NEW YORK – An exploratory analysis within the Phase I TATTON study suggests that circulating tumor DNA (ctDNA) clearance may be a valuable biomarker for evaluating treatment response in patients with EGFR-mutated, MET-amplified non-small cell lung cancer. The findings were presented during the second virtual session of the American Association of Cancer Research's annual meeting.
The multi-arm TATTON study evaluated the third-generation EGFR tyrosine kinase inhibitor osimertinib (AstraZeneca's Tagrisso) in combination with AstraZeneca's investigational MET tyrosine kinase inhibitor savolitinib in patients with EGFR-mutated, MET amplified non-small cell lung cancer (NSCLC) who had experienced disease progression after treatment with a previous EGFR inhibitor. The initial findings, presented at last year's AACR annual meeting, demonstrated the potential for the combination to overcome MET-based resistance to osimertinib.
The primary aim of the TATTON trial was to evaluate the safety and tolerability of osimertinib in combination with either the MET-inhibiting savolitinib, the MEK-inhibiting selumetinib (AstraZeneca's Koselugo), or the PD-L1-inhibiting durvalumab (AstraZeneca's Imfinzi) and to identify the maximum tolerated doses of the combinations. Beyond this, however, the researchers were also interested in several secondary endpoints, including the correlation of ctDNA clearance of EGFR mutations (exon 19 deletions and exon 21 L858R substitutions) with progression-free survival on the targeted drug combination. This was assessed in parts B and D of the multi-part study, in which patients received the osimertinib-savolitinib combination.
Ryan Hartmaier of AstraZeneca presented the findings at the AACR virtual meeting, noting that the researchers defined ctDNA clearance as patients who had detectable EGFR mutations in baseline ctDNA, which then became undetectable or dropped below a 0.5 percent allele frequency in a subsequent blood sample. Liquid biopsies were taken roughly every six to eight weeks, and the researchers used Resolution BioScience's ctDX Lung assay to detect ctDNA. Most ctDNA clearance, Hartmaier noted, occurred on the first day of the third cycle or the first day of the fourth cycle of treatment, so the researchers chose to focus their progression-free survival analyses on those two time points.
Of the patients in part B with evaluable baseline ctDNA, the median progression-free survival was 3.9 months for patients without ctDNA clearance. In patients who did demonstrate ctDNA clearance, however, that figure jumped to 9.1 months.
Hartmaier and colleagues also evaluated whether ctDNA clearance differed based on the specific dose of savolitinib patients received. Patients in part D and a subset of those in part B had not received a prior third-generation EGFR inhibitor and had tumors that were negative for T790M resistance mutations. However, patients in part B received 600 mg of savolitinib while patients in part D received 300 mg of savolitinib. Both received 80 mg of osimertinib.
Researchers found that ctDNA clearance was comparable in the two dosing groups; clearance was observed in 50 percent of patients in the part B subset and in 65 percent of patients in part D. The percent change of allele frequency from the baseline ctDNA was remarkably similar, Hartmaier pointed out.
"These results are consistent with efficacy being maintained at a lower dose [of savolitinib]," he said, adding that the efficacy of the osimertinib and savolitinib combination in EGFR-mutated NSCLC is being prospectively evaluated in two Phase II studies, SAVANNAH and ORCHARD.
As for the significance of the ctDNA clearance and progression-free survival correlation, the TATTON analysis joins previous analyses from the Phase III FLAURA and AURA3 studies evaluating osimertinib, both of which found correlations of ctDNA clearance with progression-free survival.
"Serial ctDNA analyses can provide information on the potential durability of benefit with combination targeted therapy, intra- and inter-tumor heterogeneity, and mechanisms of primary or required resistance," said Alexander Drilon of Memorial Sloan Kettering in a discussion of the findings following Hartmaier's presentation.
Drilon cautioned, however, that when studying EGFR inhibitor resistance, different assays can produce different MET amplification results. "We need to work on standardizing diagnostic definitions of MET dependence," he said, recognizing that "loose data and poly-assay use make data challenging to interpret." He pointed to the savolitinib program within the TATTON study as a positive example of the value of using a uniform assay.