CLEOPATRA

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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 trastuzumab and docetaxel improve overall and progression-free survival?

Bottom Line

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

Major Points

Among patients with breast cancer, HER2 gene amplification and protein overexpression yields an aggressive clinical phenotype. HERA demonstrated a survival benefit of 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.

Among patients with ER/PR positive disease, no trial has been performed demonstrating an overall survival benefit from adding trastuzumab (or pertuzumab) to aromatase inhibition. Though there is limited evidence for a benefit in progression-free survival from adding trastuzumab to AI, the CLEOPATRA trial did not address this comparison.

Guidelines

NCCN Breast Cancer Guidelines (2016, adapted)

  • Pertuzumab, trastuzumab, and a taxane is the preferred first-line therapy for stage IV or recurrent breast cancer that is HER2-positive and either ER/PR-negative or hormone-refractory
  • For patients with ER/PR-positive HER2-positive stage IV or recurrent breast cancer, with visceral crisis, consider first-line therapy with pertuzumab, trastuzumab, and a taxane
  • A pertuzumab-containing regimen may be administered preoperatively for HER2-positive breast cancer clinically staged as ≥T2 or ≥N1

Design

  • Multicenter, double-blind, randomized, controlled trial
  • N=808
    • Intervention (n=402)
    • Control (n=406)
  • Setting: Multiple centers in the US, France, Spain, Russia, South Korea, and others
  • Enrollment: Feb 2008 - July 2010
  • Mean follow-up: 49.5 months (intervention), 50.6 months (control)
  • Analysis: Intention-to-treat
  • Primary outcome: Progression-free survival
  • Secondary outcome: Overall survival

Population

Inclusion Criteria

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

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%

Interventions

  • Randomized to pertuzumab, trastuzumab, and docetaxel vs. placebo, trastuzumab, and docetaxel 

    • Stratified according to continent and prior treatment status (yes/no)
    • Progression-free survival (PFS) was defined by RECIST v1.0 criteria at an independent review facility

Outcomes

Comparisons are with pertuzumab vs. with 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)
Survival
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

Criticisms

  • Adverse event reporting for pertuzumab only include 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 (adjuvant/neoadjuvant) trended toward similar survival benefit, this subgroup analysis is severely limited by small sample size.

Funding

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

Further Reading