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ctDNA clearance tracks with PFS in NSCLC subtype



Clearance of circulating tumor DNA (ctDNA) correlates with longer progression-free survival (PFS) in patients with EGFR-mutant, MET-amplified non–small cell lung cancer (NSCLC) treated with EGFR- and MET-targeted therapies, according to an analysis of data from the phase 1b TATTON study.

The median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for those without ctDNA clearance three to four cycles after starting treatment with osimertinib, an EGFR tyrosine kinase inhibitor (TKI), and savolitinib, a MET TKI (P = 0.0146).

“[O]ur findings indicate that EGFR-mutant ctDNA clearance may be predictive of longer PFS for patients with EGFR-mutant, MET-amplified non–small cell lung cancer and detectable ctDNA at baseline,” said investigator Ryan Hartmaier, PhD, of AstraZeneca in Boston, Mass.

Dr. Hartmaier presented these findings at the AACR virtual meeting II.

Prior results of TATTON

Interim results of the TATTON study were published earlier this year (Lancet Oncol. 2020 Mar;21[3]:373-386). The trial enrolled patients with locally advanced or metastatic EGFR-mutant, MET-amplified NSCLC who had progressed on a prior EGFR TKI. Results included patients enrolled in parts B and D.

Part B consisted of patients who had previously received a third-generation EGFR TKI and patients who had not received a third-generation EGFR TKI and were either Thr790Met negative or Thr790Met positive. There were 144 patients in part B. All received oral osimertinib at 80 mg, 138 received savolitinib at 600 mg, and 8 received savolitinib at 300 mg daily. Part D included 42 patients who had not received a third-generation EGFR TKI and were Thr790Met negative. In this cohort, patients received osimertinib at 80 mg and savolitinib at 300 mg daily.

The objective response rate (all partial responses) was 48% in part B and 64% in part D. The median PFS was 7.6 months and 9.1 months, respectively.

Alexander E. Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York said results of the TATTON study demonstrate that MET dependence is an actionable EGFR TKI resistance mechanism in EGFR-mutant lung cancers.

“We all would welcome the approval of an EGFR and MET TKI combination in the future,” Dr. Drilon said in a discussion of the study at the AACR meeting.

According to Dr. Hartmaier, MET-based resistance mechanisms are seen in up to 10% of patients with EGFR-mutated NSCLC following progression on first- and second-generation EGFR TKIs, and up to 25% of those progressing on osimertinib, a third-generation EGFR TKI.

“Nonclinical and clinical evidence suggests that combined treatment of a MET inhibitor and an EGFR TKI could overcome acquired MET-mediated resistance,” he said.

ctDNA analysis

Patients in the TATTON study had ctDNA samples collected at various time points from baseline through cycle five of treatment and until disease progression or treatment discontinuation.

Dr. Hartmaier’s analysis focused on ctDNA changes from baseline to day 1 of the third or fourth treatment cycle, time points at which the bulk of ctDNA could be observed, he said.

Among 34 evaluable patients in part B who received savolitinib at 600 mg, 22 had ctDNA clearance, and 12 had not. Among 16 evaluable patients in part D who received savolitinib at 300 mg, 13 had ctDNA clearance, and 3 had not.

Rates of ctDNA clearance were “remarkably similar” among the dosing groups, Dr. Hartmaier said.

In part B, the median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for patients without clearance (hazard ratio, 0.34; 95% confidence interval, 0.14-0.81; P = 0.0146).

Dr. Hartmaier did not present PFS results according to ctDNA clearance for patients in part D.

Dr. Drilon said serial ctDNA analyses can provide information on mechanisms of primary or acquired resistance, intra- and inter-tumoral heterogeneity, and the potential durability of benefit that can be achieved with combination targeted therapy. He acknowledged, however, that more work needs to be done in the field of MET-targeted therapy development.

“We need to work on standardizing diagnostic definitions of MET dependence, recognizing that loose definitions and poly-assay use make data challenging to interpret,” he said.

The TATTON study was supported by AstraZeneca. Dr. Hartmaier is an AstraZeneca employee and shareholder. Dr. Drilon disclosed relationships with AstraZeneca, Pfizer, Helsinn, Beigene, and other companies.

SOURCE: Hartmaier R, et al. AACR 2020, Abstract CT303.

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