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Pertuzumab adds 16 months survival benefit to trastuzumab and chemotherapy treatment for HER2-positive metastatic breast cancer

Long-term follow-up from CLEOPATRA study presented at ESMO 2014 demonstrates ‘unprecedented’ benefit

Lugano/Madrid, 28 September 2014 -- Patients with HER2-positive breast cancer that has spread to other parts of their body live around 16 months longer if treated with a combination of pertuzumab, trastuzumab and chemotherapy compared to those treated with trastuzumab and chemotherapy alone, updated results from the CLEOPATRA study reveal.

CLEOPATRA was a pivotal phase III study where researchers evaluated the safety and efficacy of pertuzumab, trastuzumb and chemotherapy in 808 patients with previously untreated HER2-positive metastatic breast cancer. HER2-positive metastatic breast cancer has historically been one of the most aggressive forms of the disease.

“In CLEOPATRA we evaluated whether dual HER2 blockade by combining the antibody pertuzumab with trastuzumab and chemotherapy would help people live longer (overall survival, OS) or live longer without their disease worsening (progression-free survival, PFS),” explains lead author Dr Sandra Swain from Medstar Washington Hospital Center, Washington, USA.

New results presented at ESMO 2014 in Madrid showed that people treated with the combination lived 15.7 months longer than those who received trastuzumab and chemotherapy alone, with a median overall survival of 56.5 vs. 40.8 months.

“The survival improvement of nearly 16 months observed in CLEOPATRA is unprecedented among studies of metastatic breast cancer,” said Swain.

The study authors had previously reported that the pertuzumab regimen significantly extended progression-free survival and overall survival. The new data reports the results of the final analysis of survival in CLEOPATRA after a median of 50 months follow-up of patients.

In the current analysis, overall survival was analysed using all randomised patients, with no adjustments for cross-over once the study treatments were unblinded. Patients who crossed over from the placebo arm to the pertuzumab arm were analysed as part of the placebo arm, Swain explains. “As such, this is a very conservative final analysis of survival.”

The overall survival benefit observed with the pertuzumab regimen in CLEOPATRA was consistent across patient subgroups, the researchers say, and the previously observed benefit in progression-free survival was maintained after long-term follow-up. The long-term safety profile of the pertuzumab regimen also was unchanged from previous analyses and the long-term cardiac safety profile was maintained.

“This is the kind of survival improvement for which we have worked, and this data will be incredibly meaningful to patients and their families,” Swain said.

Javier Cortes, Director of the Breast Cancer Program at Vall D’Hebron Institute of Oncology in Barcelona, Spain, another author on the study, said: “The median overall survival data presented by Sandra Swain at ESMO 2014 with pertuzumab and trastuzumab-based therapy in patients with HER2-positive metastatic breast cancer is remarkable. This is one of the biggest steps toward making this disease a chronic condition in the near future.”

“What is more surprising is that the improvement in median overall survival exceeds the improvement in progression-free survival; maybe because of the different mechanisms of action that monoclonal antibodies have,” Cortes said.

“We should consider this combination as the standard of care for our patients,” Cortes added. “I can see no reason to justify the use of trastuzumab without pertuzumab. The impressive overall survival data we have observed at ESMO 2014 will help us, as physicians, to continue working; it will help patients, to fight against their disease; and it will help society to understand that people will not die of cancer in the future.”

Looking to the future, researchers need to study the mechanisms of resistance to this combination, to improve its therapeutic activity and to try to identify which patients will not need chemotherapy, Cortes concluded.

-END-

Notes to Editors

350O_PR: 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)

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Information contained in this press release was provided by the abstracts authors and reflects the content of the studies. It does not necessarily express ESMO's point of view.

Session info

350O_PR                              Sunday, September 28, 2014 – 16:00 PM – 17:30 PM  - Hall Madrid

Abstract: 350O_PR

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)

S. Swain¹, S. Kim², J. Cortes³, J. Ro⁴, V. Semiglazov⁵, M. Campone⁶, E. Ciruelos⁷, J. Ferrero⁸, A. Schneeweiss⁹, S. Heeson¹⁰, E. Clark¹⁰, G. Ross¹⁰, M.C. Benyunes¹¹, J. Baselga^12
1Medstar Washington Hospital Center, Washington Cancer Institute, Washington, DC, USA,²Department of Oncology, Asan Medical Center, Seoul, KOREA, ³Breast Cancer Program, Vall d'Hebron University Hospital, Barcelona, SPAIN, ⁴Center for Breast Cancer, National Cancer Center, Goyang, KOREA, ⁵Breast Cancer Department, N.N. Petrov Research Institute of Oncology, St. Petersburg, RUSSIAN FEDERATION, ⁶Medical Oncology, Centre René Gauducheau, St Herblain, FRANCE,⁷Medical Oncology Department, 12 de Octubre University Hospital, Madrid, SPAIN, ⁸Department of Medical Oncology, Centre Antoine Lacassagne, Nice, FRANCE,⁹University Hospital, National Center for Tumor Diseases, Heidelberg, GERMANY, ¹⁰Oncology, Roche Products Limited, Welwyn, UK, ¹¹Oncology, Genentech, South San Francisco, CA, USA, ¹²Hematology Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Aim: In CLEOPATRA, 808 pts with HER2-positive MBC were randomized to receive 1L placebo (Pla)+T+D or Ptz+T+D. At primary analysis, pertuzumab was shown to increase progression-free survival significantly, with a strong trend to OS benefit. At a second interim analysis (May 2012), OS was improved to a degree which was both statistically significant and clinically meaningful (HR = 0.66, 95% CI 0.52–0.84; P = 0.0008) but the median OS in pts who received Ptz was not reached. Here we report results of a subsequent prespecified OS analysis.

Methods: This OS analysis was planned when ≥385 deaths were reported. The log-rank test, stratified by prior treatment status and geographic region, was used to compare OS between arms, applying the Lan-DeMets α-spending function with an O’Brien-Fleming threshold of p ≤ 0.0456. The Kaplan–Meier approach was used to estimate median OS in both arms; a stratified Cox proportional hazard model was used to estimate HR and 95% CIs. Subgroup analyses of OS were performed for stratification factors and other key baseline characteristics.

Results: Median follow-up time was 50 months (mos) and the statistically significant improvement in OS in favor of Ptz+T+D was maintained (HR = 0.68, 95% CI 0.56–0.84; p = 0.0002). Median OS was 40.8 mos in the Pla arm and 56.5 mos in the Ptz arm, the difference at the medians being 15.7 mos. The OS benefit in predefined subgroups was consistent with previous observations. It is to be noted that following the previous report of OS benefit, cross-over therapy was allowed and 48 pts in the Pla arm crossed over to the Ptz arm. The safety profile of Ptz+T+D in the overall population and in pts who crossed over to the Ptz arm was consistent with the known safety profile of Ptz and the long-term cardiac safety profile was maintained.

Conclusions: 1L treatment with Ptz+T+D significantly improved OS for pts with HER2-positive MBC compared with Pla+T+D, providing a 15.7 mo increase in the median values. The 56.5 mo median OS is unprecedented in 1L MBC and this substantial improvement confirms the Ptz regimen as 1L standard of care for pts with HER2-positive MBC.

Disclosure: S. Swain: acts as an uncompensated consultant for Genentech/Roche. Her institution has received research funding from Genentech/Roche, Pfizer, Puma, Sanofi-Aventis and Bristol-Myers Squibb; S. Kim: has received research funding from Novartis; J. Cortes: has provided consultancy for Novartis, Celgene and Roche and has received honoraria from Novartis, Celgene, Eisai and Roche; M. Campone: has provided consultancy for Novartis/Servier and has received honoraria from Novartis;  J. Ferrero: has provided consultancy for Sanofi and has received honoraria from Novartis and Roche; A. Schneeweiss: has provided consultancy for Medac, Celgene and Roche, has received honoraria from Novartis, Celgene, Eisai, Astrazeneca, GlaxoSmithKline, Pfizer and Roche and has received research funding from Roche and Celgene;  S. Heeson and G. Ross: is an employee of and owns shares in Roche; E. Clark: is an employee of Roche and owns shares in AstraZeneca;
M.C. Benyunes: is an employee of Genentech/Roche; J. Baselga: has provided consultancy for Roche. All other authors have declared no conflicts of interest.

Keywords: pertuzumab, trastuzumab, HER2, metastatic breast cancer