On February 22, 2013, the FDA licensed ado-trastuzumab emtansine (Kadcyla; Genentech, Inc.) for use as a single agent for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. The clinical basis for licensure was a phase III trial in 991 patients with HER2-positive MBC that randomly allocated patients to receive ado-trastuzumab emtansine (n ¼ 495) or lapatinib in combination with capecitabine (n ¼ 496). The coprimary endpoints were progression-free survival (PFS) based on tumor assessments by an independent review committee and overall survival (OS). Statistically significant improvements in PFS and OS were observed in patients receiving ado-trastuzumab emtansine compared with patients receiving lapatinib plus capecitabine [difference in PFS medians of 3.2 months, HR, 0.65 (95% confidence interval, CI, 0.55-0.77), P < 0.0001 and difference in OS medians of 5.8 months, HR, 0.68 (95% CI, 0.55-0.85), P ¼ 0.0006]. The most common adverse reactions in patients receiving adotrastuzumab emtansine were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased aminotransferase levels, and constipation. Other significant adverse reactions included hepatobiliary disorders and left ventricular dysfunction. Given the PFS and OS results, the benefit-risk profile was considered favorable. Clin Cancer Res; 20(17); 4436-41. Ó2014 AACR.
Using indwelling crown-rump length (CRL)-measuring devices, the growth rate of sheep fetuses was monitored during late gestation and after experimental manipulation of fetal plasma cortisol by exogenous infusion and fetal adrenalectomy. In intact control fetuses, the increment in CRL declined progressively during the last 20-25 days of gestation: mean +/- S.E.M. values fell from 5.5 +/- 0.4 mm/day (n = 12) at 21-25 days before delivery to 2.5 +/- 0.3 mm/day (n = 12) in the last 5 days before birth (P < 0.01). These changes closely parallelled the normal prepartum increase in fetal plasma cortisol which rose from 19.3 +/- 3.3 nmol/l (n = 10) at 21-25 days before birth to 177.4 +/- 19.0 nmol/l (n = 10) in the final 5 days before delivery (P < 0.01). When this cortisol surge was prevented by fetal adrenalectomy, there was no decrease in CRL increment towards normal term: mean CRL increment in the 5 days before normal term (4.8 +/- 0.6 mm/day, n = 5) was similar to that observed at 21-25 days before term (4.7 +/- 0.4 mm/day, n = 5). At delivery at term, the body weight (4.116 +/- 0.280 kg, n = 5) and CRL (51.9 +/- 1.7 cm, n = 5) of the adrenalectomized fetuses were significantly greater than the corresponding values in their sham-operated controls (2.877 +/- 0.070 kg and 47.1 +/- 1.6 cm, n = 6, respectively). In contrast with the sham-operated controls, plasma glucose and insulin levels in the adrenalectomized fetuses decreased towards term. Infusion of cortisol into the preterm fetus for 5 days increased fetal plasma cortisol to term levels and decreased the CRL increment to a value (1.8 +/- 0.5 mm/day, n = 8) which was similar to that observed in untreated controls during the last 5 days before spontaneous delivery at term (2.1 +/- 0.3 mm/day, n = 6). There were no significant alterations in the fetal arterial concentrations of plasma glucose or insulin in response to fetal cortisol infusion. When all the data were combined irrespective of treatment or proximity to delivery, the fetal plasma concentrations of cortisol (P < 0.001) and glucose (P < 0.04), but not insulin (P > 0.05), had a significant effect on the fetal CRL increment measured over 5-day periods during the last 25-30 days of gestation. These findings show that cortisol inhibits growth of the axial skeleton in the sheep fetus during late gestation. They also indicate that the prepartum cortisol surge may be responsible for the normal decline in fetal growth rate observed towards term in this species.
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.
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