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Will common mutation affect the treatment effect of Alk-TKI?
In recent years, with the sustainable development of precision medicine, the treatment of (NSCLC) has been fully entered into the era of targeted therapy era.EssenceAs a "diamond mutation" in NSCLC, the treatment of intermediary lymphoma kinase (ALK) positive NSCLC is a hot spot for clinical attention in recent years. Alk-TKI represented by Lolatinib continuously refreshed the efficacy record of ALK-positive NSCLC [1].However, it is unclear that the impact of co-variants such as ALK-positive NSCLC with TP53 and other common mutations on ALK-TKI still need to be further explored.
The United States Clinical Society (ASCO) conference has published a research on the impact of ALK-positive and TP53 gene mutations on the clinical ending of NSCLC patientsAs a result, the medical community focused on ALK -positive NSCLC first -line treatment and interpreted the results of the research to readers.
Alk-TKI represented by Lolatinib has become ALK-positive NSCLC first-line treatment preferred scheme
NSCLC is the most important pathological type of lung cancer, accounting for about 85%of all patients with lung cancer.With the development of molecular detection technology and precision medicine, (EGFR) mutations, ALK fusion and other lung cancer-driven genes have been discovered one after another; among them, ALK is a member of the insulin receptor tyrosine kinase super family members.The most common ALK fusion gene among NSCLC patients is the 4-interval variability Kitase (EML4-ALK), which is 3% ~ 7% [1].
The efficacy and safety of targeting therapeutic drugs for ALK targets are significantly better than traditional chemotherapy. The continuous advent of ALK-TKI brings new hope for the treatment of Alk positive NSCLC.EssenceAs of June 27, 2023, there were 8 types of 8 kinds of Kizyinib, Sedinib, Alantinib, Endinib, Bogntininib, Loladinib, Ihoak and Yicong Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak Ak AksALK-TKI was approved by the China National Drug Administration (NMPA) (sorted by the approval of the NMPA approval of NMPA), providing targeted treatment for ALK fusion gene-positive NSCLC patients [1].Among them, Loladinib is a three-generation ALK-TKI with high intracranial infiltration. In the CROWN study in the phase III, Loladinib for the treatment of patients with previous unprecedented advanced ALK-positive NSCLC patients better than Cizitinib:60.2 months after the median follow -up, the Loladinib group has not yet reached the period of no progressive survival (PFS), and the Bikzodininib (PFS = 9.1 months) can reduce the risk of 81%of the disease progress or death;The 5 -year PFS rate of the group was as high as 60%, which was 7.5 times that of the Kazyinib group (8%).At the same time, the median time of the Lolatinini group has not yet reached, and it is 16.4 months in the clipininib group [3].Based on the results of CROWN research, Lolatini established the "model" of Alk -positive NSCLC first -line therapy, bringing preferred programs for ALK -positive NSCLC.
Although ALK-TKI shows good effectiveness on the late ALK fusion NSCLC, if TP53 and other gene mutations occur at the same time, it may have a negative impact on the efficacy of targeted therapy.In the past studies, 62%of ALK-fusion-positive NSCLC cases have at least one common mutation. Among the metastatic Alk-positive NSCLC patients treated with Alk-TKI treatment, ALK-positive and other gene mutations will lead to adverse prognosis [3].So, what impact does EML4-ALK fusion mutation and at the same time with TP53 mutations have on the efficacy of ALK-TKI?
EML4-ALK fusion variant companion TP53 mutation yield new generation Alk-The impact of TKI front -line treatment ALK -positive NSCLC duration [ 4]
ResearchBackground
Based on the results of related research, ALK-TKI has become the standard treatment plan for advanced ALK-positive NSCLC first-line therapy.Entinib, Bogntinib, Serentinib, and Loladinib) have comprehensively improved the long -term survival benefits of ALK -positive NSCLC patients; however, some patients will develop diseases during treatment.Therefore, identifying the molecular biomarkers related to the prognosis of the first-line ALK-TKI treatment may help guide the treatment options.
In the clinical study of ALK-positive NSCLC patients, liquid biopsy testing biomarkers is related to the progress of early diseases. For exampleTP53 mutation in CTDNA).This study evaluates the effects of EML4-ALK fusion variant and TP53 mutation state on the stopping time (TTD) of ALK-positive NSCLC patients in the real world receiving the new generation of Alk-TKI first-line therapy.notDuring December 31, 2021, the ALK-TKI was detected in CTDNA through the Guardant 360 liquid biopsy detectionThe advanced/metastatic NSCLC patients with the first -line treatment (data derived from the Guardant Infom real world clinical genome database).Study the median TTD of the first-line therapy of Alk-TKI for the use of Kaplan-Meier (KM) method, and evaluate the effect of EML4-ALK fusion variant and TP53 mutation status on TTD;And the baseline brain metastasis) analyzes the effect of EML4-ALK fusion variant and TP53 mutation status on TTD.
Research Results
This study was included in 164 ALK -positive late NSCLCPatients, 66 of them (40%) of TP53 mutations.At the same time, 130 patients detected EML4-ALK fusion variants, EML4-ALK fusion V1 v2 v2 v3 v3 v3 v5 v8 (48 %) VS 8 cases (6 %) VS 54 (42) (42)%) 4 cases (3%) vs (1%) (1%).Of the 117 patients with EML4-Alk V1 or V3 and TP 53 mutations, 21 patients with (8%) patients with EML4-Alk V3 and TP53 mutations occurred at the same time.
Table 1. Patients baseline features
KM curve display, TP53 mutation vs TP53 wild type wild typeThe median TTD of the patient is: 17.1 months VS 21.9 months (HR = 0.70; P = 0.1712).
Figure 1.TP53 Wild Type VS TP53 mutant TTD
and EML4-ALKCompared with patients with V3, EML4-ALK fusion V1 patients are longer in TTDs in the first 18 months; however, the curve is crossed at the end, resulting in the value of EML4-ALK integrated V1 patients and EML4-ALK fusion V3 patients.Small (19.0 months VS 21.8 months; HR = 0.73; P = 0.3039).EML4-ALK fusion V1 patients and EML4-ALK fusion of TTDs have not reached the upper limit of 95%confident interval (CI); medium-bit TTDs may further change with follow-up.
Figure 2. EML4-ALK fusion V1 patients with EML4-ALK fusion TTD
After adjusting the age, gender, and brain metastases of the patients baseline, I found that the EML4 -ALK fusion V3 and TP53 mutations were shortened with the TTD shortening of patients with late NSCLC (HR = 3.17; 95%CI: 1.32 -7.62).notIt shows that: EML4-ALK fusion in CTDNA is related to the high risk of the first-line treatment of the new generation Alk-TKI first-line treatment (probably due to the progress of the disease).
The relevant discovery in this study is consistent with previous reports: Compared with previous related genetic mutations, EML4-ALK integrates V3 and TP53 common mutations and NSCLC patientsTurn the correlation during the total survival period (OS).
Looking forward to the future, you still need to further explore new therapy or combined treatment plan, such as ALK-TKL combined chemotherapy and other strategies to further improve EML4-ALK combined V3 and TP53 common mutation NSCLC patientsPromotion.
Wonderful information is waiting for you
References :
[1]. Chinese Physician Association oncologist Branch, China Medical Care International Exchange Promotion Association Internal Science Branch. Intermediary lymphoma kinase lymidase inhibitors for advanced non -small cell lung cancer Chinese expertsSuggestion (2024) [J]. Chinese Medicine Magazine, 2024, 104 (7): 473-485.
[2] .solomon bj, et al. J clin oncol.2024 Oct 10; 42 (29): 3400-3409
[3]. Lara-Mejía L, et al. Impact of Concurrent Genomic Alterations on Clinical Outcomes In Patients K-rearrangedNsclc. J Thorac oncol. 2024 Jan; 19 (1): 119-129.
[4] .kaushal Parikh, et al. 2023 asco. Abstract#9029
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