Preface
Lung cancer ranks first in terms of incidence and mortality among malignant tumors in mainland China, with non-small cell lung cancer (NSCLC) accounting for 80 to 85 percent of lung cancers [1,2]. In recent years, with the development of science and technology, the diagnosis and treatment of lung cancer, especially NSCLC, has made rapid progress, and precision targeted therapy has significantly improved the survival benefits of patients, and now lung cancer is no longer an incurable disease in everyone's impression. April 15-21, 2024 is the 30th National Cancer Prevention and Treatment Awareness Week, and the theme of this year's Publicity Week is "Comprehensive Measures, Scientific Cancer Prevention". On this occasion, Yimaitong invited Professor Fan Yun from Zhejiang Cancer Hospital to introduce and comment on the current situation of comprehensive diagnosis and treatment and scientific management of NSCLC.
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Precision targeted therapy has significantly improved the survival benefit of patients
"High-quality and long-term survival" has become the new goal of diagnosis and treatment
Yimaitong: April 15-21, 2024 is the 30th National Cancer Prevention and Treatment Publicity Week. As we all know, the mainland is the country with the largest number of cancer patients in the world, and lung cancer is the largest cancer in the mainland, which poses a serious threat and burden to the lives and health of mainland residents. As an expert in the field of lung cancer, can you please introduce to us the current status of clinical diagnosis and treatment of lung cancer in China?
Professor Fan Yun
Zhejiang Provincial Cancer Hospital
According to the latest data released by the National Cancer Center not long ago, the number of new cases and deaths of malignant tumors in China in 2022 will be about 4,824,700 and 2,574,200, respectively, of which the number of new cases and deaths of lung cancer will be 1,060,600 and 733,300, respectively, accounting for about 22.0% and 28.5% of all malignant tumors, making it the number one cancer in mainland China [3]. In addition, relevant research data show that the overall five-year survival rate of lung cancer patients in mainland China does not exceed 20%, and nearly half of the patients are already stage III.B−IV. at the time of initial diagnosis, while previous data show that the overall five-year survival rate of patients with stage IV lung cancer is only 5.27% [4,5]. How to improve the survival benefit of lung cancer patients is a huge problem faced by clinical practice.
In addition to traditional chemotherapy drugs, new anti-tumor drugs such as molecularly targeted drugs, anti-angiogenic drugs and immune checkpoint inhibitors have become one of the basic treatment drugs for lung cancer patients, which not only enriches the treatment options of lung cancer patients in China, but also greatly improves the survival time and quality of life of patients. For example, patients with anaplastic lymphoma kinase (ALK) and c-ros proto-oncogene 1 tyrosine kinase (ROS1)-positive advanced NSCLC can survive for several years when receiving targeted therapy, and the five-year OS rate can even reach more than 60%, allowing clinicians and patients to gradually see the possibility of "chronic disease" of lung cancer in the future [6,7].
Yimaitong: With the continuous development of anti-tumor treatment technology, the survival time of lung cancer patients has been continuously extended, and the survival time of some patients with advanced NSCLC with positive driver genes such as ALK and ROS1 can reach several years or longer.
Professor Fan Yun
Zhejiang Provincial Cancer Hospital
ALK is an important therapeutic target for advanced NSCLC, and ALK-positive NSCLC has the characteristics of a low age of onset and a high incidence of brain metastases, accounting for about 3% to 7% of NSCLC patients, although the incidence rate is not high, due to the huge population base in mainland China, the number of new cases of ALK-positive NSCLC patients per year is also close to 35,000, and the number of clinical patients should not be underestimated [8].
The emergence of ALK-tyrosine kinase inhibitors (TKIs) has led to a breakthrough in the survival time of ALK-positive NSCLC patients. Previous ALEX studies have demonstrated that alectinib in the first-line treatment of ALK-positive advanced NSCLC can significantly prolong PFS and improve the 5-year OS rate of patients, resulting in a clear long-term survival benefit [6]. The ALESIA study further suggests that alectinib may demonstrate superior efficacy in Asian patients with ALK-positive advanced NSCLC [9]. In addition, real-world studies have shown that a reasonable TKI alignment can help patients achieve a median OS of nearly 90 months [10]. For ROS1-positive advanced NSCLC, data suggest that entrectinib-targeted therapy can also lead to median OS for nearly four years [7].
With the prolongation of patient survival, the clinical diagnosis and treatment of some lung cancer patients has gradually entered the era of "chronic disease management", and prolonging survival is no longer the only treatment goal of patients. According to the World Health Organization (WHO), cancer diagnosis and treatment protocols aim to cure or prolong the lives of patients and ensure the quality of life of cancer survivors [11], and the treatment concept of "high-quality and long-term survival" has gradually entered the field of vision of clinicians and patients. In order to ensure that patients can receive long-term and stable treatment and have a better quality of life, clinicians should not only conduct comprehensive consideration for patients in the process of practice, but also have better efficacy, safety and accessibility of the therapeutic drugs used, so as to help patients obtain all-round comprehensive benefits.
Indirect comparative analyses provide up-to-date clinical evidence
Alectinib & entrectinib help patients improve their comprehensive benefits
Yimaitong: Patients with ALK and ROS1-positive advanced NSCLC often have good efficacy after receiving TKI targeted therapy, so they are also named "diamond targets", combined with previous related clinical studies, what do you think are the advantages and characteristics of ALK-TKI and ROS1-TKI targeted therapy?
Professor Fan Yun
Zhejiang Provincial Cancer Hospital
For ALK-positive advanced NSCLC, a variety of ALK-TKIs including alectinib and entrectinib and ROS1-TKI have been approved for marketing or are under development in China, but there is a lack of large-scale RCT studies to evaluate the differences in efficacy and safety between different drugs, so relevant scholars have made preliminary comparisons through meta-analysis and MAIC analysis.
In a previous meta-analysis of 14 studies with nine regimens of chemotherapy, crizotinib, alectinib (600 mg BID), low-dose alectinib (300 mg BID), brigatinib, ceritinib, ensartinib, envonalkib, lorlatinib, ALK-TKI resulted in a better survival benefit compared with conventional chemotherapy [12]. Notably, alectinib is the only ALK-TKI that can clearly provide long-term survival benefits to patients with a relatively longer OS and a higher average level of OS improvement in patients with first-line therapy [6,12]. In addition, the improvement in PFS associated with first-line treatment with alectinib was also relatively higher in Asian patients [12]. A MAIC analysis reported at the 2023 WCLC also showed that alectinib and lorlatinib conferred similar PFS benefits in Asian populations, suggesting that alectinib may be more appropriate for Asian patients [13].
In the therapeutic area of ROS1-positive NSCLC, a MAIC analysis of patient data from the ALKA-372-001, STARTRK-1, and STARTRK-2 studies and data from the OxOnc study showed that the median PFS of patients in the entrectinib group was 39.4 months, far exceeding that of crizotinib by more than two years, when matched and the baseline distribution was consistent [14]. Recent data from the ALKA-372-001, STARTRK-1, and STARTRK-2 studies presented in Clinical Lung Cancer showed that entrectinib can bring long-term survival benefits to patients with ROS1-positive advanced NSCLC regardless of whether they have brain metastases at baseline, PFS of 37.7 months for patients without brain metastases at baseline, OS has not been reached, and the remission rate of intracranial lesions is as high as 80% for patients with brain metastases at baseline [ 7,15]。 Combined with relevant research data and clinical practice experience, it can be seen that targeted therapy has helped ALK and ROS1-positive NSCLC truly become a "chronic disease".
Comprehensive measures to prevent cancer scientifically
Optimizing the whole clinical process management and selecting better treatment drugs are the keys to improving the comprehensive benefits of patients
Yimaitong: For ALK and ROS1-positive NSCLC, how to further strengthen the whole process management of patients in the future, so as to help them further improve the comprehensive survival benefit, and then truly achieve the goal of chronic lung cancer?
Professor Fan Yun
Zhejiang Provincial Cancer Hospital
In order to help patients further improve their comprehensive benefits, clinicians need to optimize the management of the whole process of clinical diagnosis and treatment of patients, which can mainly focus on the following key points:
1. AE management
AE management is essential to improve medication adherence and quality of life. The ALEX, J-ALEX, and ALESIA studies all suggest that alectinib has a relatively superior incidence and severity of AEs compared with crizotinib [6,9,16]. In a meta-analysis, alectinib was the only product among the existing ALK-TKIs (brigatinib, ceritinib, ensartinib, and lorlatinib) with a lower incidence of grade 3 and 4 AEs than crizotinib, and was the safest first- or second-line option for patients regardless of dose among nine different regimens [12,17]. The MAIC analysis data published at the 2023 WCLC also suggested that alectinib had a relatively better safety profile and a significantly lower risk of grade 3 and above AEs [lorlatinib (CROWN study) versus alectinib (ALESIA study), RR=1.79, 95% CI: 1.13-2.82] [13].
In addition, data suggest that the incidence of respiratory, neurological, cardiovascular, digestive, and urinary SAEs caused by alectinib is relatively low [18]. Related pharmacokinetic reviews also suggest that alectinib is safe when used in combination with other drugs for underlying diseases, does not require excessive adjustment of dosage, and physicians have fewer concerns when treating patients, which provides a guarantee for long-term drug management of patients [19].
In addition to advanced NSCLC, the application and exploration of alectinib in the postoperative adjuvant treatment of early NSCLC further confirmed its good safety and tolerability. Data from the ALINA study showed that alectinib used in the postoperative adjuvant treatment of ALK-positive early NSCLC not only reduced the risk of disease recurrence, metastasis or death by 76% in patients. More importantly, only 5% of patients withdrew from treatment due to AEs during the median duration of treatment (DoT) of 23.9 months for alectinib [20], which undoubtedly added an extra point of insurance for patients to receive long-term treatment and obtain long-term survival benefits.
2. Arrange the drug lineup
In order to improve the comprehensive benefit of patients, the drugs used in the first-line treatment of patients need to have excellent clinical efficacy and safety, and at the same time, they need to have a relatively clear mechanism of drug resistance, so as to provide guidance for the follow-up clinical treatment of patients. Alectinib-resistant patients have been detected in up to 53 percent of patients with ALK resistance mutations, such as G1202R, V1180L, or I1171T/N/S [21]. This indicates that alectinib has a relatively clear drug resistance mechanism, and the follow-up treatment options of patients are relatively rich and clear, which can further help patients achieve long-term survival.
In addition to optimizing the management of the whole process of patient diagnosis and treatment, it is also necessary to do a good job in early diagnosis and early screening for lung cancer patients, so as to help patients achieve "early detection and early treatment", so that more early patients have the opportunity to receive radical treatment and precise targeted therapy, so as to truly achieve "comprehensive policy and scientific cancer prevention", so as to help patients achieve long-term survival benefits, and then help realize the grand vision of "Healthy China 2030 Planning Outline".
Expert Profile
Prof. Yun Fan
- Zhejiang Provincial Cancer Hospital, Director of the Department of Thoracic Medical Oncology, Chief Physician, Ph.D. Supervisor
- Executive Director of the Chinese Society of Clinical Oncology (CSCO).
- Vice Chairman of the CSCO Small Cell Lung Cancer Expert Committee
- Vice Chairman of the CSCO Patient Education Expert Committee
- Member of the Standing Committee of the Multidisciplinary Diagnosis and Treatment Committee of the Chinese Medical Doctor Association
- Chairman of the Medical Oncology Committee of Zhejiang Anti-Cancer Association
- Chairman of the Tumor Precision Treatment Committee of Zhejiang Medical Doctor Association
- Vice Chairman of Oncology Branch of Zhejiang Medical Association
Bibliography:
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[2] Lung Cancer Committee of Chinese Anti-Cancer Association, Lung Cancer Group, Oncology Branch of Chinese Medical Association. Expert consensus on multidisciplinary diagnosis and treatment of stage III. non-small cell lung cancer (2019 edition). Chin J Oncology,2019,41(12):881-890.
[3] Zheng Rongshou, Chen Ru, Han Bingfeng, et al. Prevalence of malignant tumors in China in 2022[J]. Chinese Journal of Oncology, 2024, 46(3):221-231.
[4] Oncologist Branch of Chinese Medical Doctor Association, Medical Oncology Branch of China Association for the Promotion of International Exchange in Health Care. Chinese guidelines for the treatment of stage IV primary lung cancer (2023 edition). Chin J Onc,2023,45(01):1-30.
[5] Oncology Branch of Chinese Medical Doctor Association, Medical Oncology Branch of China Association for the Promotion of International Exchange in Health Care. Guidelines for the implementation of multidisciplinary team diagnosis and treatment of stage IV primary lung cancer in China. Chin J Oncology,2022,44(07):667-672.
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[11] https://www.who.int/activities/ensuring-quality-treatment-for-cancer
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