ALK Inhibitors, Potential Market Opportunity & Clinical Pipeline Insights 2019

ALK gene alterations play a vital role in the pathogenesis of several cancers after it was first discovered in anaplastic large cell lymphoma and hence the name anaplastic lymphoma kinase (ALK).  ALK is referred as a receptor tyrosine kinase (RTK) that belongs to the insulin receptor (IR) superfamily. In humans the ALK gene encodes ALK, and immunohistochemical analysis revealed that ALK expression is scattered partially in pericytes, neural cells, and endothelial cells of adult human brain tissues. ALK mRNA is found to be expressed in the small intestine, prostate, testis, and colon. ALK was found to be rearranged, mutated, or amplified in various tumors including non-small cell lung cancer (NSCLC), diffuse large B cell lymphoma, inflammatory myofibroblastic tumors, cell carcinoma, colon cancer, breast carcinoma neuroblastoma, and esophageal cancer.

The theories and practices of the individual cancer therapy have significantly influenced the approval of the first-generation ALK inhibitor, crizotinib (Xalkori; PF-02341066; Pfizer), by the US Food and Drug Administration (FDA). Second-generation ALK inhibitors like ceritinib [Zykadia], alectinib [Alectinib], and brigatinib [Alunbrig] are developed to overcome crizotinib-resistant mutations, to increase anti-ALK activity, and to improve their activity in CNS disease.  Crizotinib was using as the reference treatment for patients with ALK+ NSCLC and as a promising treatment for tumors.  Many of the patients have developed acquired resistance in the first year of treatment, unfortunately, and thus its efficacy is limited in CNS disease. Hence strategies urgently have to be developed to overcome inherent and acquired resistance of using ALK inhibitors. Nowadays, many of the second-generation ALK inhibitors are under various stages of clinical development, which are showing activity in crizotinib-resistant disease with promising activity in CNS disease patients. The third-generation ALK inhibitors (such as lorlatinib) came into existence in patients with CNS involvement.

Currently, the marketed ALK inhibitors of Zykadia (ceritinib) and Alecensa (alectinib) are indicated for the treatment of non-small cell lung cancer and gastrointestinal cancer. The ALK inhibitors pipeline included more than 15 molecules, and they are expected to achieve regulatory approval in the near future, some of them include ensartinib (X-396), CEP-18050, X-339, X-390, EBI-215, ASP3026, and EBI-600215. Novel potent ALK inhibitors have become existence with promising results recently in the last few years, and with a good toxicity profile that includes ceritinib (LDK378), brigatinib (AP26113), alectinib (RG7853/AF-802/RO5424802/CH5424802), entrectinib (RXDX-101, NMS-E628), MEDI4736 (durvalumab), TSR-011, X-376/X-396, PF-06463922, ASP3026 and CEP-28122/CEP-37440.

The aim to increase the inhibitory activity against ALK and to defeat the inevitable development of drug resistance adds fuel to the emergence of new ALK inhibitors. The procedure of resistance presents the need for new collaborations and education within the multidisciplinary team. In the sequence of generalized progression, an understanding of the present molecular mechanism of resistance is evolved as a key to decision-making and clinical management that highlights the role of the pathologist. The strong clinical evidence has shown that ALK is one key driving factors of oncogenesis, which will make it a key drug target. A key challenge is to understand why ALK-positive patients are not getting benefit from checkpoint inhibition and the need to develop new therapeutic strategies to tackle the immune system to identify ALK-positive cancers effectively

This pipeline analysis report segments the ALK inhibitors based on therapies employed (monotherapy and undisclosed), RoA (oral and undisclosed), therapeutic modalities (small molecules and disclosed), drugs under development (discovery, pre-clinical, phase I, phase I/II, phase II, and phase III), and recruitment status (recruiting, active not recruiting, enrolling by invitation, and undisclosed).