Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trial

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Abstract

Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5–6% of non-small cell lung cancer (NSCLC) cases and associated with increased risks of central nervous system (CNS) involvement. Envonalkib, a novel ALK inhibitor, demonstrated promising anti-tumor activity and safety in advanced ALK-positive NSCLC in the first-in-human phase I study. This phase III trial (ClinicalTrials.gov NCT04009317) investigated the efficacy and safety of first-line envonalkib in advanced ALK-positive NSCLC cases. Totally 264 participants were randomized 1:1 to receive envonalkib ( n = 131) or crizotinib ( n = 133). Median independent review committee (IRC)-assessed progression-free survival (PFS) times were 24.87 (95% confidence interval [CI]: 15.64–30.36) and 11.60 (95% CI: 8.28–13.73) months in the envonalkib and crizotinib groups, respectively (hazard ratio [HR] = 0.47, 95% CI: 0.34–0.64, p < 0.0001). IRC-assessed confirmed objective response rate (ORR) was higher (81.68% vs. 70.68%, p = 0.056) and duration of response was longer (median, 25.79 [95% CI, 16.53–29.47] vs. 11.14 [95% CI, 9.23–16.59] months, p = 0.0003) in the envonalkib group compared with the crizotinib group. In participants with baseline brain target lesions, IRC-assessed CNS-ORR was improved with envonalkib compared with crizotinib (78.95% vs. 23.81%). Overall survival (OS) data were immature, and median OS was not reached in either group (HR = 0.84, 95% CI: 0.48–1.47, p = 0.5741). The 12-month OS rates were 90.6% (95% CI, 84.0%–94.5%) and 89.4% (95% CI, 82.8%–93.6%) in the envonalkib and crizotinib groups, respectively. Grade ≥3 treatment-related adverse events were observed in 55.73% and 42.86% of participants in the envonalkib and crizotinib groups, respectively. Envonalkib significantly improved PFS and delayed brain metastasis progression in advanced ALK-positive NSCLC.

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Cancer statistics, 2023

Rebecca L Siegel, Kimberly D Miller, Nikita Sandeep Wagle … (2023)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases; otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stable/increasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.

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Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer.

Ali Zeaiter, Tony Mok, Peter Morcos … (2017)

Background Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. Methods In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. Results During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib). Conclusions As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840 .).

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Author and article information

Contributors

Li Zhang: zhangli@sysucc.org.cn

Wenfeng Fang: fangwf@sysucc.org.cn

Journal

Journal ID (nlm-ta): Signal Transduct Target Ther

Journal ID (iso-abbrev): Signal Transduct Target Ther

Title: Signal Transduction and Targeted Therapy

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 2095-9907

ISSN (Electronic): 2059-3635

Publication date (Electronic): 14 August 2023

Publication date PMC-release: 14 August 2023

Publication date Collection: 2023

Volume: 8

Electronic Location Identifier: 301

Affiliations

[1 ]GRID grid.488530.2, ISNI 0000 0004 1803 6191, Department of Medical Oncology, , Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, ; Guangzhou, 510060 China

[2 ]GRID grid.233520.5, ISNI 0000 0004 1761 4404, Department of Oncology, , The Second Affiliated Hospital of Air Force Medical University, ; Xi’an, 710038 China

[3 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Medical Oncology, , Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, ; Changsha, 410013 China

[4 ]GRID grid.413431.0, Department of Medical Oncology of Respiratory, , Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, ; Nanning, 530021 China

[5 ]GRID grid.440230.1, ISNI 0000 0004 1789 4901, Department of Thoracic Medical Oncology, , Jilin Provincial Cancer Hospital, ; Changchun, 130012 China

[6 ]GRID grid.414008.9, ISNI 0000 0004 1799 4638, Department of Medical Oncology, , The Affiliated Cancer Hospital of Zhengzhou University, ; Zhengzhou, 450003 China

[7 ]GRID grid.452438.c, ISNI 0000 0004 1760 8119, Department of Respiratory, , First Affiliated Hospital of Xian Jiaotong University, ; Xi’an, 710061 China

[8 ]GRID grid.452206.7, ISNI 0000 0004 1758 417X, Department of Respiratory and Critical Care Medicine, , The First Affiliated Hospital of Chongqing Medical University, ; Chongqing, 400050 China

[9 ]GRID grid.452461.0, ISNI 0000 0004 1762 8478, Department of Respiratory, , The First Hospital of Shanxi Medical University, ; Taiyuan, 030001 China

[10 ]GRID grid.452661.2, ISNI 0000 0004 1803 6319, Department of Respiratory Disease, , The First Affiliated Hospital, Zhejiang University School of Medicine, ; Hangzhou, 310003 China

[11 ]GRID grid.415110.0, ISNI 0000 0004 0605 1140, Department of Medical Oncology, , Fujian Cancer Hospital, ; Fuzhou, 350014 China

[12 ]GRID grid.477976.c, ISNI 0000 0004 1758 4014, The First Department of Oncology, , The First Affiliated Hospital of Guangdong Pharmaceutical University, ; Guangzhou, 510699 China

[13 ]GRID grid.411395.b, ISNI 0000 0004 1757 0085, Department of Respiratory and Critical Care Medicine, , Anhui Provincial Hospital, ; Hefei, 230000 China

[14 ]GRID grid.410736.7, ISNI 0000 0001 2204 9268, Department of Respiratory Medicine, , Affiliated Cancer Hospital of Harbin Medical University, ; Harbin, 150000 China

[15 ]GRID grid.233520.5, ISNI 0000 0004 1761 4404, Department of Respiratory Medicine, , The First Affiliated Hospital of Air Force Medical University, ; Xi’an, 710032 China

[16 ]GRID grid.470124.4, Department of Cardiothoracic Surgery, , The First Affiliated Hospital of Guangzhou Medical College, Guangzhou Research Institute of Respiratory Disease and China State Key Laboratory of Respiratory Disease, ; Guangzhou, 510120 China

[17 ]GRID grid.452509.f, ISNI 0000 0004 1764 4566, Department of Medical Oncology, , The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, ; Nanjing, 210009 China

[18 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Biostatistics, , Nanjing Medical University, ; Nanjing, 211166 China

Article

Publisher ID: 1538

DOI: 10.1038/s41392-023-01538-w

PMC ID: 10423717

PubMed ID: 37574511

SO-VID: 41ccbb0c-3bff-4eb8-89f4-3a6adb1bd8f9

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 5 December 2022

Date revision received : 28 April 2023

Date accepted : 9 June 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 82072558

Award Recipient : Wenfeng Fang

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Keywords: lung cancer,cancer

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Keywords: lung cancer, cancer

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Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trial

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Most cited references 31

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Cancer statistics, 2023

Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer.

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