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Early EGFR mutation clearance predicts TKI response in NSCLC

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CHICAGO — Undetectable EGFR mutations in plasma 3 to 6 weeks after treatment with a tyrosine kinase inhibitor appears to be a prognostic factor of improved PFS among patients with advanced, EGFR-mutated non-small cell lung cancer, according to a new analysis of data from the phase 3 FLAURA trial.

The results further showed that patients who received osimertinib (Tagrisso, AstraZeneca) had significantly longer PFS vs. those who received a comparator TKI, regardless of their mutation clearance status.

“Early clearance of circulating tumor DNA (ctDNA) was found to correlate with superior PFS with second-line osimertinib treatment in the AURA trials,” Caicun Zhou, MD, PhD, director of the oncology department at Shanghai Pulmonary Hospital and the Cancer Institute of Tongji University Medical School in China, and colleagues wrote. “In this exploratory analysis, we investigated clinical outcomes associated with detection of plasma EGFR mutations at 3 or 6 weeks after start of treatment in FLAURA to determine if early ctDNA clearance predicted outcomes in patients with [EGFR-mutated], advanced NSCLC treatment with a first-line EGFR TKI.”

In the FLAURA trial, patients with advanced, EGFR-mutated NSCLC were randomly assigned to receive first-line treatment with osimertinib (n = 279) or comparator EGFR TKIs (n = 277), which included gefitinib (Iressa, AstraZeneca) or erlotinib (Tarceva; Genentech, Astellas Oncology). Results previously reported by HemOnc Today showed that first-line treatment with osimertinib had superior PFS compared with comparator EGFR TKIs in patients with previously untreated, EGFR-mutated advanced NSCLC.

For the current analysis, Zhou and colleagues used droplet digital polymerase chain reaction technology to test for mutations in plasma samples collected at baseline, week 3 and week 6 posttreatment initiation.

Of the 556 patients enrolled in the trial, 88% (n = 489) had evaluable ctDNA, including 244 in the osimertinib arm and 245 in the comparator arm. Among these patients, 70% (n = 342; 69% in osimertinib arm and 71% in comparator arm) had detectable EGFR mutations at baseline and were included in the analysis.

According to the results, 61% (n = 208) of patients at week 3 and 75% (n = 258) of patients at week 6 no longer had detectable EGFR mutations in plasma. These patients had significantly longer PFS compared with those who had detectable mutations, irrespective of TKI treatment. Median PFS was 13.5 months among patients with undetectable mutations vs. 9.5 months among those with detectable mutations at week 3 (HR = 0.57; 95% CI, 0.4-0.7) and 13.5 months vs. 8.2 months, respectively, at week 6 (HR = 0.51; 95% CI, 0.4-0.7).

In subgroup analyses, the researchers found that osimertinib was superior to comparator TKIs, regardless of clearance status. Among patients with detectable EGFR mutations, median PFS was 11.3 months in the osimertinib arm vs. 7 months in the comparator arm at week 3 (HR = .50; 95% CI, 0.3-0.8) and 11.1 months vs. 8.2 months at week 6 (HR = 0.69; 95% CI, 0.4-1.2). Among those with undetectable EGFR mutations, median PFS was 19.8 months in the osimertinib arm vs. 10.8 months in the comparator arm at week 3 (HR = 0.41; 95% CI, 0.3-0.6), and 19.8 months vs. 10.2 months, respectively, at week 6 (HR = 0.40; 95% CI, 0.3-0.6).

“These data suggest that patients at higher risk of shorter time to progression or death (in the absence of progression) with first-line osimertinib could be identified early in the treatment course,” the researchers concluded. “A serial analysis at additional timepoints over the course of treatment is underway. In addition, further analysis is ongoing to investigate the mechanism underlying the high risk of early progression in patients with detectable plasma [EGFR mutations] following EGFR TKI treatment.” – by Stephanie Viguers

Reference:

Zhou C, et al. Abstract 9020. Presented at: ASCO Annual Meeting; May 31- June 4, 2019; Chicago.

Disclosure: Zhou reports receiving honoraria from Boehringer Ingelheim, Eli Lilly, Hengrui Therapeutics, Merck, Qiru Pharmaceutical and Roche. Please see the abstract for a list of all other authors’ relevant financial disclosures.