Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer

Abstract

Purpose Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated potent activity against TKI resistance mediated by EGFR T790M. We studied whether noninvasive genotyping of cell-free plasma DNA (cfDNA) is a useful biomarker for prediction of outcome from a third-generation EGFR-TKI, osimertinib. Methods Plasma was collected from all patients in the first-in-man study of osimertinib. Patients who were included had acquired EGFR-TKI resistance and evidence of a common EGFR-sensitizing mutation. Genotyping of cell-free plasma DNA was performed by using BEAMing. Plasma genotyping accuracy was assessed by using tumor genotyping from a central laboratory as reference. Objective response rate (ORR) and progression-free survival (PFS) were analyzed in all T790M-positive or T790M-negative patients. Results Sensitivity of plasma genotyping for detection of T790M was 70%. Of 58 patients with T790M-negative tumors, T790M was detected in plasma of 18 (31%). ORR and median PFS were similar in patients with T790M-positive plasma (ORR, 63%; PFS, 9.7 months) or T790M-positive tumor (ORR, 62%; PFS, 9.7 months) results. Although patients with T790M-negative plasma had overall favorable outcomes (ORR, 46%; median PFS, 8.2 months), tumor genotyping distinguished a subset of patients positive for T790M who had better outcomes (ORR, 69%; PFS, 16.5 months) as well as a subset of patients negative for T790M with poor outcomes (ORR, 25%; PFS, 2.8 months). Conclusion In this retrospective analysis, patients positive for T790M in plasma have outcomes with osimertinib that are equivalent to patients positive by a tissue-based assay. This study suggests that, upon availability of validated plasma T790M assays, some patients could avoid a tumor biopsy for T790M genotyping. As a result of the 30% false-negative rate of plasma genotyping, those with T790M-negative plasma results still need a tumor biopsy to determine presence or absence of T790M.

A Phase I, Dose Escalation Study of Oral ASP8273 in Patients with Non–small Cell Lung Cancers with Epidermal Growth Factor Receptor Mutations

“…Limitations of plasma assays include decreased sensitivity compared with tissue testing, and results can be dependent on tumor volume and the sites of disease (14). Similar to tissue molecular genotyping, EGFR mutations identified within plasma serve as biomarkers that predict response to EGFR TKI treatment (12,15,16). Plasma assays of EGFR exon 19 deletions (ex19del), EGFR L858R, and T790M point mutations are now approved for clinical use (17).…”

EGFR inhibition in NSCLC: New findings…. and opened questions?

“…In addition Oxnard et al showed that outcomes of T790M-positive patients included in the phase I AURA study were similar if T790M was detected in plasma or tumor tissue. Conversely both RR and PFS of T790M-negative patients on plasma were significantly higher than T790M-negative on tissue, and further tumor genotyping of plasma T790M-negative patients allowed to identify a subgroup of T790M-positive patients on tumor tissues who had better outcomes (Oxnard et al, 2016). According to these data the authors suggest that plasma genotyping could represent the first step for the detection of T790M status at the time of PD.…”

“…Recently his group prospectively evaluated the sensitivity and specificity of plasma genotyping by ddPCR in 180 patients with advanced NSCLC, including 60 patients with acquired resistance to EGFR-TKI. Plasma genotyping by ddPCR exhibited 79% specificity and 77% sensitivity in the detection of T790M mutation, which are lower than those observed with EGFR-activating mutations at baseline (Oxnard et al, 2016). In addition Oxnard et al showed that outcomes of T790M-positive patients included in the phase I AURA study were similar if T790M was detected in plasma or tumor tissue.…”

“…2). Interestingly, 18/164 patients with plasma T790M-positive genotyping were T790M-negative on tissue analysis, showing favorable clinical outcomes similar to those of patients with T790M-positive tumor tissue (Oxnard et al, 2016). These data, consistently with those observed in other studies evaluating plasma genotyping approach at the time of PD (Takahama et al, 2016;Thress et al, 2015), demonstrated a lower specificity of plasma-based detection of T790M at PD compared to EGFR-activating mutations detection at baseline, likely due to the higher heterogeneity of TKI-resistant tumors.…”

Complications and Economic Burden Associated with Obtaining Tissue for Diagnosis and Molecular Analysis in Patients with Non-Small Cell Lung Cancer (NSCLC) in the US (Preprint)

“…Although tumor tissue samples remain the gold standard for cancer mutation testing, novel methods of testing are emerging that are less invasive, including those based on cytology samples and ctDNA which should be considered for patients who are ineligible for a tissue biopsy. Various studies support the use of plasma ctDNA samples for the detection of EGFR mutations at diagnosis of NSCLC, including data from the recent AURA (AURA extension, AURA2, and AURA3) and FLAURA studies [18,31,32,17]. The phase I AURA post-hoc analysis (NCT01802632) found that, in patients with advanced NSCLC and EGFR T790M-positive status (according to central tumor genotyping), the sensitivity of plasma ctDNA samples for the detection of T790M was 70% [32].…”