*For medical professionals only
The 2024 CSCO guideline meeting was grandly held, and lorlatinib was upgraded to the "Level I priority recommendation" for the first-line treatment of ALK-positive advanced NSCLC.
In order to actively promote the development of clinical oncology in mainland China, improve the clinical and scientific research level of clinical oncologists, and further promote the formulation and promotion of the diagnosis and treatment guidelines of the Chinese Society of Clinical Oncology (CSCO), the 2024 CSCO guideline meeting jointly sponsored by the Chinese Society of Clinical Oncology and Beijing Heathosco Clinical Oncology Research Foundation was held in Jinan on April 26-27.
At this conference, the "2024 CSCO Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer" also ushered in a major update. Among them, lorlatinib, the third-generation ALK-TKI, has been upgraded to the "Level I Priority Recommendation" for the first-line treatment of ALK-positive advanced non-small cell lung cancer (NSCLC). On this occasion, Professor Fan Yun from Zhejiang Provincial Cancer Hospital was invited to share and discuss the selection of ALK-positive advanced NSCLC treatment options from the perspective of this guideline update.
Where does the advantage come from? Interpret the "breakthrough" results of lorlatinib in an all-round way
ALK fusion gene is one of the important therapeutic targets of advanced NSCLC, known as "diamond mutation". The continuous iterative upgrading of ALK-TKI has enriched the clinical drug options and brought good survival benefits to patients with ALK-positive NSCLC, but there are still some unmet treatment needs in clinical practice. After continuous exploration and optimization, the third-generation ALK-TKI lorlatinib has brought new opportunities and hope to overcome these challenges. From the structural point of view, the first-generation and second-generation ALK-TKIs are acyclic and long-chain compounds, while the third-generation ALK-TKI lorlatinib has been innovative in structure and adopts a unique small molecule macrocyclic amide structure. The unique structural advantages of lorlatinib result in enhanced anti-tumor activity, a broader spectrum of anti-ALK resistance mutations, and improved central nervous system (CNS) penetration.
As the only* third-generation ALK-TKI, the efficacy and safety of lorlatinib have been widely recognized by clinicians and scholars at home and abroad, and this recognition is supported by solid clinical trial data. Data from the 36.7-month follow-up of lorlatinib in the CROWN study[1] showed that mPFS as assessed by BICR was not achieved (NR) and 9.3 months, respectively (HR=0.27), respectively, in the lorlatinib group, with a 3-year PFS rate of 64 percent in the lorlatinib arm compared with crizotinib [2].
A MAIC analysis presented at the 2023 World Congress on Lung Cancer (WCLC)[3] used the first-generation ALK-TKI crizotinib as a common "anchor" and indirectly compared lorlatinib with the second-generation ALK-TKIs alectinib and brigatinib by MAIC method. The match-adjusted results showed that mPFS data were superior to those of alectinib (HR=0.54, 95% CI, 0.33-0.88) and brigatinib (HR=0.51, 95% CI, 0.31-0.82).
In addition to the overall efficacy benefits, the results of the CROWN study also demonstrated a potent inhibitory effect of lorlatinib on intracranial effects. Among patients with measurable brain metastases at baseline, the lorlatinib group had an intracranial objective response rate (ORR) of 83.3% and an intracranial complete response (CR) rate of 72.2%, making it the only ALK-TKI that completely eliminated intracranial lesions in more than 70% of patients. For patients without brain metastases at baseline, the rate of intracranial progression after 3 years of first-line treatment with lorlatinib was as high as 99.1%, and only 1 in 112 patients had intracranial progression, pressing the "pause button" for brain metastases.
In recent years, lorlatinib has been recommended as Level I priority by many domestic and foreign guidelines, such as the National Comprehensive Cancer Network (NCCN) guidelines, the European Society for Medical Oncology (ESMO) guidelines, the American Society of Clinical Oncology (ASCO) guidelines, and the CSCO guidelines. With the increasing clinical practice and accessibility of lorlatinib, the 2024 CSCO Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer (NSCLC) have upgraded lorlatinib to a Level I priority recommendation for the treatment of AlK-positive advanced NSCLC, reaffirming its preferred position as a first-line treatment.
"Good drugs are used first" significantly improves the survival benefits of patients and leads the management of chronic lung cancer
Based on the significant efficacy advantages of lorlatinib, it is of great significance to adopt the strategy of "good drug first" in the treatment of ALK-positive advanced NSCLC to improve the quality of life and prolong the survival of patients.
More than three years of follow-up data from the CROWN study [4] showed that more than 60% of patients in the lorlatinib treatment group continued to receive treatment, while 63.6% of patients who progressed on first-line lines were treated with sequential first- and second-generation ALK-TKIs. Patients who have progressed on first-line lorlatinib can be treated with ALK-TKIs, chemotherapy± anti-angiogenic agents, and chemotherapy/immunology with an overall 3-year PFS2 (defined as the time from randomization to first sequential systemic antineoplastic therapy to disease progression or death due to any cause) with an overall 3-year PFS2 rate of up to 74%. The above data show that the 3+X treatment model brings greater benefits and better survival to patients.
At the 2023 WCLC Annual Meeting, research institutions including Memorial Sloan Kettering Cancer Center in the United States presented the results of a real-world study [5]. The study found that 42% of patients who received first-line ALK-TKI failed to receive second-line therapy, and the median duration of sequential treatment with other ALK-TKIs was only about 2.2 years for patients who received first-line ALK-TKIs, and the duration of this sequential treatment depended on first-line efficacy. Therefore, more emphasis needs to be placed on first-line treatment regimens to maximize the benefits for patients with ALK-positive advanced NSCLC. At the same time, another real-world retrospective study [6] also found that approximately 30 percent of patients with ALK-positive advanced NSCLC did not have the opportunity to receive second-line therapy. In this context, first-line selection of agents with longer mPFS is essential to achieve long-term patient survival.
The CROWN study is still being followed up and will be released at this year's American Society of Clinical Oncology (ASCO) Annual Meeting, with more than 60 months of follow-up data from the CROWN study. Previously, Professor Sai-Hong Ignatius Ou predicted in his article that assuming that the PFS rate of lorlatinib decreases by 5% per year (68.2% at 2 years and 64% at 3 years), it is likely that the PFS rate of lorlatinib will not reach 50% until the fifth to sixth year, indicating that the mPFS of lorlatinib may reach 60 months or more [9]. This prediction also reflects the academic community's expectation of the vision of "chronic disease" management of tumors, and lorlatinib is expected to promote the further chronic management of ALK-positive NSCLC.
In summary, lorlatinib, as a third-generation ALK-TKI, has shown excellent efficacy in the treatment of ALK-positive advanced NSCLC, and "good drugs first" can help patients achieve longer survival and better quality of life.
*: As of April 27, 2024.
Expert commentary
Prof. Yun Fan: As a third-generation ALK-TKI, lorlatinib has shown significant efficacy advantages in clinical trials. It has been on the market in China for two years and will be included in the National Medical Insurance Catalogue in 2023. With the increasing experience in the clinical application of lorlatinib and the continuous improvement of medical insurance accessibility, its clinical application is becoming more and more extensive, and clinicians are becoming more and more experienced. At the same time, based on the 36.7-month follow-up data of the CROWN study, lorlatinib was upgraded to a "Level I Priority Recommendation" for the first-line treatment of ALK+ advanced NSCLC in the 2024 CSCO Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer. This update of the guidelines also brings better medication guidance to our clinicians and more efficient treatment options for patients. In general, great progress has been made in the diagnosis and treatment of ALK+ advanced NSCLC, and the first-line treatment of lorlatinib has brought a stronger guarantee for the prolongation of survival time and the improvement of quality of life of patients.
SOON, 60-MONTH FOLLOW-UP DATA FROM THE CROWN STUDY WILL BE PRESENTED AT THIS YEAR'S ASCO CONFERENCE. I believe that under the general trend of precision medicine, the prognosis of ALK+ patients with advanced NSCLC will continue to improve, and eventually move towards "cure"!
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:
[1] Solomon BJ，et al. Presented at 2022 AACR. Abstract #CT223.
[2] Zhou Q， et al. 992P Updated analyses from the CROWN study of first-line lorlatinib vs crizotinib in Asian patients with ALK-positive non-small cell lung cancer. ESMO 2022.
[3] Christine Garcia,et al. Comparative efficacy and safety of lorlatinib vs alectinib and brigatinib using matching adjusted indirect comparisons (MAIC). 2023 WCLC. EP12.02-06.
[4] Solomon BJ, et al. Lancet Respir Med 2023;11:354-66.
[5] 2023 WCLC. EP12.02-11
[6] Front Oncol 2021; 11:670483
[7] 2022 ESMO. Abstract 1011P.
[8] ESMO Open. 2022 Feb; 7(1):100337
[9] Nagasaka M, Ou SI. J Thorac Oncol. 2022 Nov 29:S1556-0864(22)01880-9.
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* This article is only for the purpose of providing scientific information to medical professionals and does not represent the views of this platform
