Treatment of metastatic Her-2 positive breast cancer

CLEOPATRA had a happy ending at 2019 ASCO Annual Meeting

Fleck, JF: Anticancerweb 12(07), 2019

At the turn of the 21st century, Dr. Dennis Slamon, chief of the Hematology-Oncology Division at UCLA, pioneered customized cancer treatment by identifying an increased expression of the human epidermal growth factor receptor 2 (Her-2) in 20% of breast cancer patients. Her-2 is a transmembrane receptor associated to tyrosine kinase, whose phenotypic expression would translate into a worsening in prognosis. Hopefully, the expression of Her-2 in breast cancer cells also became a predictive factor. Two monoclonal antibodies (MoAb), showing complementary mechanisms of action were developed, disrupting Her2-mediated signaling transduction pathway. First, trastuzumab was developed, binding to the subdomain IV into the extracellular domain of the Her-2 receptor, promoting cytotoxicity and additional independent blockade of cell proliferation. Subsequently, pertuzumab was identified, binding to a distinct epitope (subdomain II) of the extracellular domain of Her-2 receptor. This action prevented receptor dimerization, leading to impaired tumor cell function. As an alternative hypothesis, the combined use of both MoAb could promote a more comprehensive blockade in the Her-2-dependent signaling transduction pathway, increasing their antitumor effects. Supported by phase II studies, the association of trastuzumab pertuzumab has been shown to be beneficial in the systemic treatment of Her-2 positive breast cancer, both in metastatic and adjuvant settings.

An elegant prospective randomized phase III trial called Clinical Evaluation of Pertuzumab and Trastuzumab  (CLEOPATRA) was designed to evaluate the combined use of the two MoAb as first line treatment for metastatic Her-2 positive breast cancer. A total of 808 patients were accrued and randomly distributed in the proportion 1:1 to a test arm (pertuzumab trastuzumab + docetaxel) or to a control arm (placebo + trastuzumab + docetaxel). Patients previously treated with trastuzumab in an adjuvant or neoadjuvant setting were admitted as long as they had completed the treatment at least 12 months prior randomization. The two arms were well matched in a group of women showing a median age of 54 years-old, predominantly presented as visceral disease (78%), which confirmed FISH-positive expression of Her-2 in 95% of the cases. Approximately half of the patients were hormone receptor positive and only 10% had previously received adjunctive trastuzumab. The primary endpoint was progression-free survival (PFS), which results were published in the New England Journal of Medicine in January 2012. The median PFS was 18.5 months for the test group and 12.4 months for the control group (HR = 0.62 P < 0.001). A second interim analysis, published in Lancet Oncology in 2013, confirmed an overall survival (OS) benefit favorable to double-blocking. Additionally, safety analysis did not show any increase in the cardiotoxicity profile associated with the addition of pertuzumab. In February 2015, the New England Journal of Medicine published updated results after a median follow-up of 50 months. In the ITT population, the median OS was 56.5 months in the test group and 40.8 months in the control group (HR = 0.68 P <0.001). Prior to progression, 50 patients on the control arm were allowed to cross over, also receiving pertuzumab. The sensitivity analysis that excluded cross over patients from the control group increased the difference between subgroups, showing a median OS of 56.5 months in the double-blockade group and 39.6 months in the control group (HR = 0.55 P <0.001). Although the subgroups were predefined, the exploratory analysis was reduced in its statistical power. In May 2019, the end-results of the CLEOPATRA study after a median follow-up of 99 months were presented at the ASCO Annual Meeting in Chicago, maintaining the benefit in both DFS and OS. The median OS difference, favoring the double blockade reached the unprecedented 16.3 months. There were two cardiac adverse events, both with satisfactory resolution within a period of 34 days, maintaining the safety profile.

ITT = Intention-to-treat



Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer, N Engl J Med 366:109-19, 2012 

Swain SM, Kim SB, 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 14:461-71, 2013 

Sandra M. Swain, M.D., José Baselga, M.D., Sung-Bae Kim, et al: Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer, N Engl J Med 372: 724 - 734, 2015 

Sandra M. Swain, David Miles, Sung-Bae Kim, et al: End-of-study analysis from the phase III, randomized, double-blind, placebo-controlled CLEOPATRA study of first-line pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer, J Clin Oncol 37, 2019 (abstract number 1020)