2. Academic Validation
  3. Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation

Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation

  • Lung Cancer. 2021 May:155:127-135. doi: 10.1016/j.lungcan.2021.03.012.
Keunchil Park 1,  Gee-Chen Chang 2,  Giuseppe Curigliano 3,  Wan-Teck Lim 4,  Ross A Soo 5,  Miguel A Molina-Vila 6,  Valérie Cattan 7,  Hélène Darville 8,  Eric Gandossi 7,  Veronika Smutna 7,  Isabelle Sudey 7,  Santiago Viteri 9
Affiliations

Affiliations

  • 1 Division of Hematology and Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, 06351, Seoul, Republic of Korea. Electronic address: kpark@skku.edu.
  • 2 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, No. 1650, Sect. 4, Taiwan Boulevard, Taichung, 407, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Road, Taichung, 402, Taiwan; School of Medicine, and Institute of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung, 402, Taiwan.
  • 3 Istituto Europeo di Oncologia, IRCCS, Divisione Sviluppo Nuovi Farmaci per Terapie Innovative,Via Ripamonti, 435, 20141, Milano, Italy; University of Milano, Milano, Italy.
  • 4 National Cancer Centre Singapore, Vision of Medical Oncology, 11 Hospital Drive, Singapore, 169610, Singapore.
  • 5 National University Cancer Institute, Department of Haematology-Oncology, 1E Kent Ridge Road, NUHS Tower Block Level 7, Singapore, 119228, Singapore.
  • 6 Pangaea Oncology, Laboratory of Molecular Biology, Quiron-Dexeus University Institute, Barcelona, Spain.
  • 7 Institut de Recherches Internationales Servier (I.R.I.S.), 50 rue Carnot, 92284, Suresnes, France.
  • 8 Institut de Recherche Servier, 125 Chemin de Ronde, 78290, Croissy-sur-Seine, France.
  • 9 Instituto Oncológico Dr. Rosell (IOR), Servicio Oncología Médica, Hospital Uni. Quirón-Dexeus, C/ Sabino Arana 5-19, 08028, Barcelona, Spain.
PMID: 33798902 DOI: 10.1016/j.lungcan.2021.03.012
Abstract

Background: MET and Axl dysregulation is reported as a bypass mechanism driving tumour progression in non-small cell lung Cancer (NSCLC) with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This non-comparative phase I study investigated the combination of gefitinib with S49076, a MET/Axl Inhibitor, in advanced EGFR TKI-resistant NSCLC patients with MET and/or Axl dysregulation.

Methods: Patients received S49076 at escalating doses of 500 or 600 mg with a fixed dose of 250 mg gefitinib orally once daily in continuous 28day cycles. MET and Axl dysregulation and EGFR/T790M mutation status were centrally assessed in tumour biopsies at screening. Tumour response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). EGFR TKI resistance mechanisms were analysed by next-generation Sequencing. The clonal evolution of tumours was monitored with the analysis of circulating tumour DNA.

Results: Of 92 pre-screened patients, 22 met the molecular inclusion criteria and 14 were included. The recommended dose was 600 mg daily S49076. Best overall responses were 2 partial responses (1 patient with MET dysregulation only, 1 MET and Axl co-dysregulation) and 8 patients with stable disease. Other potential concomitant mechanisms of resistance to EGFR TKI were identified in more than half of the included patients.

Conclusions: S49076 plus gefitinib demonstrated a good tolerability with limited anti-tumour activity. Due to the low number of eligible patients, no tendency in term of activity appeared in any specific molecular subset and the data did not allow for identification of Axl overexpression as an oncogenic driver.

Keywords

AXL; Epidermal growth factor receptor; Gefitinib; MET; Non-small cell lung cancer; Tyrosine kinase inhibitors.

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