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Proffered paper session - NSCLC, metastatic

5153 - Phase 2 study of tepotinib + gefitinib (TEP+GEF) in MET-positive (MET+)/epidermal growth factor receptor (EGFR)-mutant (MT) non-small cell lung cancer (NSCLC)

Date

19 Oct 2018

Session

Proffered paper session - NSCLC, metastatic

Topics

Cytotoxic Therapy;  Targeted Therapy

Presenters

Yi-Long Wu

Citation

Annals of Oncology (2018) 29 (suppl_8): viii493-viii547. 10.1093/annonc/mdy292

Authors

Y. Wu1, J. Zhou2, S. Lu3, Y. Zhang4, J. Zhao5, H. Pan6, Y. Chen7, C. Chian8, R. Bruns9, A. Johne10, J. Scheele11, Y. Cheng12

Author affiliations

  • 1 Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, 510080 - Guangzhou/CN
  • 2 Department Of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University, 310003 - HangZhou/CN
  • 3 Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai/CN
  • 4 Thoracic Medical Oncology, Zhejiang Cancer Hospital, 310022 - HangZhou/CN
  • 5 Key Laboratory Of Carcinogenesis And Translational Research (ministry Of Education/beijing), Department Of Thoracic Medical Oncology, Peking University Cancer Hospital & Institute, 100142 - Beijing/CN
  • 6 School Of Medicine, Sir Run Run Shaw Hospital, Zhejiang Medical University, 310016 - Zhejiang Sheng/CN
  • 7 Department Of Chest Medicine, Taipei Veterans General Hospital, 112 - Taipei/TW
  • 8 Department Of Internal Medicine, Tri-Service General Hospital, National Defence Medical Center, 114 - Taipei/TW
  • 9 Biostatistics, Merck KGaA, 64293 - Darmstadt/DE
  • 10 Global Clinical Development, Merck KGaA, 64293 - Darmstadt/DE
  • 11 Global Clinical Development, Merck KGaA, Darmstadt/DE
  • 12 Medical Oncology, Jilin Province Cancer Hospital, 130012 - Changchun/CN
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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 assessedMedian PFS [90% CI], monthsObjective 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

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