A Companion Diagnostic With Significant Clinical Impact in Treatment of Breast and Gastric Cancer

Abstract

The development of trastuzumab (Herceptin®) was one of the most significant cancer drug development projects of the 20th century. Not only was it a scientific and medical achievement but it also paved the way for the drug-diagnostic codevelopment model, where a predictive biomarker assay is developed in parallel to the drug. One of the challenges in the development of trastuzumab was to select the right patient population likely to respond and here, it was critical to have access to an accurate, robust and reliable assay for detection of HER2 overexpression in tumors. In the clinical development of trastuzumab, a clinical trial assay (CTA), developed by Genentech, was used for selection of HER2 positive patients. However, during the phase III trial with trastuzumab, a new optimized IHC assay, HercepTest™ was designed and developed by Dako. In the final stage of its development, a comparative study with the CTA was conducted in order to show concordance between the two assays. In September 1998, the Food and Drug Administration (FDA) simultaneously granted approval to trastuzumab and HercepTest™. The assay has been used for patient selection in a number of significant breast cancer clinical trials such as the HERA, CLEOPATRA, EMILIA and more. In these trials, HercepTest™ demonstrated its clinical utility in the neoadjuvant, adjuvant, and metastatic setting as well as in relation to different types of HER2 targeted therapies. Likewise, the assay was used for selection of HER2 positive gastric cancer patients in the important ToGA trail. HercepTest™ was the first companion diagnostic ever approved by the FDA, and more than 20 years of use has documented its clinical impact.

Comparison of HercepTest™ mAb pharmDx (Dako Omnis, GE001) with Ventana PATHWAY anti-HER-2/neu (4B5) in breast cancer: correlation with HER2 amplification and HER2 low status

“…IHC stains of the two assays were read after a 2-week wash-out period, and all the pathologists were blinded to the FISH results. In addition to a pre-study training provided by Dako/Agilent, all investigators had extensive experience in HER2 evaluation, having served over the past 20 years as readers in most of the trastuzumab, pertuzumab, and T-DM1 approval BC studies by Targos GmbH (Kassel, Germany) (for a review of studies screened by first-generation HercepTest (poly), see [ 23 ]).…”

HER2/positive and HER2/low in inflammatory breast cancer recurrence

“…HER-2 immunohistochemistry was performed according to the generally accepted methodology ( Table 1 ). Each of these outcomes necessitates specific patient management [ 20 ].…”

Target Antigen Attributes and Their Contributions to Clinically Approved Antibody-Drug Conjugates (ADCs) in Haematopoietic and Solid Cancers

“…In this context, it is interesting to note that, of the twelve currently FDA-approved ADCs, only three (Kadcyla ® , Enhertu ® and Elahere ® ) have a formal requirement in their licensing for an antigen test (e.g., the HER2 HercepTest ® , Ventana PATHWAY anti-HER-2/neu (4B5) rabbit monoclonal primary antibody assay, the INFORM HER2 Dual ISH DNA Probe Cocktail assay for Kadcyla ® , and the FRα Ventana FOLR-2.1 RxDx companion diagnostic test for Elahere ® ) prior to the commencement of treatment [ 172 , 178 , 179 ]. This may, in part, relate to the fact that Kadcyla ® and Enhertu ® are based on trastuzumab, for which there is a long history of the HercepTest ® being successfully used to select patients [ 179 ], and there is a similar history in the development of FRα diagnostics [ 180 ]. However, it may also reflect the relatively poor correlation between antigen expression levels and clinical efficacy for other approved ADCs such as Polivy ® [ 87 ].…”