Companion Diagnostics Are Driving Support in the Evolving Regulatory Landscape

Paul Watson
Published Online: Monday, December 30, 2013
Dr. Kwok-Kin Wong

Kwok-Kin Wong, MD, PhD

Owing to the high clinical failure rates, genetically variable tumor characteristics, and skyrocketing drug development costs, the era of traditional blockbuster oncology agents has come to an end. With the advent of personalized medicine, we have entered the “niche-buster” era, defined as effective products delivered to identifiable patient segments. The good news is that all cancer stakeholders— oncologists, payers, drug manufacturers, and of utmost importance, the patients—benefit from delivering the right drug to the right person. Companion diagnostics, necessary for safe and effective use of targeted cancer therapies, are making a valuable contribution to patient outcomes as well as providing faster time to market and lower development cost for pharmaceutical companies.

With the success of targeted treatments such as Gleevec (imatinib mesylate; Novartis) and Herceptin (trastuzumab; Roche/Genentech) generating billion dollar sales revenue, the switch to personally-tailored medicine is a fait accompli. In this brave new world of personalized medicine, companion diagnostics have become the industry’s Rosetta Stone and allow researchers to decode which patients will best respond to specific treatments, conduct smaller clinical trials, improve efficacy, reduce side effects, lower development costs, and streamline regulatory approval.

Predictive Versus Reactive Medicine

It’s been 13 years since the FDA approved Herceptin with its eventual companion diagnostic Dako’s HercepTest™ for the treatment of HER2+ breast cancer. Since then, a groundswell of activity and regulatory support for the co-development of targeted therapies with companion diagnostics has only increased in recent years. Companion diagnostic testing predicts treatment response byidentifying alterations in genes such as the wild type K-ras in colorectal cancer, anaplastic lymphoma kinase (ALK), in non-small cell lung cancer (NSCLC), and the mutation in the BRAF gene associated with metastatic melanomas.

Because the wild-type K-ras gene may be a reliable predictor of treatment response to Erbitux (cetuximab; ImClone/Bristol-Myers Squibb/Eli Lilly)and Vectibix (panitumumab; Amgen) in colorectal cancer patients, the European Medicines Agency (EMA) recommends that the label indication for Erbitux be revised in the UK to focus on metastatic colorectal patients with the wild-type K-ras gene. If clinical trials prove equally compelling, the FDA may follow suit and recommend that a companion diagnostic for K-ras testing be included in the metastatic colorectal indication. A number of diagnostic companies have already announced plans to develop and market K-ras assays and in vitro diagnostic (IVD) test kits in anticipation of the future regulatory rulings.

Identifying patients with ALK-positive NSCLC using the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc) resulted in significantly better outcomes for patients with late-stage NSCLC. In the pivotal trial for crizotinib (Xalkori; Pfizor), ALK-positive NSCLC patients treated with the ALK inhibitor resulted in an objective response rate of 50% to 61% in patients who would typically experience a 10% response rate to second- and third-line chemotherapies.1

Recently, the FDA approved Tarceva (erlotinib) for first-line use in metastatic NSCLC patients who test positive for EGFR mutations in exons using the cobas® EGFR Mutation Test. Research demonstrated that EGFR-positive patients receiving Tarceva experienced 10.4 months progression-free survival versus 5.2 months with standard combination therapy. This test should prove valuable since EGFR mutations are typically found in 10% to 30% of NSCLC patients. MolecularMD also has an exclusive patent for diagnostic technology that identifies patients with EGFR T790M mutations, which can predict which patients will be resistant to treatment with Tarceva or Iressa (gefitinib).

Patients with the BRAF V600E mutation receiving Zelboraf (vemurafenib, Roche) experienced improved rates of overall and progression-free survival compared with standard therapy. In this case, the drug company partnered with the diagnostic company Plexxikon during preclinical development of Zelboraf, using the cobas® 4800 BRAF V600 Mutation Test, which resulted in accelerated approval of the drug. Whereas most agents take 10 to 15 years to reach the market, Zelboraf reached the market in less than six.2,3

The FDA approved both Xalkori and Zelboraf in August 2011 with the requirement that the two targeted therapies be used in conjunction with their companion diagnostic tests.

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