![Sample our Medicine, Dentistry, Nursing & Allied Health journals, sign in here to start your FREE access for 14 days]({"type":"image" , "src" : "/sda/5944/TOC-Subject-Sample-2021-Medicine-Dentistry-Nursing-Allied-Health.jpg"})
ABSTRACT
Introduction
Advances within molecular diagnostics have enabled us to identify a number of oncogenic drivers across different cancers. Many cancers can now be divided into subgroups based on molecular characteristics, and an increasing number of targeted anticancer drugs have been developed together with a predictive biomarker assay using the drug-diagnostic codevelopment model. With the recent approval of entrectinib, larotrectinib, and pembrolizumab for site-agnostic indications, biomarker-guided drug development has entered into a new phase.
Areas covered
The review focuses on the general principles of drug-diagnostic codevelopment, especially basket trials and site-agnostic drug development. Special attention is paid to entrectinib, larotrectinib, and pembrolizumab.
Expert opinion
The recent approval of entrectinib, larotrectinib, and pembrolizumab must be regarded as a paradigm shift in biomarker-guided oncology drug development. For a site-agnostic indication, it is important to have in mind the central role of the companion diagnostic (CDx), as the assay defines the ‘disease’ and the patient population to be treated. A number of site-agnostic drugs are currently in development and here, it is important that CDx assay development is given high priority, so an analytical and clinical validated assay is available at the time of drug approval.
Article Highlights
With the development of trastuzumab for the treatment of metastatic HER2 positive breast cancer, oncology drug development entered a new era where predictive biomarkers came to play a decisive role in the drug development process.
The advances within molecular diagnostics have enabled us to identify a number of oncogenic drivers across different cancers. Many cancers can now be divided into subgroups based on molecular characteristics and an increasing number of targeted anticancer drugs have been developed together with a predictive biomarker assay using the drug-diagnostic codevelopment model.
The recent site-agnostic approval of larotrectinib and entrectinib for patients with NTRK gene fusion-positive tumors and pembrolizumab for treatment of patients with MSI-H tumors must be regarded as a paradigm shift in biomarker-guided oncology drug development.
The efficacy of a site-agnostic anticancer drug is independent of anatomical site and histology and the treatment is instituted based on the presence of a specific molecular tumor characteristic. This means that the drug can be used for treatment across a number of different tumor types harboring the specific molecular characteristic.
For a site-agnostic indication, molecular testing is essential as it is a biomarker or group of biomarkers that defines the ‘disease’ and the patient population. It must be considered a major drawback that a number of different local laboratory-developed assays were used during the clinical development of pembrolizumab, larotrectinib, and entrectinib.
A number of site-agnostic drugs is currently under development and it is important that the biomarker assay development is given higher priority, so that a validated CDx assay is ready for regulatory approval together with drug it is meant to guide.
Declaration of interest
Jan Trøst Jørgensen has worked as a consultant for Agilent/Dako, Euro Diagnostica, Oncology Venture, Azanta and Alligator Biosciences and has given lectures at meetings sponsored by AstraZeneca, Merck Sharp & Dohme, and Roche. The authors has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewers Disclosure
A reviewer on this manuscript has disclosed research support from Loxo and Merck which are mentioned in the paper. Another reviewer has disclosed that they have consulted for Novartis, Bayer, Loxo Oncology, and Eli Lilly, and have received research funding from Bayer, Novartis and Pfizer. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.