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In the process of diagnosis and treatment of advanced non-small cell lung cancer (NSCLC), the discovery of anaplastic lymphoma kinase (ALK) fusion gene is like a flower blooming in the dark, bringing hope for long-term survival for patients. Now, with the imminent approval of alectinib in China, the treatment of ALK-positive NSCLC has gradually moved forward from late to early, improving the prognosis of more patients. In order to further explore the history and development direction of ALK-positive NSCLC treatment, Yimaitong specially invited Professor Li Gaofeng from Yunnan Provincial Cancer Hospital and Professor Yan Xiaolong from Tangdu Hospital of Air Force Military Medical University to participate in the discussion.
Alectinib is used in patients with ALK-positive advanced NSCLC
Bringing hope for a "clinical cure".
The EML4-ALK fusion gene has been shown to play a key role in controlling cell proliferation, and Professor Li Gaofeng said that the fusion gene has a high incidence in young, adenocarcinoma, non-smokers or light smokers in NSCLC patients, and those who are positive for expression can benefit from ALK-tyrosine kinase inhibitors (ALK-TKIs)1. At present, 7 ALK-TKIs have been approved for marketing in China, showing a scene of "three generations in the same house". Among them, the second-generation ALK-TKI alectinib is currently the most widely used ALK-TKI in the first-line clinical trial, and has rich evidence-based medical evidence. The ALEX study demonstrated that alectinib in the first-line treatment of ALK-positive advanced NSCLC significantly prolonged survival2. The ALESIA study further suggests that alectinib demonstrated superior efficacy in Asian patients with ALK-positive advanced NSCLC, with a median progression-free survival (PFS) of 41.6 months (HR 0.33) and a 5-year survival rate (OS rate) of 66.4%3. Meta-analyses showed that in the first-line treatment of ALK-positive advanced NSCLC, alectinib brought a PFS benefit comparable to that of lorlatinib, a third-generation ALK-TKI, in Asian patients, and was the only ALK-TKI4,5 with a clear trend of benefit in 5-year OS rate compared with crizotinib.
As a "classic" drug that has been marketed in China for nearly 6 years, the clinical efficacy of alectinib has been verified many times in the real world. Previously, a domestic real-world study (RWS) study showed significant efficacy in the first-line treatment of ALK-positive Chinese NSCLC patients, with an objective response rate (ORR) of 88.5%, a two-year progression-free survival rate (PFS) of 81.1%, an intracranial response rate (CNS-ORR) of 92.9%, and a grade 3-4 adverse event incidence of only 6.4%6.
Fig.1 PFS of alectinib studied by RWS in China
The remarkable efficacy and good safety profile of alectinib in the actual clinical setting further confirm its superiority as a first-line treatment option, Professor Li Gaofeng emphasized. In addition, alectinib has been reported in patients with ALK-positive advanced NSCLC during pregnancy7, which further expands the use of alectinib.
Facing the problem of drug resistance to ALK-TKI targeted therapy
The choice of alectinib posterior line regimen is adequate
Although ALK-TKI has achieved good efficacy in patients with ALK-positive NSCLC, the majority of patients eventually develop drug resistance. A retrospective, real-world study conducted by Prof. Yao Yu's team showed that patients with ALK-positive NSCLC who are resistant to alectinib may be considered to continue receiving an alectinib-based combination regimen (TBP) to prolong survival8. Professor Li Gaofeng said that this means that patients who have progressed after receiving first-line or late-line alectinib therapy do not need to immediately switch to other ALK-TKIs, and some patients can still achieve improved survival through alectinib combined with other treatments.
In addition, alectinib also has a relatively well-defined resistance mechanism, with up to 53% of alectinib-resistant patients developing ALK resistance mutations such as G1202R, V1180L, or I1171T/N/S9. The third-generation ALK-TKI lorlatinib inhibits multiple mutations, including G1202R, and studies have found that patients who fail alectinib can continue to benefit from lorlatinib. In an international multicenter retrospective study of 106 TKI-experienced ALK-positive NSCLC, the median duration of treatment (mDoT) was 23.9±1.6 months and the mOS was 89.1±19.6 months10. In another real-world study of 38 patients with ALK-positive NSCLC, 37 of whom had received lorlatinib in the second line or later, had a complete response (CR) rate of 24 percent, a partial response (PR) rate of 46 percent, a stable disease (SD) rate of 24 percent, a mPFS failure (95% CI: 24.3 months-NR), and an mOS of up to 93.1 months11.
Fig. 2 PFS and OS of second-line and late-line treatment with lorlatinib
Professor Yan Xiaolong said: With the emergence of ALK-TKIs, it has opened the skylight for the long survival of ALK fusion-positive NSCLC patients, ALK+ NSCLC patients are usually very young, and the quality of life of patients is very important, compared with the EGFR mutation pathway, the vast majority of ALK+ NSCLC patients can achieve 2+3 treatment mode, and lorlatinib basically covers all the resistance sites of alectinib, and alectinib is still available after disease progression. It can provide high-quality, long-term survival protection for ALK-positive NSCLC patients. Alectinib is a second-generation ALK-TKI with a balance between efficacy and safety that has been validated by extensive real-world data, and can be used as a first-line preferred.
broke the game, and alectinib led
ALK-positive early-stage NSCLC "towards a cure"
Recently, alectinib will be approved in China for postoperative adjuvant therapy, becoming a new option for adjuvant therapy for ALK-positive early-stage NSCLC in mainland China, pushing precision targeted therapy to a higher clinical status and a wider range of beneficiary groups.
In recent years, with the promotion of early screening or early diagnosis and the improvement of people's health awareness, early lung cancer has become a relatively important type of lung cancer. However, surgery is the main treatment for ALK-positive early-stage NSCLC, but the 5-year survival rate of patients after surgery is unsatisfactory and needs to be improved urgently. In this context, the ALINA study was conducted by scholars around the world to try to apply alectinib to the perioperative treatment of ALK-positive early-stage NSCLC, and the results of the study showed that compared with chemotherapy, alectinib had the advantage of significantly prolonging disease-free survival (DFS) (HR: 0.24, 95% CI: 0.13-0.43, P<0.0001)12, helping to reduce the risk of disease recurrence or death by 76% in patients with early-stage ALK-positive NSCLC.
Fig.3 DFS results of the ALINA study in the ITT population
The just-concluded 2024 American Society of Clinical Oncology (ASCO) Annual Meeting presented results from the ALINA study related to health-related quality of life (HRQoL), which showed that adjuvant alectinib is effective compared with chemotherapy in improving the quality of life of patients with ALK-positive NSCLC and facilitating the return to normal work and life after surgery13. Professor Yan Xiaolong said that in the ALINA study, China not only contributed to the world's second largest number of patients, but also made outstanding contributions from research ideas, study design and other aspects, from the results published so far, the success of alectinib in ALK-positive early NSCLC patients is highly consistent with its in advanced patients, from early to late, alectinib started precision therapy "earlier", so that the "road to cure" for ALK-positive NSCLC patients is broader. It also provides further evidence support for the clinical application of alectinib in mainland China. On the basis of the ALINA study, further exploration should be made in the direction of the duration of adjuvant therapy, the biological characteristics of patients with recurrence in the short term after surgery, and the treatment options after recurrence.
summary
The history of ALK-positive NSCLC has been a journey full of hope and breakthroughs, and the emergence of alectinib has brought new hope and survival opportunities to patients. With the advancement of research, the use of alectinib has been expanded to the early stage of lung cancer, which can provide earlier treatment and improve patient outcomes. Although the performance of alectinib in the treatment of ALK-positive NSCLC has been encouraging, further research is needed to refine the treatment regimen. In the future, with the publication of more research data, we can expect alectinib to bring good news to more patients!
Expert Profile
Prof. Li Gaofeng
- Second-level professor and chief physician
- Doctoral supervisor and postdoctoral cooperative supervisor
- Vice President of Yunnan Provincial Cancer Hospital and the Third Affiliated Hospital of Kunming Medical University
- National outstanding scientific and technological worker, expert enjoying special allowance of the State Council
- Winner of the National May Day Labor Medal, Yunnan Provincial Medical Leading Talent, Yunling Famous Doctor
- Yunnan Province has outstanding professional and technical personnel with outstanding contributions and experts contacted by the provincial party committee
- Yunnan Health Guard, Provincial Association for Science and Technology Outstanding Society Worker
- Member of the International Association for the Study of Lung Cancer
- He is a member of the Standing Committee of the Mediastinal Tumor Professional Committee of the Chinese Anti-Cancer Association
- Member of the Thoracoscopic Surgery Group of the Thoracic and Cardiovascular Surgery Branch of the Chinese Medical Association
- Member of the National Lung Cancer MDT Expert Committee
- President of Yunnan Translational Medicine Society
- Vice Chairman of Yunnan Anti-Cancer Association
- Chairman of the Minimally Invasive Treatment Committee of Thoracic Tumors of Yunnan Anti-Cancer Association
- Executive Director of Yunnan Preventive Medicine Association and Chairman of Lung Cancer Professional Committee
- Vice Chairman of Thoracic and Cardiovascular Surgery Branch of Yunnan Medical Association
Prof. Xiaolong Yan
- Ph.D., Researcher, Ph.D. and Postdoctoral Supervisor
- Director of the Department of Thoracic Surgery, Tangdu Hospital
- Shaanxi Provincial Special Support Program Leading Talent in Science and Technology Innovation, Shaanxi Provincial Health Care Expert
- Member of the Director of Shaanxi Provincial Thoracic Surgery Medical Quality Control Center
- Member of the Thoracic Surgeon Branch of the Chinese Medical Doctor Association
- Vice President of Thoracic Surgeon Branch of Shaanxi Medical Doctor Association
- Deputy head of the Trauma Surgery Group of the Thoracic Surgery Branch of the Chinese Medical Doctor Association
- Member of the Standing Committee of the Thoracic Surgery Professional Committee of the Integrative Medicine Branch of the Chinese Medical Doctor Association
- Member of the Medical Robot Branch of the Chinese Medical Doctor Association
- Member of the Robotics Group of the Thoracic Surgery Branch of the Chinese Medical Doctor Association
- He is a member of the Lung Cancer Professional Committee of the Chinese Anti-Cancer Association
- Translational Lung Cancer Research编委
bibliography
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