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    • Recently a Phase III study demonstrated

    2024-03-02

    Recently, a Phase III study demonstrated that alectinib, the second-generation ALK inhibitor, might have a better response to ALK-rearrangement patients than crizotinib [10]. Should alectinib replace crizotinib as the frontline treatment for ALK-rearranged patients? Or should those patients be treated with a sequential approach frontline crizotinib followed by alectinib when the crizotinib resistance occurs? To answer these questions, more study should be done to investigate the heterogeneous response to crizotinib. In our study, we explored the PFS to crizotinib of ALK-rearranged lung cancer. By using next-generation sequencing technology (NGS), we also aimed to investigate the responsiveness of various ALK-rearrangement variants to crizotinib.
    Materials and methods
    Results
    Discussion NSCLC patients harboring ALK rearrangement are sensitive to ALK inhibitor, and crizotinib was the first ALK TKI approved by FDA. However, it purinergic receptor has been noticed that the clinical benefits have large variability. Research has been conducted on the clinical outcomes among different ALK variants, with contradict conclusions. We extend our study to analyze the influences of the different ALK variants on clinical efficacy of crizotinib in a large Chinese population. In our study, we analyzed 96 patients who were diagnosed with advanced ALK-positive NSCLC and received crizotinib. The median PFS was 14.17 months [95%CI: 11.63-21.63] and the ORR was 64.21%. These efficacy results observed were consistent with the published data [[6], [7]]. Patients who received crizotinib as first-line treatment had longer PFS compared to others. Similar results were reported by Lei Y and colleagues among 61 ALK-positive patients [14]. Based on the results from 60 patients with NGS, we found that variant 3a/b (33.33%) and variant 1 (23.33%) were the most frequent variants, followed by variant 2 (15.00%). Other EML4-ALK variants (10.00%) and nonEML4-ALK variants (18.33%) were also detected. In our study, variant 2 had a better PFS than other variants. This is consistent with the in vitro study conducted by Heuckmann [9]. The proposed explanation by Heuckmann was that the various parts of EML4 fused to ALK influenced the protein stability, inhibitor-induced protein degradation, and drug sensitivity. Their findings were also supported by analyses of artificial ALK-fusion variants of various lengths [9]. Although several studies reported prolonged PFS of variant 1 compared with non-v1 EML4-ALK group [8], we did not observe the same difference. In our study, no significant difference were observed between PFS of EML4-ALK and nonEML4-ALK, which is consistent with Yoon Jin Cha’s study of 52 patients with advanced ALK-rearrangement lung adenocarcinoma [15]. C.G. Woo has reported that variant 3a/b were resistant to ALK inhibitors with >10-fold higher half maximal inhibitory concentration in vitro [16]. In our study, we also found that patients with variant 3a/b had a shorter duration of response to crizotinib than those with other EML4-ALK variants with a borderline p value. However, the PFS was not significantly different between these two groups. Woo’s in vitro study reported that EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance [16]. We believed that further studies with a larger cohort should be done to prove that the variant 3a/b is more likely to develop resistance to crizotinib.
    Conclusions In summary, we reported the patterns of ALK variants in Chinese patients with ALK-positive NSCLC, and investigated the clinical outcomes among different ALK variants. Our study showed that compared with other EML4-ALK variants, variant 2 was more sensitive to crizotinib and had a better PFS. Therefore, the treatment strategy for ALK-positive NSCLCs should be determined by the precise ALK variant. Our results might explain some of the heterogeneous responses of ALK-positive tumors to crizotinib and can provide valuable inputs for clinicians treating ALK-positive NSCLC patients in carpels regard.