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In-depth interpretation by top domestic lung cancer experts-how lorlatinib consolidates its position as the king in the first-line treatment of ALK+ NSCLC!
The annual European Society of Medical Oncology (ESMO) has concluded successfully on September 13, 2022, Paris time. It is worth noting that at this ESMO conference, the CROWN study, which once made a sensation with its first-line median progression survival time (PFS) results of more than three years, has announced some subgroup analysis results and has been selected as poster papers (abstract numbers are respectively 992P, 979P, 1104P, 1008P), based on first-line treatment, Asian patients can achieve a median PFS of more than three years, have excellent control effects on brain metastases, and significantly improve the quality of life of patients. Lorlatinib has once again aroused heated discussion among scholars at home and abroad.
In response to this, the "medical community" specially held a "Expert Group Takes You to See ESMO" online live event , inviting Professor Zhou Qing of Guangdong Provincial People's Hospital and the Cancer Hospital of the University of Chinese Academy of Sciences ( Zhejiang Provincial Cancer Hospital ) Professor Fan Yun, Professor Li Ziming of Shanghai Chest Hospital, and Professor Zhang Xinwei of Tianjin Medical University Cancer Hospital, interpreted some subgroup analysis results of the CROWN study, and deeply discussed the profound impact of the research results on the first-line treatment pattern of ALK+ non-small cell lung cancer (NSCLC).
Figure 1. The expert team shows you the ESMO
conference speech
Figure 2. Professor Zhou Qing and Professor Fan Yun’s speech
This conference specially invited Professor Zhou Qing and Professor Fan Yun to serve as the chairman of the conference and deliver a speech. The two professors
jointly said that the Asian subgroup analysis of the CROWN study published by the Chinese team led by Professor Wu Yilong is a highlight of this ESMO conference. In this study, lorlatinib showed highly consistent results with global populations, adding strong confidence to clinicians in applying lorlatinib to Asian populations. The two professors at are very honored to invite leading figures in the field of lung cancer in China to bring authoritative interpretation and discussion of CROWN's latest subgroup analysis. They hope that through relevant academic exchange activities, they can better realize the full management of ALK+ NSCLC patients and help patients achieve better survival.
The first-line median PFS exceeds three years, and the intracranial CR rate exceeds 70%.
The hard power of lorlatinib Asians is impeccable.
In this session, Professor Fan Yun invited Professor Li Ziming to give a wonderful academic report on the theme of "CROWN Research Asian Data Interpretation".
Figure 3. Professor Li Ziming teaching
Professor Li Ziming introduced that the CROWN study is an ongoing, international, randomized, phase III study, comparing lorlatinib vs. crizotinib for previously untreated ALK+ For NSCLC patients, the primary endpoint is progression-free survival (PFS) by blinded independent central review (BICR). This time, the data of the Asian subgroup with a sample size of 120 cases was released [1].
When the median follow-up reached 36 months, the median PFS in the lorlatinib group had not yet been reached, and the PFS curve declined and flattened after 2 years. The PFS rate in the third year (63%) was only 4% lower than the second year (67%). [1] The benefit trend is highly consistent with the ITT population [2]. At the same time, compared with crizotinib (median PFS was 9.2 months), lorlatinib significantly reduced the risk of disease progression or death by 76% (HR=0.24; 95% CI, 0.139-0.406). Professor Li Ziming emphasized that when the vision is expanded to the entire ALK treatment field, the data of lorlatinib in Asian patients is still impressive.
Figure 4. The 3-year PFS rate of CROWN Asians reaches 63%
At the same time, after Asian patients receive first-line treatment with lorlatinib, the three-year intracranial progression-free rate of is as high as 98%, and the risk of intracranial progression is reduced by 97%[1]. The intracranial benefit trend of the Asian population is consistent with that of the ITT population (3-year intracranial progression-free rate of 92.3%), and is numerically significantly better than that of the ITT population [1,2].
Figure 5. CROWN study intracranial efficacy benefit in Asian patients
As evaluated by BICR, compared with crizotinib, lorlatinib significantly improved the objective response rate (ORR, 78% vs. 57%), intracranial objective response rate (IC-ORR, 73% vs. 20%) and intracranial complete response rate (IC-CR, 73% vs. 13%)[1].It is worth noting that the intracranial ORR and intracranial CR rates of lorlatinib in Asian patients with brain metastases are consistent (both 73%) and better than the overall population (ORR=65%, CR=60%), indicating that Asian patients achieve more profound clinical remissions after first-line treatment with lorlatinib[1,2].
Figure 6. In the CROWN study, intracranial ORR and CR in Asian patients are better than those in the ITT population
Professor Li Ziming pointed out that throughout the entire ALK treatment field, the intracranial CR rate data of lorlatinib as high as 73% in Asian patients is still worthy of attention.
During the 36-month visit, no new safety signals appeared in the Asian subgroup, and the safety profile of was consistent with that of the CROWN population. The proportion of patients in the lorlatinib group who discontinued treatment due to adverse events (AEs) was only 8%, which was similar to 7.4% in the total CROWN population. fully confirmed the good safety profile of lorlatinib in Asian patients [1,2].
Figure 7. The safety profile of lorlatinib is consistent with that of the general population.
The long-term intracranial efficacy, safety, and quality of life advantages are significant.
Lorlatinib comprehensively consolidates the kingship in the ALK field.
Under the chairmanship of Professor Fan Yun, Professor Zhang Xinwei gave a wonderful academic report on the "Interpretation of ESMO Updated Data from the CROWN Study—Analysis of Long-term Intracranial Efficacy and Safety, Quality of Life and Drug Resistance Mechanisms" .
Figure 8. Professor Zhang Xinwei lectures
Long-term treatment and long-term stability: Lorlatinib has obvious long-term intracranial efficacy and safety advantages
Professor Zhang Xinwei pointed out that the treatment of brain metastases has always been the focus of the ALK field Hot topic, CROWN study confirmed that for patients with or without brain metastases at baseline, lorlatinib showed superior efficacy in preventing or treating brain metastases: for patients with ALK+NSCLC with brain metastases at baseline, compared with crizotinib, lorlatinib first-line treatment can significantly extend the time to intracranial progression (TTP, NR vs. 7.3 months); reduces the risk of intracranial progression by 90% [HR=0.10 (0.037-0.268)]; the three-year intracranial progression-free rate reaches 72.8%. For patients without brain metastases at baseline, during more than three years of follow-up, only 1 of 112 patients in the lorlatinib group developed intracranial progression, and the intracranial progression-free rate was as high as 99.1%, which was significantly better than crizotinib [HR=0.02 (0.002-0.136)][2]. This result suggests that for patients with ALK+NSCLC without brain metastasis at baseline, only CT follow-up can be performed without MRI follow-up during treatment with lorlatinib.
Figure 9. Lorlatinib shows good intracranial efficacy in patients with/without brain metastasis at baseline
Professor Zhang Xinwei emphasized that from the perspective of global ALK-targeted drugs, lorlatinib can reduce the risk of intracranial progression by 90% in patients with baseline brain metastasis; the intracranial efficacy of lorlatinib in reducing the risk of intracranial progression by 98% in patients without brain metastasis at baseline is still noteworthy [2].
Professor Zhang Xinwei believes that the reason why lorlatinib can achieve such promising intracranial efficacy is inseparable from its high intracranial ORR and CR rates. In terms of ORR: In patients with brain metastases at baseline, the CROWN study [2] showed that compared with crizotinib, the absolute value of intracranial ORR of lorlatinib increased by 60.2%. In terms of CR rate: Among patients with brain metastases at baseline, in the CROWN study [2], the intracranial CR rate of lorlatinib reached 72.2%.
Professor Zhang Xinwei pointed out that safety is also the focus of attention in the treatment of brain metastasis with ALK-targeted drugs. The results of the CROWN study on intracranial efficacy and subgroup analysis [3] showed that central nervous system (CNS) AEs in the lorlatinib group mainly included cognitive, emotional, language and mental effects. Long-term analysis showed that CNS AEs were mostly grade 1-2, and the incidence rate decreased within 3 years. After 73 years, only 2 cases (2%) of grade 1 CNS AEs occurred; and the cumulative incidence of CNS AEs showed an overall downward trend.
Of note, CNS AEs can resolve spontaneously or be effectively intervened with therapy. 59% of CNS AEs improved spontaneously without any intervention; 26 events were managed with dose reduction and/or dose interruption, with or without concomitant medication. Surprisingly, lorlatinib dose reduction by did not affect intracranial TTP.
Figure 10. Lorlatinib has good safety profile, and the cumulative incidence of CNS AEs shows an overall downward trend
Figure 11. Most CNS AE can improve without intervention or dose adjustment
Guard: Lorlatinib significantly improves the HRQoL of ALK+NSCLC patients
In Professor Zhang Xinwei’s view, in addition to safety, the quality of life (HRQoL) of ALK+NSCLC patients is also an issue that should be paid attention to in research. CROWN study quality of life subgroup analysis [4] showed that compared with crizotinib, first-line treatment with lorlatinib improved the HRQoL of patients with advanced ALK+NSCLC ; compared with baseline, patients treated with lorlatinib had higher EQ VAS and EQ-5D-5L index scores, and the score improvement was maintained throughout the treatment process; in the overall population, EQ in the lorlatinib and crizotinib groups after treatment VAS scores were significantly different.
Figure 12. After lorlatinib treatment, the patient's HRQoL was improved
Exploring the mechanism of lorlatinib resistance to assist the full management of ALK+NSCLC
Professor Zhang Xinwei emphasized that treatment selection after lorlatinib resistance is an important part of the full management of ALK+NSCLC patients. The CROWN study resistance mechanism subgroup analysis [5] results showed that regardless of whether the patient had a TP53 mutation or not, in V1/V2 and V3, the PFS of first-line lorlatinib was better than that of crizotinib. Professor Zhang Xinwei believes that ALK-TKI, which has a strong inhibitory effect on the ALK target, may reduce the occurrence of drug-resistant mutations in the ALK target.
Figure 13. The efficacy of lorlatinib is stable in different ALK variants
Surprisingly, the relevant subgroup analysis of the CROWN study [6] showed that after progression on first-line lorlatinib, 63.6% of patients followed other ALK-TKIs. Compared with sequential non-ALK-TKI, patients treated with sequential ALK-TKI achieved higher ORR (28.6% vs. 16.7%) and CR rate (9.5% vs. 0%). Professor Zhang Xinwei speculated that this difference may be related to the resistance mechanism of lorlatinib, but further exploration is still needed. In addition, current research shows that the median PFS2 of sequential treatment after progression of first-line lorlatinib has not yet been reached, and the three-year PFS2 rate is as high as 74%, which helps ALK+ NSCLC patients achieve chronic disease management.
Figure 14. After progression on first-line lorlatinib, 63.6% of patients received ALK-TKI sequentially and achieved better ORR
Experts discussed the remarkable efficacy and clinical application prospects of lorlatinib
The discussion session was moderated by Professor Fan Yun, Professors Li Ziming and Zhang Xinwei each expressed their opinions and discussed lorlatinib in depth Clinical advantages and application prospects of first-line treatment:
Figure 15. Discussion session
Setting a new benchmark for first-line treatment of ALK+ NSCLC in China, lorlatinib has unlimited potential
The two professors spoke highly of the superior efficacy of lorlatinib in the world, especially in Asian subgroups. They jointly stated that the analysis results of the Asian subgroup of the CROWN study are exciting, and lorlatinib is the first-line treatment of ALK+ The three-year PFS rate of NSCLC has exceeded 60%, and the intracranial CR rate has exceeded 70%, and it has significantly reduced the risk of intracranial progression and new disease [1]. It is more prominent among many ALK-TKIs. At the same time, its safety is consistent with the global population. It is expected to change the first-line treatment pattern of ALK+ NSCLC in China. In addition, relevant subgroup analysis showed that treatment-related CNS AEs significantly decreased with the extension of treatment time and could be well controlled through clinical management. In summary, the two professors believe that lorlatinib can be used as the first-line drug of choice for Asian ALK+ NSCLC patients, and the two professors also recommend lorlatinib for the first-line treatment of Chinese ALK+ NSCLC patients.
Professor Zhang Xinwei also shared the clinical experience of lorlatinib. He introduced that the patient had previously achieved CR with alectinib treatment, but developed brain metastases 2 months after stopping the drug due to the epidemic. After continuing alectinib treatment to achieve remission, the patient progressed again. Subsequently, the headache was relieved after one week after switching to lorlatinib, and CR was achieved after one month, with good safety profile. He emphasized that lorlatinib is the drug of choice with both efficacy and safety in mind.
Optimize the full management of ALK+NSCLC, and lorlatinib is expected to bring greater clinical benefits when used in first-line treatment.
In terms of the resistance mechanism of lorlatinib, the two professors jointly stated that based on the superior efficacy of lorlatinib in ALK patients with TP53 mutations, further and more in-depth clinical research needs to be carried out in the future, such as combining anti-angiogenic drugs, combined with radiotherapy, etc., to obtain better treatment results. The current understanding of the resistance mechanism of lorlatinib is still limited, and longer follow-up time and larger sample size are still needed to explore.
uses lorlatinib as first-line treatment. While achieving high-quality long-term survival, there are still many options for later-line treatment. After lorlatinib resistance, continued use of lorlatinib or combined with local treatment can still bring good clinical benefits. In addition, other first/second-generation ALK-TKIs, new-generation ALK-TKIs, chemotherapy drugs, and multi-drug combination models can be used as treatment options after lorlatinib resistance.
Conference Summary
Figure 15. Professor Zhou Qing and Professor Fan Yun summarized the conference.
At the end of the conference, the conference chairmen Professor Zhou Qing and Professor Fan Yun gave a wonderful summary. The two professors expressed their sincere gratitude to Professor Li Ziming and Professor Zhang Xinwei for their wonderful interpretation and in-depth discussion. They jointly stated that judging from the Asian subgroup data and other subgroup analysis results of the CROWN study announced at this ESMO conference, the third-generation ALK-TKI lorlatinib is effective in ALK+ patients with or without brain metastasis. It has significant advantages in the first-line treatment of NSCL, providing a powerful weapon for the first-line treatment of Chinese ALK+NSCLC patients, and also adding evidence-based basis for the widespread application of lorlatinib in Chinese patients. Up to now, the first-line median PFS result of lorlatinib in the overall population and Asian patients has not been reached, and it is still a mysterious number. The two professors are very much looking forward to the announcement of the final PFS results of the CROWN study, and also hope that lorlatinib can be included in medical insurance as soon as possible and widely benefit more ALK+ NSCLC patients in China.
Reference:
[1].Qing Zhou, et al. 2022 ESMO. Abstr#992
[2].Solomon BJ, et al. Presented at 2022. Abstract #CT223.
[3].Alessandra Bearz, et al. 2022 ESMO. Abstr#979P
[4].Geoffrey Liu, et al. Presented at 2022 ESMO. Abstract 1104P.
[5].Felip E, et al. 2022 ESMO. Abstract 1008P.
[6].Solomon BJ, et al. Presented at 2022 ASCO, abstract 9069.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform
