Pertuzumab is a monoclonal antibody with a distinct binding site from trastuzumab, which inhibits a process know as receptor dimerization. In recent studies, the addition of pertuzumab to combination therapy has led to significant improvements in progression-free survival (PFS) in patients with HER2-positive MBC and higher response rates in the preoperative setting. Pertuzumab (Omnitarg / now FDA-approved as "Perjeta") is like trastuzumab, a humanized anti-HER2 monoclonal antibody, which appears to have some unique synergy with trastuzumab.
The Evidence of Efficacy
The Phase III, double- blind CLEOPATRA trial of pertuzumab + trastuzumab, where patients were randomly assigned to treatment with docetaxel plus trastuzumab (TH), combined with either placebo or pertuzumab, showed an objective response rate of 24.2% (CR + PR) and clinical benefit rate of 50% (CR + PR + SD) in patients who had progressed on prior trastuzumab therapy, with five patients (7.6%) experiencing a complete response, eleven patients (16.7%) experiencing a partial response, and 17 patients (25.8%) experiencing stable disease for 6 or more months; representing overall a 38% reduction in risk. Overall, the combination of pertuzumab and trastuzumab was well tolerated, and AEs were mild to moderate. The investigators called the magnitude of effects with the pertuzumab combination “unprecedented,” and speculated that the new HP regimen could be a practice-changing discovery for the treatment of patients with HER2-positive, first-line metastatic breast cancer, especially since subgroup analyses revealed that the beneficial effect of pertuzumab on PFS occurred regardless of the patients’ prior exposure to adjuvant or neoadjuvant chemotherapy, or their hormone receptor status, or their HER2 positivity from IHC versus FISH. I have some reservations as to the methodology of the CLEOPATRA trial, and would mute the claims somewhat, although coupled with the other data I briefly note below, it is reasonably clear that pertuzumab can positively affect outcome when added to trastuzumab therapy.
In addition, the randomized open-label phase II neoadjuvant trial [NEOSPHERE] reported pathologic complete response (pCR) rates of 45.8% and 29% in patients treated with TPH ( docetaxel, , pertuzumab, trastuzumab) and versus TH (docetaxel plus trastuzumab), respectively, and this was confirmed in the recent TRYPHAENA trial,, while a recent phase III clinical trial [Baselga 2012] showed that the combination of trastuzumab plus pertuzumab (PH) and chemotherapy increased both PFS AND improved overall survival (OS) when compared with trastuzumab plus chemotherapy. But note that the non-randomized Cortés trial (2012) that tested pertuzumab monotherapy versus pertuzumab + trastuzumab showed disease progression in all patients treated with pertuzumab monotherapy, suggesting strongly that single-agent pertuzumab has minimal activity. Thus, we can conclude that the combination trastuzumab plus pertuzumab appears to be a highly active and effective therapeutic strategy even despite previous progression on trastuzumab.
Where Pertuzumab Fits in, In the Anti-Her2 Arsenal
So it is clear the pertuzumab joins the ranks of T-DM1 as the most important breakthroughs in treating HER2+ disease since trastuzumab itself was introduced (with for me T-DM1 holding the easy edge of higher efficacy), and unlike T-DM1 which is only now available on clinical trial, pertuzumab is now FDA approved. However, bear in mind that currently the approval is only in combination with trastuzumab + docetaxel chemotherapy, and solely for HER2-positive women in the first line, who have not received prior chemotherapy, or anti-HER2 therapy for metastatic disease. Note however that this still allows having received chemotherapy and/or anti-HER2 therapy in the adjuvant or neoadjuvant therapy. As with most therapies for advanced disease, it is likely that oncologists may deploy pertuzumab beyond its label indication, although insurance coverage might then be the issue.
For me, who am always an advocate of pushing the envelop of therapies in clinical practice before reverting to clinical trials, I make any exception here: I find the evidence sufficiently compelling - and exciting - for both pertuzumab and T-DM1 that clinical access or clinical trials, if eligibility is met, can and should be considered on a par with the best of standard anti-HER2 therapies.
Breast Cancer Watch