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Lecia V. Sequist, MD
The badociation of osimertinib (Tagrisso) and MET inhibitor, savolitinib, has demonstrated encouraging clinical activity and an acceptable risk-benefit profile in patients EGFR-mutant, MEETamplified non-small cell lung cancer (NSCLC) that had previously received EGFR TKIs, based on the results of the intermediate phase Ib of 2 TATTON cohorts presented at the 2019 AACR annual meeting.1.2
The updated interim data pertained to 2 TATTON study extension cohorts on the combination of osimertinib and savolitinib: in patients EGFRnon-mutant NSCLC with acquired MEET the amplification following the ITK of the first or second generation EGFR, and in patients EGFRnon-mutant NSCLC with acquired MEET amplification after osimertinib or another third generation EGFR TKI.
"These two extension arms of the TATTON study show that osimertinib plus savolitinib has an acceptable safety profile," said Lecia V. Sequist, MD, who presented a exposed on the cohort of expansion at a press conference during the meeting. "The combination showed encouraging anti-tumor activity in EGFR-Muting patients with MEET amplification as a mechanism of resistance after the progression of the disease or first, second and third generation TKI. "
MEET amplification is observed in 5% to 10% of NSCLC patients with disease progression after first- or second-generation EGFR TKI, and in approximately 25% of patients whose disease progresses after EGFR TKI third generation. In addition, preliminary data on the Next Generation Sequencing (NGS) of circulating tumor DNA, presented at the ESMO 2018 conference, demonstrated that MEET Amplification is the most common resistance mechanism (15%) after the first line osimertinib.3
Sequist added that previous combination studies did not show success rates, partly because of the drugs studied and that there was no selection of patients based on biomarkers.
Preliminary results from the expansion phase of the TATTON trial involving multiple cohorts showed acceptable tolerance and clinical activity with savolitinib and osimertinib in patients EGFRMutagenic NSCLC.4
"In the TATTON trial, newer TKIs with increased specificity for EGFR and MET are used, and patients with EGFRnon-mutants must have documentation MEET– motivated resistance, "she added.
In the first cohort, 46 patients with locally advanced or metastatic cancer EGFRNSCLC negative for mutant T790M with acquisition MEET amplifications after ≥ 1 first- or second-generation ITK EGFR were treated with osimertinib 80 mg once daily and 600 mg daily savolitinib, the latter being a potent oral MET-TKI and highly selective. Patients in this cohort were 18 years of age and older and had a WHO performance index of 0 to 1; they were also recruited based on the results of fluorescence in situ hybridization tests (FISH), NGS or local immunohistochemistry (IHC) for MEET positivity. Criteria for MEET positivity differs between FISH (MEET gene copy ≥5 or METICEP7 ratio ≥2), NGS (≥20% of tumor cells, ≥200x depth of sequencing coverage, and ≥1.8 Log2 baduming a tumor fraction of 50%) and IHC (+3 in ≥50% of tumor cells).
The median age was 59 years (range: 41-92), 67% (n = 31) were women and 80% (n = 37) were Asian patients. The majority of patients (67%) had previously received an EGFR-directed treatment line.
The primary endpoint of the two cohorts was safety and tolerability; the secondary endpoints were the badessment of antitumor activity – overall response rate (ORR), response time (DOR), and response time, as badessed by RECIST criteria v1.1.
The results showed that the ORR with the combination was 52%, all composed of partial responses (PR). In addition, 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 (DS) and 7% (n = 3) had progression disease (SD); 3 patients were not evaluable.
In terms of safety, the most common adverse events (≥ 20%) were: nausea (n = 17), diarrhea (n = 14), fatigue (n = 13), decreased heart rate (n = 17), appetite (n = 13), pyrexia (n = 12) and vomiting (n = 10). Grade 3/4 AEs were increases in aspartate aminotransferase (n = 4), decreased neutrophil count (n = 4), fatigue (n = 3), pain (n = 4), = 3), vomiting (n = 2), rash (n = 2). ), nausea (n = 2), decreased white blood cell count (n = 1), and peripheral edema (n = 1).
Sixteen patients stopped treatment with the badociation because of adverse effects. There were 2 deaths related to adverse events; one was due to acute kidney injury potentially related to savolitinib and one to pneumonia considered unrelated to the badociation.
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