Roxanne Nelson

September 28, 2014

MADRID — Final results from the CLEOPATRA study show that the combination of 2 targeted agents, trastuzumab (Herceptin, Roche/Genentech) and pertuzumab (Perjeta, Roche/Genentech), significantly prolonged survival in HER2-positive metastatic breast cancer, compared with trastuzumab alone. The targeted agents were added to chemotherapy with docetaxel.

Patients treated with the combination plus chemotherapy lived 15.7 months longer than those who received trastuzumab and chemotherapy (median overall survival, 56.5 vs. 40.8 months; hazard ratio [HR], 0.68; P = .0002).

Dr. Sandra Swain

"The follow-up is 20 months longer than the last presentation," said first author Sandra Swain, MD, from the MedStar Washington Hospital Center in DC. "What's more important for us as clinicians, aside from the statistics, are the numbers — the median survival."

"I think these results are phenomenal," said Dr. Swain, who spoke during a press briefing here at the European Society for Medical Oncology (ESMO) Congress 2014. "We all believe that the 56.5-month median overall survival is unprecedented in this indication and confirms that the pertuzumab plus trastuzumab regimen is a first-line therapy for patients with HER2-positive metastatic breast cancer."

I think these results are phenomenal.

She noted that the median survival with trastuzumab is already very good, at 40.8 months. "That already changed things for patients with HER2-positive breast cancer, but adding pertuzumab has increased that by 15.7 months," Dr. Swain continued. " I've never seen that in any other trial of metastatic breast cancer," she said, noting that she has worked in the field for 30 years.

These final results add another 20 months of follow-up to the last presentation of the data, Dr. Swain said. The new results include an updated progression-free survival analysis, which was 18.7 months, an improvement of 6.3 months, compared with a median of 12.4 months with trastuzumab and chemotherapy alone. "This is also very good," she said. "For those who are looking at different end points in this blinded study, progression-free survival was a good surrogate end point for overall survival."

"We should consider this combination as the standard of care for our patients," coauthor Javier Cortés, MD, director of the breast cancer program at Vall d'Hebron Institute of Oncology in Barcelona, Spain, said in a statement. "I can see no reason to justify the use of trastuzumab without pertuzumab."

"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," he explained.

Dr. Cortés added that "this is one of the biggest steps toward making this disease a chronic condition in the near future."

Interim Analyses

The phase 3 CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study involved 808 patients with previously untreated HER2-positive metastatic breast cancer. At the primary analysis, pertuzumab was shown to increase progression-free survival significantly, with a strong trend toward an overall survival benefit. A second interim analysis, published in May 2012, showed that overall survival was improved to a degree that was both statistically significant and clinically meaningful (HR, 0.66; P = .0008); at the time, the median overall survival in women receiving pertuzumab had not been reached.

The current analysis was planned when at least 385 deaths were reported. At a median follow-up of 50 months, there was a statistically significant improvement in overall survival for patients receiving both targeted therapies, as reported above.

In response to a question from the audience about whether both monoclonal antibodies are needed in the regimen, Dr. Swain noted that she would recommend both. She added that although there is a study evaluating the need for trastuzumab, patients should get the combination now. "When the study comes out, we will see if we need to give both, but I don't think the data will show that," she reported.

Establishes New Standard of Care

"The CLEOPATRA trial changes clinical practice. We now have a new standard of care," Giuseppe Curigliano, MD, director of the division of experimental therapeutics in Milan, said in a statement released by ESMO.

"In the future, in any country of the world, when you have a patient with metastatic breast cancer that is HER2-positive, the proposal for treatment should include dual targeting with pertuzumab and trastuzumab plus chemotherapy," he added.

"The results of the study are really outstanding, because there is a 56.5-month median overall survival — that is unprecedented in first-line metastatic breast cancer. And the difference in overall survival between the previous standard of care (trastuzumab alone) and the new standard of care (dual targeting) is 15 months. This study provides sufficient evidence to demonstrate that dual targeting is better than monotargeting in the metastatic setting," he said.

Similar efficacy results have been reported in the neoadjuvant setting, he noted. The NeoSphere trial found that dual targeting with pertuzumab and trastuzumab plus chemotherapy significantly improved the percentage of patients with early HER2-positive breast cancer who had a complete pathologic response.

The potential of dual targeting in the adjuvant setting is being investigated in the ongoing APHINITY trial, which is comparing the dual targeting of pertuzumab plus trastuzumab with trastuzumab alone. Dr. Curigliano said: "If data from the metastatic setting are confirmed in the adjuvant setting, we will also have a new standard of care in the adjuvant setting."

Other trials are studying dual targeting with chemotherapeutic agents other than docetaxel. These include the PERUSE trial, a study of pertuzumab in combination with trastuzumab and a taxane in the first-line treatment of patients with HER2-positive advanced breast cancer, and the VELVET trial, which is testing a combination of pertuzumab, trastuzumab, and vinorelbine in the first-line treatment of patients with HER2-positive metastatic breast cancer.

Dr. Curigliano highlighted safety data from the trial. "The safety profile of pertuzumab and trastuzumab plus chemotherapy was consistent with the known safety profile of patients with long-term exposure to dual targeting. It means that we now have a treatment that improves overall survival and progression-free survival without affecting the quality of life of patients in terms of cardiac safety."

"This is a very important point because we know that long-term exposure to trastuzumab may decrease left ventricular ejection fraction. CLEOPATRA did not find excessive toxicity in the dual targeting arm," he said.

Future Directions

No matter how successful the data are, oncologists are always looking for the next step and ways to improve these results, said study discussant Luca Gianni, MD, director of the Department of Medical Oncology at the San Raffaele Cancer Center in Milan.

HER2-positive breast cancer is not a homogenous disease, and it might be possible to improve outcomes even more by addressing factors like hormonal receptors and mutations, Dr. Gianni explained.

The different biology and different drug sensitivity seen in patients should be considered when looking for therapeutic approaches to improve these overall results.

"CLEOPATRA did not allow for endocrine therapy for patients with ER-positive tumors," he pointed out. "Can the addition of endocrine therapy after chemotherapy increase this already substantial benefit?" he wondered.

Another potential area to address is PIK3CA mutations. "Resistance due to PIK3CA mutation was associated with a poorer prognosis in CLEOPATRA, despite the better activity of a dual blockade," Dr. Gianni reported, noting that PIK3CA status can easily be assessed in patients.

Finally, the immune environment might offer opportunities for improving outcomes, he noted, with the possibility of testing anti-PDL-1 or anti-CTLA-4 therapies in this setting.

For now, the results of the CLEOPATRA study represent "the new standard of care, not an option for HER2-positive metastatic breast cancer, as a first-line treatment," Dr. Gianni summarized.

The CLEOPATRA trial was funded by Genentech/Roche, the manufacturer of both trastuzumab and pertuzumab. Dr. 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. Several coauthors report relationships with industry, as noted in the abstract.

European Society for Medical Oncology (ESMO) Congress 2014: Abstract 350O_PR. Presented September 28, 2014.

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