Tepotinib Plus Gefitinib Demonstrates PFS Improvement Versus Chemotherapy in MET+ EGFR-Mutant NSCLC

October 31, 2018

Both&nbsp;progression-free survival and overall response were improved in patients with&nbsp;<em>MET</em> mutated <em>EGFR</em>-positive non&ndash;small cell lung cancer resistant to prior EGFR TKI therapy who were treated with&nbsp;tepotinib plus gefitinib compared with chemotherapy. These phase II findings were presented at the&nbsp;2018 ESMO Congress.

Yi Long Wu, MD

Both progression-free survival (PFS) and overall response were improved in patients with METmutatedEGFR-positive non—small cell lung cancer (NSCLC) resistant to prior EGFR TKI therapy who were treated with tepotinib plus gefitinib (Iressa) compared with chemotherapy. These phase II findings were presented at the 2018 ESMO Congress.

According to the results, the median PFS by investigator assessment in the intent-to-treat population of patients withMET-positive tumors was 4.9 months (90% CI, 3.9-6.9) with tepotinib/gefitinib (n = 31) versus 4.4 months (90% CI, 4.2-68) for the chemotherapy arm (n = 24; HR, 0.71; 90% CI, 0.36-1.39).

In patients withMETamplification, the increase in median PFS was over 5 times that of chemotherapy. Median PFS for patients withMETamplification treated with tepotinib plus gefitinib was 21.2 months (90% CI, 8.3-21.2) compared to only 4.2 months (90% CI, 1.4-7.0) with chemotherapy.METamplification was defined as mean gene copy number ≥5 and/or MET/CEP-7 copy number ratio ≥2.

There was an increased in PFS with tepotinib/gefitinib is those who had highMET-expressing tumors, as well. Median PFS for those that received the combination (n = 19) was 8.3 months (90% CI, 4.1-21.2) compared with 4.4 months (90% CI, 4.1-6.8) with chemotherapy (HR, 0.35; 90% CI, 0.17-0.74).

A high overall response rate (ORR) was also observed in patients with highMET-expressing andMET-amplified tumors. ORR in the overall population (n = 55) was 45.2% (90% CI, 29.7-61.3) with tepotinib plus gefitinib compared with 33.3% (90% CI, 17.8-52.1) with chemotherapy. For those withMET-expressing tumors (IHC3+; n=34), the ORR was 68.4% (90% CI, 47.0-85.3) with the combination and 33.3% (90% CI, 14.2-57.7) with chemotherapy. ORR forMET-amplified tumors was comparable at 66.7% (90% CI, 39.1-87.7) versus 42.9% (90% CI, 12.9-77.5), respectively.

“This is the first randomized study to compare tepotinib plus gefitinib with chemotherapy in relapsedEGFR-mutant NSCLC withMEToverexpression orMETamplification,” said Yi-Long Wu, MD, director of the Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangzhou, China, when presenting the findings.

Tepotinib is a potent highly-selective oral MET tyrosine kinase inhibiter (TKI) that has previously shown activity in solid tumors. Preclinical data have shown that tepotinib has the ability to overcome acquired resistance to EGFR TKIs due to aberrantMETactivation. Wu noted that activeEGFRdriver mutations occur in about 50% of Asian and 10% of Caucasian patients with NSCLC.

This study was done in Asian patients with locally advanced or metastatic stage IVEGFR-positive,MET-mutated NSCLC. Patients either received 500 mg of oral tepotinib plus 250 mg of oral gefitinib, or pemetrexed and cisplatin intravenously.

Additional criteria included resistance to prior EGFR TKIs and no prior HGF/MET pathway-directed therapy. Stratification factors were type ofMETmutation and prior EGFR TKI treatment. The primary endpoint of the study was primary investigator-assessed PFS. ORR and safety were secondary endpoints.

Tepotinib has been shown to have an acceptable safety profile. In this analysis, although 100% of patients in both arms experienced treatment-emergent adverse events (TEAEs), serious TEAS occurred in only 11 patients (35.5%) who received tepotinib/gefitinib and 8 patients (34.8%) in the chemotherapy group.

“Treatment with tepotinib and gefitinib was generally well-tolerated and most AEs were mild to moderate in severity,” explained Wu.

The most common TEAEs were amylase increase (19.4% vs 8.7%) and decrease in neutrophil count (6.5% vs 13%) in the tepotinib/gefitinib and chemotherapy arms, respectively. In the chemotherapy arm, 7 (30.4%) patients experienced anemia and 3 (13%) had hypokalemia. Three patients in the tepotinib/gefitinib arm discontinued treatment due to a TEAE, versus 1 in the chemotherapy arm. Additionally, there was 1 TEAE-related death in the experimental arm versus 0 in the control arm. The death was not considered to be related to study treatment.

Reference:

Cheng Y, Zhou J, Lu S, et al. Phase II study of tepotinib + gefitinib (TEP+GEF) in MET-positive (MET+)/epidermal growth factor receptor (EGFR)-mutant (MT) non-small cell lung cancer (NSCLC). Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 1377O.