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Oncocyte AACR Data Expands Potential Applications for Immunotherapy Response Predictor

NEW YORK – Oncocyte added new evidence this week that the DetermaIO technology it secured in its acquisition of Insight Genetics last year can predict which cancer patients are likely to respond to immune checkpoint inhibitors (ICIs) across a growing collection of tumor types.

In a presentation at the American Association for Cancer Research's annual meeting on Saturday, researchers from the company shared results from a study evaluating the performance of the firm's test in bladder cancer. The data also demonstrated that the 27-gene expression score likely identifies a different population of patients than established immunotherapy biomarkers, such as tumor mutational burden.

According to Oncocyte, the results in bladder cancer — the third tumor type the company has targeted with the assay — bode well for the test's potential multi-cancer or pan-cancer utility, similar to how biomarkers like tumor mutational burden (TMB) and microsatellite instability/mismatch repair deficiency have been implemented.

DetermaIO measures the expression of 27 genes associated with components of the tumor immune microenvironment that influence both immunotherapy sensitivity and resistance. These are then weighted using a proprietary algorithm.

Earlier studies have demonstrated the test's ability to predict immunotherapy response in lung and breast cancers in cohorts treated with four US Food and Drug Administration-approved ICIs: pembrolizumab (Merck's Keytruda), nivolumab (Bristol Myers Squibb's Opdivo), atezolizumab (Genetech's Tecentriq) and durvalumab (AstraZeneca's Imfinzi).

At the AACR meeting this week, Robert Seitz, head of immune oncology at Oncocyte, shared new results from his team's prospectively defined analysis of retrospective clinical trial results from the IMvigor210 study of atezolizumab in patients with metastatic urothelial carcinoma.

The study cohort included 119 patients who had been deemed ineligible for platinum chemotherapy, and another 310 who had progressed after platinum treatment. Although both indications were granted accelerated approval — the former in patients with a certain degree of PD-L1 positivity and the latter with no biomarker requirement — Genentech recently voluntarily withdrew the second post-platinum bid.

The Oncocyte team ran the DetermaIO signature on publicly available RNA-seq data for 348 patients from the trial, comparing results to these individuals' overall survival at two years. According to Seitz, the results demonstrate a significant correlation between DetermaIO and outcomes, with a "highly significant" hazard ratio of .612.

The improved-survival population that DetermaIO identified was also fairly large, representing 41 percent of treated patients in the study. This group survived 12.9 months, on average, versus 8 months for those who tested negative.

The researchers were also able to compare the Oncocyte assay to other biomarkers and biomarker signatures using data published in the initial clinical reports from the trial, and in a later biomarker analysis published in 2018.

Seitz said the results from these bivariate analyses show that DetermaIO was independent of both clinical factors and of these alternative biomarkers and suggested that it is identifying additional responsive patients that would be missed by currently used tests, including PD-L1 and TMB.

TMB also retained its own independence in these statistical comparisons, which led the team to consider whether the two biomarkers might work synergistically in a decision-tree model.

To explore this, they focused on the subset of trial patients who had been previously treated with platinum chemotherapy, the group for which Genetech recently withdrew its bid for atezolizumab approval.

For these 272 patients, the hazard ratio for two-year overall survival in DetermaIO-positive versus -negative patients was .585, very similar to the overall cohort.

Hypothesizing a decision-tree setting combining either a DetermaIO positive result or TMB of at least 15 mutations per megabase, Seitz and colleagues calculated that they could identify an improved survival group representing nearly half the cohort.

Because TMB only stratified 20 percent of patients in the study to a higher survival curve when used alone, the addition of DetermaIO represents a significant improvement, Seitz said.

Moreover, looking at double-positives — patients who were both DetermaIO-positive and TMB-high — there was no meaningful improvement in response or survival. This suggests that the value of combining the two tools is likely a result of uniting the unique patient groups they identify as opposed to a function of identifying patients carrying both biomarkers, Seitz added.

As the field strives to find ways to identify as many immunotherapy-responsive patients as possible, gene expression and RNA is not the only area of interest. Other efforts are also investigating genomic signatures that could be layered on TMB to capture additional groups that stand to benefit from these drugs.

In another presentation at the same AACR session, for example, researchers from the Dana-Farber Cancer Institute reported on their analysis of aneuploidy levels in a group of non-small-cell lung cancer patients treated with ICIs, concluding that tumors with low aneuploidy appear to have a distinct immune microenvironment and more favorable outcomes to ICIs.

Similar to what Oncocyte has been observing with DetermaIO, the discrimination offered by this aneuploidy approach also seemed to be independent of PD-L1 expression levels and  TMB.

According to Oncocyte Chief Science Officer Doug Ross, the company's bladder cancer data is particularly exciting because it illustrates how tools like DetermaIO could potentially help resuscitate failed therapy indications.

"We look forward to sharing data in additional tumor types as the year progresses and also to working with biopharma and pharma companies to improve outcomes for their trials," he said in a statement.

Mamta Parikh, a medical oncologist and assistant professor at the UC Davis Comprehensive Cancer Center further noted in a statement that Oncocyte's results are "provocative" considering recent voluntary withdrawals of atezolizumab and durvalumab in patients with platinum-refractory advanced bladder cancer based on lagging efficacy in randomized Phase III studies.

"Even in these studies" Parikh said, "there remain patients who benefit from ICIs and have durable responses to treatment. Thus, a biomarker strategy to identify these patients remains a significant unmet medical need and has the potential to explain a lack of efficacy seen in unselected patient populations."

"As new treatments for metastatic urothelial cancer have emerged, a better predictive biomarker for ICIs has become even more important as a means to identify those patients likely to benefit from immunotherapy and spare those unlikely to benefit so that they may be treated with other active agents," she noted.

Thus far, all of Oncocyte's efforts around DetermaIO have been retrospective, and Seitz said during the presentation that the firm's next data will continue that trend, as the company works to complete another prospectively defined analysis of retrospective data in collaboration with researchers from the NeoTRIP trial of atezolizumab in early, high-risk triple-negative breast cancer.

The company does not yet sell the test for use in patients but has validated it to run in its CLIA lab, which would make prospective use in drug trials a possibility.

In a discussion following the AACR presentation, Alexandra Snyder, associate vice president of translational oncology at Merck, said that the fact that transcriptional profiling can be used to define subsets of patients more likely to benefit from checkpoint blockade is exciting, but there are still unanswered questions and hurdles to turning signatures like DetermaIO "into tests that can be used in clinical trials and ultimately in clinical practice."

"It's challenging to figure out how to develop selection markers when the therapeutic paradigms are changing so fast … [and to] apply biomarkers developed from retrospective analyses of single agents to trials that are in flight," she said.

Although Oncocyte is hopeful that its growing data in multiple tumor types portends pan-cancer utility, Snyder said it's not yet clear which signatures are likely to be tumor-specific and which will be reliably universal.

"As recent debate over TMB has shown, as a field we are really struggling to strike a balance between the practical, regulatory, and scientific considerations of developing a pan-cancer versus an indication-specific test," she added.

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