* is for medical professionals to read and refer to only
The first and third generations of ALK-TKI are reasonably sequential, striving for the greatest survival benefit!
With the continuous progress in lung cancer screening, diagnosis and treatment, the survival period of lung cancer patients is gradually prolonging. In 2019, the GO2 Lung Cancer Foundation proposed to manage advanced lung cancer as a chronic disease in order to achieve longer survival time and better quality of life [1].
ALK fusion positive (ALK+) advanced non-small cell lung cancer (NSCLC) is a group of people that cannot be ignored and exists in about 5% of NSCLC cases [2]. After the first generation of ALK tyrosine kinase inhibitor (TKI) crizotinib entered the clinical stage, it significantly prolonged the survival of ALK+ patients. However, as the treatment time extends, ALK+NSCLC will eventually develop resistance to crizotinib . In recent years, second-generation and third-generation ALK-TKI have emerged one after another, enriching clinical treatment options, and posing challenges in how to formulate reasonable sequential treatment plans in order to help patients achieve ideal survival benefits.
From the perspective of efficacy, ALK-TKI sequential treatment optimization selection
Currently, there are many ALK-TKIs that can be used for the treatment of ALK+ advanced NSCLC. In addition to the classic drug crizotinib, there are also second-generation and third-generation ALK-TKIs such as aletinib, seretinib, and lorlatinib. Faced with the three generations of ALK-TKI living together, how to choose suitable first-line and backline solutions to achieve optimal sequential treatment effects is related to the long-term survival of the patient.
More and more real-world data show that crizotinib's first-line sequential offspring ALK-TKI can bring longer survival benefits to patients. The WJOG 9516L study reviewed the clinical data of sequential second-generation ALK-TKI after the progression of crizotinib treatment in patients with advanced ALK+ NSCLC. The study found that the median overall survival (OS) of crizotinib sequential second-generation ALK-TKI was 88.4 months. The real-world study FCT-1302 CLINALK from France suggested that crizotinib sequential ceretinib or aletinib can bring 89.6 months of OS benefits to patients. Real-world studies from the United States show that crizotinib is sequentially progeny ALK-TKI, with OS up to 86 months. These studies show that the median OS of first-generation crizotinib treated with first-line sequential second-generation ALK-TKI reached [3-5] for more than 7 years.
Figure 1. Median OS for sequential treatment of first-line crizotinib. At the same time, the GLASS study showed that the median OS of sequential third-generation ALK-TKI lorlatinib after previous treatment (most patients were crizotinib) can last up to 89.1 months. In other words, first-line sequential treatment of first-generation crizotinib, whether 1+2 or 1+3, can bring long-term survival benefits.
Figure 2. Crizotinib sequential lorratinib, OS up to 89.1 months
1+3 regimen is better than 1+2 regimen
In terms of sequential treatment, the 1+3 regimen shows better efficacy than the 1+2 regimen. Several studies have shown that the progression-free survival (PFS) of the first-generation ALK-TKI sequential third-generation ALK-TKI sequential third-generation ALK-TKI sequential second-generation ALK-TKI sequential second-generation ALK-TKI sequential second-generation ALK-TKI sequential second-generation ALK-TKI sequential second-generation ALK-TKI sequential second-generation ALK-TKI sequential second-generation ALK-TKI sequential second-generation ALK-TKI sequential only 7.1 months [7-8].
1+3 scheme is better than 2+3 scheme
In addition, 1+3 scheme also shows better efficacy than 2+3 scheme. The global multicenter phase II clinical study of showed [9]. In Asian patients, crizotinib sequential third-generation ALK-TKI sequential loratinib versus second-generation ALK-TKI sequential loratinib PFS was longer, 13.6 months and 6.9 months, respectively. Similar results were also obtained in non-Asian patients. Ccrizotinib sequential loratinib sequential loratinib, with longer PFS, 12.5 months and 5.5 months, respectively. At the same time, compared with the second-generation ALK-TKI and the third-generation ALK-TKI, first-line crizotinib and third-generation ALK-TKI can obtain better ORR and intracranial ORR, and the efficacy of Asian population is better, reaching 82.4% and 80% respectively. The overall ORR and intracranial ORR of non-Asian populations reached 63.6% and 61.9%, respectively.
Figure 3. Comparison of different sequential schemes ORR and intracranial ORR with
It can be seen that the 1+3 scheme is better than the 1+2 scheme and the 2+3 scheme. The "1+3" scheme of crizotinib first-line sequential lorratinib is a better sequential scheme for ALK+NSCLC.
From the drug resistance mechanism and subsequent sequential treatment ratio, ALK+ advanced NSCLC first-line treatment choice
The reason why patients enter second-line treatment is often first-line treatment drug resistance.Therefore, a thorough understanding of the resistance mechanism of ALK-TKI targeted drugs can help clinicians better implement sequential treatment of [10].
As a classic ALK-TKI that has been used in clinical practice for many years, the resistance mechanism of crizotinib has gradually been clarified. The study found that among crizotinib-resistant patients, only 6.5% were primary drug resistance, while the rest were secondary drug resistance. Among secondary drug resistance, 65% are pharmacologically resistant, while the rest are biologically resistant. In terms of biological resistance of crizotinib, it is divided into secondary mutations and off-target resistance of ALK targets, including secondary mutations of ALK (20%-30%), ALK amplification (6%-18%), bypass activation (15%), and histological type conversion [11-14].
But fortunately, pharmacological resistance, ALK mutation and ALK amplified resistance in crizotinib can be dealt with through sequential progeny ALK-TKI, especially third-generation ALK-TKI.
In terms of pharmacological resistance, offspring ALK-TKI, especially loratinib, has good blood-brain barrier penetration ability and can better cope with crizotinib's pharmacological resistance. In terms of ALK mutations, the proportion of secondary mutations induced by first-line treatment of crizotinib is only about 20%-30%, and its drug resistance sites, such as L1196M and G1269A, can be covered by offspring ALK-TKI, which means that after crizotinib is resistant to drugs, it is likely that offspring TKI can still be treated with offspring TKI. In terms of ALK amplification, the progeny ALK-TKI, especially lorratinib, has lower IC50, which may overcome the problem of ALK amplification [15-19].
From the perspective of sequential treatment ratio, after the first-line crizotinib treatment of ALK+NSCLC progresses, sequential ceroxinib has rich evidence of evidence-based medical for sequential offspring ALK-TKI. Most patients can sequential offspring ALK-TKI, among which the sequential ratio of alexinib, seretinib and lorlatinib can reach 100% [20-21].
The second-generation ALK-TKI resistance mechanism is mainly based on secondary mutations and bypass activation. The secondary mutation of ALK is as high as 50%-70%, and the bypass activation reaches 45% [22]. Among them, G1202R is the most common drug-resistant mutation in patients treated with second-generation ALK-TKI, and the drug-resistant mutation spectrum is more complex. The study found that after the second-generation ALK-TKI was resistant to drug resistance, the efficacy of other second-generation ALK-TKI was not ideal, with median PFS of only 1.9-6.4 months [23], and only third-generation lorlatinib available. In addition, the study found that the sequential proportion after the first-line treatment of second-generation ALK-TKI was low and the chance of sequentiality was small. In the J-ALEX study and the ALEX study, only 25.2% and 38.1% of patients received sequential treatment [19-20], respectively.
The resistance mechanisms of third-generation ALK-TKI loratinib treatment are divided into ALK-dependent resistance (in-target resistance, mainly mediated by acquired resistance mutations in the ALK kinase domain) and ALK-independent resistance (off-target resistance, mediated by non-target kinase changes, such as bypass signal activation or phenotypic transformation). Among them, the independent drug resistance mechanisms include EGFR activation, NF2 function deletion mutation, EMT and other [24]. At present, the fourth generation of ALK-TKI that overcomes intra-target resistance is under development, and we look forward to new solutions to bring more benefits to patients.
Therefore, from the perspective of drug resistance mechanism, all types of drug resistance occurring in first-generation crizotinib can be dealt with through sequential progeny ALK-TKI, especially third-generation ALK-TKI. Second-generation ALK-TKI resistance is mainly based on secondary mutations and bypass activation, and bypass activation is difficult to handle, follow-up treatment is limited, and the patient's chance of sequentiality is low, which may affect the final OS.
Summary
ALK mutation can be called the "diamond mutation" of lung cancer. Through the sequential use of targeted drugs in various generations, some patients have achieved long-term survival. Judging from the efficacy data, drug resistance mechanism and subsequent sequential treatment ratio, sequential third-generation ALK-TKI after first-line treatment with crizotinib has certain advantages, and patients can obtain a longer survival period, which is an ideal treatment option. In the future, I believe that as the third-generation drug is launched in China and the fourth-generation drug research and development is on track, the prognosis of ALK patients will be further improved, and the management of chronic tumors will be truly realized.
Expert profile
Song Qibin Professor
First-level chief physician/professor/doctoral supervisor
Wuhan University People's Hospital Oncology Center Director and Director of Oncology Teaching and Research Department
National Health Commission Medical Administration Medical Administration Bureau "Cancer Diagnosis and Treatment Guide" Expert Group Member
National Cancer Center Lung Cancer Quality Control Expert
Chinese Medical Association Continuing Medical Education Textbook "Lung Cancer" Volume Deputy Editor-in-Chief
Hubei Province "323" Lung Cancer Expert Committee Chairman
Multidisciplinary oncology diagnosis and treatment professional committee of the Chinese Medical Association Deputy Chairman and Director-General
Chinese Society of Clinical Oncology (CSCO) Standing Director
CSCO Senior Tumor Committee Deputy Chairman, Lung Cancer and Big Data Committee Standing Committee
Hubei Provincial Clinical Oncology Society (ESCO) Chairman and Chairman of the Lung Cancer Committee
Wuhan Medical Association Radiation Oncology Therapy Branch Chairman
Published articles: More than 100 articles were published, including in Nature Communication, The EMBO Journal, BMJ and other magazines published more than 60 SCI articles
References:
[1].M. Rigney.Journal of Thoracic Oncology .2019;14(10):S25.
[2].Sun M, et al. Transl Cancer Res. 2019 Nov;8(7):2581-2592.
[3].Ito K, et al. 2019 ASCO Abstract #9038.
[4].Duriisseaux M, et al. Oncotarget. 2017; 8(13):21903-21917.
[5].Pacheco JM, et al. J Thorac Oncol. 2019;14(4):691-700.
[6].Peled N, et al. Lung Cancer. 2020;148:48-54.
[7].Shaw AT, et al. J Clin Oncol. 2019 Jun 1;37(16)1370-1379.
[8].Novello S, et al. Ann Oncol. 2018 Jun 1;29(6)1409-1416.
[9].Soo RA,et al. Lung Cancer. 2022 Jul;169:67-76.
[10].Sukrithan V, et al. Future Oncol. 2019 Sep;15(25):2899-2904.
[11].Ma D, et al. Thorac Cancer. 2019;10(5):1213-1219.
[12].Costa DB. Cell Cycle. 2017;16(1):19-20.
[13].Lin JJ, et al. Cancer Discov. 2017;7(2):137-155.
[14].Transl Lung Cancer Res. 2020; 9(6):2545–2556.
[15].Chen J, et al. Clin Pharmacokinet. 2021 Oct;60(10):1313-1324.
[16].Cheng HY, et al. Lancet Oncol 2018; 19: e43–55.
[17].Singh A, Chen H. Cancer Manag Res. 2020 Jul 30;12:6615-6628.
[18].Gainor JF, et al. Cancer Discov. 2016 Oct;6(10):1118-1133.
[19].Naito T, et al. Jpn J Clin Oncol. 2021;51(1):37-44.
[20].Novello S, et al. Ann Oncol. 2018;29(6)1409-1416.
[21].Lucio Crino, et al. J Clin Oncol. 2016,34 :2866- 2873.
[22].Costa DB. Cell Cycle. 2017;16(1):19-20.
[23].Remon J, et al. Clin Transl Oncol. 2020;22(9):1425-1429.
[24].Haratake N, et al. Expert Rev Anticancer Ther 2021;21(9):975-988
*This article is only used to provide scientific information to medical personnel and does not represent the views of this platform
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-