New Standard of Care in HER2-Positive Metastatic Breast Cancer

Roxanne Nelson

February 20, 2015

Combining two targeted agents, pertuzumab (Perjeta, Roche/Genentech) and trastuzumab (Herceptin, Roche/Genentech), with docetaxel has resulted in unprecedented survival in women with HER2-positive metastatic breast cancer.

Treatment with the combined therapy boosted survival by an average of nearly 16 months in the CLEOPATRA study.

The results, presented first at the 2014 European Society for Medical Oncology (ESMO) Congress, as reported by Medscape Medical News, were published in the February 19 issue of the New England Journal of Medicine.

There was a 15.7-month survival advantage with pertuzumab. Median overall survival was significantly better with the combination of pertuzumab, trastuzumab, and docetaxel than with the combination of trastuzumab and docetaxel (56.5 vs 40.8 months; hazard ratio [HR], 0.68; P < .001).

"I think these results are phenomenal," lead investigator Sandra M. Swain, MD, medical director at the Washington Cancer Institute at MedStar Washington Hospital Center in Washington, DC, said at the ESMO congress.

"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," she said at the time.

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

Costly Option

Pertuzumab and trastuzumab are both humanized anti-HER2 monoclonal antibodies. They are more active in combination than when used alone because the combination results in more comprehensive signaling blockade, the investigators explain.

However, the cost of cancer treatment has become a mounting concern during the past decade, as new therapies come down the pipeline with ever-increasing price tags. Trastuzumab costs around $4500 a month, and the newer pertuzumab runs about 30% higher, at $6000 a month. For a full course of treatment, the cost of the pertuzumab and trastuzumab combination could go as high as $195,000, depending on the duration of therapy and the choice of taxane.

In a panel discussion that took place in 2012, after the initial CLEOPATRA results were announced, Lee Newcomer, MD, MHA, senior vice president of oncology at UnitedHealthcare, represented the payer's point of view.

The trial showed a "clear benefit, and the benefit was probably one of the larger ones we've seen in a long time," Dr Newcomer said. He acknowledged that the combination therapy is expensive, but noted that the treatment regimen is only applicable to a small subgroup of patients (those with previously untreated HER2-positive metastatic disease).

Even though insurers will most likely cover the regimen, the cost will eventually be passed along to the consumers. "The way that we deal with that, as does every payer in the country, is we simply build it into the premium, and the premium for the next quarter goes up," he said. "There isn't a way to pay for this other than simply passing the costs on in the premium, which means everyone who buys health insurance will see a slight increase."

Study Details

In the primary analysis, reported in 2011, pertuzumab significantly increased progression-free survival, and there was a strong trend toward an overall survival benefit.

An interim analysis conducted the next year showed that overall survival improved significantly and was clinically meaningful (HR, 0.66; P = .0008). At that time, median overall survival in women receiving pertuzumab had not been reached.

The final analysis was planned when at least 385 deaths were reported. At a median follow-up of 50 months, there was a significant improvement in overall survival for patients receiving both pertuzumab and trastuzumab.

The CLEOPATRA trial involved 808 patients with previously untreated HER2-positive metastatic breast cancer who were treated from 2008 to 2010.

All received docetaxel 75 mg/m² on day 2 of cycle 1 and on day 1 of the remaining cycles, and all received trastuzumab 8 mg/kg of body weight on day 2 of cycle 1 and 6 mg/kg on day 1 of the remaining cycles.

In addition, women were randomized to pertuzumab 840 mg on day 1 of cycle 1 and 420 mg on day 1 of the remaining cycles, or to placebo.

Pertuzumab, trastuzumab, and placebo were administered until disease progression or the occurrence of unmanageable toxic effects. Dose reductions were not allowed.

There were fewer deaths in the pertuzumab group than in the placebo group (168 vs 221; 41.8% vs 54.4%; HR, 0.68; P < .001). The most common cause of death was disease progression in the pertuzumab and placebo groups (36.8% vs 49.5%).

Median progression-free survival was 6.3 months longer in the pertuzumab group than in the placebo group (18.7 vs 12.4 months).

Independent evaluators confirmed a partial or complete response in 275 patients in the pertuzumab group and 233 in the placebo group. The duration of response was longer with pertuzumab (20.2 vs 12.5 months).

Safety Data Unchanged

The safety profile of the combination of pertuzumab and trastuzumab plus docetaxel was consistent with the known safety profile of long-term dual targeting, and the rates of adverse events were consistent with those in the primary analysis, Dr Swain and colleagues report.

Most adverse events were grade 1 or 2 and occurred during the administration of docetaxel. Long-term cardiac safety was maintained throughout the study, although the rate of left ventricular dysfunction was slightly lower in the pertuzumab group than in the placebo group (6.6% vs 8.6%).

The study was supported by F. Hoffmann–La Roche and Genentech. Dr Swain reports acting 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 publication.

N Engl J Med. 2015;372:724-734. Abstract

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