ctDNA EGFR Testing Identifies Proper Patients for Frontline Osimertinib

There was a high concordance between central tissue and plasma circulating tumor DNA (ctDNA) testing for EGFR mutations in patients enrolled in the phase III FLAURA study of frontline osimertinib (Tagrisso) in non—small cell lung cancer (NSCLC).

“These results support the clinical utility of plasma ctDNA EGFR mutation testing for selecting patients eligible for first-line osimertinib treatment,” said Jhanelle E. Gray, MD, a medical oncologist and the director of clinical research in the Department of Thoracic Oncology at H. Lee Moffitt Cancer Center and Research Institute.

Gray presented the plasma ctDNA analysis from the FLAURA study at the 18th World Conference on Lung Cancer.

Overall, in the double-blind FLAURA trial, 556 treatment-naïve patients with EGFR-positive locally advanced or metastatic NSCLC were randomly assigned to osimertinib (n = 279) or a standard TKI (gefitinib/erlotinib; n = 277). Patients with CNS metastases were allowed on the trial and all patients had exon 19 deletions or L858R EGFR mutations.

Daily oral therapy was given with osimertinib at 80 mg, gefitinib at 250 mg, or erlotinib at 150 mg. Patients who progressed on standard care who developed a T790M mutation were allowed to cross over to osimertinib.

At baseline, patients provided tumor tissue samples for central analysis of EGFR mutation status (cobas® EGFR Mutation Test) and blood samples for retrospective analysis of EGFR mutation status by plasma ctDNA (cobas^® EGFR Mutation Test v2).

The primary endpoint of the trial was progression-free survival (PFS) by investigator assessment. PFS by EGFR mutation status detectable in plasma ctDNA was a secondary endpoint.

Among the 556 patients with EGFR mutations who were randomized, 65% (n = 359) were plasma ctDNA EGFR-positive and 22% (n = 124) were plasma ctDNA EGFR-negative. The remaining 13% (n = 73) of patients had plasma ctDNA EGFR mutation data that were missing.

There were 486 patients screened with both valid central tissue and plasma EGFR mutation test results. Among patients with exon 19 deletions, 228 were both tissue and plasma positive, while 60 patients were tissue positive but plasma negative. For patients with L858R mutations, 117 patients were both tissue and plasma positive, while 55 patients were tissue positive and plasma negative. Two patients in the exon 19 deletion subgroup and 4 patients in the L858R subgroup were tissue negative, but plasma positive.

The overall concordance was 87% (95% CI, 84-90) for tissue exon 19 deletion—positivity with plasma. For tissue L858R–positivity, the overall concordance with plasma was 88% (95% CI, 85-91).

In the 556-patient full analysis set (tissue positive), the median PFS was 18.9 months with osimertinib versus 10.2 months with standard of care, representing a 54% reduction in the risk of progression or death (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).

The PFS benefit in the 359-patient plasma ctDNA EGFR—positive subgroup was similar to the full analysis set. The median PFS was 15.2 months with osimertinib versus 9.7 months with standard care, representing a 56% reduction in the risk of progression or death (HR, 0.44; 95% CI, 0.34-0.57; P <.0001). Among the 124-patient plasma ctDNA EGFR—negative subgroup, the median PFS was 23.5 and 15.0 months, respectively, representing a 52% reduction in the risk of progression or death (HR, 0.48; 95% CI, 0.28-0.80; P = .0047).

Summarizing these data, Gray said, “The PFS benefit in the tissue positive/plasma positive subgroup and the tissue positive/plasma negative subgroup is similar.”

For the full analysis set, the overall response rate (ORR) was 80% with osimertinib versus 76% with standard of care (odds ratio [OR], 1.27; 95% CI, 0.85-1.90; P = .2421). For plasma ctDNA EGFR—positive and –negative patients, the ORR rates were 86% versus 82% (OR, 1.33; 95% CI, 0.75-2.37; P = .3294) and 78% versus 66% (OR, 2.08; 95% CI, 0.93-4.80; P = .0764), respectively.

“The ORR benefit in the plasma-positive and the plasma-negative subgroups is consistent with the full analysis set.”

Earlier this month, the FDA awarded a breakthrough therapy designation to osimertinib for the first-line treatment of patients with metastatic EGFR-positive NSCLC, based on the FLAURA findings. If osimertinib is eventually approved in this setting, plasma ctDNA will facilitate patient selection by providing a “less invasive and lower-risk alternative to tumor biopsy when testing for EGFR mutations,” said Gray.

Gray JE, Okamoto I, Sriuranpong V, et al. Osimertinib vs SoC EGFR-TKI as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA): Plasma ctDNA analysis. Presented at: the IASLC 18th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Abstract 8978.