Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Abstract

Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient.

Keywords: EML4-ALK rearrangement; Non-small-cell lung cancer (NSCLC); anaplastic lymphoma kinase inhibitors (ALK inhibitors); crizotinib.

Figure 1

Different ALK staining expression at IHC with clone 5A4 (A) and Ventana D5F3 CD assay (B). Insert in image (A) shows the ALK positivity in signet ring tumor cells with a thin rim of brownish-stained cytoplasm dislocated under the nuclear membrane. FISH analysis showing tumor cells with normal ALK set-up with one normal fusion signal and one single red/orange signal (C); ALK positivity by gene deletion with single 3' orange rearranged signals (deleted green signal) (D, arrowheads) and ALK positivity by inversion with “broken apart” signals, 2 or more signal diameters apart (E, arrows). IHC, immunohistochemistry; ALK, anaplastic lymphoma kinase; FISH, fluorescence in situ hybridization.

Figure 2

AIFA-based scheme in detecting ALK-positive NSCLC using an integrated approach with IHC and FISH. All antibody clones against ALK are accepted employing a scoring system, then requiring FISH confirmation in indeterminate cases at IHC (scores 1+ and 2+). AIFA, Agenzia Italiana del Farmaco; ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization.