Utilizing Companion Diagnostics to Drive Clinical Decisions

Precision oncology originates from the discovery of relevant, unique molecular abnormalities associated with specific cancers. It focuses on the selection of a specific anticancer therapy based upon the presence of an actionable target and disrupting that target’s role in driving cancer growth, thereby optimizing clinical benefit to the patient. Fundamental to the practice of precision oncology is the ability to accurately detect clinically relevant mutations, interpret test results, and apply the genomic information to the selection of the most appropriate agent.

During the past 30 years, the standard of care has transitioned from treating patients exclusively based upon the cancer’s histology, stage, and line of therapy to considering its molecular composition. A new generation of therapies emerged that target specific molecular defects found in tumor cells. Current treatment guidelines for multiple cancers have incorporated the cancer’s genomics into treatment guidelines, stratifying recommendations based upon the molecular signature of the cancer. This shift toward precision oncology seeks to tailor patient treatment plans according to the individual’s unique biological makeup to achieve optimal patient outcomes.

Precision oncology shifts from a one-size-fits-all approach to an emphasis on targeted testing and treatment. It depends upon an understanding of the molecular pathophysiology of cancer, in addition to the capability of a corresponding diagnostic assay to accurately, reliably detect molecular biomarkers. Precision oncology relies on the use of genomic technologies to detect actionable mutations to inform clinical treatment decisions, allowing for selection of therapies that are most likely to benefit specific patients. As precision oncology evolves, companion diagnostics (CDx) are utilized to guide treatment decisions, allowing clinicians to select and sequence therapies to individual patients that best suit their cancer’s unique genomic profile.

A CDx assay is an in vitro diagnostic device that facilitates safe, effective use of a corresponding therapeutic product.^1,2 Testing with this type of assay is mandatory and is included in the drug labeling.³ The success of a biomarker-based treatment lies in the accurate identification of patients exhibiting a required biomarker; therefore, there is a natural dependency between the biomarker-based treatment and the test.⁴

For many therapies, CDx assumes the role of a decisive stratification factor during the clinical development phases and after approval for use in the clinic. The regulatory requirements for CDx assays need to be at a consistent level for their companion drug therapies. To that end, predictive molecular tests are regulated by the FDA. Currently, there are more than 40 cleared CDx assays for oncology indications. The FDA maintains a website of the cleared CDx and their associated therapeutic product(s).⁵

The field of diagnostic testing has also recently undergone exponential growth. The first FDA cleared CDx were single-analyte tests, focusing on a single gene (or protein) of interest. Under the single-testing concept, each treatment is accompanied by a respective biomarker and diagnostic test. The early CDx relied upon more primitive molecular methods, such as in situ hybridization, polymerase chain reaction (PCR) followed by Sanger sequencing, and real-time PCR to interrogate tumor specimens.⁶ This required patients to be tested for different biomarkers in a step-by-step process: if a tumor specimen is negative for the first biomarker tested, then the second biomarker is tested, and if negative, then a third biomarker is tested, and so on. Traditionally, testing for driver mutations in non—small cell lung cancer (NSCLC) followed this process.⁷ Many of the older CDx are classified as single-analyte tests. However, CDx based on next generation sequencing (NGS) are becoming more prevalent as technology advances and new CDx assays are developed and cleared.⁶

NGS tests differ from single-analyte tests by the number of genomic targets being studied within the panel. NGS assays generate robust platforms capable of detecting multiple molecular alterations in multiple genes in a single multiplexed assay. The ability of NGS to comprehensively assess the molecular profile of a tumor has transformed the clinical testing landscape in oncology, facilitating the shift from a paradigm involving 1 gene and 1 drug to a model with multiple genes and many drugs. Cancer, which has several potential causative mutations driving oncogenesis, has the greatest potential to benefit from multiplexed molecular CDx.⁶ Targeted NGS panels are now a mainstay in patient management and are utilized to interrogate a specific set of clinically relevant cancer-related genes. An example of an NGS panel is Foundation Medicine’s 359-gene FoundationOne test. This CDx test can determine the molecular characteristics of NSCLC, melanoma, breast, ovarian, and colorectal cancers, in addition to providing information on microsatellite instability and tumor mutational burden.⁸

NGS panels are increasingly preferred over single- analyte tests because they provide a comprehensive multianalyte solution that conserves time and tissue.⁹ NGS testing minimizes the amount of tissue consumed by avoiding the need for iterative reflex testing as described above with the single-analyte-based assays.¹⁰ This comprehensive tumor genetic profile reduces morbidity from repeat biopsies and potentially lowers health care costs, from fewer procedures required and fewer independent single-drug, single genetic tests ordered. Additionally, the ability to interrogate hundreds of genes and thousands of tumor variants simultaneously with 1 test has the potential to improve our understanding of the complex interactions between overlapping genetic aberrations in a tumor. This enhanced understanding of tumor biology and molecular pathways of therapeutic resistance may ultimately lead to the development of more effective combination therapies to optimize efficacy and delay the development of resistance. Finally, multiplexed tests have the potential to enhance detection of rare variants to guide patients toward appropriate clinical trials, such as the NCI-MATCH (NCT02465060), to enhance the efficacy of drug development, lower drug development costs, and accelerate development timelines.¹¹

There are several challenges facing the utilization of CDx in oncology. The majority of CDx require a tumor tissue sample for analysis. Access to tissue for molecular profiling purposes may be complicated and anatomically limiting for certain types of cancers. Cancer is a diverse group of diseases, and biological heterogeneity exists not only among patients with a similar cancer diagnosis, but also within an individual’s cancer cell populations. The discovery of intratumor heterogeneity has proven particularly challenging to address with current tissue-based assays. Often, tumor tissue may be sampled at a single site and a single point in time, which is susceptible to sampling bias, giving clinicians an incomplete picture of the cancer’s genomic landscape. Additionally, cancer has been found to be a very dynamic process; the cancer a patient is initially diagnosed with is likely molecularly different from the one that will cause a relapse or progresses over time and treatment. Therefore, when patients progress on systemic therapies, repeat biopsy is required to determine the molecular evolution underlying tumor progression.

A novel technology that may alleviate the difficulty in obtaining representative tumor tissue is liquid biopsy. Tumor liquid biopsy technology captures the circulating tumor DNA (ctDNA) in the bloodstream and analyzes it to identify genomic alterations and track the cancer’s genomic evolution over time.¹¹ The utility of ctDNA in response to systemic treatment was demonstrated in multiple studies.¹² Liquid biopsies, compared to their tissue counterparts, are minimally invasive and may be obtained at any time. Theoretically, liquid biopsies are less prone to sampling bias and may circumvent the challenge of intratumor heterogeneity, providing a more comprehensive genomic picture of the cancer.⁹ Liquid biopsies may aid the process of evaluating patients whose tumors have progressed on treatment.

The biology of drug-resistant tumors may significantly evolve over time, and the choice of subsequent treatment depends upon the spectrum of newly acquired targets. The evolution of tumor-resistant lesions under the pressure of systemic treatment may utilize multiple alternative pathways within the same patient. The analysis of treatment-resistant tumors requires repeat biopsies, which may not be feasible or desirable for the patient. Sequential liquid biopsy shows great promise in clarifying the molecular evolution underlying tumor progression as compared to a single, traditional tissue biopsy.¹²

Several barriers to the implementation of CDx into the treatment pathway exist in current clinical practice. The most significant barrier is that the test is not requested. Physicians must be aware of currently available CDx biomarker tests, because treating physicians initiate the testing sequence by ordering the tests. If providers are unaware and not current with the CDx testing available, they will not initiate testing, causing patients to not be given consideration for the associated targeted therapies. Another potential barrier is that the sample is not available for the required test. The accessibility, availability, and quality of sampling is paramount for CDx testing, where the accuracy of the test is compromised if the sample tissue is lacking in quantity or quality. Other times, testing may not be offered by existing labs. An often-cited barrier to the CDx incorporation into clinical treatment pathways is that the test result is not available on time. Oncologists cite test turnaround time and its interaction with the treatment decision window as a key factor in the delivery of precision oncology. A final barrier to the utilization of CDx is that the test may be insufficiently reimbursed.⁴

Precision oncology remains a cornerstone of care for patients with cancer. CDx are an integral part of the process by identifying actionable mutations, allowing clinicians to tailor treatment to the molecular signature of the patient’s cancer. NGS allows a comprehensive description of the cancer’s genome, and when coupled with novel approaches such as liquid biopsy, has the potential to provide insights not only in what is the best treatment option for the patient at diagnosis, but also inform subsequent therapy based upon the cancer’s specific molecular mechanisms of resistance.

KATHERINE LIN, PHARMD, BCOP, is the manager of oncology clinical programs for PANTHERx Rare Pharmacy in Pittsburgh, Pennsylvania.

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