Reviewer: Dr. Sunil Verma Date posted: December 12th, 2011 SABCS 2011 CLEOPATRA A phase III, randomized, double-blind, placebo-controlled registration trial to evaluate the efficacy and safety of pertuzumab + trastuzumab + docetaxel vs. placebo + trastuzumab + docetaxel in patients with previously untreated HER2-positive metastatic breast cancer (CLEOPATRA) (Baselga J, et al) Reviewer: Dr. Sunil Verma Date posted: December 12th, 2011

Background We have seen tremendous improvement in the outcome of Her 2 positive metastatic breast cancer with the integration of anti-her2 therapy in MBC There is considerable interest in combining targeted therapies targeting Her 2 and Her 3 receptors given pre-clinical synergy Pertuzumab, a monoclonal antibody blocks the dimerization of Her 2 and Her 3 and has shown promising activity in combination with Herceptin in phase II studies

R CLEOPATRA Treatment A: Docetaxel + Herceptin + Pertuzumab N= 808 Her2 positive Metastatic Breast Cancer Primary Outcome: Progression Free Survival First Line MBC Could have received prior adjuvant Trastuzumab Treatment A: Docetaxel + Herceptin + Pertuzumab R Treatment B: Docetaxel + Herceptin + Placebo   First Line Her 2 positive MBC

RESULTS DHPertuzumab DHPlacebo <0.0001 69.3 80.2 Overall survival HR p-value PFS (months) 18.5 12.4 0.62 <0.0001 RR (%) 69.3 80.2 Overall survival Median not reached HR 0.64 (interim analysis)

CLEOPATRA Key Conclusions The addition of Pertuzumab to standard Docetaxel and Herceptin leads to a clinically and statistically significant improvement in PFS (about 6.1 months) Interim analysis for OS shows a promising trend, however it didn’t meet the pre-defined statistical p-value and final analysis is eagerly awaited There was no additional cardiac toxicity seen. However there were increased rates of diarrhea and febrile neutropenia (7.6% vs 13.8%)

CLEOPATRA Bottom Line for Oncologists We have a new standard option in the first line treatment of Her 2 positive MBC – docetaxel + Herceptin + pertuzumab We have limited data on the use of this combination in patients who have had prior adjuvant trastuzumab (only 10% of patients on this trial had prior adjuvant T) There is also limited data on this combination with other chemotherapy regimens, namely paclitaxel/vinorelbine, which are increasingly being used in the first line setting The cost of such a regimen may be too prohibitive in many parts of the world and the full funding decisions need to be made once we have updated survival analysis. There also needs to be additional research done on identifying biomarkers that will help guide us to which patients need both of these targeted agents There is great interest in developing this combination for patients with early stage breast cancer and enrolment in the ongoing APHINITY trial should be encouraged