Plasma Genotyping for EGFR-Mutant Non–Small-Cell Lung Cancer

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI), is FDA-approved for patients with refractory non–small-cell lung cancer (NSCLC) whose tumors carry the EGFR-resistant T790M mutation. Given the difficulty of repeat tumor biopsy, plasma genotyping to detect resistant mutations is under development. Researchers (some with a pending patent on a plasma genotyping method) retrospectively compared plasma genotyping with tumor genotyping in 216 osimertinib-pretreated patients with EGFR-mutant NSCLC who had been enrolled in the AURA trial (NEJM JW Oncol Hematol Jul 2015 and N Engl J Med 2015; 372:1689).

Plasma genotyping by BEAMing (a digital polymerase-chain-reaction test) had a sensitivity of 70% for T790M, 82% for exon 19 deletions, and 86% for L858R mutations. Sensitivity for plasma EGFR-sensitizing mutations was significantly higher when patients had liver metastases (94% vs. 79%) and nonsignificantly higher when patients had any extrathoracic metastases (86% vs. 75%). Of 59 patients with T790M-negative tumors, 18 (31%) had T790M identified in plasma.

Rates of response and progression-free survival (PFS) were similar between patients with T790M-positive plasma and those with T790M-positive tissue. However, patients with T790M-positive plasma and T790M-negative tumors, versus those with both plasma and tissue that were T790M-positive, had significantly lower rates of overall response (28% vs. 64%) and PFS (median, 4.2 vs. 9.3 months). Patients with plasma T790M allelic frequency >10% had significantly better response than patients with <10% frequency, suggesting that T790M is a minor clone in patients with T790M-positive plasma and T790M-negative tumors.