Merck (MSD) and Britsh Columbia-based SignalChem Lifesciences, a clinical-stage biotechnology company developing novel targeted therapies for oncology, have agreed to collaborate in evaluating the combination of SLC-391, a selective AXL inhibitor, with the anti-PD-1 therapy pembrolizumab (Keytruda®) in patients with advanced non-small-cell lung cancer (NSCLC).

Unmet medical need
Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. One type of lung cancer, NSCLC is the most common type of lung cancer, accounting for 84% of all lung cancer diagnoses.[1]

This year, an estimated 235,760 adults (119,100 men and 116,660 women) in the United States will be diagnosed with lung cancer.  The overall 5-year survival rate for NSCLC is 24%, ranging from 61% for localized NSCLC to 6% for metastatic disease.[1]

Lung cancer is also the second most common cancer and the leading cause of cancer death for men and women. And each year, more people die of lung cancer than colon, breast, and prostate cancers combined. This year, the American Cancer Society estimates that 131,880 (69,410 men and 62,470 women) will die of the disease this year.[1]

And while mortality rates for NSCLC have declined by 54% since 1990 in men and 30% in women since 2002, there is still a major unmet medical need.

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Inhibiting AXL
One of the targeted approaches for the treatment of NSCLC includes inhibiting AXL, a member of the TAM family protein tyrosine kinases (Tyro3, AXL and Mer), with the high-affinity ligand growth arrest-specific protein 6 (GAS6). plays a key role in cell survival, angiogenesis, metastasis, and therapeutic resistance.

AXL is a member of the TAM family.* The Gas6 (Growth arrest specific gene 6)/AXL signaling pathway is associated with tumor cell growth, metastasis, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, drug resistance, immune regulation, and stem cell maintenance. Different therapeutic agents targeting AXL have been developed, typically including small molecule inhibitors, antibodies, nucleotide aptamers, soluble receptors, and several natural compounds.

SLC-391 is a potent, selective, and orally bioavailable small molecule AXL inhibitor, disrupts cell division, inhibiting tumor growth and causing cancer cells to die. Currently, phase I clinical trial is ongoing in Canada to evaluate the safety and tolerability of SLC-391 in cancer patients with solid tumors.

Based on emerging evidence, a clinical investigation has been initiated to evaluate SLC-391 in combination with pembrolizumab in the treatment of patients with advanced NSCLC.

As part of the agreement with Merck, SignalChem will conduct the study in multiple cancer centers in the Uni and Canada to evaluate the clinical outcome of combining SLC-391 and pembrolizumab. The two companies plan to conduct the SKYLITE trial, a phase II study for patients with NSCLC.

The SKYLITE trial is a multi-center, single-arm, open-label, Phase II Study of SLC-391 in combination with pembrolizumab in subjects with NSCLC. Subjects will receive daily doses of SLC-391 orally for 21-day cycles in combination with the commercially approved dose and schedule of pembrolizumab. The trial is designed to evaluate the safety and efficacy of the combination therapy and includes the exploration of biomarkers relating to AXL signaling that may correlate with anti-tumor activity.

“We welcome the collaboration with Merck. We consider Merck’s clinical development expertise to be valuable and believe this relationship may contribute to the development of SLC-391 for the treatment of patients with advanced-stage lung cancer. These patients experience aggressive tumors that are often difficult to treat. We hope this collaboration with Merck will lead to a new approach that addresses this important unmet need,” says Mr. Jun Yan, President, SignalChem Lifesciences.

“We look forward to partnering with Merck as we aim to deliver new cancer treatments and advance SLC’s drug discovery platform. We at SLC are working hard to identify new anti-tumor, anti-metastatic, and anti-chemo-resistance therapies that provide meaningful alternatives to existing treatments,” Yan concluded.

* The protein encoded by the AXL gene is AXL (UFO, ARK, Tyro7, or JTK11), a member of the TAM family of receptor tyrosine kinases or RTKs. AXL is composed of an extracellular, transmembrane, and intracellular domain [2]. The extracellular structure consists of two immunoglobulin (Ig)-like repeats and two fibronectin type III (Fro III)-like repeats that resemble neural cell adhesion molecules or NCAMs [3]. The Ig motifs are involved in the binding of AXL with its ligand Gas6 under regulation by Fro III [5]. The intracellular domain is critical for auto-phosphorylation and subsequent kinase activity [6]. The TAM family-specific KW(I/L)A(I/L)ES sequence resides within this intracellular domain, which shares homology with AXL-related RTKs, such as RET [7], and plays an important role in tyrosine kinase activity. The TAM family is widely expressed in normal cells and tissues, such as monocytes, platelets, endothelial cells, hippocampus, cerebellum, heart, and liver [8–15], wherein it regulates cell survival, the non-inflammatory clearance of apoptotic cells by phagocytic cells, natural killer cell differentiation, platelet aggregation, etc. [5][16-18] Available evidence also suggests a role for TAM receptors in oncogenic mechanisms as family members are overexpressed in a spectrum of human cancers and have prognostic significance in some.[5]

Clinical trials
Safety Study of SLC-391 in Subjects With Solid Tumors [NCT03990454]

Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co., Inc) [Prescribing Information]

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Featured image: Merck | MSD Exhibition booth at the 2019 annual meeting of the American Society of Medical Oncology (ASCO). Photo courtesy: © 2019 – 2021 Sunvalley Communication. Used with permission.

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