Abstract 5153
Background
NSCLC can acquire resistance to EGFR tyrosine kinase inhibitors (EGFR TKIs) via MET activation; dual MET/EGFR inhibition may have potential in EGFR TKI-resistant NSCLC. TEP is a potent, selective MET TKI. We report randomized phase 2 data from a phase 1b/2 signal detection trial of TEP+GEF vs chemotherapy (pemetrexed + cisplatin/carboplatin) in patients (pts) with MET+/EGFR+T790M- NSCLC (NCT01982955).
Methods
Asian pts with advanced MET + (IHC2+, IHC3+, gene amplification) NSCLC, acquired resistance to 1st-line EGFR TKI and ECOG performance status 0–1 were eligible. Tumors had an EGFR-activating mutation (T790M-). Pts received TEP+GEF 500/250mg once-daily. Primary endpoint: progression-free survival (PFS by investigator). Secondary endpoints: safety, antitumor activity, pharmacokinetics.
Results
Due to low recruitment, enrolment was halted after 55 pts were randomized to TEP+GEF (n = 31) or chemotherapy (n = 24): male n = 23, median age 60.4 (range 42–82) years. There was a numeric trend towards TEP+GEF on PFS in the intent-to-treat analysis set (hazard ratio [HR]: 0.71 [0.36, 1.39]), driven by the IHC3 + (HR: 0.35 [0.17, 0.74]) and gene-amplified (HR: 0.17 [0.05, 0.57]) pts (Table) confirming these as predictive biomarkers as indicated by phase 1b data. All pts had treatment-related (TR) treatment-emergent adverse events (TEAEs). In the TEP+GEF vs chemotherapy arms, respectively, 9.7 vs 4.3% had TEAEs leading to permanent discontinuation, 3.2 vs 0% had TEAEs leading to death (none were TRTEAEs), 16.1 vs 30.4% had serious TRTEAEs, 51.6 vs 52.2% had Grade ≥3 TRTEAEs, 12.9 vs 8.7% had a TRTEAE of special interest (lipase/amylase increase ≥3).
Conclusions
TEP+GEF shows promising antitumor activity in pts with MET protein overexpression (IHC3+) and gene amplification EGFR-MT NSCLC and was generally well-tolerated. This positive signal warrants further exploration in this pt population.
Clinical trial identification
NCT01982955.
Legal entity responsible for the study
Merck KGaA.
Funding
Merck KGaA.
Editorial Acknowledgement
Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Lisa Jolly PhD of Bioscript Science (Macclesfield, UK).
Disclosure
S. Lu: Research support: AstraZeneca; Speaker fees: AstraZeneca, Eli Lilly, Roche, Pfizer; Advisor, consultant role: AstraZeneca, Hutchison MediPharma, Simcere, BMS, Roche, Pfizer. R. Bruns, A. Johne, J. Scheele: Employee: Merck KGaA. Y-L. Wu: Speaker fees: AstraZeneca, Eli Lilly, Pfizer, Roche, Sanofi. All other authors have declared no conflicts of interest.Table: 1377O
| Investigator assessed | Median PFS [90% CI], months | Objective response rate, n (%) [90% CI] |
|---|---|---|
| Overall intent-to-treat (MET + [IHC 2+/IHC 3+/gene amplification]/EGFR T790M-) | ||
| Tepotinib + gefitinib (n = 31) | 4.86 [3.88, 6.87] | 14 (45.2) [29.7, 61.3] |
| Pemetrexed + cisplatin/carboplatin (n = 24) | 4.37 [4.17, 6.80] | 8 (33.3) [17.8, 52.1] |
| Stratified HR [90% CI] or odds ratio (OR) adjusted by randomization strata [90% CI] | HR: 0.71 [0.36, 1.39] | OR: 1.99 [0.56, 6.87] |
| IHC3+/EGFR T790M- | ||
| Tepotinib + gefitinib (n = 19) | 8.31 [4.11, 21.16] | 13 (68.4) [47.0, 85.3] |
| Pemetrexed + cisplatin/carboplatin (n = 15) | 4.37 [4.11, 6.80] | 5 (33.3) [14.2, 57.7] |
| Unstratified HR [90% CI] or OR [90% CI] | 0.35 [0.17, 0.74] | 4.33 [1.03, 18.33] |
| Gene Amplification (GCN ≥5 or MET/CEP7 ratio ≥2/EGFR T790M-) | ||
| Tepotinib + gefitinib (n = 12) | 21.16 [8.31, 21.16] | 8 (66.7) [39.1, 87.7] |
| Pemetrexed + cisplatin/carboplatin (n = 7) | 4.21 [1.35, 6.97] | 3 (42.9) [12.9, 77.5] |
| Unstratified HR [90% CI] or OR [90% CI] | 0.17 [0.05, 0.57] | 2.67 [0.37, 19.56] |
MET+: Met overexpression by immunohistochemistry (IHC2+ or 3+) and/or MET gene amplification and/or increased gene copy number (GCN ≥5 or MET/CEP7 ratio ≥2) by in-situ hybridisation