IntroductionDuring 2006, nearly 16 000 people will be diagnosed with acute leukemia in the United States and despite many important advances in diagnosis and therapy, the majority will die of their disease. 1 Acute myeloid leukemia (AML), which accounts for 75% of acute leukemias, is a disease predominantly of adults with a median age at diagnosis of 68 years and a 75% overall mortality. 2 The mortality rate of AML is highly age related with 5-year survival of approximately 50% in children, approximately 30% in adults younger than age 60, and less than 5% in those over age 60 years. 3-5 Acute lymphocytic leukemia (ALL) comprises approximately 25% of acute leukemia cases. Two thirds of ALL cases occur in children who have, on average, cure rates approaching 85% with contemporary therapy. 6 The prognosis is poorer for adults, with a cure rate of approximately 35% in those aged 20 to 60 years, but only 5% in those older than 60 years. 7 Thus, acute leukemia in adults and children represents a spectrum of diseases ranging from those with a very poor prognosis, such as AML in older patients, to diseases such as childhood ALL where cure rates are high. However, even for those subtypes with high cure rates, the "cost" of cure may be substantial with short-and long-term side effects. Therefore, new agents are needed to extend survival, improve cure rates, and avoid undesired treatment-related toxicities.

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 ¼ 402) or placebo (n ¼ 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 ¼ 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.

On December 20, 2017, the FDA granted regular approval to pertuzumab in combination with trastuzumab and chemotherapy for the adjuvant treatment of patients with HER2positive 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 ¼ 171) in the pertuzumab arm and 8.7% (n ¼ 210) for placebo [hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.67-1.00; P ¼ 0.047]. The proportion of IDFS events in patients with hormone receptor-negative disease was 8.2% (n ¼ 71) and 10.6% (n ¼ 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 ¼ 139) and 12.1% (n ¼ 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.