Tepotinib and Gefitinib Show Long OS in EGFR+ NSCLC With MET Amplification

The combination of tepotinib (Tepmetko) and gefitinib (Iressa) demonstrated an improvement in both progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in patients with EGFR-mutant non–small cell lung cancer (NSCLC) who developed MET-driven resistance to prior EGFR tyrosine kinase inhibitors (TKIs), according to findings from the final analysis of the phase 2 INSIGHT trial (NCT01982955).¹

In updated findings presented at the International Association for the Study of Lung Cancer 2022 North America Conference on Lung Cancer, patients with MET amplification demonstrated a median PFS of 16.6 months (90% CI, 8.3-22.1) with tepotinib and gefitinib treatment compared with 4.2 months (90% CI, 1.4-7.0) with chemotherapy (unstratified HR, 0.13; 90% CI, 0.04-0.43). The median OS was 37.3 months (90% CI, 21.1-52.1) compared with 13.1 months (90% CI, 3.3-22.6) with tepotinib plus gefitinib vs chemotherapy, respectively (unstratified HR, 0.10; 90% CI, 0.02-0.36).

Objective response rate (ORR) by investigator assessment was 66.7% in the tepotinib and gefitinib arm compared with 42.9% in the chemotherapy arm (odds ratio [OR], 2.67; 90% CI, 0.37-19.6). By independent review committee (IRC), the ORRs were 75% and 42.9%, respectively (OR, 4.00; 90% CI, 0.51-31.38).

“The median OS of 37.3 months with tepotinib plus gefitinib in patients with MET [amplification] is in the same range as that reported for first-line osimertinib [Tagrisso] in EGFR-[mutant] NSCLC, and should be considered in the context of the median duration of prior EGFR TKI therapy, which was 10.6 months in our cohort,” the study authors, led by Richard O’Hara, MD, wrote in their poster.

INSIGHT was an open-label, randomized, multicenter phase 1b/2 clinical trial of tepotinib and gefitinib in patients with locally advanced or metastatic NSCLC. The study had a preplanned subgroup analysis that evaluated patients with MET amplification or high MET expression (immunohistochemistry [IHC] 3+).

O’Hara et al noted that this was the first randomized trial of a targeted therapy vs chemotherapy and in patients with EGFR-mutated NSCLC and MET-driven resistance.

The patients had an activating EGFR mutation, were T790M negative, had an acquired resistance to a first- or second-generation EGFR TKI therapy, and had an ECOG performance status of 0 or 1. All participants were randomly assigned to receive the combination regimen (n = 31) of 500 mg tepotinib and 250 mg gefitinib administered orally once daily, or chemotherapy (n = 24) of pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 to 6 administered intravenously on day 1 of each 3-week cycle for up to 6 cycles, or 4 cycles plus pemetrexed maintenance.

PFS by investigator assessment was the primary end point, and secondary end points included OS, ORR, duration of response, PFS by IRC, and safety. Nineteen patients in the study had a MET amplification. Of these patients, most were women, never smokers, had an ECOG performance status of 1, and had an EGFR mutation of exon 19 deletion or L858R. Prior gefitinib use was noted in 58% of patients, prior afatinib (Gilotrif) use in 21%, prior erlotinib (Tarceva) in 11%, and prior icotinib in 11%. The median duration of prior EGFR TKI therapy was 10.6 months in the combination arm and 9.5 months in the chemotherapy arm.

The final analysis was conducted with a median follow-up of 57.5 months. At this time, patients had a median duration of treatment with tepotinib and gefitinib of 11.3 months (range, 1.1-56.5), with 3 patients receiving treatment for over 4 years. Two patients were still receiving therapy as of the data cutoff date.

Treatment-related adverse events (TRAEs) were reported in all patients, with the most common in the combination arm being diarrhea (50%), amylase and lipase increase (41.7% each), alanine aminotransferase increase (33.3%), and peripheral edema (33.3%). In the chemotherapy arm, the most common TRAEs were white blood cell and neutrophil count decreases (57.1% each), anemia (42.9%), and nausea (42.9%). TRAEs of grade 3 or higher were observed in 7 patients (58.3%) in the combination arm and in 5 (71.4%) in the chemotherapy arm.

Efficacy by MET Subgroups

In patients with MET IHC 3+ (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 vs 17.9 months with tepotinib plus gefitinib and chemotherapy, respectively (unstratified HR, 0.44; 90% CI, 0.23-0.84).

In the overall population (n = 55), the median PFS was 4.9 months with tepotinib plus gefitinib and 4.4 months with chemotherapy (stratified HR, 0.67; 90% CI, 0.35-1.28). The median OS was 17.3 months vs 19.5 months with tepotinib plus gefitinib and chemotherapy, respectively (stratified HR, 0.67; 90% CI, 0.34-1.32).

The study authors also noted that in initial findings from the ongoing phase 2 INSIGHT 2 trial (NCT03940703) of tepotinib plus osimertinib, the combination showed high efficacy in patients with resistance to frontline osimertinib treatment because of MET amplification.

REFERENCE

1. O’Hara R, Liam CK, Ahmad AR, et al. Tepotinib + gefitinib in patients with EGFR-mutant NSCLC with MET amplification (METamp): final analysis of INSIGHT. Presented at: IASLC 2022 North America Conference on Lung Cancer; September 23-25, 2022; Chicago, IL.