CLEOPATRA 8-Year Findings Support Pertuzumab Use For HER2-Positive Metastatic Breast Cancer

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Long-term results from the CLEOPATRA trial show that the addition of pertuzumab to trastuzumab and docetaxel provides a significant and durable overall survival (OS) benefit for women with HER2-positive metastatic breast cancer. 

“A trial in the metastatic setting with a median follow-up exceeding 8 years is an extraordinary and unprecedented achievement”, write the authors of a comment accompanying the research published in The Lancet Oncology. 

“Median overall survival for patients with HER2-positive metastatic breast cancer was less than 2 years before the introduction of anti-HER2 targeted therapies”, observe Matteo Lambertini, from the University of Genova in Italy, and Ines Vaz-Luis, from Institut Gustave Roussy in Villejuif, France. 

The phase III double-blind trial, conducted in 25 countries compared 3-week cycles of pertuzumab (840 mg loading dose, 420 mg ongoing) or placebo, given alongside trastuzumab (8 mg/kg loading dose, 6 mg/kg ongoing) plus docetaxel (initial dose 75 mg/m2, increasing to 100 mg/m2 where tolerated). 

After a median follow-up of 99.9 months, median OS was 57.1 months for the 402 treatment-naïve patients who were randomly assigned to receive pertuzumab, significantly longer than the median OS of 40.8 months for the 406 placebo-treated patients who were followed-up for a median of 98.7 months.  

This translated to a significant OS survival advantage for pertuzumab therapy, with a hazard ratio of 0.69 in favour of the combination anti-HER2 strategy. At 8 years, landmark analysis shows that 37% of the pertuzumab-treated arm and 23% of the placebo-treated arm were alive, and progression-free survival was achieved by 16% and 10% of the groups, respectively. 

And Sandra Swain, from the Georgetown University Medical Center in Washington DC, USA, and co-investigators note that the OS “analyses were not adjusted for crossover to the pertuzumab group” by 50 patients between July 2012 and clinical cutoff, and are therefore “likely to be conservative.” 

They describe 99 pertuzumab-treated patients who remained on treatment after 35 months as long-term responders; these patients were more likely than those with a shorter response to have non-visceral metastases, progesterone receptor-positive and HER2 immunochemistry 3+ disease, no PIK3CA mutations, and a longer time on average from initial diagnosis to metastases. 

“Patients with specific characteristics could benefit from the addition of pertuzumab to trastuzumab and chemotherapy”, the team suggests.

Since the time of the previous analysis, one patient in the pertuzumab group had developed congestive heart failure and there was one new case of symptomatic left ventricular dysfunction in a patient who crossed over from the placebo arm. Febrile neutropenia (11%) was the most common serious adverse event in the pertuzumab arm, while febrile neutropenia (5%) and neutropenia (5%) were the most common for the placebo counterparts.  

Matteo Lambertini and Ines Vaz-Luis caution that “[w]hen translating these results into current clinical practice, it should be considered that more than half (54%) of the enrolled patients did not receive any previous adjuvant or neoadjuvant treatment, and only 11% were previously exposed to trastuzumab.” 

Noting that the majority of patients with new stage IV disease now will have received single-agent or dual anti-HER2 blockade, the commentators say that “[t]he performance of the current standard pertuzumab-based first-line treatment in patients previously exposed to adjuvant or neoadjuvant anti-HER2 therapy remains to be clarified.”

They conclude: “Results from several ongoing prospective cohort studies investigating real-world patterns of care and outcomes of patients with HER2-positive metastatic breast cancer will help to clarify this important issue and optimise treatment sequencing.” 

References  

Swain SM, Miles D, Kim S-B, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol; Advance online publication 12 March 2020. https://doi.org/10.1016/S1470-2045(19)30863-0

Lambertini M, Vaz-Luis I. Is HER2-positive metastatic breast cancer still an incurable disease? Lancet Oncol; Advance online publication 12 March 2020. https://doi.org/10.1016/S1470-2045(20)30058-9