ctDNA Clearance Predicts Progression-Free Survival With Osimertinib/Savolitinib in EGFR-Mutant, MET-Amplified NSCLC
Circulating tumor DNA (ctDNA) clearance of EGFR mutation—that is, detectable mutation at baseline that became undetectable or dropped below a predetermined threshold—appears to be predictive of extended progression-free survival for patients with EGFR-mutant, MET-amplified non–small cell lung cancer (NSCLC) with detectable ctDNA at baseline, according to an analysis of the phase I TATTON study presented at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II.1 The study also showed that most ctDNA-evaluable patients had a molecular response to the combination of osimertinib (targeted to EGFR) and savolitinib (a highly selective MET inhibitor).
Ryan Hartmaier, PhD
“Up to 10% of patients with EGFR-mutated NSCLC who have disease progression on first- and second-generation EGFR tyrosine kinase inhibitor therapy and up to 25% of those who have disease progression on osimertinib have MET amplification and other types of MET-based resistance. The TATTON study explored whether combined treatment with a potent, highly selective MET inhibitor and a third-generation EGFR tyrosine kinase inhibitor could overcome MET-mediated resistance to prior EGFR tyrosine kinase inhibitor therapy,” explained lead author Ryan Hartmaier, PhD, Associate Director of Translational Science at AstraZeneca in Waltham, Massachusetts.
TATTON had a complex design, and Dr. Hartmaier presented exploratory analyses of parts B and D at the AACR meeting.
TATTON Parts B and D
TATTON Part B had three dose-expansion cohorts characterized by prior exposure to an EGFR tyrosine kinase inhibitor and T790M mutation status, and all patients received osimertinib at 80 mg and savolitinib at 600 mg or 300 mg. Part B1 consisted of 69 patients treated with a prior third-generation EGFR tyrosine kinase inhibitor; part B2 included 51 patients with EGFR T790M mutation–negative tumors who had not had prior treatment with a third-generation EGFR tyrosine kinase inhibitor; and part B3 had 18 patients with EGFR T790M–positive tumors who had not received a prior third-generation EGFR tyrosine kinase inhibitor.
Parts B2 and B3 (no prior treatment with third-generation EGFR tyrosine kinase inhibitor) revealed the highest objective response rates and median progression-free survival on the combination therapy: 65% and 67%, respectively. Median progression-free survival was 9 months for patients in part B2 and 11 months for those in part B3. For part B1 (prior treatment with third-generation EGFR tyrosine kinase inhibitor), the objective response rate was 30%, and median progression-free survival was 5.4 months.
The TATTON part D cohort consisted of 42 patients with no prior third-generation EGFR tyrosine kinase inhibitor treatment who received osimertinib at 80 mg and savolitinib at 300 mg. The objective response rate was 64%, and median progression-free survival was 9.1 months, comparable to results in part B2, the analogous 600-mg savolitinib cohort, Dr. Hartmaier observed.
Post Hoc ctDNA Analysis
An analysis was performed on 49 patients enrolled in part B and 20 patients from part D of the TATTON trial to determine whether longitudinal clearance of baseline ctDNA could be a predictor of progression-free survival in patients with EGFR-mutant, MET-amplified NSCLC. ctDNA sampling was performed every 6 to 8 weeks, and ctDNA clearance was defined as detectable EGFR mutation at baseline that became undetectable or dropped below 0.5% allele frequency in a longitudinal sample assessed by the Resolution ctDx lung assay. Of patients enrolled in parts B and D evaluable by ctDNA, 38 (78%) and 16 (80%), respectively, had detectable EGFR at baseline.
A waterfall plot of EGFR mutation allele frequency change during therapy in patients with detectable ctDNA at baseline “clearly shows that most patients display a major molecular response to this combination therapy, including those with a partial response and stable disease,” Dr. -Hartmaier said. For patients with and without ctDNA clearance, median progression-free survival was 9.1 months vs 3.9 months, respectively—a 66% improvement for those with ctDNA clearance (P = .0146).
Next, the researchers explored alterations in ctDNA related to osimertinib in combination with savolitinib at 600 mg or 300 mg in 13 patients from part B2 and 16 patients from part D (no prior EGFR tyrosine kinase inhibitor and T790M-negative disease). ctDNA clearance was observed in 50% and 65% of patients, respectively. Partial responses and stable disease were observed in both groups.
The combination of savolitinib at 300 mg and osimertinib at 80 mg is being evaluated in the phase II SAVANNAH study in EGFR-mutant, MET-amplified NSCLC treated with prior osimertinib, as well as in the phase II ORCHARD study in patients with advanced NSCLC who had disease progression on front-line treatment with osimertinib.
DISCLOSURE: Dr. Hartmaier is an employee and stockholder of AstraZeneca.
1. Hartmaier R, Han JY, Ahn MJ, et al: The effect of savolitinib plus osimertinib on ctDNA clearance in patients with EGFR mutation positive MET-amplified NSCLC in the TATTON study. 2020 AACR Virtual Meeting II. Abstract CT303.
Alexander Drilon, MD
Discussant of the TATTON study presentation, Alexander Drilon, MD, Chief of Early Drug Development at Memorial Sloan Kettering Cancer Center, New York, finds the idea of combination therapy with a MET inhibitor and an EGFR tyrosine kinase inhibitor attractive for the...