The comparator arm will consist of the same adjuvant CT backbone with trastuzumab and placebo for 1 year

The comparator arm will consist of the same adjuvant CT backbone with trastuzumab and placebo for 1 year. Adverse events and cardiac safety of pertuzumab HER2 and HER4 are crucial for mouse embryonic heart development, and studies have shown that HER2 expression is required for the development of ventricular muscles and valves in rodents, while the activation of HER2 promotes cardiomyocyte survival.27C30 Trastuzumab may cause an asymptomatic decline in the left ventricular ejection fraction (LVEF), known as left ventricular systolic dysfunction (LVSD).21 However, symptomatic heart failure (HF) under trastuzumab is relatively uncommon. may have optimal therapeutic effects when given to patients with HER2-positive cancers, in combination with trastuzumab. This observation is usually supported by recent clinical trials in the metastatic as well as neoadjuvant setting. Intravenous pertuzumab had an acceptable tolerability profile when added to trastuzumab and chemotherapy. This overview will review recent advances in the clinical development of this HER2-targeted therapy. mutation, unfavorable estrogen receptor (ER) status, absence of Placebo plus trastuzumab plus docetaxelPertuzmab plus trastuzumab plus docetaxel? Median PFS was 12.4 months vs 18.5 months in the pertuzumab group (HR for progression or death, 0.62; 0.001)21TRYPHAENA(n = 75) FEC + trastuzumab + pertuzumab 3, docetaxel + trastuzumab + pertuzumb 3(n = 75) FEC 3 trastuzumab + pertuzumab + docetaxel 3(n = 75) Carboplatin + docetaxel + trastuzumab + pertuzumab NSC 663284 6? Regardless of chemotherapy chosen, the combination of pertuzumab and trastuzumab resulted in high pCR rates (57%C66%)20NEOSPHERE= 0.0141). Twenty-three of 96 (24.0% [95% CI: 15.8C33.7]) women who received pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16.8% [95% CI: 10.3C25.3]) who received pertuzumab and trastuzumab (group C). Pathologic complete response was up to 63.2% with the combination of the two antibodies and docetaxel in the hormone receptor-negative subgroup. NSC 663284 The most common AEs of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious AEs was comparable in groups A, B, and D (15C20 serious AEs per group in 10%C17% of patients), but was significantly lower in group C (four serious AEs in 4% of patients). The study concluded that patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel alone, which indicates that a chemotherapy backbone is necessary to improve the pCR rate. The efficacy of neoadjuvant pertuzumab was confirmed by the recently presented TRYPHAENA Study.20 The trial examined patients with newly diagnosed HER2-positive early breast cancer and investigated three experimental neoadjuvant regimens. The common feature of all three regimens was the combination of pertuzumab and trastu-zumab for at least three cycles. Each regimen combined these two HER2-directed antibodies with anthracyclineC taxane-based or carboplatinCtaxane-based standard chemotherapy backbones either concomitantly or sequentially for six cycles. NSC 663284 Following surgery, all patients received 1 year of adjuvant trastuzumab. The primary endpoint was assessment of the safety and tolerability of neoadjuvant treatment. During neoadjuvant treatment, the left ventricular ejection fraction was monitored on a regular basis. The key secondary endpoint was the pCR rate Approximately 75 patients were randomized to each of the three neoadjuvant regimens, and all were well tolerated with no symptomatic cardiac toxicity even if both HER2-directed antibodies were given concomitantly with anthracyclines. Treatment with each regimen yielded impressive NSC 663284 pCR rates, ranging from 45% to 66% with little difference between them. However, pCR rates were substantially higher in patients with ER-negative and progesterone receptor (PR)-unfavorable tumors (up to IL23P19 83.8%), compared to patients with ER-negative and/or PR-positive tumors. These findings, together with the previously reported results of the NEOSPHERE trial described above, clearly illustrate the potential benefits of dual HER2 inhibition using pertuzumab and trastuzumab; however, the long-term benefits of the neoadjuvant regimens investigated in the TRYPHAENA trial are still unknown. At the time of the writing, only 16% of patients had completed adjuvant therapy. Based on the encouraging phase II data, a NSC 663284 randomized Phase III trial has begun that enrolled women with metastatic HER2/neu positive breast malignancy in first-line treatment consisting of docetaxel and trastuzumab with placebo or pertu-zumab.21 In CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), an international, Phase III, double-blind, randomized registration trial, 808 patients (mean age, 54 years) received either placebo plus trastuzumab (an 8-mg/kg loading dose, followed by a 6-mg/kg maintenance dose) plus docetaxel (75 mg/m2, escalating to 100 mg/m2 if tolerated, for six cycles or more, as recommended) or pertuzumab (an 840-mg loading dose, followed by a 420-mg maintenance dose) plus trastuzumab (an 8-mg/kg loading dose, followed by a 6-mg/kg maintenance dose).21 Patients were allowed to receive one previous hormonal treatment for metastatic breast malignancy and/or prior systemic.