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Old 03-23-2010, 09:35 AM   #1
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Pertuzumab plus trastuzumab for Her2+ MBC

Supplementary editorial provided by OncologySTAT


Pertuzumab plus trastuzumab proved safe with promising clinical activity when given after trastuzumab failure in HER2-positive metastatic breast cancer.


Despite the success of the HER2-targeted monoclonal antibody trastuzumab in improving survival in patients with advanced HER2-positive breast cancer, there is still a need for treatment options in metastatic disease when trastuzumab fails. Pertuzumab is a humanized monoclonal antibody that inhibits HER-mediated signaling by binding to a different HER2 epitope than trastuzumab. Because trastuzumab and pertuzumab have complementary mechanisms of action, pertuzumab is a good candidate for use in combination with trastuzumab, to provide a potentially broader blockade of the HER2 tumor cell proliferation and survival signaling. To test this theory, Baselga et al performed a phase II trial of pertuzumab plus trastuzumab in 66 patients with HER2-positive metastatic breast cancer that had progressed during prior treatment with trastuzumab. The single-arm study was conducted at 16 centers in 5 countries. Eligible patients had at least one measurable lesion and no history of cardiac disease.

Patients were administered trastuzumab at the same dose schedule they had received before enrolling in the study. For the first cycle, trastuzumab was given on day 1, and a loading dose of pertuzumab on day 2. In cycle 2 and thereafter, the agents were given on the same day. The protocol called for 8 cycles of treatment, and patients who were progression free could continue treatment.

All 66 patients received the pertuzumab/trastuzumab combination; the median number of cycles administered was 9 (range, 1 to 26 cycles). Only 2 patients withdrew due to adverse events (somnolence and diplopia, which were not treatment related). During the 8-cycle treatment period and during the follow-up, 25 patients (38%) and 17 patients (26%), respectively, withdrew because of progressive disease. Four patients who completed the first 8 cycles did not receive follow-up treatment.

The combination was well tolerated. Grade 1 or 2 events included diarrhea (64%), fatigue (33%), and nausea (27%). Only 4 patients had a grade 3 treatment-related event (2 cases of diarrhea, 1 central line infection, and 1 pruritic rash). None of these patients required drug discontinuation. Notably, there were no clinically significant cardiac events. Three patients had a significant decrease in left ventricular ejection fraction, but none of these patients had related clinical symptoms.

The overall response (OR) rate was 24.2%. There were 5 complete responses (CRs) (7.6%), 11 partial responses (16.7%), and 17 patients (25.8%) with stable disease lasting 6 months or longer, for a clinical benefit rate of 50%. The median time to response was 2.6 months (range, 1.1 to 8.6 months). Importantly, the combination was effective in both soft tissue and visceral lesions. The clinical benefits were durable. Overall median progression-free survival was 5.5 months (range, 0.9 to 17.0 months). Median duration of response was 5.8 months (range, 2.9 to 15.3 months). Among the patients who progressed (n = 45), median time to progression was 3.9 months (range, 0.9 to 17.0 months).

The efficacy and low rate of severe adverse events, including cardiac events, achieved with the combination are encouraging. The OR and CR rates, the primary endpoints, in particular, exceeded study expectations. The efficacy results of the current study compare favorably with those from a recent randomized trial of lapatinib and capecitabine in a similar patient population. The lapatinib/capecitabine study, however, had a high rate of grade 3 or 4 diarrhea and rash. This suggests that a combination such as trastuzumab/pertuzumab could be a nonchemotherapy-containing treatment option for patients who have progressed on first-line anti-HER2 therapy.

The results also indicate that pertuzumab is more active in HER2-positive tumors. All patients in the current study had HER2-positive disease, and a previous study demonstrated only modest antitumor activity for single-agent pertuzumab in HER2-negative breast cancer.

Planned or ongoing studies will further evaluate pertuzumab in HER2-positive breast cancer patients. These include trials of pertuzumab as a single agent after trastuzumab failure in metastatic disease, combined with trastuzumab as neoadjuvant therapy, and combined with trastuzumab/docetaxel in first-line metastatic breast cancer.

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