Foreword
, the launch of the first-generation ALK tyrosine kinase inhibitor (ALK-TKI) crizotinib opened the era of targeted therapy for ALK-positive non-small cell lung cancer (NSCLC).1. However, first-generation ALK-TKI first-line therapy still faces the risk of rapid progression2. In recent years, second-generation ALK-TKIs have come to the fore and have become the new standard of first-line treatment. Among various second-generation ALK-TKIs, brigatinib has outstanding strength, showing comprehensive benefits as first-line treatment in the global phase III ALTA-1L study and the Japanese phase II J-ALTA study3,4.
On March 22, 2022, the my country National Medical Products Administration has approved brigatinib for ALK-positive locally advanced or metastatic NSCLC The treatment of patients, which means that there is another strong player in the field of first-line treatment of ALK-positive NSCLC. At the same time, at the just-concluded 2022 ACSO annual meeting, the results of the ALTA-1L exploratory study and the final results of the J-ALTA study were also stunningly presented. On this occasion, Yimaitong specially invited Professor Zhong Wenzhao from Guangdong Provincial People’s Hospital to interpret the results of ALTA-1L and J-ALTA research, exchange and share diagnosis and treatment experience, in order to provide guidance for the clinical practice of ALK-positive NSCLC in my country.
Professional Profile
” width=”600″> >Professor Zhong Wenzhao
Chief Physician and Doctoral Supervisor of Guangdong Provincial People’s Hospital
Director of Guangdong Lung Cancer Research Institute
Research at Guangdong Provincial People’s Hospital Deputy Director
Director of the Chinese Society of Clinical Oncology, Vice Chairman of the Youth Committee
Chinese Medical Association-Deputy Head of Cancer Early Diagnosis and Treatment
Chinese Hospital Association Health and Medical Big Data Committee Standing Committee
Vice-chairman of the Lung Oncology Branch of Guangdong Medical Association
- < p>J Thorac Oncol associate editor
< span>The first generation of ALK-TKI has a lot of challenges, and the second generation of ALK-TKI comes later
lung cancer is It is the largest cancer type in China, and its morbidity and mortality ranks first among all malignant tumors5. In the past ten years, with the progress of molecular medicine and the continuous emergence of targeted drugs, the treatment of NSCLC has shifted from chemotherapy to the era of individualized molecular targeted precision therapy. Among them, ALK is an important therapeutic target for NSCLC, and the number of new cases of ALK-positive NSCLC in my country is close to 35,000 each year6. After the advent of ALK-TKI targeted drugs, it broke the dilemma of traditional chemotherapy, making ALK mutation truly a “diamond mutation”.
PROFILE 1014 study showed that compared with traditional chemotherapy, first-generation ALK-TKI crizotinib in first-line treatment of ALK-positive advanced NSCLC significantly improved With prolonged median PFS, the risk of disease progression or death decreased by 55% (10.9 months vs 7.0 months, HR=0.45, P<0.001) 2. Although first-generation ALK-TKIs have shown better efficacy than chemotherapy, patients usually progress or die within 1 year, and there is an unmet need for clinical treatment. With the continuous improvement and accumulation of evidence-based evidence, the second-generation ALK-TKI surpassed the efficacy of the first-generation ALK-TKI, further improved the survival benefit of patients, and became a better choice for the first-line treatment of ALK-positive advanced NSCLC.
Professor Zhong Wenzhao said, ALK positive Lung cancer accounts for about 6% of all lung cancers. Although the incidence of ALK mutation in lung cancer is low, due to the large population base in my country, the number of new cases of ALK-positive lung cancer is still high each year. In addition, most of the patients with ALK gene mutation are relatively young, and most of the disease is at stage III/IV at the time of discovery, and the degree of malignancy is extremely high, so it has attracted much attention. As one of the second-generation ALK-TKIs, brigatinib has shown very good prospects in clinical application.
Brigatinib fully benefits first-line treatment, helping patients enter the “long-term survival era”
ALTA-1L Study 3 was an evaluation of brigatinib versus crizotinib in patients who had not received ALK- An international multicenter, open-label, randomized phase III study of TKI-treated patients with ALK-positive advanced NSCLC, with the primary endpoint of PFS assessed by a blinded independent review center (BIRC). The final results showed that, in the intention-to-treat (ITT) population, BICR-assessed mPFS was 24.0 and 11.1 months, respectively, reducing the risk of disease progression or death by 52% (HR=0.48, p<0.0001); investigator (INV)-assessed mPFS was 30.8 and 9.2 months, reduced the risk of disease progression or death by 57% (HR=0.43, p<0.0001). 47% of patients in the crizotinib group crossed over to brigatinib after progression, and after adjustment for crossover by the MSM method, < strong>Brigatinib reduced the risk of death by 46% (HR=0.54, P=0.02); Brigatinib group The 4-year OS rate reached 66%.
In addition to good efficacy, the disease management of patients with ALK-positive NSCLC is also inseparable from good tolerability and improved quality of life. In this regard, the ALTA-1L study showed that the first-line treatment of brigatinib has good safety, long-term tolerance, and long-term maintenance of high quality of life.
Figure: mPFS of ITT population assessed by BIRC (top) and INV (bottom)
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2022 ASCO discloses stunning first-line data of brigatinib J-ALTA
J -ALTA is a multicenter, open-label, single-arm phase II study to explore the efficacy and safety of brigatinib in patients with TKI-refractory and naïve ALK-positive NSCLC4. The final results of the J-ALTA study reported at the 2022 ASCO Annual Meeting showed that among 32 TKI-naïve patients, the ORR assessed by IRC was as high as 97%, and the 12-month PFS rate was as high as 90%, and the 24-month PFS rate was 73%.
remarks that first-line treatment with brigatinib greatly reduces the risk of disease progression or death, and is a patient with ALK-positive advanced NSCLC important treatment options.
Based on the durable benefits brought by first-line treatment of brigatinib, it has been listed as one of the “NCCN Clinical Practice Guidelines for Oncology”. The first-line preferred drug 7. Regarding the exploration of the treatment of ALK-positive lung cancer, Professor Zhong Wenzhao shared that in addition to simple drug treatment, local treatment Such as surgery and radiotherapy are also an important part of multidisciplinary comprehensive treatment of lung cancer. In addition, in the field of neoadjuvant therapy and adjuvant therapy for ALK-positive lung cancer, the application of ALK-TKI is also being actively explored. At the same time, the combination of ALK inhibitors with other drugs, including anti-angiogenesis and immunotherapy drugs, is also a direction worthy of further study in patients with ALK-positive NSCLC.
References:
1. Dickran Kazandjian, Gideon M Blumenthal, Huan-Yu Chen, et al. FDA approval summary: crizotinib for the treatmentof metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements[J]. Oncologist. 2014 Oct;19(10):e5-11.
2. Benjamin J Solomon , Tony Mok, Dong-Wan Kim, et al. Solomon BJ, et al. N Engl J Med. 2014 Dec 4;371(23):2167-77[J].N Engl J Med. 2014 Dec 4;371( 23):2167-77.
3. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib Versus Crizotinib in ALK Inhibitor-Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial. J Thorac Oncol. 2021;16(12):2091-2108.
4. Brigatinib in Japanese patients (pts) with ALK+ NSCLC : Final results from the phase 2 J-ALTA trial. 2022 ASCO.Abstract #9075
5. R. Zheng, S. Zhang, H. Zeng et al. Cancer incidence and mortality in China, 2016[J].Journal of the National Cancer Center 2 (2022):1–9.
6. Zhang Xuchao, Lu Shun, Zhang Li et al. China Guidelines for the diagnosis and treatment of anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer[J].Chinese Journal of Pathology,2015,44(10):696-703.
7 .NCCN Guidelines.Non-Small Cell Lung Cancer.Version: 3.2022.
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Approval code: C-APROM/CN/ALUN/0174
Approval date: July 2022
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