Study of AXL Inhibitor DS-1205 in EGFR-Mutated Metastatic Non-Small Cell Lung Cancer Initiated

A first patient has been dosed in a first-in-human phase I study assessing the safety and tolerability of DS-1205, a highly selective investigational AXL inhibitor, in combination with gefitinib has been initiated in patients with metastatic or unresectable epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who have progressed on therapy with tyrosine kinase inhibitors (TKIs).

A part of the investigational Breakthrough Science pipeline of Daiichi Sankyo Cancer Enterprise, DS-1205 is an investigational highly selective AXL inhibitor currently being evaluated in a phase 1 clinical study in combination with gefitinib for metastatic or unresectable EGFR-mutated NSCLC. DS-1205 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

Clinical trial
The multicenter Phase I, open-label, two-part study will enroll patients with metastatic or unresectable EGFR-mutated NSCLC who have T790M mutation-negative tumors and have experienced disease progression during treatment with erlotinib, gefitinib or afatinib, or developed disease progression while on osimertinib.

The first part of the study (dose escalation) will assess the safety, tolerability, pharmacokinetics and efficacy of DS-1205 in combination with gefitinib to determine the recommended dose for expansion.

The second part of the study (dose expansion) will evaluate the safety, tolerability, pharmacokinetics and efficacy of the combination therapy. Study endpoints include safety, pharmacokinetics, objective response rate, duration of response, disease control rate, time to response, progression-free survival, overall survival and exploratory biomarker analyses.

The new study, which is to build upon preclinical research indicating that the addition of DS-1205 at beginning of treatment with tyrosine kinase inhibitors (TKIs) might delay onset of resistance to gefitinib and other TKI therapies, is expected to enroll approximately 60 patients at approximately 20 sites in Japan and other countries. [1][2]

For patients with metastatic EGFR-mutated NSCLC, targeted EGFR TKI therapies such as gefitinib, erlotinib, afatinib or osimertinib represent the first-line treatment of choice.[3][4][5][6]

However, patients eventually develop resistance to these treatments, typically experiencing disease progression within a year.[3][4][5][6]

Once a patient is resistant to all possible EGFR TKIs, there are limited treatment options, including chemotherapy, immunotherapy or investigational agents.[3][6]

?This first-in-human trial will build upon preclinical research to evaluate the potential of our AXL inhibitor, DS-1205, in combination with gefitinib in EGFR-mutated NSCLC that has progressed on TKI therapy,? said Eric Slosberg, PhD, Head, Oncology Translational Development, Oncology Research and Development, Daiichi Sankyo.

?We are evaluating for the first time in a clinical setting whether inhibition of the AXL pathway with DS-1205 may help prevent, delay or overcome the onset of resistance to EGFR TKIs, as we continue to research and develop new targeted therapy approaches for patients with metastatic NSCLC,? Slosberg added.

Unmet medical need
Lung cancer is the most common cancer in the world and the leading cause of cancer deaths.7, 8 There were approximately 1.8 million new cases of lung cancer reported globally and 1.69 million deaths from lung cancer in 2012.8 NSCLC is the most common form of lung cancer, accounting for approximately 80 to 85 percent of all cases. It is difficult to treat, particularly in advanced disease, and the five-year survival rate for metastatic NSCLC is only one percent.[9]

In the past decade, significant improvements in treatment have occurred due to the development of targeted therapies, such as EGFR TKIs, for advanced NSCLC.[3] EGFR mutations have been reported in a wide range of NSCLC patients (from 10 to 50%), and frequency may vary based on ethnicity and other factors.[3][10]

While the majority of patients with EGFR-mutated tumors respond to EGFR TKIs, resistance eventually develops in more than half of these patients, and they typically experience disease progression within a year.[11]

Resistance may be acquired or intrinsic.[3]

The most common mechanism for acquired resistance to gefitinib, erlotinib or afatinib involves a secondary EGFR mutation called T790M, which may be treated with the EGFR TKI osimertinib.[3][4][5][6] However, patients who experience disease progression following treatment with gefitinib, erlotinib or afatinib and whose tumors lack the T790M mutation, and patients who experience disease progression following osimertinib treatment have limited options such as chemotherapy, immunotherapy or investigational treatments.[5][6]

Researchers are exploring specific therapeutic strategies to overcome acquired resistance to EGFR TKIs.[3] Studies have demonstrated that up-regulation of AXL, a receptor tyrosine kinase, may develop in some patients with EGFR-mutated NSCLC who experience disease progression on TKI therapy, and this up-regulation might be a mechanism of resistance to EGFR TKI treatment.[11][12][13] Accordingly, inhibition of AXL might restore sensitivity to EGFR TKI treatment.11 While preclinical research has demonstrated that inhibition of AXL by DS-1205 restored sensitivity to erlotinib and the addition of DS-1205 to TKI therapy at the beginning of treatment delayed the onset of resistance to gefitinib, erlotinib or osimertinib, it is as yet to be confirmed that DS-1205 will work similarly in humans.[1][2]

Abnormal expression and activation of AXL have been correlated with poor prognosis, increased growth and metastasis, and drug resistance in many cancers including NSCLC.[12][13]

References
[1] Jimbo T et al. European Society for Medical Oncology. 017 Sept 8; Madrid, Spain: ESMO, 2017.
[2] Jimbo T et al. IASLC 18th World Conference on Lung Cancer. 017 Oct 18; Yokohama, Japan: IASLC, 2017.
[3] Wang J, Wang B, Chu H, Yao Y. Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations. Onco Targets Ther. 2016 Jun 22;9:3711-26. doi: 10.2147/OTT.S106399. eCollection 2016.[Pubmed]
[4] Zhou C, Yao LD.Strategies to Improve Outcomes of Patients with EGRF-Mutant Non-Small Cell Lung Cancer: Review of the Literature. J Thorac Oncol. 2016 Feb;11(2):174-86. doi: 10.1016/j.jtho.2015.10.002. Epub 2015 Dec 19.[PubMed]
[5]. The National Comprehensive Care Network (NCCN). NCCN Clinical Practice Guidelines in Non-Small Cell Lung Cancer Version 3. 2018.
[6] Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG, Kerr K, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v1-v27.[PubMed]
[7] World Health Organization Cancer Fact Sheet. 2017.
[8] Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer. 2015 Mar 1;136(5):E359-86. doi: 10.1002/ijc.29210. Epub 2014 Oct 9.[PubMed]
[9] American Cancer Society. Lung Cancer (Non-Small Cell) Overview. 2017.
[10] Ko B, Paucar D, Halmos B. EGFR T790M: revealing the secrets of a gatekeeper. Lung Cancer (Auckl). 2017 Oct 9;8:147-159. doi: 10.2147/LCTT.S117944. eCollection 2017.[PubMed]
[11] Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, Abdel-Rahman M, Wang X, Levine AD, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet. 2012 Jul 1;44(8):852-60. doi: 10.1038/ng.2330.[PubMed]
[12] Wu X, Liu X, Koul S, Lee CY, Zhang Z, Halmos B. AXL kinase as a novel target for cancer therapy. Oncotarget. 2014 Oct 30;5(20):9546-63.[PubMed]
[13] Ji W, Choi CM, Rho JK, Jang SJ, Park YS, Chun SM, Kim WS,et al.Mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitor in Korean patients with lung cancer. BMC Cancer. 2013 Dec 27;13:606. doi: 10.1186/1471-2407-13-606.[PubMed]


Last Editorial Review: October 19, 2018

Featured Image: Doctor examining a lung radiography. Courtesy: ? 2010- 2018 Fotolia. Used with permission.

Copyright ? 2010 ? 2018 Sunvalley Communication, LLC. All rights reserved. Republication or redistribution of Sunvalley Communication content, including by framing or similar means, is expressly prohibited without the prior written consent of Sunvalley Communication. Sunvalley Communication shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Onco?Zine, Oncozine and The Onco?Zine Brief are registered trademarks and trademarks of Sunvalley Communication around the world.