Abstract
Background
This study aimed to evaluate the efficacy and safety of anlotinib as a third-line and subsequent treatment for patients with small cell lung cancer (SCLC).
Methods
We conducted this Phase 2 trial at 11 institutions in China. Patients with pathologically confirmed SCLC who failed at least two lines of chemotherapy were enrolled. Subjects were randomly assigned in a 2:1 ratio to receive either anlotinib 12 mg orally once daily for 14 days every 3 weeks or placebo. The primary endpoint was progression-free survival (PFS).
Results
Between March 30, 2017 and June 8, 2018, a total of 82 and 38 patients were randomly assigned to receive anlotinib and placebo. The median PFS was significantly longer in the anlotinib group compared with the placebo group (4.1 months [95% confidence interval (CI), 2.8–4.2] vs 0.7 months [95% CI, 0.7–0.8]; hazard ratio (HR) 0.19 [95% CI, 0.12–0.32], p < 0.0001). Overall survival (OS) was significantly longer with anlotinib than placebo (7.3 months [95% CI, 6.1–10.3] vs 4.9 months [95% CI, 2.7–6.0]; HR 0.53 [95% CI, 0.34–0.81], p = 0.0029).
Conclusions
Anlotinib as a third-line or subsequent treatment for Chinese patients with SCLC showed improved PFS and OS than placebo with favourable safety profile.
Clinical Trial Registration
ClinicalTrials.gov, number NCT03059797.
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References
Ardizzoni, A., Hansen, H., Dombernowsky, P., Gamucci, T., Kaplan, S., Postmus, P. et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J. Clin. Oncol. 15, 2090–2096 (1997).
Antonia, S. J., López-Martin, J. A., Bendell, J., Ott, P. A., Taylor, M., Eder, J. P. et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 17, 883–895 (2016).
Chung, H. C., Piha-Paul, S. A., Lopez-Martin, J., Schellens, J., Kao, S., Miller, W. H. et al. Pembrolizumab after two or more lines of previous therapy in patients with recurrent or metastatic small-cell lung cancer: results from the KEYNOTE-028 and KEYNOTE-158 studies. J. Thorac. Oncol. 15, 618–627 (2020).
Ready, N., Farago, A. F., de Braud, F., Atmaca, A., Hellmann, M. D., Schneider, J. G. et al. Third-line nivolumab monotherapy in recurrent SCLC: CheckMate 032. J. Thorac. Oncol. 14, 237–244 (2019).
Horn, L., Mansfield, A. S., Szczęsna, A., Havel, L., Krzakowski, M., Hochmair, M. J. et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med. 379, 2220–2229 (2018).
Trigo, J., Subbiah, V., Besse, B., Moreno, V., López, R., Sala, M. A. et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 21, 645–654 (2020).
Lucchi, M., Mussi, A., Fontanini, G., Faviana, P., Ribechini, A. & Angeletti, C. A. Small cell lung carcinoma (SCLC): the angiogenic phenomenon. Eur. J. Cardiothorac. Surg. 21, 1105–1110 (2002).
Fontanini, G., Boldrini, L., Chinè, S., Pisaturo, F., Basolo, F., Calcinai, A. et al. Expression of vascular endothelial growth factor mRNA in non-small-cell lung carcinomas. Br. J. Cancer 79, 363–369 (1999).
Ioannou, M., Papamichali, R., Kouvaras, E., Mylonis, I., Vageli, D., Kerenidou, T. et al. Hypoxia inducible factor-1 alpha and vascular endothelial growth factor in biopsies of small cell lung carcinoma. Lung 187, 321–329 (2019).
Tanno, S., Ohsaki, Y., Nakanishi, K., Toyoshima, E. & Kikuchi, K. Human small cell lung cancer cells express functional VEGF receptors, VEGFR-2 and VEGFR-3. Lung Cancer 46, 11–19 (2004).
Shinohara, E. T., Gonzalez, A., Massion, P. P., Olson, S. J., Albert, J. M., Shyr, Y. et al. PDGFR-beta expression in small cell lung cancer patients. Int. J. Radiat. Oncol. Biol. Phys. 67, 431–437 (2007).
Hida, T., Ueda, R., Sekido, Y., Hibi, K., Matsuda, R., Ariyoshi, Y. et al. Ectopic expression of c-kit in small-cell lung cancer. Int. J. Cancer 8, 108–109 (1994).
Han, J. Y., Kim, H. Y., Lim, K. Y., Han, J. H., Lee, Y. J., Kwak, M. H. et al. A phase II study of sunitinib in patients with relapsed or refractory small cell lung cancer. Lung Cancer 79, 137–142 (2013).
Han, J. Y., Kim, H. Y., Lim, K. Y., Hwangbo, B. & Lee, J. S. A phase II study of nintedanib in patients with relapsed small cell lung cancer. Lung Cancer 96, 108–112 (2006).
Xie, C., Wan, X., Quan, H., Zheng, M., Fu, L., Li, Y. & Lou, L. Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci. 109, 1207–1219 (2018).
Sun, Y., Niu, W., Du, F., Du, C., Li, S., Wang, J. et al. Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J. Hematol. Oncol. 9, 105 (2016).
Simos, D., Sajjady, G., Sergi, M., Liew, M. S., Califano, R., Ho, C. et al. Third-line chemotherapy in small-cell lung cancer: an international analysis. Clin. Lung Cancer 15, 110–118 (2014).
Ott, P. A., Elez, E., Hiret, S., Kim, D. W., Morosky, A., Saraf, S., et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J. Clin. Oncol. 35, 3823–3829 (2017).
Coutinho, A. D., Shah, M., Lunacsek, O. E., Eaddy, M. & Willey, J. P. Real-world treatment patterns and outcomes of patients with small cell lung cancer progressing after 2 lines of therapy. Lung Cancer 127, 53–58 (2019).
Calvo, E., Moreno, V., Flynn, M., Holgado, E., Olmedo, M. E., Lopez Criado, M. P. et al. Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study. Ann. Oncol. 28, 2559–2566 (2017).
Saruwatari, K., Umemura, S., Nomura, S., Kirita, K., Matsumoto, S., Yoh, K. et al. Prognostic factor analysis in patients with small-cell lung cancer treated with third-line chemotherapy. Clin. Lung Cancer 17, 581–587 (2016).
Steffens, C. C., Elender, C., Hutzschenreuter, U., Dille, S., Binninger, A., Spring, L. et al. Treatment and outcome of 432 patients with extensive-stage small cell lung cancer in first, second and third line - results from the prospective German TLK cohort study. Lung Cancer 130, 216–225 (2019).
Koinis, F., Agelaki, S., Karavassilis, V., Kentepozidis, N., Samantas, E., Peroukidis, S. et al. Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group. Br. J. Cancer 117, 8–14 (2017).
Liu, X., Jiang, T., Li, W., Li, X., Zhao, C., Shi, J. et al. Characterization of never-smoking and its association with clinical outcomes in Chinese patients with small-cell lung cancer. Lung Cancer 115, 109–115 (2018).
Acknowledgements
We thank the patients and their families, all the investigators and the study personnel involved in the study.
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Authors and Affiliations
Contributions
Y.C., Y.L. and S.W. designed the study. Y.C., D.L. and H.Y. analysed the data. Y.C., Q.W., K.L., J.S., Y.L., L.W., B.H., G.C., J.H., J.W., D.L., H.Y., H.Q. and X.L. contributed to data collection, data interpretation, and writing of the report. All authors reviewed and approved the article to be submitted.
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Ethics approval and consent to participate
The study was performed in accordance with the Declaration of Helsinki and Guidelines for Good Clinical Practice, as well as laws and regulations in China. The study protocol was approved by the institutional review board in each participating institution. All patients provided written informed consent before any study-related procedure.
Data availability
The data used and analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
S.W. is a senior engineer of Chia-tai Tianqing Pharmaceutical Group Co., Ltd. All the other authors declare no conflict of interests.
Funding information
This work was supported by Chia-tai Tianqing Pharmaceutical Group Co., Ltd. The funder had no role in the design the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. The funder provided the study drug. This paper is supported by the Special Project for Significant New Drug Research and Development in the Major National Science and Technology Projects of China (project no. 2020ZX09201-024).
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Cheng, Y., Wang, Q., Li, K. et al. Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: a randomised, double-blind, placebo-controlled Phase 2 study. Br J Cancer 125, 366–371 (2021). https://doi.org/10.1038/s41416-021-01356-3
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DOI: https://doi.org/10.1038/s41416-021-01356-3
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