On June 8, 2012, the U.S. Food and Drug Administration approved pertuzumab (Perjeta®, Genentech) for use in combination with trastuzumab (Herceptin®, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1:1) to receive pertuzumab (n=402) or placebo (n=406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS), and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR 0.62 (95% CI: 0.51, 0.75), p< 0.0001]. A planned interim analysis suggested an improvement in OS [HR 0.64 (95% CI: 0.47, 0.88), p=0.0053] but the HR and p-value did not cross the stopping boundary. Common adverse reactions (>30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. Based on substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The Applicant agreed to multiple manufacturing and testing post-marketing commitments under third-party oversight to resolve manufacturing issues.