NEW YORK – Lung cancer diagnostics firm Oncocyte celebrated a new milestone last week as investigators shared data from a prospective study adding to evidence that its DetermaRx test can predict both outcomes and adjuvant chemotherapy benefit in patients with early-stage non-small lung cancer.
According to researchers from Yale and UCSF who presented the data in a poster at the online 2020 IASLC World Conference on Lung Cancer, the results reiterate prior findings for the utility of the 14-gene expression assay and show that its predictive power is independent of EGFR mutation status.
Based on these findings and conversations with thoracic oncologists, Oncocyte believes there could be value in testing patients with DetermaRx and for EGFR mutations in parallel, given new data on adjuvant use of EGFR inhibitors. As a result, the company said it is planning to implement in-house EGFR testing alongside its molecular risk panel.
According to Michael Mann, a co-author of the poster and a lung surgeon at UCSF, tools for guiding adjuvant therapy in NSCLC are a substantial unmet need.
"The desperate problem is that we're losing way too many patients to recurrence of 'early stage' lung cancer — way beyond what's considered reasonable or acceptable in most other solid tumors," he said.
Studies have shown that chemotherapy helps, but applied indiscriminately across the whole population of early-stage lung cancer patients, that benefit has been hard to quantify.
"In stage IA, for example, we're up to 70 percent of patients being cured in the operating room, so it's difficult, if not impossible, to demonstrate the benefit to the other 30 percent by treating all patients because the chemotherapy is not perfectly effective, and it has morbidity and even mortality associated with it," Mann said. Meanwhile, clinical risk assessment doesn’t seem to do a good job of segregating patients who stand to benefit from chemotherapy from those who can be cured by surgery alone.
Chemotherapy aside, investigators have also been working to try to bring EGFR inhibitors into adjuvant treatment, Mann added, with EGFR mutation status acting as a companion biomarker. Most recently, early results from AstraZeneca's ADAURA trial demonstrated a disease-free survival benefit in patients with stage I to IIIA EGFR-mutant tumors treated with adjuvant osimertinib (Tagrisso). The US Food and Drug Administration subsequently accepted a supplemental new drug application from the pharma firm this month.
But according to Mann, there has been some hesitation about the ADAURA results. More specifically, it remains unclear if the early survival data will translate to improved overall survival.
"It's almost certain that you can prolong disease-free survival, which means that you delay the recurrence or the detection of the recurrence. But early studies also indicated … that you could actually worsen overall survival. And what we think might have been the biological explanation there is that by using a [tyrosine kinase inhibitor], you're actually eliminating the most sensitive populations of tumor cells," leaving a cancer more deadly when it does eventually evade EGFR inhibition.
According to Mann, current National Comprehensive Cancer Network (NCCN) guidelines recommend using adjuvant platinum-doublet chemotherapy for stage IB-IIA NSCLC patients if they are considered by their doctors to be at "high risk." However, the recommendations don't endorse specific methods for determining this risk status.
"They already recommend that physicians attempt to try in some way to identify high-risk patients and then intervene … because when we leave them alone, we lose too many of them. But then there's an asterisk to that term, 'high risk' … and when you go down to the bottom of the page and you read that footnote, you're banging your head against the wall because they are saying, 'sorry, doctor, even though we just told you to treat high-risk patients with adjuvant chemotherapy, we have no idea exactly how to identify those high-risk patients. Here are some examples of criteria that you might be able to use, but they may not work.'"
Previous retrospective data on DetermaRx, which is a PCR-based gene expression assay performed on tissue samples, had shown that the test can stratify NSCLC outcomes better than either conventional TNM staging or NCCN high-risk criteria. The Yale and UCSF team extended that in a 2018 study by demonstrating that molecular high-risk patients treated with adjuvant chemotherapy have markedly improved disease-free survival compared to those who don't get treatment.
In their new study, the team hoped to recapitulate the prognostic and chemopredictive findings and to explore how they do or don't relate to EGFR status.
The team followed a group of 250 stage I-IIA non-squamous NSCLC patients, all of whom received DetermaRx molecular risk stratification and whose physicians decided whether or not to treat them with adjuvant chemotherapy based on the results. A subset of patients also received a sequencing test to identify mutations in EGFR, which have emerged as a biomarker for guiding adjuvant therapy with anti-EGFR drugs.
None of the patients deemed low risk based on their molecular test result received adjuvant chemotherapy, but a platinum doublet was recommended for high-risk patients (defined as having a high or intermediate risk score) without consideration of EGFR status. Doctors could choose whether to treat high-risk patients, so while many received therapy, some did not, according to Gavitt Woodard, a Yale thoracic surgeon and the study's first author.
"It's important to note that this is outside of the guidelines," she added. "So this is a group of patients who in general otherwise wouldn't have received adjuvant therapies."
The team used statistical analyses to evaluate differences in freedom from recurrence (FFR) and disease-free survival (DFS) across the cohort. At a median follow up of 29 months, they calculated an FFR rate of 95 percent in molecular low-risk patients, compared to 72 percent in untreated high-risk patients.
According to Woodard, an FFR of 95 percent in low-risk patients is especially notable. "We have an assay that's basically predicting with 95 percent accuracy the group of patients who are cured with surgery … and you can compare that number to the high-risk people who did not receive adjuvant chemotherapy where there is a 30 percent recurrence rate."
In addition to this, there was a clear survival improvement for high-risk patients who received adjuvant chemotherapy compared to those who did not. Treated patients had an FFR of 97 percent, a significant improvement over the 72 percent seen in the untreated group.
Looking just at stage IA patients, for whom current guideline recommendations don't include any use of adjuvant therapy, there was a similar trend. FFR of 97 percent, 73 percent, and 100 percent was seen in low-risk, untreated high-risk, and treated high-risk patients in that group, respectively.
For those patients undergoing EGFR profiling, the team found EGFR mutations in 56 individuals, or about 37 percent. They saw no significant association between EGFR status and recurrence, and although low-risk results were more frequent in EGFR mutation-positive patients, more than a third of them were high risk according to DetermaRx.
More importantly, molecularly-defined risk continued to predict both survival and response to adjuvant chemo within the EGFR-positive group, with DFS of 90 percent, 61 percent, and 100 percent for low-risk, untreated high-risk, and treated high-risk patients, respectively, the authors wrote.
"It is important to know and to understand that this was a prospective study … and it was not randomized … but the question that this study answers, I think, very unequivocally is the lingering question of whether the high-risk patients identified by this assay might be such high risk that they would be recalcitrant to any benefit from any intervention whatsoever," Mann added.
"And with this study, randomized or not, I think it's unequivocal that the high-risk patients who received intervention … had a much better outcome … so clearly, there's the potential for benefit through early intervention."
In some ways, DetermaRx is similar to the recurrence prediction assays that have become ubiquitous in the care of early breast cancer patients. But Mann said that there is an important difference in terms of the precision oncology impact of molecular risk testing in lung cancer versus breast cancer — namely that testing in breast cancer, though also chemopredictive, mainly serves to avoid overtreatment.
In contrast, DetermaRx, if the current data on the assay hold strong, stands to select more patients for adjuvant treatment than currently receive it.
"In lung cancer, the other personalization that exists [mainly] selects patients for late-stage therapies that prolong life but do not result in cure. And so this is really a unique opportunity because of the adjuvant setting, where the disease burden is microscopic still and can be eradicated. It's the first time that we'll be identifying patients through a precision approach and saving their lives on a fairly large scale," Mann said.
Padma Sundar, Oncocyte's senior VP of marketing, said that the new data definitely add credibility to prior findings, especially in terms of survival benefit for molecularly-informed adjuvant treatment in high-risk patients, and will hopefully help persuade oncologists who remained skeptical regarding the weight of evidence for DetermaRx.
The company said on Tuesday that its early testing volume more than doubled from what the firm saw last quarter, reaching 175 billable samples, though this still represents a tiny fraction of the overall market. Sixty-seven hospitals have now contracted to use the test.
According to Sundar, the company's decision to use in-house EGFR testing alongside its own assay is based on feedback from the oncology community as the new evidence for osimertinib has emerged.
"Some physicians want to wait for the overall survival data … but others feel that the disease-free survival data is good enough for stage IB, IIA, and up, so there was a demand created to offer EGFR testing," she said.
"The other thing they said is, if we could offer the testing on the same sample, not only would it be convenient, but then if patients ended up being DetermaRx high and EGFR positive, that might guide them to use [both adjuvant drugs]."
Mann said that he, Woodard and their colleagues, for their part, have already begun recruiting for a prospective randomized trial, largely focused on stage IA patients — who current guidelines recommend avoid adjuvant treatment altogether, but who still recur at rates up to 30 percent. The trial should yield results in about three or four years.
"We are at a point in 21st century medicine where we really, really do not like to implement or recommend a toxic, potentially deadly intervention without prospective randomized evidence of benefit. But we absolutely have equipoise to march forward and do the randomized study that will prove that those patients should not be left to die but deserve this testing and deserve the intervention based on this test," Mann said.