ELCC 2016: Studies Confirm Benefit of Plasma Genotyping to Predict Treatment Benefit in Patients With Non–Small Cell Lung Cancer
The benefit of plasma genotyping to predict treatment benefit in patients with non–small cell lung cancer (NSCLC) was confirmed in three studies presented April 15 at the European Lung Cancer Conference (ELCC) 2016 in Geneva. However, researchers warned that plasma tests are unlikely to fully replace tissue biopsies.
Patients with NSCLC are tested for epidermal growth factor receptor (EGFR) mutations, which indicate their suitability for targeted EGFR tyrosine kinase inhibitor therapy. Tissue biopsies are the gold standard, but are not possible in around 20% of NSCLC patients. Plasma is a potential alternative for EGFR mutation analysis through extraction of circulating tumor DNA (ctDNA).
Normanno et al
The primary results of the ASSESS trial, presented at ELCC 2015, demonstrated that ctDNA is suitable and feasible for EGFR mutation analysis in real-world practice.
The first analysis presented at ELCC 2016 on the topic by Normanno et al (Abstract 58O_PR) examined whether patient disease or demographic characteristics influenced the detection of EGFR mutations in plasma. There was increased sensitivity of EGFR mutation detection in plasma associated with increasing number and severity of metastases. EGFR mutation detection in plasma was also significantly higher in patients aged less than 65 years old compared with older patients. These findings were independently confirmed by the companion IGNITE study.
“Further studies are required to confirm these findings and identify potential underlying biologic mechanisms—the age finding in particular is interesting,” said Nicola Normanno, MD, Chief of the Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Naples. “The increased ability to detect EGFR mutations in plasma from patients with a higher number of organs with metastases makes sense biologically, as these patients have higher tumor burden and we could expect more ctDNA to be released in the blood. The same could also be true for patients who have metastases to organs further away from the lungs (M1b).”
He continued, “The link with age is more difficult to understand. Evidence suggests that the biologic features of certain tumors change with age. However, the specific biologic mechanisms underlying the correlation between the success of plasma analysis and age will need to be investigated further.”
Commenting on the implications of the findings for clinical practice, Dr. Normanno said, “If plasma testing is more reliable for some patients with certain characteristics, this may have implications in the way that we conduct mutation testing for patients with NSCLC, and ultimately impact upon treatment decisions. Our data suggest that for the majority of patients with metastatic disease, a plasma test could be sufficient to determine EGFR mutation status particularly when a robust and reliable methodology is used. Due to the low sensitivity of plasma genotyping (60%–70%), a biopsy will still be recommended in plasma-negative cases.”
Oxnard et al
Also presented by Oxnard et al (Abstract 135O_PR) was an analysis from the phase I AURA trial of osimertinib (Tagrisso), a third-generation T790M-targeting EGFR inhibitor. Eligibility for the drug is currently determined through a positive biopsy test for T790M. The study evaluated the effectiveness of osimertinib, based on tumor results or plasma results, in patients with acquired resistance to first-line EGFR inhibitors who had the T790M mutation L858R or exon 19 deletion.
Positive T790M biopsies correlated with high response rates and long progression-free survival, while those with T790M-negative tumors had a low response rate and modest progression-free survival. Patients with T790M-positive plasma had high response rates and long progression-free survival. But those with T790M-negative plasma had mixed outcomes.
“The first conclusion is that a noninvasive blood test appears to have the ability to find T790M-positive patients very effectively,” said lead author Geoffrey Oxnard, MD, a thoracic cancer physician at Dana-Farber Cancer Institute. “But the blood test only has a sensitivity of 70% or 80%, so there are false-negatives. In other words, if you have a negative result in the blood test, it may be that the mutation was present but not detected.”
Dr. Oxnard continued, “When we studied the tumor results on patients who were T790M-negative in the blood, we could differentiate those who do better or worse on osimertinib, meaning that a biopsy is an effective fallback to clarify who should and who shouldn’t get the drug. We conclude that a two-stage approach is needed, starting with the blood test. Patients who test positive for T790M on the blood test can receive osimertinib. Those who test negative should have a biopsy test to clarify their T790M status.”
A surprising result was that some patients were T790M-negative in the tumor but T790M-positive in the blood test. “This suggests that the resistant mutation might be present in just a subset of the cells, or only in some sites of the tumor,” said Dr. Oxnard. “A biopsy may not capture the cancer’s resistance across all sites of disease, but a blood test does. Patients with this apparent false-negative tissue result did not respond as well to osimertinib as patients with a positive test. It could be that if T790M is only in a subset of resistance cells, there may be other resistance mechanisms hidden in the tumor that reduce the effect of the drug.”
Jenkins et al
A second study of osimertinib presented by Jenkins et al (Abstract 134O_PR), limited to patients with an EGFR T790M mutation in whom a previous EGFR inhibitor had failed, found a high concordance between plasma-positive and tissue-positive tests. Patients with either positive test responded to the drug to a similar degree.
“The data demonstrates that the responses are equivalent, which hopefully will ultimately lead us to a point where we no longer have to do a biopsy in every patient,” said study coauthor Pasi Jänne, MD, PhD, Professor of Medicine at Dana-Farber Cancer Institute. “I think we will see more and more plasma testing for genetic alterations in lung cancer, where we are trying to treat a genetically defined patient population.”
He added, “Blood can be drawn on every patient, whereas biopsies are not feasible in everybody, so that opens up the spectrum of patients who can be tested. With a blood test, you can isolate and analyze the DNA much faster than you can do a biopsy, so eligibility for treatment could be determined more quickly.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
