Combination Therapy with Pertuzumab Offers New Option in Metastatic Breast Cancer

JHOP - March 2012, VOL 2 NO 1 - From the Literature, From the Literature
Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
Clinical Professor Emeritus
University of California, San Francisco
Professor of Pharmacy
College of Pharmacy, Touro University–California
Mare Island, Vallejo, CA

Background: Although trastuzumab, an HER2 inhib­itor that binds to subdomain IV of the HER2 extracellular growth domain, is effective in inhibiting tumor growth in HER2-positive metastatic breast cancer, the disease often progresses after therapy. Pertuzumab, which binds to subdomain II of the growth domain, offers a complementary mechanism of action that, in combination with that of trastuzumab, enhances the blockade of HER2 signaling and potentially produces greater antitumor activity, as has been demonstrated in phase 2 studies. A new, phase 3 study investigated the efficacy of pertuzumab in combination with trastuzumab and docetaxel for this patient population.

Design: In the international phase 3 Clinical Eval­uation of Pertuzumab and Trastuzumab (CLEOPATRA) study, 808 patients from 25 countries with HER2-positive metastatic breast cancer were randomized to receive trastuzumab (6 mg/kg every 3 weeks or until progression) plus docetaxel (75 mg/m2) plus either pertuzumab (420 mg every 3 weeks or until progression or unmanageable toxicity occurred) or placebo. The primary end point was PFS; objective response rate (ORR) was a secondary end point.

Summary: The median duration of treatment was 18.1 months in the pertuzumab group and 11.8 months in the placebo group. At approximately 34 months, the independently assessed PFS was 6.1 months longer in the pertuzumab group (18.5 months vs 12.4 months, respectively; HR, 0.62; 95% CI, 0.51-0.75; P <.001). In addition, after a median follow-up period of 19.3 months in both treatment groups, the ORR was 80.2% in the pertuzu­mab group versus 69.3% in the placebo group  (P = .001). Adverse events occurring more frequently (≥5%) in the pertuzumab group included diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin. The rates of grade ≥3 febrile neutropenia and diarrhea were also ≥2% higher in the pertuzumab group (13.8% and 7.9%, respectively) than in the placebo group (7.6% vs 5.0%). The rates of symptomatic or asymptomatic cardiac dysfunction did not increase in the pertuzumab group, however.

The PFS benefit with pertuzumab was similar to that of 288 patients in the study who had received previous adjuvant or neoadjuvant chemotherapy without trastuzumab (HR, 0.60; 95% CI, 054-0.78; P <.001).

Takeaway: Although this study appears to be strongly positive for the targeted combination therapy, the results should be considered preliminary. This is because the median PFS of 12.4 months in the control group is similar to that seen in previous studies of trastuzumab plus docetaxel (11.1 and 11.7 months, respectively). Furthermore, the survival data are not yet fully mature: reaching only 43% of that specified for the final analysis. In addition, the toxicity profile was expanded with the addition of pertuzumab and included more frequent events of diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin. Pertuzumab is currently an investigational agent, but, if approved by the US Food and Drug Administration (FDA), it will likely be priced like other costly targeted agents. It will require a detailed pharmacoeconomic analysis to assess its role in the management of metastatic breast cancer.

Baselga J, et al. Pertuzumab plus trastuzumab plus docetaxel for meta­static breast cancer. N Engl J Med. 2012;366:109-119.

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