The value of companion diagnostics in oncology drug development

KEYWORDS:

• Companion Diagnostics
• Precision Medicine
• Oncology
• Molecular Diagnostics
• Clinical Trials

1. Introduction

An increased understanding of the biology of cancer is leading to a dramatic shift in oncology drug development from a largely nonspecific all-comers approach to a mechanistic driven, precision medicine approach leveraging predictive biomarkers for targeted therapeutics. This shift in oncology drug development is supported by an increase in the development and clinical adoption of companion diagnostic tests that are designed to identify patients that will derive the most benefit from these targeted therapeutics or to exclude patients who are unlikely to benefit from such therapeutics. The use of companion diagnostic assays to select patients are enabling drug developers to address unmet medical needs more effectively by providing tools that facilitate delivery of the right drug to the right patient at the right time. New technological advancements are enabling more sensitive, specific, and tissue sparing methods to assess the level and status of disease associated oncology biomarkers in a clinically meaningful way. It has been demonstrated that biomarker-directed drug development programs are associated with a higher level of success compared to drug development programs that are not biomarker directed [1,2]. This targeted approach where a companion diagnostic is used to identify patients that will derive the most benefit from a drug can streamline drug development and spare patients from being subjected to treatments and their associated side effects when the likelihood of response is low. Given the tremendous value that diagnostics can provide in oncology drug development, their use is increasing and expected to grow further in the future. Here, we describe some of the primary areas where companion diagnostics are currently being used to advance oncology drug development and provide some relevant key examples.

2. Selecting patients with companion diagnostic assays can enrich for robust clinical activity in clinical development

Broadly speaking, predictive biomarkers which are used in oncology drug development are typically genomic alterations or based on protein expression. For the latter, implementation of diagnostics that assess these continuous variables into a drug development program affords the opportunity to explore a putative relationship between the level of a biomarker and response to the drug. A great example of this is HER2, where the semi-quantitative assessment of the HER2 protein using an immunohistochemistry assay led to the first co-approval of a drug (Herceptin) with a companion diagnostic, HercepTest [3]. More recently, drug developers are using the level of PD-L1 expression to enrich for activity with immune checkpoint inhibitors, thereby increasing the benefit–risk ratio for PD-1 directed therapies. From a drug development perspective, utilization of a companion diagnostic for a continuous variable biomarker that is likely to associate with clinical activity for the drug can enable clinical study designs in early development that permit quicker proof-of-concept by restricting initial clinical evaluation to subjects with the highest likelihood of response and simultaneously reducing the number of subjects required to reach this milestone. Adaptive trial designs are increasingly being leveraged to explore the relationship between levels of predictive biomarkers and clinical activity with investigational therapeutics, enabling quicker identification of optimal thresholds for clinical benefit and regulatory approvals in these subsets of patients.

3. Companion diagnostics can be used to exclude patients who are not expected to derive benefit from treatment

In addition to selecting patients who are most likely to derive benefit from a given therapeutic, companion diagnostics have proven valuable in identifying patients with underlying alterations that render them resistant to the drug and thereby provide a tool to identify and exclude these patients from treatment. Alterations that drive resistance to treatment with a given therapeutic can be primary in nature or acquired over the course of treatment. Interrogation of both forms of these resistance mechanisms with companion diagnostics are invaluable approaches in drug development. In the case of primary mutations, companion diagnostics can be used to restrict the treatment with targeted therapeutics to patients that are devoid of alterations that render them insensitive to the drug. A classic example of this exists in metastatic colorectal cancer where companion diagnostics are used to identify patients whose tumors harbor KRAS and NRAS mutations and exclude them from treatment with anti-EGFR treatment [4]. In addition to providing a means to identify and exclude patients from treatment that harbor primary resistance mutations, companion diagnostics can provide a means to identify patients with resistance mutations that are acquired over the course of treatment. Coupling diagnostics that interrogate resistance mutations that arise over the course of treatment with second-generation therapeutics that are rationally designed to target these alterations is an approach that can provide tremendous value to patients and drug developers alike. To assess acquired resistance mutations post disease progression, a re-biopsy needs to be performed which may pose additional risk to patients. In such cases, the use of minimally invasive methods such as blood-based testing is preferred. Circulating tumor DNA (ctDNA) shed from tumor cells into the blood can be used to detect DNA alterations and was first approved as a companion diagnostic to detect EGFR T790M in NSCLC, a resistance mutation to EGFR TKIs. Patients with EGFR T790M mutations detected in either blood or tissue samples are eligible for Osimertinib, a third-generation EGFR TKI [5]. Due to its minimal invasiveness, liquid biopsies are rapidly being adopted in clinical practice for patient management. However, given the high risk of false negatives with liquid biopsies, re-testing with tissue is strongly recommended for cases with negative results [6,7].

4. Companion diagnostics can be used to identify patients based on molecular profile in a tissue agnostic manner

Historically, oncology drug clinical trials have been performed in a site of origin and histology directed manner. An increased understanding of the molecular underpinnings of cancer is paving the way for drug development approaches that are guided by the molecular alterations driving the disease, irrespective of the tissue of origin. Successful implementation of such an approach requires a test that can accurately and reproducibly identify these molecular alterations. Companion diagnostics make tissue agnostic, biomarker-driven drug development efforts a reality by providing a means to identify such alterations. Recent success with therapies designed for patients with NTRK alterations, microsatellite instability (MSI) and tumor mutation burden (TMB) have demonstrated that the presence of these individual biomarkers can be predictive of response to therapeutics in a tissue agnostic manner and have established proof-of-concept for a biomarker-directed/tissue agnostic drug development approach [8]. The potential for tissue agnostic, biomarker-directed drug development creates tremendous opportunities for rapid expansion across indications in drug development and makes development programs in ultra-rare indications commercially feasible by increasing the collective market opportunity.

5. Companion diagnostics to assess disease burden and guide treatment discontinuation

An intriguing area of emerging interest is the use of diagnostics to assess disease burden and guide treatment discontinuation. As treatments improve the outcomes of patients with cancer, more indications are being managed as a chronic condition. With this improvement in disease management, a need arises to identify patients who are in stable remission and can safely discontinue treatment. Assessment of BCR-ABL levels to guide treatment discontinuation in CML represents the first companion diagnostic approved by the US FDA for this utility [9]. Similar approaches are bringing value to oncology drug development through the use of diagnostics for the general evaluation of minimal or measurable residual disease (MRD) where circulating tumor DNA or other biomarkers can be used to assess residual tumor burden and guide treatment discontinuation, treatment-free intervals, or other treatment decisions through adaptive designed clinical trials [10]. MRD is a rapidly expanding area that is currently being investigated in both hematological and solid tumor malignancies as a means to enable a more sensitive assessment of disease burden with multiple areas of potential utility in clinical development ranging from evaluation of the depth of response with new therapeutics to use as a surrogate endpoint, the latter of which could enable shorter clinical development timelines and deliver innovative therapies to patients in need in an expeditious manner.

6. Conclusions and future outlook

In conclusion, a deeper understanding of the association of biomarkers with neoplastic disease, coupled with an increase in the availability and clinical adoption of assays to interrogate these biomarkers is leading to a dramatic shift in oncology drug development and clinical practice [11]. This shift from a nonspecific ‘all-comers’ approach to a targeted ‘biomarker-directed’ approach creates both opportunities and challenges in oncology drug development. This increased focus on a biomarker-directed approach can streamline drug development and give way to therapies with large effect sizes while limiting treatment to patients with the greatest likelihood of clinical benefit. With this comes the challenge to align the co-development of a therapeutic and a diagnostic. However, the rapid pace of innovation in biomarker discovery along with novel ways to assess these biomarkers will no doubt lead to a greater emphasis on the utilization of diagnostics in drug development programs. Increased implementation of comprehensive genomic profiling in both academic and community oncology settings is expected to accelerate participation in biomarker-defined clinical trials with novel targeted therapeutics bringing value to drug developers and patients alike. While significant advancements have been realized in the utilization of companion diagnostics within oncology drug development, the field is still in its infancy and will likely see significant growth going forward.

Declaration of interest

Both authors hold stock in AbbVie. The authors have 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

One of the reviewers declares working as a consultant for Agilent Technologies, Alligator Bioscience, Argenx, and Biovica International within the past 2 years. The other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.