medwireNews: Preliminary data from the INSIGHT 2 study suggest that the combination of tepotinib and osimertinib has activity in patients with EGFR-mutated advanced non-small-cell lung cancer (NSCLC) with MET amplification who have progressed on first-line osimertinib.
MET amplification is a known key mechanism of resistance to front-line osimertinib, observed in 15–30% of patients, and “is associated with a poor prognosis,” explained presenter Julien Mazieres, from CHU de Toulouse in France, at the ESMO Congress 2022 in Paris, France.
He added that combining the MET inhibitor tepotinib with the EGFR–tyrosine kinase inhibitor gefitinib showed clinical activity in this patient population in the INSIGHT study leading the authors to investigate tepotinib plus osimertinib in INSIGHT 2.
A total of 425 patients with acquired resistance to first-line osimertinib were screened and MET amplification was centrally detected in 153 (36%) by fluorescent in situ hybridization (FISH) in tissue biopsy and/or next-generation sequencing (NGS) of liquid biopsy samples. At the time of analysis, 100 patients had received treatment with tepotinib 500 mg/day plus osimertinib 80 mg/day (n=80) or tepotinib alone (n=12).
Mazieres presented the initial results, which revealed an objective response rate (ORR) with tepotinib plus osimertinib of 54.5% among the 22 patients with FISH-detected MET amplification and at least 9 months of follow-up, and of 45.8% among the 48 participants with follow-up of 3 months or more.
The ORRs for those with NGS-detected MET amplification were 50.0% for the 16 patients who were followed up for 9 months or more and 56.5% for the 23 followed up for 3 months or more.
The 12 patients who received tepotinib monotherapy all had FISH-detected MET amplification and at least 6 months of follow-up, and among these patients, the ORR was 8.3%.
The presenter noted that responses to tepotinib plus osimertinib “mostly occurred within 6 weeks and half of the responders had a duration of treatment higher than 6 months.” At the time of analysis, the median duration of response had not been reached, he added.
Turning to the safety data, Mazieres said that “[t]he safety profile of the combination was consistent with the known safety profiles of tepotinib and osimertinib.”
Any-grade and grade 3 or worse treatment-related adverse events (AEs) occurred in a respective 73.9% and 23.9% of participants given tepotinib plus osimertinib, with diarrhea the most common any-grade event, reported in 40.9%, and peripheral edema the most frequent higher-grade event, in 4.5%.
A total of 18.2% of combination-treated participants required a dose reduction of any drug and 6.8% discontinued treatment due to AEs. Two deaths due to AEs – one case each of pneumonia/pneumonitis and pleural effusion – were considered potentially related to either trial drug.
Tepotinib plus osimertinib “appears to be an active oral regimen, providing a potential chemotherapy-sparing targeted therapy option for patients with EGFR-mutated non-small-cell lung cancer with MET amplification after progression on first-line osimertinib,” a population that has “a high unmet need,” concluded Mazieres.
Discussant Helena Yu (Memorial Sloan Kettering Cancer Center, New York, USA) outlined several key takeaways from the study, the first one – in light of the low ORR with tepotinib monotherapy – being that “to address acquired MET amplification in EGFR-mutant lung cancer, single-agent MET inhibition is not helpful without continued EGFR inhibition.”
She believes that “MET amplification can be effectively targeted using MET plus EGFR combination therapy but further work is needed to define appropriate MET biomarkers.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group