FDA Approval Summary: Pertuzumab for Adjuvant Treatment of HER2-Positive Early Breast Cancer.

On December 20, 2017, the FDA granted regular approval to pertuzumab in combination with trastuzumab and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer (EBC) at high risk of recurrence. Approval was based on data from the APHINITY trial, which randomized patients to receive pertuzumab or placebo in combination with trastuzumab and chemotherapy. After 45.4-month median follow-up, the proportion of invasive disease-free survival (IDFS) events in the intent-to-treat population was 7.1% (n = 171) in the pertuzumab arm and 8.7% (n = 210) for placebo [hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.67-1.00; P = 0.047]. The proportion of IDFS events in patients with hormone receptor-negative disease was 8.2% (n = 71) and 10.6% (n = 91) in the pertuzumab and placebo arms, respectively (HR, 0.76; 95% CI, 0.56-1.04). The proportion of IDFS events for patients with node-positive disease was 9.2% (n = 139) and 12.1% (n = 181) in the pertuzumab and placebo arms, respectively (HR, 0.77; 95% CI, 0.62-0.96). Adverse reactions in ≥30% of patients receiving pertuzumab were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting. From a regulatory standpoint, the benefits of the addition of pertuzumab to adjuvant treatment outweighed the risks for patients with EBC at high risk of recurrence.

First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer.

On June 8, 2012, the U.S. Food and Drug Administration (FDA) 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% confidence interval (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. On the basis of 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 postmarketing commitments under third-party oversight to resolve manufacturing issues.

End points to establish the efficacy of new agents in the treatment of acute leukemia.

Federal regulations provide 2 pathways for approval of new agents for the treatment of acute leukemia, regular and accelerated approval. Regular approval requires evidence of clinical benefit, which is generally defined as either prolongation of life or improved quality of life, or an effect on an end point established as a surrogate for clinical benefit. Accelerated approval can be obtained based on demonstration of an effect on a surrogate measure "reasonably likely" to predict clinical benefit, but requires demonstration of clinical benefit after approval as well. The acute leukemias are a heterogeneous and relatively uncommon group of diseases. The design and execution of prospective randomized clinical trials demonstrating prolongation of life or improved quality of life for patients with these disorders can be difficult and costly and require lengthy follow-up. Thus, the development of novel trial design and inclusion of validated surrogate markers for clinical benefit are needed. To explore some of the issues pertinent to the choice of end points for drug approval in acute leukemia, the Food and Drug Administration invited the American Society of Hematology to participate in the organization and conduct of a joint workshop. In this report, we present the results of that effort.

U.S. Food and Drug Administration drug approval summaries: imatinib mesylate, mesna tablets, and zoledronic acid.

The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: Gleevec (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.