Real-World Data Validate Liquid Biopsy For T790M Resistance Mutation

Clinical practice results confirm that liquid biopsy can be used to identify patients with the T790M epidermal growth factor receptor mutation who may benefit from osimertinib therapy

medwireNews: Circulating tumour DNA (ctDNA) can be used as a surrogate for the T790M epidermal growth factor receptor (EGFR) inhibitor resistance mutation in tumour tissue samples, study findings indicate.

“To the best of our knowledge, our analysis is the first to prospectively test in a real-world setting the efficacy of osimertinib according to ctDNA results”, say Benjamin Besse, from University Paris-Sud in France, and co-workers.

The investigators used the proprietary InVision enhanced Tagged Amplicon-Sequencing assay (Inivata Ltd, Cambridge, UK) to process blood samples taken at the time of disease progression from 48 patients with EGFR-mutated advanced NSCLC who had acquired resistance to EGFR tyrosine kinase inhibitor (TKI) therapy.

Fifty percent of the patients tested positive for the ctDNA T790M mutation, including nine patients who had an allele fraction for the aberration of less than 0.5%, the authors report in the Annals of Oncology.

T790Mmutations were detected in 61% of the 33 patients who had originally been diagnosed with an EGFR Del19 activating mutation and 27% of 15 with an EGFR L858Ractivating mutation.

Eighteen patients were treated at time of progression with the third-generation EGFR TKI osimertinib, which targets the T790Mmutation, at a dose of 80 mg/day, and 16 were evaluated for response.

In all, 62.5% of the patients achieved a RECIST-defined partial response to osimertinib therapy and 37.5% had stable disease.

“These results are comparable to the efficacy reported with osimertinib in patients with [T790M] mutation detected in a tumour tissue biopsy”, the researchers comment.

After a median of 8 months, the median progression-free survival (PFS) defined using RECIST criteria had not been reached, but 66.7% and 52.0% of patients achieved 6-month and 12-month PFS, respectively. The investigator-assessed median PFS was 13 months, with 6- and 12-month checkpoints reached by a corresponding 79% and 70% of patients.

And one-year overall survival was reached by 78% of the assessed patients, the researchers add.

Benjamin Besse et al note that response to osimertinib was not significantly associated with the T790M allele fraction, which “suggests that any level of [T790M] positivity may be clinically relevant”.

However, there was a trend towards greater tumour shrinkage with smaller mutant allele fractions of T790M and activating EGFR mutations; three of the seven patients who achieved 50% or greater tumour shrinkage had T790M detected at less than 0.25%.

While acknowledging that the delay of up to 6 weeks between the blood test and osimertinib administration may mean the allele fraction was higher at time of treatment, they conclude: “Our data suggests a possible importance for detection of [T790M]at low allele fractions, but additional studies are needed to confirm the minimum biological threshold with clinical relevance.”

Reference

Remon J, Caramella C, Jovelet C, et al. Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA. Ann Oncol; Advance online publication 19 January 2017. DOI: https://doi.org/10.1093/annonc/mdx017

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