatment, or disease type.

Adverse Events

  • Grade 1-2 (97%), Grade 3 (2%), Grade 4 (1%), Grade 5 (none)
  • Diarrhea (28.1% vs. 14.2%), Rash (18.3% vs. 8.0%), URI (18.3% vs. 12.3%), Pruritus (13.7% vs. 5.7%), Muscle spasm (7.8% vs 2.3%)
  • No relative increase in cardiac dysfunction in the pertuzumab arm


  • Adverse event reporting for pertuzumab only included events after completion of docetaxel, excluding the majority of events.
  • Does not address an important comparison of pertuzumab to hormone treatment among ER/PR+ patients, limiting generalizability
  • Though patients who had received trastuzumab in the adjuvant/neoadjuvant setting trended toward similar survival benefit, this subgroup analysis is severely limited by small sample size.


Funded by the makers of pertuzumab, F. Hoffmann–La Roche and Genentech

Further Reading