Lecia V. Sequist, MD
The combination of osimertinib (Tagrisso) and the MET inhibitor savolitinib demonstrated encouraging clinical activity and an acceptable risk-benefit profile in patients with EGFR
-amplified non–small cell lung cancer (NSCLC) who previously received EGFR TKIs, according to interim phase Ib findings from 2 cohorts of the TATTON trial presented at the 2019 AACR Annual Meeting.1,2
The updated interim data were of 2 expansion cohorts of the TATTON study looking at the combination of osimertinib and savolitinib: in patients with EGFR
-mutant NSCLC with acquired MET
amplification following first- or second-generation EGFR TKIs, and in patients with EGFR
-mutant NSCLC with acquired MET
amplification following osimertinib or another third-generation EGFR TKI.
“These two dose-expansion arms of the TATTON study show that osimertinib plus savolitinib has an acceptable safety profile,” said Lecia V. Sequist, MD, who presented on both expansion cohorts in a press briefing during the meeting. “The combination showed encouraging antitumor activity in EGFR
-mutant patients with MET
amplification as a resistance mechanism after disease progression or first-, second- and third-generation TKIs.”MET
amplification is seen in 5% to 10% of patients with NSCLC who have disease progression following first- or second-generation EGFR TKIs, and in about 25% of patients whose disease progresses after third-generation EGFR TKIs. Moreover, preliminary circulating tumor DNA next-generation sequencing (NGS) data, which were presented at the 2018 ESMO Congress, demonstrated that MET
amplification is the most common resistance mechanism (15%) following frontline osimertinib.3
Prior similar combination studies did not show success rates, Sequist added, partially due to the drugs studied and that there was no patient selection based on biomarkers.
Preliminary findings of the expansion phase of the multi-cohort TATTON trial demonstrated acceptable safety and clinical activity with savolitinib and osimertinib in patients with EGFR
“In the TATTON trial, newer TKIs that have increased specificity for EGFR and MET are used, and patients with EGFR
-mutant NSCLC are required to have documented MET
-driven resistance,” she added.
In the first cohort, 46 patients with locally advanced or metastatic EGFR
-mutant, T790M-negative NSCLC with acquired MET
amplification following ≥1 first- or second-generation EGFR TKIs were treated with osimertinib at 80 mg once daily and 600 mg daily of savolitinib, the latter of which is an oral, potent, highly selective MET-TKI. Patients in this cohort were ≥18 years and had a WHO performance status of 0 to 1; they were also enrolled based on local fluorescence in situ hybrization (FISH), NGS, or immunohistochemistry (IHC) test results for MET
positivity. Criteria for MET
positivity differed between FISH (MET
gene copy ≥5 or METICEP7 ratio ≥2), NGS (≥20% tumor cells, ≥200x sequencing depth of coverage, and ≥1.8 Log2 ratio assuming 50% tumor fraction), and IHC (+3 in ≥50% of tumor cells).
The median age was 59 years (range, 41-92), 67% (n = 31) were female, and 80% (n = 37) of patients were Asian. The majority of patients (67%) had 1 prior line of EGFR-directed therapy.
The primary endpoint of both cohorts was safety and tolerability; secondary endpoints were assessment of antitumor activity—overall response rate (ORR), duration of response (DOR), and time to response, as assessed by RECIST v1.1 criteria.
Results showed that the ORR with the combination was 52%, all of which were comprised of partial responses (PRs). Additionally, the median DOR was 7.1 months, and the median time to response was 43 days (range, 40-43). Thirty-five percent (n = 16) of patients had stable disease (SD), and 7% (n = 3) had progression disease (SD); 3 patients were not evaluable.
Regarding safety, the most common (≥20%) all-grade adverse events (AEs) were nausea (n = 17), diarrhea (n = 14), fatigue (n = 13), decreased appetite (n = 13), pyrexia (n = 12), and vomiting (n = 10). Grade 3/4 AEs were increased aspartate aminotransferase (n = 4), decreased neutrophil counts (n = 4), fatigue (n = 3), pain (n = 3), vomiting (n = 2), rash (n = 2), nausea (n = 2), decreased white blood cell counts (n = 1), and peripheral edema (n = 1).
Sixteen patients discontinued treatment with the combination due to AEs. There were 2 AE-related deaths; one was due to acute kidney injury potentially related to savolitinib, and one was due to pneumonia that was considered unrelated to the combination.