Dual MET–EGFR inhibition promising for relapsed MET-high NSCLC
medwireNews: Combining the highly selective MET inhibitor tepotinib with gefitinib could benefit patients with non-small-cell lung cancer (NSCLC) that has progressed on first-line treatment with an EGFR–tyrosine kinase inhibitor (TKI) and has high levels of MET, suggest phase II trial results.
The study – which compared tepotinib plus gefitinib with chemotherapy – was reported at the ESMO 2018 Congress in Munich, Germany, by Yi-Long Wu, from Guangdong General Hospital and Guangdong Academy of Medical Sciences in China.
He explained that in light of phase Ib results pointing to a greater benefit with tepotinib plus gefitinib in patients with tumors harboring MET amplifications, they specifically recruited individuals with MET-positive disease, as indicated by an immunohistochemistry (IHC) score of either 2+ or 3+ and/or the presence of MET amplification by in situ hybridization. Additionally, patients had to have EGFR mutation-positive, T790M-negative, locally advanced or metastatic disease with acquired resistance to prior EGFR–TKI therapy.
In the intention-to-treat (ITT) analysis, median progression-free survival (PFS) was comparable for the 31 participants who were randomly assigned to receive oral tepotinib 500 mg/day alongside gefitinib 250 mg/day and the 24 patients who received pemetrexed plus cisplatin or carboplatin, with a nonsignificant hazard ratio (HR) of 0.71.
However, when the analysis was restricted to patients with an IHC score of 3+ (n=34), the combination of tepotinib and gefitinib was associated with significantly better PFS relative to chemotherapy, at a median of 8.31 versus 4.37 months and an HR for progression or death of 0.35.
This was also the case in the MET-amplified subgroup (n=19), in which the median PFS was 21.16 months with tepotinib–gefitinib and 4.21 months with chemotherapy, giving a significant HR of 0.17 in favor of the combination.
Similarly, although the overall response rate was higher with tepotinib–gefitinib than chemotherapy in the ITT population, at 45.2% versus 33.3%, the difference was more marked in the IHC 3+ and MET amplification subgroups, at 68.4% versus 33.3% and 66.7% versus 42.9%, respectively.
The presenter concluded that dual inhibition of MET and EGFR appeared to have antitumor activity in this patient population but highlighted the small size of the trial, which was due to early termination of enrolment due to difficulties in identifying patients who met the eligibility criteria.
Nevertheless, he believes that the combination merits further study in patients with MET-high disease.
Discussant Egbert Smit (Netherlands Cancer Institute, Amsterdam) said that tepotinib plus gefitinib appears to have “clinically relevant activity” in these NSCLC patients, and is likely superior to chemotherapy.
However, the exact magnitude of benefit cannot be established in a study with such low numbers, he commented.
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