August 23, 2016
4 min read

Plasma analysis shows promise for NSCLC T790M genotyping

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Patients with T790M–positive advanced non–small cell lung cancer demonstrated similar outcomes with osimertinib whether the T790M mutation was detected using plasma analysis or a tissue-based assay, according to a retrospective analysis of the AURA trial.

Thus, plasma analysis may provide a less invasive diagnostic alternative to undergoing a tumor biopsy to detect acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors, according to the researchers.

Geoffrey Oxnard
Geoffrey R. Oxnard

Previous data from the AURA trial showed that osimertinib (Tagrisso, AstraZeneca) — a third-generation EGFR TKI — demonstrated a superior response rate (61% vs. 21%) and prolonged median PFS (9.6 months vs. 2.8 months) in patients with T790M–positive vs. –negative tumor genotyping.

“This mutation has emerged as a new biomarker for guidance of treatment in patients with NSCLC with acquired resistance to prior EGFR TKI,” Geoffrey R. Oxnard, MD, physician at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, and colleagues wrote. “This represents a clinical challenge because tumor genotyping for EGFR T790M requires a biopsy to be performed after resistance develops, which is a procedure that carries risks, can delay subsequent therapy and may not always be feasible.”

Oxnard and colleagues performed a post-hoc analysis using plasma samples from the AURA trial to determine whether noninvasive genotyping of cell-free plasma DNA — performed using BEAMing (Sysmex Inostics) — is a useful biomarker to predict outcomes with osimertinib.

The analysis included 308 patients who had acquired EGFR–TKI resistance and presented with evidence of a common EGFR–sensitizing mutation. Patients were eligible for the current analysis based on central tumor genotyping for T790M (n = 237), central plasma genotyping (n = 271) or both (n = 216).

Researchers used the diagnostic analysis set of 216 patients with central tissue genotype as the reference cohort. In this cohort, sensitivity of plasma genotyping for T790M was 70% (95% CI, 63-77) in patients positive for T790M on central tumor genotyping.

“Of note, T790M was detected in 80% of patients with vs. only 5% of patients without a detectable EGFR–sensitizing mutation in plasma, which indicates that detection of the resistance mutation in plasma is unlikely when a sensitizing mutation is not detected,” the researchers wrote.

Of 58 patients who were T790M negative on central tumor genotyping, 18 were T790M positive in plasma. However, researchers attributed the heterogeneous presence of resistance mutations across disease sites, rather than the false positives of the assay, as the source of this discordance between tissue and plasma results.

The clinical outcomes analysis included 231 of the 237 patients with central tumor genotyping and all 271 patients with central plasma genotyping.

Results showed the overall response rate to osimertinib was comparable among patients with T790M detected in plasma and tumor tissue (63% vs. 62%). Median PFS also was comparable between these cohorts (9.7 months for both).

Patients with T790M–negative plasma demonstrated favorable outcomes (ORR, 46%; median PFS, 8.2 months), whereas patients with T790M–negative tumor tissue had poorer outcomes (ORR, 26%; median PFS, 3.4 months).

Researchers then divided patients with T790M–negative plasma results based on their tumor tissue biopsy results. Results showed patients with T790M–positive tumors compared with T790M–negative tumors had a better ORR (69% vs. 25%) and longer median PFS (16.5 months vs. 2.6 months).

“Our data suggest that plasma and tumor genotyping can have complementary roles for T790M testing, where plasma genotyping could be the initial step and a biopsy for tumor genotyping could be supplementary,” Oxnard and colleagues wrote. “In contrast, if plasma genotyping for T790M is negative, this result cannot fully obviate need for a tumor biopsy. As the plasma T790M–negative population is a mixture of true and false negatives, biopsy to further investigate the presence of T790M–positive tumor tissue is warranted.”

The researchers acknowledged this was not a preplanned analysis of the AURA trial. Further, the study population may not be representative of all patients with acquired EGFR–TKI resistance because it was enriched for T790M–mutation positive patients, which could limit the results.

“Given the ease and reduced risk of plasma analysis compared with an invasive biopsy procedure, data support a new paradigm for resistance management, with rapid plasma genotyping as a diagnostic option before undergoing a tumor biopsy,” Oxnard and colleagues wrote. “Patients negative for T790M in plasma, however, should undergo a biopsy to determine T790M status because of the risks of false-negative plasma results.”

Genomic analysis focused on the primary tumor genome at the time of diagnosis provides limited information on therapy-induced changes during treatment, Rafael Rosell, MD, PhD, director of the Cancer Biology and Precision Medicine Program at Catalan Institute of Oncology of Hospital Germans Trias i Pujo in Barcelona, Spain, and Niki Karachaliou, MD, medical oncologist and member of the Translational Research Group at Pangaea Biotech SA of Quiron-Dexeus University Hospital in Barcelona, Spain, wrote in an accompanying editorial.

“The study by Oxnard [and colleagues] ushers in the forthcoming broad application of blood assays for detection and monitoring of EGFR acquired resistance mutations ... as well as first-line monitoring therapies of NSCLC to prevent development of T790M,” they wrote. “Next-generation sequencing methods can also detect co-occurring additional mutations.” – by Kristie L. Kahl

Disclosure: Oxnard reports honoraria from AstraZeneca, Boehringer Ingelheim and Chugai Pharma, and consulting fees from ARIAD Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Genentech, Inivata and Sysmex. Please see the full study for a list of all other researchers’ relevant financial disclosures. Rosell and Karachaliou report no relevant financial disclosures.