ALK Inhibitors in the Treatment of ALK Positive NSCLC

Abstract

Background: ALK inhibitors have shown positive advance in the treatment of ALK+ NSCLC. They have achieved better results in prolonging the progression free survival and improving quality of life in comparison to chemotherapy. We have assembled the evidence related to the efficacy and safety of these agents in the treatment of ALK positive NSCLC. Materials and Methods: A comprehensive search was conducted using electronic databases of PubMed, Medline and Cochrane Library to identify the studies involving comparison of ALK inhibitors to chemotherapy and Next generation ALK inhibitors to crizotinib. PFS was the primary outcome while other outcomes like ORR, adverse events, quality of life and OS were also analyzed and compared. Hazard ratios and odds ratios obtained were analyzed using fixed effect or random effects model in Review Manager Software. Results: A total of 12 studies (n = 3,297) met the criteria for inclusion in this review and meta-analysis. ALK inhibitors including crizotinib, ceritinib and alectinib revealed significantly better PFS (HR 0.42 [0.35, 0.50; p < 0.00001]), ORR (Overall OR 6.59 [4.86, 8.94; p < 0.00001] as compared to chemotherapy in the first line as well as second line treatment settings. Intracranial response rate was better with ALK inhibitors (ceritinib and alectinib) as compared to chemotherapy OR 6.51 [2.86, 14.83; p < 0.00001]. No significant increase in grade 3 or 4 adverse events was observed with crizotinib (OR 1.21 [0.82, 1.77; p = 0.34]) or ceritinib (OR 1.49 [0.86, 2.57; p = 0.17]) when compared to chemotherapy individually. Quality of life indicators assessed were significantly improved with ALK inhibitors. Next generation agents (ceritinib, alectinib and brigatinib) revealed significant improvement in PFS (HR 0.50 [0.43, 0.57; p < 0.00001]), ORR (OR 1.57 [1.21, 2.04; p = 0.0006]) in comparison to crizotinib. Next generation agents (Alectinib and brigatinib) yielded better response intra-cranially than crizotinib in terms of objective response rate (OR 5.87 [3.49, 9.87; p < 0.00001]) and time to CNS progression (HR 0.25 [0.13, 0.46; p < 0.0001]). Alectinib by far resulted in fewer adverse events than chemotherapy or crizotinib. Conclusions: Overall ALK inhibitors are safe and effective treatment option in ALK+ non-small cell lung cancer. Of the ALK inhibitors, Next generation agents in particular alectinib and brigatinib are safer and more effective intra-cranially and can be preferred as first option.

Keywords: anaplastic lymphoma kinase (ALK); chemotherapy; molecular targeted agents; non-small cell lung cancer (NSCLC); progression free survival (PFS); quality of life (Qol).

Figure 1

The flow diagram of literature search and selection process.

Figure 2

Forest plot of meta-analysis of the progression-free survival (PFS) showing comparison of ALK inhibitors to chemotherapy in ALK positive NSCLC.

Figure 3

Forest plot of meta-analysis of the progression-free survival (PFS) showing comparison of Next generation agents to crizotinib in ALK positive NSCLC.

Figure 4

Forest plot of meta-analysis of the objective response rate (ORR) showing comparison of ALK inhibitors to chemotherapy in ALK positive NSCLC.

Figure 5

Forest plot of meta-analysis of the objective response rate (ORR) showing comparison of Next generation agents to crizotinib in ALK positive NSCLC.

Figure 6

Forest plot of meta-analysis of the Intra-cranial response rate (ICRR) showing comparison of ALK inhibitors to chemotherapy in ALK positive NSCLC.

Figure 7

Forest plot of meta-analysis of the Intra-cranial response rate (ICRR) showing comparison of Next generation agents to crizotinib in ALK positive NSCLC.

Figure 8

Forest plot of meta-analysis of the Time to CNS progression showing comparison of Next generation agents to crizotinib in ALK positive NSCLC.

Figure 9

Forest plot of meta-analysis of the overall survival (OS) showing comparison of ALK inhibitors to chemotherapy in ALK positive NSCLC.

Figure 10

Forest plot of meta-analysis of the overall survival (OS) showing comparison of Next generation agents to crizotinib in ALK positive NSCLC.

Figure 11

Forest plot of meta-analysis of discontinuation due to adverse events showing comparison of ALK inhibitors to chemotherapy in ALK positive NSCLC.

Figure 12

Forest plot of meta-analysis of the Grade 3 or 4 adverse events (AEs) showing comparison of Next generation agents to crizotinib in ALK positive NSCLC.

Figure 13

Forest plot of meta-analysis of the time to deterioration with respect to a composite end point of three symptoms–cough, dyspnea or chest pain showing comparison of ALK inhibitors to chemotherapy in ALK positive NSCLC.