First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with
trastuzumab and docetaxel for HER2-positive metastatic breast cancer.
Author(s): Blumenthal GM(1), Scher NS, Cortazar P, Chattopadhyay S, Tang S, Song P, Liu Q,
Ringgold K, Pilaro AM, Tilley A, King KE, Graham L, Rellahan BL, Weinberg WC, Chi
B, Thomas C, Hughes P, Ibrahim A, Justice R, Pazdur R.
Affiliation(s): Author information:
(1)Authors' Affiliation: Center for Drug Evaluation and Research, U.S. Food and Drug
Administration, White Oak, Maryland.
Publication date & source: 2013, Clin Cancer Res. , 19(18):4911-6
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.
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