Tepotinib and gefitinib show long OS in MET-amplified EGFR+ non-small cell lung cancer

Patients with EGFR-mutant non-small cell lung cancer (NSCLC) develop MET in response to prior EGFR tyrosine kinase inhibitors (TKIs), according to final analysis of the phase 2 INSIGHT trial (NCT01982955) Driven by drug resistance, the combination of Tepotinib and Gefitinib improved both progression-free survival (PFS) and overall survival (OS) compared with chemotherapy.

In new findings presented at the meeting of the International Association for the Study of Lung Cancer, patients with MET amplification had a median progression-free survival of when treated with tepotiniband gefitinib. /span> 16.6 months (90% CI, 8.3-22.1) compared with 4.2 months (90% CI, 1.4-7.0, ungraded HR, 0.10; 90% CI, 0.02-0.36) among patients who received chemotherapy. The median OS was 37.3 months (90% CI, 21.1-52.1), compared with 13.1 months (90% CI, 3.3-22.6) in the tepotinib plus gefitinib group and the chemotherapy group (unstratified HR, 0.10; 90% CI, 0.02-0.36).

The investigator-assessed objective response rate (ORR) was 66.7% in the tepotinib and gefitinib arms and 42.9% in the chemotherapy arm (odds ratio [OR], 2.67; 90% CI, 0.37-19.6). The independent review committee (IRC) ORRs were 75% and 42.9%, respectively (OR, 4.00; 90% CCI, 0.51-31.38). TepotinibTreatment with gefitinibThe median OS of patients with MET amplification was 37.3 months, which is in the same range as the reported median OS of first-line Osimertinib in EGFR-mutated non-small cell lung cancer. The median duration of previous EGFR TKI therapy should be taken into account, which was 10.6 months in the cohort.

INSIGHT is an open-label, randomized, multicenter Phase 1b/2 clinical trial of tepotinib and gefitinib in patients with locally advanced or metastatic non-small cell lung cancer. The study had a preplanned subgroup analysis evaluating patients with MET amplification or high MET expression (immunohistochemistry [IHC] 3+). This is the first randomized trial of targeted therapy versus chemotherapy in patients with EGFR-mutated NSCLC and methotrexate (MET-driven) resistance. These patients have an activating EGFR mutation, T790M negative, first or second generation EGFR-Acquired resistance to TKI therapy, ECOG performance status 0 or 1. All participants were randomly assigned to receive a combination of tepotinib 500 mg and gefitinib 250 mg orally once daily, chemotherapy with pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2, or carboplatin with an area under the curve of 5 to 6 intravenously on day 1 of each 3-week cycle for up to 6 cycles, or 4 cycles plus pemetrexed maintenance.

Investigator-assessed PFSPFS is the primary endpoint, and secondary endpoints include OS, ORR, duration of response, IRC PFS and safety. Nineteen patients in the study had MET amplification. Among these patients, the majority were female, never smokers, had an ECOG performance status of 1, and had exon 19 deletions or EGFR mutations of L858R. Fifty-eight percent of patients had previously used gefitinib, 21% had previously used afatinib, 11% had previously used erlotinib, and 11% had previously used icotinib. The median duration of prior EGFR TKI therapy was 10.6 months in the combination group and 9.5 months in the chemotherapy group.

The final analysis was conducted at a mean follow-up time of 57.5 months. At this time, patients had been receiving tepotinib and gefitinib for a median duration of 11.3 months (range, 1.1-56.5), with three patients receiving treatment for more than 4 years. Treatment-related adverse events (TRAEs) were reported by all patients, with the most common being diarrhea (50%), increased amylase and lipase (41.7% each), increased alanine aminotransferase (33.3%), and peripheral edema (33.3%). In the chemotherapy group, the most common TRAEs were decreased white blood cell and neutrophil counts (57.1%, respectively), anemia (42.9%), and nausea (42.9%). Seven patients (58.3%) in the combination therapy group and five patients (71.4%) in the chemotherapy group experienced grade 3 or higher TRAEs.

In MET IHC3+ patients (n=34), the median PFS was 8.3 months with tepotinib and gefitinib compared with 4.4 months with chemotherapy (unstratified HR, 0.35; 90% CI, 0.17-0.74). The median OS in this population was 29.1 months compared with 17.9 months for tepotinib plus gefitinib plus chemotherapy (unstratified HR, 0.44; 90% CCI, 0.23-0.84). In the overall population (n=55), the median PFS was 4.9 months with tepotinib and 4.4 months with gefitinib and chemotherapy, respectively (stratified HR, 0.67; 90% CI, 0.35-1.28). TepotinibThe median OS for tepotinib and chemotherapy were 17.3 months and 19.5 months, respectively (stratified HR, 0.67%; 90% CCI, 0.34-1.32).

Tepotinib plus osimertinibIn preliminary results from the phase 2 INSIGHT 2 trial (NCT03940703), the combination showed superior efficacy in patients refractory to first-line osimertinib therapy due to methionine (MET) amplification.