CLEOPATRA Trial Update Shows Dramatic OS Benefit

Sandra M. Swain, MD

Dual HER2 blockade with pertuzumab and trastuzumab plus chemotherapy for the treatment of HER2-positive metastatic breast cancer improved median overall survival (OS) by almost 16 months over standard first-line therapy, according to long-term follow-up from the CLEOPATRA study.

Pertuzumab added to trastuzumab and chemotherapy extended median OS to 56.5 months and did not introduce any new safety concerns, including no increase in cardiac toxicity, said Sandra M. Swain, MD, who presented the data at ESMO 2014.

“The 56.5-month median OS is unprecedented in this indication and confirms the pertuzumab regimen as first-line standard of care for patients with HER2-positive metastatic breast cancer,” said Swain, medical director of the Washington Cancer Institute at Medstar Washington Hospital Center, in Washington, DC.

CLEOPATRA was a pivotal phase III study in which the safety and efficacy of pertuzumab, trastuzumab, and chemotherapy were evaluated in 808 patients with previously untreated HER2-positive metastatic breast cancer that was confirmed centrally by immunohistochemistry. It was conducted in 204 centers in 25 countries. Patients were randomized to either placebo or pertuzumab, given as an 840-mg loading dose followed by a 420-mg maintenance dose, plus trastuzumab, given as an 8-mg/kg loading dose followed by a 6-mg/kg maintenance dose, and 6 cycles of docetaxel, 75 mg/m² with escalation to 100 mg/m² if tolerated. Treatments were administered every 3 weeks and continued until disease progression.

“Pertuzumab binds at a different site of the HER2 receptor than trastuzumab, and preclinical and clinical data support using the two together, not sequentially,” said Swain.

The primary analysis showed that pertuzumab increased progression-free survival (PFS) significantly, with a strong trend for an OS benefit. A second interim analysis at a median follow-up of 30 months demonstrated an improvement in OS that was both statistically significant and clinically meaningful (hazard ratio [HR] = 0.66; P=.0008), but the median OS in patients randomized to pertuzumab was not reached.

The data presented here were those from the final OS analysis after a median follow-up of 50 months. The results were called “phenomenal” by Swain, who said that median OS with trastuzumab and docetaxel was already “very good” at 40.8 months. Adding pertuzumab to the regimen increased median OS by 15.7 months, yielding an HR of 0.68 (P=.0002) compared with standard first-line treatment. “We haven’t ever seen that in any other trial of metastatic breast cancer,” she said.

An updated analysis of median PFS was consistent with previous analyses, showing an improvement of 6.3 months in the pertuzumab arm. “It clearly does suggest…that in this blinded study, PFS was a good surrogate of OS,” she said.

Because the analysis made no adjustment for crossover once the study treatments were unblinded, patients who crossed over from the placebo arm to the pertuzumab arm were analyzed as part of the placebo arm, making the favorable survival benefit with pertuzumab quite conservative, she added.

The long-term safety profile of the pertuzumab regimen was unchanged from previous analyses. The rate of symptomatic left ventricular dysfunction was actually less with the addition of pertuzumab versus standard first-line therapy (1.5% vs. 1.8%). A decline in left ventricular ejection fraction to <50% and by ≥10% points from baseline was also more common in placebo recipients compared with pertuzumab recipients (7.4% vs. 6.1%). Declines in left ventricular ejection fraction reversed in 88% of the patients randomized to pertuzumab, Swain noted.

“Based upon the study results, I would recommend personally that all patients have an opportunity to get dual antibody therapy—pertuzumab and trastuzumab,” she said.

Swain S, Ro J, Campone M. Final overall survival analysis from the Cleopatra study of first-line pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. Presented at: the 2014 Congress of the European Society of Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract 350O&shy;_PR.

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