Professor Gao Beili: Comprehensive treatment + full management help ALK-positive NSCLC patients to survive better and longer

*Only for medical professionals to read.
How does ALK-TKI change? What are the future prospects? Let's listen to Professor Gao Beili's in-depth interpretation.

Anaplastic lymphoma kinase (ALK) fusion gene is an important therapeutic target for advanced non-small cell lung cancer (NSCLC).

After the discovery of the EML4-ALK fusion gene in 2007, targeted drugs emerged, opening a new chapter for the treatment of ALK-positive NSCLC patients.

The first, second and third generation ALK targeted drugs in the world have all been approved.

At present, the first-line treatment drugs approved in China include first-generation crizotinib, second-generation aletinib, and ceritinib.

 With the birth of highly effective targeted drugs, the treatment of ALK-positive advanced NSCLC patients has undergone radical changes-towards the era of "chronic disease".

The "medical community" sincerely invites Professor Gao Beili from the Department of Respiratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, to share relevant insights and clinical experience in the treatment of ALK-positive advanced NSCLC.

 "Diamond mutation" targeted drug changes In 2007, Professor Soda discovered the EML4-ALK fusion gene for the first time in NSCLC samples.
Later experiments in mice proved that the gene has strong carcinogenicity.

At present, it has been found that there are 27 fusion forms of ALK, the main fusion partner gene is EML4, and all ALK gene fusions occur in a sequence encoded by exon 20, including a complete tyrosine kinase domain, which is carcinogenic [1 ].

Under normal circumstances, TKI drugs bind to the ATP (adenosine triphosphate) pocket area in the EML4-ALK receptor groove to competitively inhibit ATP binding and produce anti-tumor effects.

 Professor Gao Beili said: "Internationally, the incidence of ALK mutations in NSCLC patients is about 5%, and that in the Chinese population is about 5%-8%.

Although ALK-positive NSCLC accounts for a very low proportion of lung cancer, the number of new cases in my country each year is still close to 39,000.

Before the advent of ALK inhibitors, this type of patient had a poor prognosis.

Clinical studies have shown that its objective response rate (ORR) to chemotherapy is only 25%.

With the continuous development of medical technology, ALK inhibitors have also been replaced in recent years, and a huge breakthrough has been made in the diagnosis and treatment of ALK-positive advanced NSCLC patients.

"In 2011, the first ALK-TKI crizotinib was approved.
The PROFILE 1014 study confirmed that first-line crizotinib is better than platinum-containing dual-agent chemotherapy, and the median progression-free survival (PFS) was significantly prolonged (10.
9 months vs.
7.
0 months, P <0.
001), ORR significantly increased (74% VS 45%, P <from 0.
001) [2].

1029 Research PROFILE for ALK positive Asians also reached the primary end point [3].

 as The first-line data of the second-generation ALK-TKI has been announced successively, and the treatment of ALK-positive advanced NSCLC has gradually entered the "2+X" treatment era.

Compared with the first-generation ALK-TKI, the second-generation ALK-TKI has more precise targets and higher selectivity.
The
"Chinese Society of Clinical Oncology Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer" (2020 edition) pointed out: The results of the Phase III clinical study ALESIA[4] which compares aletinib and crizotinib head-to-head in Asian populations are compared with ALEX [5] Consistently, the PFS of the aletinib group was significantly prolonged (median PFS did not reach vs 11.
1 months, HR 0.
22, P <0.
001) (Figure 1).

Based on the results of this study, the National Medical Products Administration (NMPA) ) In 2018, aletinib was approved for ALK-positive locally advanced or metastatic NSCLC, including first-line and second-line treatment after crizotinib treatment progressed.

Since aletinib first-line treatment has a median PFS time of 34.
8 months , This guide regards it as the first-line preferred recommendation for the first-line treatment of ALK-positive patients (Table 1). Figure 1.
ALESIA study PFS results Table 1.
The Chinese Society of Clinical Oncology 2020 version of the non-small cell lung cancer diagnosis and treatment guidelines recommends the treatment of ALK fusion-positive non-small cell lung cancer.
The "sorrow" of advanced lung cancer-brain metastasis, no longer without medicine Relieving the brain is one of the most common distant metastases of lung cancer, and the prognosis of patients with lung cancer with brain metastasis is poor, and the natural average survival time is only 1-2 months.

How to improve the quality of life and prolong the survival time of patients with lung cancer with brain metastases is a realistic problem that every clinician needs to solve urgently.

 Although the first-generation ALK-TKI crizotinib has a significantly better efficacy than chemotherapy and also brings considerable benefits to patients, the disease usually progresses within 1 year after first-line treatment with crizotinib, and about 40% of patients have brain metastases.

Because crizotinib and ceritinib are both substrates of P-glycoprotein, the blood-brain barrier efflux pump, the central nervous system (CNS) has low permeability and cannot achieve effective drug concentration.
Therefore, the curative effect of brain metastasis cannot be controlled.
good.

Studies have shown that patients with advanced NSCLC who have brain metastases at baseline have an intracranial ORR of only 18% after crizotinib treatment, and a 12-week intracranial disease control rate of 56%.

Therefore, how to further improve the efficacy of ALK-TKI, control brain metastasis, and reduce patient mortality has become the focus of clinical attention.

 With the continuous update of clinical data, the dominant position of the second-generation ALK-TKI blood-brain barrier permeability has been highlighted.

"Chinese treatment guidelines for lung cancer brain metastases" (2021 edition) pointed out [6]: Compared with pemetrexed combined with platinum chemotherapy, crizotinib has the control rate of intracranial metastases in patients with ALK fusion gene-positive NSCLC brain metastases Higher, but compared with the second-generation ALK-TKIs, the efficacy of intracranial metastases is not good.

In a phase III clinical study of aletinib versus crizotinib in the first-line treatment of ALK fusion gene-positive advanced NSCLC patients, analysis of the brain metastasis subgroup of patients showed that the intracranial ORR of aletinib was 81%, and the intracranial remission was sustained The time (DOR) was 17.
3 months; the intracranial ORR of crizotinib was 50%, and the intracranial DOR was 5.
5 months.  At the 2021 European Lung Cancer Conference (ELCC), Professor Li Junling's team from the Cancer Hospital of the Chinese Academy of Medical Sciences released a multi-center retrospective study to evaluate the treatment of ALK-positive advanced NSCLC with central nervous system (CNS) metastasis in the domestic real world with aletinib The patient's efficacy.

The researchers divided the patients with parenchymal brain metastasis (BM) or meningeal metastasis (LM) into three cohorts.
Cohort 1 was patients who did not receive ALK-TKI treatment (n=20), and cohort 2 was after first-line crizotinib treatment Patients with or without extracranial progression (n=32), cohort 3 were patients with only CNS metastasis after other second-generation TKI treatments (n=13).

 The results of the study showed that among patients with evaluable CNS lesions (lesions ≥ 1 cm) at baseline, the total intracranial response rate (ic-ORR) of cohort 1 was 82%, which was consistent with the CNS ORR of 81% in the ALEX study.

In patients with brain metastases after crizotinib treatment and other second-generation TKI treatments, aletinib also has a good effect, with cohort 2 ic-ORR of 76.
5% and cohort 3 ic-ORR of 43%.

The maximum shrinkage rates of CNS target lesions in each cohort were 56%, 57.
3%, and 42%, respectively.
The proportion of patients with significant improvement in symptoms related to CNS metastasis was 75%, 77%, and 83%, respectively [7] (Table 2).

Therefore, patients with brain metastases positive for ALK fusion genes are preferentially recommended for second-generation ALK-TKIs therapy.

 Table 2.
Intracranial efficacy of aletinib in the real world in China, Professor Gao Beili said: "Regardless of the control of extracranial lesions or intracranial lesions, the second-generation TKI has proved its strength.
The
second-generation TKI aletinib is in Data from the ALESIA study in Asian populations show that intracranial ORR exceeds 80%.

Based on current clinical data, authoritative guidelines at home and abroad have given aletinib as the first-line treatment of ALK-positive advanced NSCLC patients with priority and high-level evidence recommendations, especially For patients with intracranial metastases, aletinib is also one of the preferred ones, and it has good safety.

"ALK-positive NSCLC treatment has more possibilities.
In the future, with the continuous development of ALK-positive NSCLC treatment, the first, second and third generation ALK-TKIs have been born, forming a "three generations in one house" clinical treatment pattern.
In the
future .
What is the development trend of ALK-TKI? Which aspects of the potential and possibility of ALK-TKI will be explored in clinical research? Professor Gao Beili made the following conclusion: Can ALK-TKI be “forwarded”? At present, ALK-TKI is mainly used for advanced ALK positive For patients with NSCLC, compared with the success of another targeted drug-EGFR-TKI in adjuvant treatment of lung cancer, can ALK-TKI be used in adjuvant therapy or even neoadjuvant therapy? A large multi-center phase III clinical study is urgently needed Evidence to confirm.

Aletinib is currently carrying out the ALINA study of adjuvant therapy nationwide and is currently recruiting for clinical trials.
When will the
 "chemo-free" era come? There are some clinical patients who cannot tolerate adjuvant chemotherapy or because of organ function Adjuvant chemotherapy had to give up.

so how to break through the limitations of chemotherapy so that more patients benefit? At present, some small studies have demonstrated the feasibility and benefits of targeted adjuvant therapy, still need large sample studies verify the results.

Secondly, the target Whether the treatment can be combined with anti-angiogenic drugs and immunotherapy is a more clinically concerned aspect, which needs to be explored and explored.

 How to accurately select targeted drugs for patients with co-mutation? In clinical diagnosis, except for patients with simple mutations, co-mutation Lung cancer patients are not uncommon.

Therefore, is the combination of targeted drugs and targeted drugs feasible? How to reduce the toxicity while ensuring the efficacy is the direction that requires comprehensive research.

 In addition to the prospects of clinical diagnosis and treatment, Professor Gao Beili The department helps the development of lung cancer diagnosis and treatment put forward a message: "Lung cancer patients are usually diagnosed in the respiratory department for the first time.
At present, more and more lung cancer patients are admitted to the respiratory department.

I hope that the respiratory department can give full play to its diagnostic advantages and increase the rate of early diagnosis of lung cancer.

Secondly, it is hoped that respiratory doctors will improve their understanding of lung cancer genes, development mechanisms and treatment hotspots, and further in-depth exploration.

Third, it is hoped that respiratory doctors can comprehensively and accurately deal with the safety of medications and comorbidity management for lung cancer patients, so as to help the entire management of lung cancer.

"Professor Gao Beili, Chief Physician, Department of Respiratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine Chairman, Member of the Lung Cancer Group of the Respiratory Branch of the Chinese Medical Doctor Association, Deputy Leader of the Lung Cancer Group, Shanghai Medical Association Pulmonary Science Association, Standing Committee Member of the Lung Cancer Committee of the Chinese Medical Education Association Standing Committee of the Shanghai Anti-Cancer Association Lung Cancer Molecular Targeting and Immunotherapy Professional Committee Member of the Thoracic Oncology Branch of the China Association for the Promotion of International Medical Care and Health Care Member of the Thoracic Oncology Group of the Oncology Society of Shanghai Medical Association Member of Annals of Oncology, Chinese edition of Lung Cancer Special Issue Editorial Board Reference Materials: [1].
Yin Weiwei, Yang Zhenhua, Ye Liang, et al.
Research progress on drug resistance mechanisms of EML4-ALK inhibitors in non-small cell lung cancer.
International Respiratory Journal.
2014; 34(16): 1249-1253.
[2].
WU YL, LU S, LU Y, et al.
Resultsof PROFILE 1029, a Phase III Comparison of First-Line Crizotinib versusChemotherapy in East Asian Patients with ALK -Positive Advanced Non-Small CellLung Cancer.
J Thorac Oncol, 2018, 13(10): 1539-1548.
[3]SOLOMON BJ, MOK T, KIM DW, et al.
First-linecrizotinib versus chemotherapy in ALK-positive lung cancer .
N Engl J Med, 2014,371(23): 2167-77.
[4] PETERS S, CAMIDGE DR, SHAW AT, et al.
Alectinibversus Crizotinib in Untreated ALK-Positive Non-SmallCell Lung Cancer.
N Engl JMed, 2017, 377(9): 829-838.
[5]ZHOU C, LU Y, KIM SW, et al.
Primary results of ALESIA: Phase III, randomised open-label study of alectinib[6] Oncologist Branch of Chinese Medical Doctor Association, Oncology Branch of Chinese Medical Care International Exchange Promotion Association.
Chinese Treatment Guidelines for Lung Cancer Brain Metastasis (2021 Edition)[J].
Chinese Journal of Oncology, 2021, 43( 03):269-281.
[7]Intracranial efficacy of Alectinib in ALK-positiveNSCLC patients with CNS metastases——A multicenterretrospective study.
2021 ELCC.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform[7]Intracranial efficacy of Alectinib in ALK-positiveNSCLC patients with CNS metastases——A multicenterretrospective study.
2021 ELCC.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform[7]Intracranial efficacy of Alectinib in ALK-positiveNSCLC patients with CNS metastases——A multicenterretrospective study.
2021 ELCC.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform