Cancer diagnostic developer Oncocyte is pioneering early-stage detection with novel RNA-based tests for lung cancer.

Limitations of Current Biomarkers

Most blood-based early cancer detection diagnostics in development are based on the analysis of cell-free and tumor-circulating DNA. In order for tumor DNA to be present in the blood of a cancer patient, however, the tumor must be quite large. These diagnostics, therefore, typically only detect mid- to late-stage cancers, and await demonstration that early detection of these large tumors impacts outcomes.

Likewise, although tumor mutation burden (TMB) has been attracting significant attention as a technology for the prediction of patient response to checkpoint inhibitor immunotherapies, its performance has been less than stellar in several recent clinical trials.

Benefits of Using RNA Signatures

TMB diagnostics start in the right place — with the detection of the antigenic trigger of the immune response as a biomarker that can provide the early indication of checkpoint inhibitor potential. However, RNA signatures directly measure that response and may provide much more reliable information.

The presence of mutated or aberrantly modified DNA suggests what could happen in the future, but RNA provides information on what is actually happening within a patient’s cells. Furthermore, by looking at RNA signatures within the innate immune system and how they differ in the presence of disease, it may be possible to monitor disease progression.

Focus on Lung Cancer Detection

Oncocyte is a molecular diagnostics company developing RNA-based diagnostics for cancer, starting with lung cancer, the leading cause of cancer death. Our three product areas target early cancer detection, identification of early-stage patients at high risk for recurrence who may benefit from adjuvant chemotherapy, and prediction of patient response to immunotherapy treatment.

DetermaDx, our foundational product, is a multigene assay that measures gene expression in circulating blood cells to help rule out cancer in patients with lung nodules identified by CT scans. The test utilizes a proprietary immune system interrogation approach and algorithm to integrate the results from RNA sequencing and clinical factors to deliver actionable findings to physicians — identifying a nodule as “likely benign” or “suspicious” — thus enabling patients to avoid potentially risky invasive biopsy procedures.

Every year, more than 1.6 million lung nodules are detected via imaging, but a majority of these nodules are found to be benign following an invasive diagnostic procedure such as a tissue biopsy. According to a JAMA publication, 1 in 5 patients undergoing these procedures has an adverse event, including serious adverse events such as pneumothorax. DetermaDx has the potential to reduce the number of unnecessary procedures by identifying patients with likely benign nodules who could be routed to surveillance instead of an invasive diagnostic procedure.

Oncocyte has completed a CLIA validation study confirming the reproducibility, accuracy, and precision of the gene measurements and the combined multivariate assay. Once clinical validation is completed (summer 2020), Oncocyte will begin preparations for commercial availability. We will work directly with pulmonologists in the United States, and we are currently seeking an external partner with an appropriate platform suitable for building a kit that can be marketed to the rest of the world.

DetermaRx is a treatment stratification test obtained through the acquisition of Razor Genetics. It enables the identification of early-stage lung cancer (stage I and IIA non-squamous non-small-cell lung cancer (NSCLC)) patients who may benefit from adjuvant chemotherapy following surgical resection. The PCR test, which is performed on resected tumor tissue, uses a gene expression analysis of 14 specific genes from a patient’s tumor and a proprietary algorithm to stratify early-stage NSCLC patients into one of two groups: those that may benefit from chemotherapy because of high risk of recurrence and those with low recurrence risk that may avoid chemotherapy.

Identifying patients who may benefit from chemotherapy following surgery allows them to be treated when their cancer may be more responsive to adjuvant chemotherapy. Published clinical studies of over 1,500 patients have shown that high-risk patients identified by this test postsurgery who were treated with adjuvant chemotherapy had a significant increase in survival rates from 49% to 92%. This test has been extensively published in multiple peer-reviewed publications, including in the Lancet, JAMA, and Journal of Thoracic Oncology. DetermaRx became commercially available in the United States in early 2020.

Through our acquisition of Insight Genetics (IG), we are developing a third platform, including the “Immune Modulation” (IM) Score Test, a PCR-based, 30-gene expression test that measures the state of the immune system in biopsies from cancer patients to identify patients more likely to respond to PD-1/PD-L1 immunotherapies. This test looks at the “field of injury," or the tumor tissue field itself, to evaluate the types of immune cells present and to determine with a very high degree of fidelity if a patient will respond to immunotherapy.

In studies in lung and breast cancers, the IM Score Test outperformed PD-1/PD-L1 IHC staining and TMB, two currently marketed predictive companion diagnostic tests for immunotherapy selection, in identifying performers as well as non-performers. This test also addresses an important unmet need: according to a recent JAMA publication, more than 750,000 patients are eligible for immunotherapy annually. However, the response rate for this treatment has only been 12.5%. Given the side effects and high costs of immunotherapy, it is very important to accurately identify responders.

The CLIA-certified and College of American Pathology–accredited lab obtained as part of the IG acquisition has the capacity to support clinical trials or assay design across a range of currently available commercial platforms and has successfully completed audits by major pharmaceutical and diagnostic companies. It also develops and performs proprietary cancer tests. As a result, Oncocyte is now in a position to recruit pharma trials and become a leading companion diagnostics laboratory.

It is worth noting that the two tissue-based PCR tests are advantageous not only because they are based on RNA analysis, but also because they require much less RNA (~50 ng) compared with tests that require extracted DNA (~200 ng). PCR tests can be turned around within 3–5 days, versus the 21 days required for the sequencing technology used by most large laboratories today. Overall, these tests will offer high fidelity while requiring less patient tissue, time, and cost.

Continuum of Care

Our mission at Oncocyte is to provide actionable answers at critical decision points across the cancer care continuum, initially in lung cancer, to improve patient outcomes by accelerating and optimizing diagnosis and treatment. We are developing diagnostic products that will enable physicians to find lung cancer patients at earlier stages, determine whether they need biopsies, identify those that can benefit from chemotherapy or will respond to immunotherapy, monitor disease progression, and determine whether it will return after successful tumor elimination.

While our initial focus is in lung cancer, our tests have applications across all solid tumors. Oncocyte is looking for partners to expand these technologies into other indications. The speed of change in the field of cancer diagnostics over the next 10 years will warp that seen over the last five decades. Oncocyte is excited to lead the industry in the move from late-stage disease management to early-stage detection.