Companion diagnostics: Essential tools for a targeted therapy approach

Companion diagnostic devices were first introduced in the field of oncology. For decades chemotherapy and radiation therapy were the standard of care for cancer patients, however, for some patients, the side effects of these therapies can outweigh the clinical benefit.^1,2 The main reason for this is the inability to target cancerous cells over healthy cells, resulting in off-target side effects.³ In addition, with the knowledge that cancer is not just one disease, but a collection of diseases driven by multiple genes, therapeutic options are now available that are designed to target genetic changes or mutations in cancer cells without harming healthy cells.³ 

To help inform physicians whether targeted therapy will be appropriate for an individual patient, a companion diagnostic is required. As defined by the U.S. Food and Drug Administration (FDA), companion diagnostics ‘provide information that is critical for the safe and effective use of targeted therapies’ and enable physicians to:⁴ 

• Identify patients who are most likely to benefit from a particular therapeutic product
• Identify patients likely to be at increased risk for serious side effects as a result of treatment with a particular therapeutic product; or
• Monitor response to treatment with a particular therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness

The first companion diagnostic was approved in 1998 when an optimized immunohistochemistry (IHC) assay was developed during trials for the breast cancer drug Herceptin (trastuzumab). The assay detected HER2 overexpression in tumors, meaning the patient population most likely to respond to the drug could be identified.⁵

By targeting cancer at its genetic roots Herceptin has saved millions of lives since approval, and has been called the drug that ‘changed the breast cancer treatment landscape’.⁶  Without its companion diagnostic, the HercepTest, this might not have been possible. According to former American Society of Clinical Oncology (ASCO) president Gabriel Hortobagyi, “If an assay did not exist to identify the patient population likely to respond to therapy, trastuzumab might have been discarded during development because of insufficient activity in an unselected patient population.”⁵ The success of this innovative approach to cancer care paved the way for the widely adopted drug and diagnostic co-development model.⁵

Despite this innovation, by 2010 only nine companion diagnostics had been approved by the FDA, with IHC and in situ hybridization (ISH) technologies dominating development.⁷ However, in 2011 the first-ever polymerase chain reaction (PCR) method was approved as a diagnostic test for advanced melanoma patients with a BRAF mutation. The research identified several BRAF mutations responsible for driving melanoma progression, with over 90% at codon 600. This led to the development of vemurafenib, a first-in-class kinase inhibitor of mutant BRAF. The accompanying test detects patients whose tumors express the BRAF V600E gene mutation, allowing physicians to identify patients who could benefit from treatment with vemurafenib.^8,9,10 Since its introduction, the number of approved companion diagnostics has increased dramatically with more than 35 approved between 2011 and 2020.7 PCR-based platforms now represent the largest proportion of assays.¹¹

In 2016 another advancement came when the first liquid biopsy companion diagnostics were approved to utilize blood samples to confirm EGFR exon19 deletions, L858R, and  T790M mutations in patients with metastatic non-small cell lung cancer.¹² Compared to tissue samples, there are several advantages to collecting plasma to evaluate somatic mutations in circulating free DNA. One advantage is that liquid biopsy is significantly less invasive than tissue biopsy, which is particularly important when patients are significantly ill and cannot undergo an invasive procedure. With plasma collection, patient samples can be obtained on multiple occasions without putting their well-being at significant risk. Another advantage is the time to generate results from plasma collection which is much shorter than for tissue samples.¹³

While the ever-increasing number of companion diagnostics and targeted therapies allows for more precise patient care with better outcomes than previous regimens, it brings with it a complexity for the clinician in determining which tests to order and in selecting the best therapy available.¹⁴ Recognizing this situation, in April 2020 the FDA released guidance for device manufacturers regarding procedures on supporting broader claims for companion diagnostics associated with a group of cancer medicines.⁴ This approach was designed to improve patient care by decreasing the need for physicians to order multiple companion diagnostic tests and additional biopsies for patients. According to the FDA, this type of companion diagnostic expansion "could enable greater flexibility for clinicians in choosing the most appropriate therapeutic product based on a patient’s biomarker status”.¹⁵

The first companion diagnostic to be approved using the FDA’s guidance on group claims allowed a single test to be used for a broad group (five at the time) of approved therapies for NSCLC. This enabled the treatment of patients with exon19 deletions and L858R mutated EGFR without requiring a specific clinical trial for each test and therapeutic combination.¹⁶

Today, almost five years after the updated guidance from the FDA was released, only five devices are approved for use with a group of oncology therapeutic products. This means that physicians are still faced with a complex clinical landscape where limited awareness and understanding of biomarker testing available could result in appropriate tests not being ordered, leading to missed opportunities for patients to benefit from targeted treatments.^17,18

Even if physicians are up to speed with available therapies and companion diagnostics, there can be a disconnect with access to testing. Research shows that in the oncology space, it can take up to three years after the launch of a companion diagnostic to achieve sufficient coverage in labs to provide required testing to oncologists.¹⁷ Further challenges exist such as the availability of quality samples, test turnaround time, and reimbursement.¹⁸

Despite these challenges, there are huge benefits to be gained from precision medicine guided by companion diagnostics. Traditional approaches, where prescribers select treatment and dosage with limited biological information, can lead to high rates of ineffective therapies.¹⁹ This can prove to be very costly for healthcare providers through the additional cost of treating adverse events, ongoing testing, and disease progression due to lack of effective treatment.¹⁹

As precision medicine is only used in those patients who are likely to respond, treatment outcomes are improved and health services can operate more efficiently, enabled by companion diagnostics. One study estimated that there would be a 34% reduction in chemotherapy use in women with breast cancer if genetic tests were received prior to treatment, and another estimated cost savings of over $600 billion if patients with metastatic colorectal cancer received testing for the KRAS gene prior to treatment.¹⁹

Emerging technology promises to make the process even more efficient. ‘Next-generation sequencing’ (NGS) is DNA sequencing on a massive scale, which enables multiple tests to be performed on limited amounts of a patient’s tumor tissue within a rapid timeframe allowing physicians to build a comprehensive profile of the patient’s cancer.²⁰

Results from NGS via comprehensive genomic profiling (CGP) can help physicians make data-driven clinical decisions and get patients on the right personalized treatment plan. As it requires only one sample for multiple tests, CGP can decrease the need for repeated invasive procedures for diagnostic testing, reducing unnecessary discomfort for the patient, and in general, healthcare spending.^21,22 Data show that cancer patients treated with a targeted therapy, based on genomic mutations diagnosed via CGP, have better outcomes, including improved overall survival.²³

Despite their challenges, companion diagnostics have transformed the treatment of patients, enabling personalized medicines to treat cancer based on genetic markers. With advancing technology and understanding enabling physicians to uncover the genetic fingerprints of individual cancers, truly personalized healthcare may soon become a reality.

If you want to learn more about comprehensive genomic profiling, click here.