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With the rapid development of molecular biotechnology, mutations in oncogenic driver genes in non-small cell lung cancer (NSCLC) have been identified in the past few decades [1]. Based on the results of molecular screening, NSCLC has gradually changed from traditional chemotherapy to targeted therapy. Anaplastic lymphoma kinase (ALK) mutations, also known as "diamond" mutations, can achieve better efficacy and longer survival compared with other mutation sites. Real-world data [2,3] suggest that patients with advanced ALK-positive NSCLC can achieve a median overall survival (mOS) of more than 7 years after treatment with an ALK tyrosine kinase inhibitor (ALK-TKI).
In recent years, the first, second, and third generation of ALK-TKIs have been approved one after another, which has completely changed the treatment landscape of ALK-positive NSCLC patients, but how to effectively select targeted therapy drugs has become a problem worthy of in-depth discussion. The relative efficacy and safety of most first- and second-line treatments for ALK-TKIs remain unknown due to the lack of head-to-head randomized controlled (RCT) clinical trials, while network meta-analyses (NMAs) provide an analytical method that integrates direct and indirect evidence and have become an important method for comparative effectiveness studies and health technology assessments. Based on this, Professor Yang Nong from the Second People's Hospital of Hunan Province conducted an in-depth analysis of a number of NMA results on the efficacy and safety of ALK-TKI in the treatment of NSCLC, in order to fully understand the advantages and disadvantages of different ALK-TKIs and facilitate clinical treatment selection.
Flowers bloom and stalk
Alectinib has a double harvest of efficacy and safety
An NMA [4] compared efficacy and safety in 2194 patients with NSCLC who received lorlatinib, brigatinib, alectinib, ceritinib, crizotinib, and platinum-based chemotherapy from eight studies, and compared progression-free survival (PFS), overall survival (OS), and grade ≥3 adverse events (AEs) in total participants, Asian and non-Asian patients, respectively.
Fig.1 Network diagram of the six treatment groups
There was no significant difference in PFS between lorlatinib and alectinib in the overall population (HR: 0.742, 95%CI: 0.466~1.180). Subgroup analysis showed that although the PFS data of alectinib treatment were slightly inferior to that of lorlatinib in the non-Asian population (HR: 0.388, 95%CI: 0.195~0.769), there was no significant difference between the PFS data of alectinib and lorlatinib in the Asian population. In addition, the results of the Asian subgroup ranking evaluation based on SUCRA values showed that among the Asian population, alectinib patients had the highest PFS (SUCRA=91.2%), followed by brigatinib (SUCRA=78.1%), lorlatinib (SUCRA=70.4%), crizotinib (SUCRA=39.3%), ceritinib (SUCRA=20.1%), and chemotherapy (SUCRA=0.9%).
Fig. 2 Comparison of PFS in the Asian population of ALK-TKI
In patients with brain metastases/PS 0-1 points, the PFS of alectinib versus lorlatinib was not distributed: a subgroup analysis based on the presence or absence of central nervous system metastases showed that there was no significant difference in PFS data between lorlatinib and alectinib regardless of the presence of (HR: 0.542, 95%CI: 0.229~1.285)/absence (HR: 0.705, 95%CI: 0.402~1.234) central nervous system metastases.
Note: a: Presence of central nervous system metastases; B: No central nervous system metastases
Fig.3 PFS comparison of ALK-TKI-naïve NSCLC patients with and without brain metastases
In the results of subgroup analysis of patients with PS 0-1 in the five treatment groups of lorlatinib, brigatinib, alectinib, crizotinib and chemotherapy, there was still no significant difference in PFS between lorlatinib and alectinib (HR: 0.774, 95%CI: 0.486~1.233).
The safety profile of alectinib is also one of the best: in the process of clinical application, in addition to focusing on the efficacy of the drug, it is also necessary to ensure the tolerability and safety of the treatment. The results showed that alectinib was the safest treatment (SUCRA=100.0%), followed by crizotinib (SUCRA=60.7%), brigatinib (SUCRA=35.4%), and finally lorlatinib (SUCRA=3.9%). Moreover, the G3-AEs of lorlatinib were higher than those of alectinib (RR: 1.918, 95%CI: 1.486-2.475) and crizotinib (RR: 1.300, 95%CI: 1.085~1.554). In addition, alectinib ranked first, first, and second in the secondary safety endpoints of any grade SAE incidence (AG-SAEs), grade 3 SAE incidence (G3-SAE), and any grade AE incidence (AG-AEs), respectively, while lorlatinib ranked the lowest. In addition, alectinib remained the most favorable in terms of AG-pneumonia and G3-pneumonia, followed by lorlatinib and crizotinib. In terms of AG-diarrhea, alectinib was significantly lower than lorlatinib (RR=1.869, 95% CI: 1.167-2.988).
Fig.4 Comparison of G3-AEs in patients with ALK-TKI-naïve NSCLC
run neck and neck
The first-line short-term/long-term benefits of alectinib are fully covered
A comprehensive NMA [5] included 14 RCTs involving a total of 3474 patients with ALK-positive NSCLC comparing the safety and efficacy of current therapies (chemotherapy, crizotinib, alectinib [600 mg BID], low-dose alectinib [300 mg BID], brigatinib, ceritinib, ebona, and lorlatinib) in the first- and second-line treatment of patients with ALK-positive NSCLC, and to evaluate the impact of these therapies on quality of life.
In terms of first-line PFS, the time-limited survival model (RMST) for Asian patients showed that alectinib significantly improved PFS over a 21-month period compared with crizotinib (RSMD 5.73 months, 95% CI: 3.70~7.74). All ALK-TKIs significantly improved PFS compared to chemotherapy, with alectinib performing best. The best-fit piecewise polynomial (FP) model (P=1) predicted that alectinib may be the best choice for PFS at longer follow-up.
Fig. 5 Comparison of first-line PFS in Asian populations
Evidence from the ALK-TKI:RMST model showed that alectinib had the highest mean OS improvement compared with crizotinib up to 33 months (the shortest follow-up of all included trials) compared with crizotinib (RSMD, 1.13 months, 95% CI, -1.32 ~3.61). In addition, alectinib also had the highest OS rate. The proportional risk (PH) hypothesis showed that only alectinib significantly improved OS compared to coxotinib when compared with other ALK-TKIs and chemotherapy (HR, 0.67 [0.46 ~ 0.98]).
Fig.6 Comparison of OS in first-line treatment
The first-line benefit of alectinib in the treatment of ORR is among the best: in systemic ORR, low-dose alectinib, lorlatinib, ceritinib, alectinib, and ebonac are superior compared with crizotinib.
Fig.7 Comparison of ORR in first-line treatment
Alectinib is the safest first-line option: In addition to significant efficacy data, the safety data for alectinib are also compelling. Low-dose alectinib and alectinib demonstrated superior overall performance in any grade of AE & grade 3. Among them, compared with crizotinib, low-dose alectinib significantly reduced the incidence of any grade of AEs and grade 3/4 AEs in first-line therapy. In contrast, lorlatinib and ceritinib significantly increased the incidence of any grade AEs, with lorlatinib and brigatinib performing significantly worse than crizotinib in the incidence of grade 3/4 AEs, and lorlatinib performing the worst in grade 5 or fatal AEs.
Fig.8 Comparison of any grade AE/grade 3-4 AE/grade 5 or fatal AE in first-line treatment
Alectinib also performed well in patient-reported outcomes (PRO): the FP model (P=0.5) showed a slight advantage over other treatments in the long term, and alectinib was considered the next best option.
Fig.9 QLQ-LC13 for first-line treatment (survival curve based on FP model)
Today, the concept of cancer treatment has shifted to "better control of disease and better quality of life". Alectinib is superior to other treatments in terms of OS, is the best choice for Asian patients in terms of PFS, and has a higher safety profile and good QoL, so alectinib is expected to be the preferred initial treatment option for advanced ALK.
Avoid annoying the "brain"
Alectinib is highly effective, low toxicity and safer
ALK-mutant NSCLC is prone to brain metastasis, and nearly 10%~30% of NSCLC patients have brain metastases. An NMA [6] included 12 RCTs with a total of 3156 patients with ALK-positive NSCLC to analyze the efficacy and safety of ALK-TKI in patients with ALK-positive NSCLC lung cancer brain metastases.
Efficacy and safety, alectinib may be the best choice: compared with other ALK-TKIs and chemotherapy, alectinib is the only second-generation TKI with fewer serious adverse events. The relative ranking of each treatment based on SUCRA values showed that alectinib (SUCRA=0.01) had the lowest toxicity, followed by crizotinib (0.24), ensartinib (0.39), brigatinib (0.61), lorlatinib (0.79), and ceritinib (0.87) (Figure 11).
Note: a: summary estimate; b: Relative ranking of ALK-TKI
Fig.10 Comparison of intracranial responses of ALK-TKI in patients with ALK-positive NSCLC
Note: a: summary estimate; b: Relative ranking of ALK-TKI
Fig.11 Comparison of any grade AE and ≥ grade 3 AE in ALK-positive NSCLC
With the continuous research and development of ALK-TKI, the first, second, and third generation ALK-TKI have entered clinical application successively, which has significantly improved the PFS of ALK-positive NSCLC patients. However, it is worth exploring how to reasonably and effectively use each generation of ALK-TKI in the treatment of patients with brain metastases in NSCLC. Further Bayesian network analysis showed that for patients with brain metastases who had not been treated with ALK-TKIs before, it was recommended to choose second- and third-generation ALK-TKIs to replace chemotherapy and first-generation TKIs for initial treatment. Compared with crizotinib, the intracranial response rate of second- and third-generation ALK-TKIs was significantly higher (OR=8.77, 95% CI: 3.89~19.78, P<0.001). In addition, alectinib has a longer PFS, higher intracranial ORR, and lower toxicity than crizotinib, other second-generation ALK-TKIs, and chemotherapy.
【Analysis】The first, second, and third generation ALK-TKI were included in the "net", and the efficacy and safety inventory were sorted
The vigorous development of precision medicine has enabled the treatment of NSCLC with gene mutations to successfully enter the era of targeted therapy, and for patients with ALK-mutant NSCLC, the successive approval of first, second and third generation ALK-TKIs provides a variety of options for the treatment of patients, and how to prioritize the selection of drugs is the focus of current scholars. However, there is a lack of head-to-head RCTs to compare the efficacy and safety of different drugs, resulting in a lack of evidence-based support for clinical treatment options. The NMA, on the other hand, provides an analytical approach that integrates direct and indirect evidence.
NMA can effectively fill the evidence gap that cannot be addressed by RCTs or traditional meta-analyses by pooling research evidence from multiple interventions for the treatment of the same disease, conducting quantitative statistical comparisons, and ranking the efficacy/safety of all study groups. Three recently published NMA articles on ALK-TKI compare and analyze the current first-, second- and third-generation ALK-TKIs from the aspects of efficacy and safety, first-line and second-line and brain metastases, respectively, aiming to comprehensively rank ALK-TKIs in order to provide evidence-based basis for clinical practice to select the optimal regimen.
From the above research, it is not difficult to find that at present, the efficacy of the treatment of cancer patients is not the only indicator for evaluating the treatment plan, and for cancer patients, it is not emphasized that "live long", but on the basis of "living well", so safety and quality of life are also one of the important indicators of evaluation when judging clinical choice. The results of the above studies all showed that alectinib was one of the best and two therapeutic drugs in terms of efficacy, safety, and quality of life of patients, and showed consistent benefit performance regardless of whether there were brain metastases.
It can be seen that based on the results of the above NMA analysis, considering the efficacy and safety, alectinib may become the preferred first-line treatment for ALK mutation-positive NSCLC patients, especially Asian patients. Considering the efficacy and tolerability of central nervous system and systemic therapy, alectinib is also expected to be the best choice for patients with ALK-positive NSCLC with brain metastases.
Although NMA can maximize the use of existing evidence and conserve research resources, it also has limitations. First, the NMA has high requirements for the quality of the included studies, and the key protocol as a bridge can affect the reliability of the evidence across the network. Second, the large number of included studies may increase the heterogeneity of the studies. The choice of different statistical methods will also have an impact on the results. In addition, when circumstantial evidence conflicts with direct evidence, the results are also affected. Finally, the follow-up updates of different trials are different, and the research data are not mature, etc., which will also affect the results of the NMA analysis. Therefore, more head-to-head RCT studies are urgently needed to directly compare the efficacy and safety of ALK-TKI in order to verify the conclusions of NMA.
Expert Profile
Prof. Nong Yang
- Vice President of the Second People's Hospital of Hunan Province, Chief Physician and Doctoral Supervisor
- He is a long-term expert from Hainan Tropical Oncology Institute, Hainan Provincial Cancer Hospital, and Hainan Chengmei Hospital
- 2017-2023 7th National "Good Doctor of the Year"
- The 6th National Famous Doctor, Excellent Style
- Chief expert of major national science and technology projects
- Member of the Lung Cancer Quality Control Committee of the National Cancer Quality Control Center
- Vice Chairman of the Tumor Immunotherapy Committee of the Chinese Medical Education Association
- Vice Chairman of the Special Committee for Innovation and Development of Cancer Clinical Research of China Medical Education Association
- He is a member of the Chinese Society of Clinical Oncology and a member of the Special Committee on Tumor Immunotherapy, Non-small Cell Lung Cancer and Drug R&D
- He is a member of the Standing Committee of the Anti-tumor Drug Committee of the Chinese Anti-Cancer Association and a member of the Lung Cancer Committee
- He is a member of the Oncology Branch of the Chinese Medical Doctor Association
- Chairman of the Tumor Precision Medicine Committee of Hunan Anti-Cancer Association
- Chairman of the Clinical Oncology Branch of the Hunan Geriatrics Society
- Director of Hunan Provincial Key Laboratory of Precision Diagnosis and Treatment of Lung Cancer
- Director of Hunan Provincial Clinical Research Center for Respiratory Oncology
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参考文献：[1]Zou Z, et al. Transl Lung Cancer Res. 2022 Dec; 11(12):2495-2506.
[2] Duruisseaux M, et al. Oncotarget 2017;8:21903-17.
[3] Ito K, et al. Eur J Cancer 2021;145:183-93.
[4] Ando K, et al. Cancers (Basel). 2021 Jul 23; 13(15):3704.
[5] Zhao M, et al. BMC Cancer. 2024 Feb 8; 24(1):186.
[6] Jiang J, et al. BMJ Open. 2022 Sep 19; 12(9):e060782.
* This article is only for the purpose of providing scientific information to medical professionals and does not represent the views of this platform