Combining osimertinib with the MET inhibitor savolitinib demonstrated encouraging antitumor activity and an acceptable safety profile in patients with <em>EGFR</em>-mutant, <em>MET</em>-amplified non–small cell lung cancer who previously received EGFR TKIs, suggesting the regimen could be successful in overcoming <em>MET</em>-driven resistance.
Lecia V. Sequist, MD
Combining osimertinib (Tagrisso) with the MET inhibitor savolitinib demonstrated encouraging antitumor activity and an acceptable safety profile in patients withEGFR-mutant,MET-amplified nonsmall cell lung cancer (NSCLC) who previously received EGFR TKIs, suggesting the regimen could be successful in overcomingMET-driven resistance.1,2
Interim phase Ib findings from 2 cohorts of the TATTON trial were presented during the 2019 AACR Annual Meeting looking at the combination of osimertinib and savolitinib. The cohorts included patients withEGFR-mutant NSCLC with acquiredMETamplification following first- or second-generation EGFR TKIs, and patients withEGFR-mutant NSCLC with acquiredMETamplification 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 inEGFR-mutant patients withMETamplification as a resistance mechanism after disease progression or first-, second- and third-generation TKIs.”
METamplification 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 thatMETamplification 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 withEGFR-mutant NSCLC.4
“In the TATTON trial, newer TKIs that have increased specificity for EGFR and MET are used, and patients withEGFR-mutant NSCLC are required to have documentedMET-driven resistance,” she added.
In the first cohort, 46 patients with locally advanced or metastaticEGFR-mutant, T790M-negative NSCLC with acquiredMETamplification 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 forMETpositivity. Criteria forMETpositivity differed between FISH (METgene 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 activityoverall 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.
In the second cohort, 48 patients with locally advanced or metastaticEGFR-mutant NSCLC with acquiredMETamplification following an EGFR TKI, which included osimertinib or an investigational third-generation EGFR TKI, were treated with osimertinib at 80 mg once daily and 600 mg daily of savolitinib. Patients in this cohort had a WHO performance status 0 to 1; they were also enrolled based on the similar testing forMETpositivity.
The median age was 59 years (range, 28-82), 56% (n = 27) of patients were male, and 77% (n = 37) were Asian. Forty-four percent (n = 21) of patients received 2 prior lines of therapy, 27% (n = 13) received 3, and 27% (n = 13) received ≥3 lines of treatment; 1 patient received 1 prior therapy.
Findings showed that, as of the data cutoff in February 2018, 43 patients who had ≥1 post-baseline scan were eligible for an efficacy analysis. The ORR was 25% and there were 12 PRs. Moreover, the median DOR was 9.7 months and the median time to response was 46 days (range, 43-51). The SD rate was 44% (n = 21), the progressive disease (PD) rate was 13% (n = 6), and 9 patients were not evaluable.
Regarding safety, the most common (≥20%) all-grade AEs were nausea (n = 25), vomiting (n = 18), diarrhea (n = 13), fatigue (n = 12), decreased appetite (n = 11), and pyrexia (n = 10). Treatment-related AEs were reported in 43 patients and 23% (n = 11) were classified as grade ≥3. Grade 3/4 AEs were decreased appetite (n = 3), fatigue (n = 2), vomiting (n = 2), nausea (n = 1), diarrhea (n = 1), and myalgia (n = 1).
Ten patients discontinued savolitinib due to AEs and 5 discontinued osimertinib due to AEs. There were 2 patient deaths in this cohort, which were considered to be unrelated to study treatment.
Since TATTON was initiated, frontline osimertinib was approved by the FDA in April 2018 for patients with NSCLC whose tumors harborEGFRmutations (exon 19 deletions or exon 21 L858R substitution mutations). Due to this regulatory decision, only a subset of patients on the study had received frontline osimertinib and had developedMET-driven resistance.
“Our data suggest that the combination of osimertinib and savolitinib could overcomeMET-driven resistance, but certainly further research is needed to determine the final effectiveness of this therapy,” said Sequist during the presentation.
The ongoing phase II SAVANNAH study (NCT03778229) will further evaluate the combination of osimertinib and savolitinib in these patients withEGFR-mutant,MET-positive NSCLC whose disease has progressed on prior osimertinib. Moreover, the planned phase II ORCHARD trial will evaluate both targeted and non-targeted combination treatments in patients with advancedEGFR-mutant NSCLC who have progressed on frontline osimertinib.