Comparative efficacy and safety of first-line treatments for advanced non-small cell lung cancer with ALK-rearranged: a meta-analysis of clinical trials

Abstract

Background: Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC.

Methods: We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases.

Results: A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg and 600 mg), brigatinib, lorlatinib and ensartinib yielded the most favorable PFS. Whereas there was no significant OS or ORR difference among the ALK-TKIs. According to Bayesian ranking profiles, lorlatinib, alectinib 600 mg and alectinib 300 mg had the best PFS (63.7%), OS (35.9%) and ORR (37%), respectively. On the other hand, ceritinib showed the highest rate of severe adverse events (60%).

Conclusion: Our analysis indicated that alectinib and lorlatinib might be associated with the best therapeutic efficacy in first-line treatment for major population of advanced NSCLC patients with ALK-rearrangement. However, since there is little comparative evidence on the treatment options, there is need for relative trials to fully determine the best treatment options as well as the rapidly evolving treatment landscape.

Keywords: ALK; First-line treatment; Lung cancer; Network meta-analysis.

Fig. 1

Flowchart of study selection

Fig. 2

Network plot comparing different treatment outcomes in different groups of patients with advanced ALK-rearranged NSCLC

Fig. 3

Pooled estimates of the network meta-analysis. (A) Pooled hazard ratios (95% credible intervals) for progression free survival. (B) Pooled odds ratios (95% credible intervals) for overall survival. Data in each cell are hazard or odds ratios (95% credible intervals) for the comparison of row-defining treatment versus column-defining treatment. Hazard ratios less than 1 favour row-defining treatment. Significant results are in bold. Ale 300 mg, alectinib 300 mg; Ale 600 mg, alectinib 600 mg; Bri, brigatinib; Cer, ceritinib; Chemo, chemotherapy; Cri, crizotinib; Ens, ensartini; Lor, lorlatinib

Fig. 4

Bayesian ranking profiles of comparable treatments on efficacy for patients with advanced ALK-rearranged, non-small cell lung cancer. The profiles indicate the probability of each comparable treatment being ranked from first to last on progression free survival, overall survival, objective response rate, and grade ≥ 3 adverse events. Ale 300 mg, alectinib 300 mg; Ale 600 mg, alectinib 600 mg; Bri, brigatinib; Cer, ceritinib; Chemo, chemotherapy; Cri, crizotinib; Ens, ensartini; Lor, lorlatinib

Fig. 5

Pooled estimates of the network meta-analysis. (A) Pooled odds ratios (95% credible intervals) for objective response rate. (B) Pooled odds ratios (95% credible intervals) for adverse events of grade 3 or higher. Data in each cell are hazard or odds ratios (95% credible intervals) for the comparison of row-defining treatment versus column-defining treatment. Odds ratios more than 1 favour row-defining treatment. Significant results are in bold. Ale 300 mg, alectinib 300 mg; Ale 600 mg, alectinib 600 mg; Bri, brigatinib; Cer, ceritinib; Chemo, chemotherapy; Cri, crizotinib; Ens, ensartini; Lor, lorlatinib; Grade ≥ 3 AEs, adverse events of grade 3 or higher

Fig. 6

Pooled estimates of the network meta-analysis. (A) Pooled hazard ratios (95% credible intervals) for patients with the baseline CNS metastases. (B) Pooled hazard ratios (95% credible intervals) for patients without baseline CNS metastases. Data in each cell are hazard (95% credible intervals) for the comparison of row-defining treatment versus column-defining treatment. Hazard ratios less than 1 favour row-defining treatment. Significant results are in bold. Ale 300 mg, alectinib 300 mg; Ale 600 mg, alectinib 600 mg; Bri, brigatinib; Cer, ceritinib; Chemo, chemotherapy; Cri, crizotinib; Ens, ensartini; Lor, lorlatinib; CNS, central nervous system