S-49076 / Servier - LARVOL DELTA

Phase I/II Study of S49076, a MET/AXL/FGFR Inhibitor, Combined with Gefitinib in NSCLC Patients Progressing on EGFR TKI (WCLC 2017) - "According to preliminary data, the frequency of MET and AXL dysregulations is consistent with the literature. Combination of S49076 and gefitinib is well tolerated and safety data are consistent with the overall safety profile of each drug. The phase II part of this study will start once the RP2D is defined to evaluate the anti-tumour activity of the combination."

P1/2 data • Non Small Cell Lung Cancer

Phase I/II study of S 49076, a MET/AXL/FGFR inhibitor, in combination with gefitinib in EGFR-mutated NSCLC patients who progress on EGFR tyrosine kinase inhibitor (ESMO 2017) - "The primary objective will be to determine the objective response rate according to RECIST and the secondary objectives will be to evaluate survival rate, progression free survival, clinical benefit rate and response duration as well as safety. An interim analysis will be performed in each cohort for futility."

Combination therapy • P1/2 data • Non Small Cell Lung Cancer

Modeling restoration of gefitinib efficacy by co-administration of MET inhibitors in an EGFR inhibitor-resistant NSCLC xenograft model: A tumor-in-host DEB-based approach. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The population DEB-based tumor growth inhibition (TGI) model well-described the effect of gefitinib and of two MET inhibitors, capmatinib and S49076, on both tumor growth and host body weight when administered alone or in combination in an NSCLC mice model involving the gefitinib-resistant tumor line HCC827ER1. In summary, the DEB-based tumor-in-host framework proposed here can be applied to routine combination xenograft experiments, providing an assessment of drug interactions and contributing to rank investigated compounds and to select the optimal combinations, based on both tumor and host body weight dynamics. Thus, the combination tumor-in-host DEB-TGI model can be considered a useful tool in the preclinical development and a significant advance toward better characterization of combination therapies."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation. (PubMed, Lung Cancer) - "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."

Clinical • Journal • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • EGFR

Aurora B, a potential new target in non-T790M lung cancer cells with acquired resistance to anti-EGFR therapy, is effectively blocked by the MET/AXL/FGFR inhibitor S49076 (AACR 2018) - "...S49076 is a potent ATP-competitive tyrosine kinase inhibitor of MET, AXL/MER and FGFR1/2/3 currently in a phase I clinical trial in combination with Gefinitib in NSCLC resistant to EGFR inhibitors. We generated 6 resistant lines by treating EGFR-mutated, TKI sensitive PC9 cells with increasing concentrations of gefitinib (GR1-5) or erlotinib (ER)...Six additional cell lines resistant to osimertinib were derived from GR1 and GR4 by exposure to increasing concentrations of the inhibitor...Treatment with S49076 or barasertib down-regulated pH3 and induced G1/S arrest and polyploidy... AURKB is a novel target in non-T790M NSCLC with acquired resistance to first and third line EGFR TKIs. Multitargeted agents such as S49076, which inhibit not only AXL, MET or FGFR1 but also AURKB, might be more effective in this setting than agents targeting the receptor tyrosine kinases alone."

IO Biomarker • Preclinical • Non Small Cell Lung Cancer

AURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy. (PubMed, Nat Commun) - "Here, we show that resistant cells without the p.T790M or other acquired mutations are sensitive to the Aurora B (AURKB) inhibitors barasertib and S49076. Finally, in NSCLC patients, pH3 levels are increased after progression on EGFR TKIs and high pH3 baseline correlates with shorter survival. Our results reveal that AURKB activation is associated with acquired resistance to EGFR TKIs, and that AURKB constitutes a potential target in NSCLC progressing to anti-EGFR therapy and not carrying resistance mutations."

Journal • Preclinical

Molecular profiling of T790M-negative NSCLC patients progressing on EGFR-TKI enrolled in the CL1-49076-003 trial with a MET/AXL/FGFR inhibitor in combination with gefitinib (AACR 2019) - "The CL1-49076-003 trial of the MET/AXL/FGFR inhibitor S49076 in combination with gefitinib enrolled T790M-negative patients in progression to first-line EGF TKIs and showing dysregulation of MET and/or AXL. Among the 4 patients with more than 6 months of progression free survival, 2 had MET amplifications. The patient with the p.G724S experienced rapid progression of target lesions.Conclusion Next Generation Sequencing can be used to determine mechanisms of resistance to EGFR TKIs at progression, and can give useful clinical information in order to select therapies for second line treatment"

Clinical • Combination therapy