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.

Cost-effectiveness of ensartinib, crizotinib, ceritinib, alectinib, brigatinib and lorlatinib in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer in China

“…Therefore, we could expect that for alectinib and lorlatinib, there are trends toward improved OS. This assumption is also supported by the relatively low HR generated by the NMAs (28,36,37).…”

“…Given the absence of head-to-head clinical trials that directly compared these six ALK-TIKs, we used the HRs of OS and PFS for ensartinib, ceritinib, alectinib, brigatinib, and lorlatinib vs. crizotinib extracted from a published network meta-analysis (NMA) ( 28 ) to estimate the transition probabilities for all ALK-TIKs except for crizotinib. The transition probabilities of the other five ALK-TIKs were obtained using the adjusted Weibull scale λ other − ALK − TKIs = λ crizotinib × HR and shape γ other − ALK − TKIs = γ crizotinib parameters.…”

“…In addition, the utility decrements that arise from grade III/IV AEs were also estimated in the model ( 30 ). Briefly, the disutility associated with crizotinib was included as a frequency-weighted sum based on the reported grade III/IV AEs data in the PROFILE 1,029 trial; disutilities associated with ensartinib, ceritinib, alectinib, brigatinib, and lorlatinib were calculated using the HRs for AEs derived from the NMA mentioned above ( 28 ). The algorithm used to estimate utility decrements is provided in Supplementary Appendix 3 , and all survival and health state utilities parameters are summarized in Table 1 .…”

Beyond Crizotinib: A Systematic Review and Meta-Analysis of the Next-Generation ALK Inhibitors as First-Line Treatment for ALK-Translocated Lung Cancer

“…Other meta-analyses have been published on the same topic ( 13 – 15 ). Different from the others, we compared next-generation ALKIs to crizotinib or chemotherapy, or the standard of care before their approval.…”

“…Previous systematic reviews and meta-analyses of ALKIs for the treatment of NSCLC have highlighted improved OS and PFS of crizotinib and other ALKIs versus chemotherapy ( 10 – 12 ). None of the recently published meta-analyses on the same topic ( 13 – 15 ) has specifically investigated the role of next-generation ALKIs towards crizotinib or chemotherapy. As head-to-head comparisons between next-generation ALKIs are unavailable, we conducted a systematic review of randomized phase III controlled trials where untreated patients received a second or third-generation ALKI as the experimental treatment for advanced ALK-positive NSCLC.…”