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Clinical Trial
. 2013 May;14(6):461-71.
doi: 10.1016/S1470-2045(13)70130-X. Epub 2013 Apr 18.

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

Sandra M Swain  1 , Sung-Bae Kim, Javier Cortés, Jungsil Ro, Vladimir Semiglazov, Mario Campone, Eva Ciruelos, Jean-Marc Ferrero, Andreas Schneeweiss, Adam Knott, Emma Clark, Graham Ross, Mark C Benyunes, José Baselga
Affiliations
Clinical Trial

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

Sandra M Swain et al. Lancet Oncol. 2013 May.

Abstract

Background: CLEOPATRA is a phase 3 study to compare the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive first-line metastatic breast cancer. The results of the primary analysis showed significantly longer median progression-free survival in the pertuzumab group than in the placebo group. Interim analysis of overall survival favoured the pertuzumab group but was not significant. Here, we report results for overall survival after an additional year of follow-up.

Methods: The study was a double-blind randomised trial undertaken at 204 centres in 25 countries. Patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy or biological treatment for their metastatic disease were randomly assigned to receive either pertuzumab, trastuzumab, and docetaxel (n=402) or the same regimen with a matching placebo replacing pertuzumab (n=406). Randomisation was in a 1:1 ratio, stratified by geographical region and previous treatment status. The primary endpoint was progression-free survival (assessed independently), which has been reported previously; no follow-up data were gathered for the primary endpoint. Secondary endpoints included overall survival, progression-free survival (assessed by investigator), objective response rate, and safety. Median follow-up was 30 months in both groups. Efficacy endpoints were analysed in the intention-to-treat population and safety was analysed by treatment received. The study is completed but safety and survival data continue to be followed up. This trial is registered with ClinicalTrials.gov, number NCT00567190.

Findings: In the intention-to-treat population, 267 patients died by data cutoff (May 14, 2012), 154 (38%) of 406 in the placebo group and 113 (28%) of 402 in the pertuzumab group. Median overall survival was 37.6 months (95% CI 34.3-NE [not estimable]) in the placebo group but had not been reached (95% CI 42.4-NE) in the pertuzumab group (hazard ratio 0.66, 95% CI 0.52-0.84; p=0.0008). Investigator-assessed median progression-free survival was 12.4 months (95% CI 10.4-13.5) in the placebo group and 18.7 months (16.6-21.6) in the pertuzumab group (hazard ratio 0.69, 95% CI 0.58-0.81). Serious adverse events were reported in 115 (29%) of 396 patients who received placebo, trastuzumab, and docetaxel and 148 (36%) of 408 who received pertuzumab, trastuzumab, and docetaxel, and included febrile neutropenia, neutropenia, diarrhoea, pneumonia, and cellulitis. Overall, adverse events were similar to those reported at the primary analysis with respect to frequency, severity, and specificity.

Interpretation: Our analysis shows a significant improvement in overall survival with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer, compared with placebo, trastuzumab, and docetaxel. Since this effect was not achieved at the expense of adverse events, this regimen represents a substantial improvement on the standard of care for this population of patients.

Funding: F Hoffmann-La Roche, Genentech.

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Conflict of interest statement

Conflicts of interest

SMS discloses an uncompensated consultant/advisory role for Roche/Genentech; her institution has received research funding from Roche/Genentech, Agendia, and Pfizer/PUMA. JC is a consultant for Roche, Celgene, and Novartis and has received honoraria from Roche, Celgene, Novartis, and Eisai. J-MF has received honoraria from Roche, Pfizer, and Sanofi-Aventis. AS is a consultant for Roche and Sanofi-Aventis and has received honoraria from both companies. AK, ECl, and GR are employees of Roche Products Limited. ECl discloses stock ownership from AstraZeneca. GR discloses stock ownership from Roche and GlaxoSmithKline; an immediate family member owns stocks from GlaxoSmithKline. MCB is an employee of Genentech. JB discloses a consultant/advisory role for Roche/Genentech and Sanofi-Aventis. S-BK, JR, VS, MC, and ECi have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1
CONSORT diagram
Figure 2
Figure 2. Confirmatory analysis of overall survival
Figure 2A shows Kaplan-Meier estimates of overall survival in patients in the intent-to-treat population, stratified by prior treatment status and region. The tick marks indicate censoring events. Figure 2B shows hazard ratios and 95% confidence intervals for overall survival in all pre-specified subgroups according to baseline characteristics. It should be noted that the number of patients with unknown hormone receptor status was very small (n=12) resulting in very wide 95% confidence intervals. CI, confidence interval; D, docetaxel; ER, oestrogen receptor; FISH, fluorescence in situ hybridisation; HER2, human epidermal growth factor receptor; HR, hazard ratio; IHC, immunohistochemistry; PgR, progesterone receptor; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Race was determined by the investigator. The category of “Other” includes American Indian and Alaska Native.
Figure 2
Figure 2. Confirmatory analysis of overall survival
Figure 2A shows Kaplan-Meier estimates of overall survival in patients in the intent-to-treat population, stratified by prior treatment status and region. The tick marks indicate censoring events. Figure 2B shows hazard ratios and 95% confidence intervals for overall survival in all pre-specified subgroups according to baseline characteristics. It should be noted that the number of patients with unknown hormone receptor status was very small (n=12) resulting in very wide 95% confidence intervals. CI, confidence interval; D, docetaxel; ER, oestrogen receptor; FISH, fluorescence in situ hybridisation; HER2, human epidermal growth factor receptor; HR, hazard ratio; IHC, immunohistochemistry; PgR, progesterone receptor; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Race was determined by the investigator. The category of “Other” includes American Indian and Alaska Native.
Figure 3
Figure 3. Investigator-assessed progression-free survival
Figure 3A shows Kaplan-Meier estimates of PFS in the intent-to-treat population, stratified by prior treatment status and region. The tick marks indicate censoring events. Figure 3B shows hazard ratios and 95% confidence intervals for PFS in all pre-specified subgroups according to baseline characteristics. The hazard ratio for the category of unknown hormone receptor status was not quantifiable due to the small number of patients in this group. CI, confidence interval; D, docetaxel; ER, oestrogen receptor; FISH, fluorescence in situ hybridisation; HER2, human epidermal growth factor receptor; HR, hazard ratio; IHC, immunohistochemistry; PgR, progesterone receptor; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Race was determined by the investigator. The category of “Other” includes American Indian and Alaska Native.
Figure 3
Figure 3. Investigator-assessed progression-free survival
Figure 3A shows Kaplan-Meier estimates of PFS in the intent-to-treat population, stratified by prior treatment status and region. The tick marks indicate censoring events. Figure 3B shows hazard ratios and 95% confidence intervals for PFS in all pre-specified subgroups according to baseline characteristics. The hazard ratio for the category of unknown hormone receptor status was not quantifiable due to the small number of patients in this group. CI, confidence interval; D, docetaxel; ER, oestrogen receptor; FISH, fluorescence in situ hybridisation; HER2, human epidermal growth factor receptor; HR, hazard ratio; IHC, immunohistochemistry; PgR, progesterone receptor; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Race was determined by the investigator. The category of “Other” includes American Indian and Alaska Native.
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Comment in

References

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Appendix

References used for systematic review
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    1. Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011;29:264–71. - PubMed
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