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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2022, Vol. 16 Issue (5) : 766-772    https://doi.org/10.1007/s11684-021-0916-8
RESEARCH ARTICLE
Anlotinib as third- or further-line therapy for short-term relapsed small-cell lung cancer: subgroup analysis of a randomized phase 2 study (ALTER1202)
Jianhua Shi1, Ying Cheng2(), Qiming Wang3, Kai Li4, Lin Wu5, Baohui Han6, Gongyan Chen7, Jianxing He8, Jie Wang9, Haifeng Qin10, Xiaoling Li11
1. Department of Medical Oncology, Linyi Cancer Hospital, Linyi 276002, China
2. Department of Thoracic Medical Oncology, Jilin Cancer Hospital, Changchun 130012, China
3. Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450003, China
4. Department of Pulmonary Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
5. Department of Thoracic Medical Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University (Hunan Cancer Hospital), Changsha 410031, China
6. Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
7. Department of Respiratory Medicine, Harbin Medical University Cancer Hospital, Harbin 150081, China
8. Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
9. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
10. Department of Pulmonary Oncology, The Fifth Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
11. Department of Medical Oncology, Liaoning Cancer Hospital, Shenyang 110042, China
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Abstract

Patients with small-cell lung cancer (SCLC) relapse within months after completing previous therapies. This study aimed to investigate the efficacy and safety of anlotinib as third- or further-line therapy in patients with short-term relapsed SCLC from ALTER1202. Patients with short-term relapsed SCLC (disease progression within 3 months after completing ≥ two lines of chemotherapy) in the anlotinib (n = 67) and placebo (n = 34) groups were analyzed. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival, objective response rate (ORR), disease control rate, and safety. Anlotinib significantly improved median PFS/OS (4.0 vs. 0.7 months, P < 0.0001)/(7.3 vs. 4.4 months, P = 0.006) compared with placebo. The ORR was 4.5%/2.9% in the anlotinib/placebo group (P = 1.000). The DCR in the anlotinib group was higher than that in the placebo group (73.1% vs. 11.8%, P < 0.001). The most common adverse events (AEs) were hypertension (38.8%), loss of appetite (28.4%), and fatigue (22.4%) in the anlotinib group and gamma-glutamyl transpeptidase elevation (20.6%) in the placebo group. No grade 5 AEs occurred. For patients with short-term relapsed SCLC, third- or further-line anlotinib treatment was associated with improved survival benefit. Further studies are warranted in this regard.

Keywords anlotinib      chemotherapy      short-term relapsed      small-cell lung cancer     
Corresponding Author(s): Ying Cheng   
Just Accepted Date: 01 June 2022   Online First Date: 20 July 2022    Issue Date: 18 November 2022
 Cite this article:   
Jianhua Shi,Ying Cheng,Qiming Wang, et al. Anlotinib as third- or further-line therapy for short-term relapsed small-cell lung cancer: subgroup analysis of a randomized phase 2 study (ALTER1202)[J]. Front. Med., 2022, 16(5): 766-772.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0916-8
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I5/766
Variable Anlotinib (total = 67) Placebo (total = 34) P　　
n % n %
Median age, year (range) 57 (31–71)　　　　　　 58.5 (43–75)　　　　　 0.1621
Sex 0.1986
Male 45 67.2 27 79.4
Female 22 32.8 7 20.6
ECOG performance status 0.0916
0 3 4.5 0 0
1 60 89.6 28 82.4
2 4 6.0 6 17.6
Smoking history 0.0958
Never 28 41.8 8 23.5
Former 37 55.2 26 76.5
Current 2 3.0 0 0
Disease stage 0.1211
Limited stage 6 9.0 7 20.6
Extensive stage 61 91.0 27 79.4
Previous lines of chemotherapy 0.9687
two 51 76.1 26 76.5
≥ three 16 23.9 8 23.5
Previous radiotherapy 0.6186
No 32 47.8 14 41.2
Yes 35 52.2 20 58.8
Tab.1  Baseline characteristics
Fig.1  Kaplan–Meier curves. (A) Progression-free survival (PFS). Median PFS was 4.0 months in the anlotinib group and 0.7 months in the placebo group. (B) Overall survival (OS). Median OS was 7.3 months in the anlotinib group and 4.4 months in the placebo group.
Variable Anlotinib (total = 67) Placebo (total = 34) P
Best response, n (%)
CR 0 0
PR 3 (4.5) 1 (2.9)
SD 46 (68.7) 3 (8.8)
PD 15 (22.4) 22 (64.7)
NE 3 (4.5) 8 (23.5)
ORR, n (%) 3 (4.5) 1 (2.9) 1.000
DCR, n (%) 49 (73.1) 4 (11.8) < 0.001
Tab.2  Response rate
Variable Anlotinib (total = 67) Placebo (total = 34)
　　　Any grade, n (%) 　　　　Grades 3–4, n (%) 　　　　Any grade, n (%) Grades 3–4, n (%)
Hypertension 26 (38.8) 9 (13.4) 2 (5.9) 1 (2.9)　　　　　
Loss of appetite 19 (28.4) 1 (1.5) 4 (11.8) 0　　　　　　　
Fatigue 15 (22.4) 1 (1.5) 4 (11.8) 0　　　　　　　
ALT elevation 12 (17.9) 1 (1.5) 5 (14.7) 2 (5.9)　　　　　
Hypertriglyceridemia 12 (17.9) 3 (4.5) 1 (2.9) 0　　　　　　　
Decreased lymphocyte count 12 (17.9) 2 (3.0) 0　　 0　　　　　　　
AST elevation 12 (17.9) 2 (3.0) 5 (14.7) 0　　　　　　　
TSH elevation 12 (17.9) 0 　　 0　　 0　　　　　　　
QT prolongation 11 (16.4) 0 　　 3 (8.8) 1 (2.9)　　　　　
Hand-foot syndrome 11 (16.4) 1 (1.5) 0　　 0　　　　　　　
GGT elevation 8 (11.9) 4 (6.0) 7 (20.6) 3 (8.8)　　　　　
Tab.3  Treatment-emergent adverse events with incidence ≥ 15% in either group
1 S Yang, Z Zhang, Q Wang. Emerging therapies for small cell lung cancer. J Hematol Oncol 2019; 12( 1): 47
https://doi.org/10.1186/s13045-019-0736-3
2 RL Siegel, KD Miller, A Jemal. Cancer statistics, 2020. CA Cancer J Clin 2020; 70( 1): 7– 30
https://doi.org/10.3322/caac.21590
3 CM Rudin, G Giaccone, N Ismaila. Treatment of small-cell lung cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline. J Oncol Pract 2016; 12( 1): 83– 86
https://doi.org/10.1200/JOP.2015.008201
4 M Früh Ruysscher D De S Popat L Crinò S Peters E; ESMO Guidelines Working Group Felip. Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi99– vi105
5 S Zimmerman, A Das, S Wang, R Julian, L Gandhi, J Wolf. 2017–2018 scientific advances in thoracic oncology: small cell lung cancer. J Thorac Oncol 2019; 14( 5): 768– 783
https://doi.org/10.1016/j.jtho.2019.01.022
6 T Ito, S Kudoh, T Ichimura, K Fujino, WA Hassan, N Udaka. Small cell lung cancer, an epithelial to mesenchymal transition (EMT)-like cancer: significance of inactive Notch signaling and expression of achaete-scute complex homologue 1. Hum Cell 2017; 30( 1): 1– 10
https://doi.org/10.1007/s13577-016-0149-3
7 SN Waqar, D Morgensztern. Treatment advances in small cell lung cancer (SCLC). Pharmacol Ther 2017; 180 : 16– 23
https://doi.org/10.1016/j.pharmthera.2017.06.002
8 C MacCallum, HH Gillenwater. Second-line treatment of small-cell lung cancer. Curr Oncol Rep 2006; 8( 4): 258– 264
https://doi.org/10.1007/s11912-006-0030-8
9 J von Pawel, JH Schiller, FA Shepherd, SZ Fields, JP Kleisbauer, NG Chrysson, DJ Stewart, PI Clark, MC Palmer, A Depierre, J Carmichael, JB Krebs, G Ross, SR Lane, R Gralla. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999; 17( 2): 658– 667
https://doi.org/10.1200/JCO.1999.17.2.658
10 A Ardizzoni, M Tiseo, L Boni. Validation of standard definition of sensitive versus refractory relapsed small cell lung cancer: a pooled analysis of topotecan second-line trials. Eur J Cancer 2014; 50( 13): 2211– 2218
https://doi.org/10.1016/j.ejca.2014.06.002
11 N Asai, Y Ohkuni, N Kaneko, E Yamaguchi, A Kubo. Relapsed small cell lung cancer: treatment options and latest developments. Ther Adv Med Oncol 2014; 6( 2): 69– 82
https://doi.org/10.1177/1758834013517413
12 N Ready, AF Farago, F de Braud, A Atmaca, MD Hellmann, JG Schneider, DR Spigel, V Moreno, I Chau, CL Hann, JP Eder, NL Steele, A Pieters, J Fairchild, SJ Antonia. Third-line nivolumab monotherapy in recurrent SCLC: CheckMate 032. J Thorac Oncol 2019; 14( 2): 237– 244
https://doi.org/10.1016/j.jtho.2018.10.003
13 HC Chung, SA Piha-Paul, J Lopez-Martin, JHM Schellens, S Kao, WH Jr Miller, JP Delord, B Gao, D Planchard, M Gottfried, A Zer, SI Jalal, N Penel, JM Mehnert, I Matos, J Bennouna, DW Kim, L Xu, S Krishnan, K Norwood, PA Ott. Pembrolizumab after two or more lines of previous therapy in patients with recurrent or metastatic SCLC: results from the KEYNOTE-028 and KEYNOTE-158 Studies. J Thorac Oncol 2020; 15( 4): 618– 627
https://doi.org/10.1016/j.jtho.2019.12.109
14 C Xie, X Wan, H Quan, M Zheng, L Fu, Y Li, L Lou. Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci 2018; 109( 4): 1207– 1219
https://doi.org/10.1111/cas.13536
15 G Shen, F Zheng, D Ren, F Du, Q Dong, Z Wang, F Zhao, R Ahmad, J Zhao. Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol 2018; 11( 1): 120
https://doi.org/10.1186/s13045-018-0664-7
16 D Chen, J Xu, Y Zhao, T Chu, H Zhong, B Han, R Zhong. Prognostic value of tumor cavitation in extensive-stage small-cell lung cancer patients treated with anlotinib. J Cancer Res Clin Oncol 2020; 146( 2): 401– 406
https://doi.org/10.1007/s00432-019-03064-1
17 B Han, K Li, Q Wang, L Zhang, J Shi, Z Wang, Y Cheng, J He, Y Shi, Y Zhao, H Yu, Y Zhao, W Chen, Y Luo, L Wu, X Wang, R Pirker, K Nan, F Jin, J Dong, B Li, Y Sun. Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: the ALTER 0303 phase 3 randomized clinical trial. JAMA Oncol 2018; 4( 11): 1569– 1575
https://doi.org/10.1001/jamaoncol.2018.3039
18 Y Cheng, Q Wang, K Li, J Shi, Y Liu, L Wu, B Han, G Chen, J He, J Wang, D Lou, H Yu, S Wang, H Qin, X Li. 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 2021; 125( 3): 366– 371
https://doi.org/10.1038/s41416-021-01356-3
19 Y Cheng, Q Wang, K Li, J Shi, L Wu, B Han, G Chen, J He, J Wang, H Qin, X Li. OA13.03 Anlotinib as third-line or further-line treatment in relapsed SCLC: a multicentre, randomized, double-blind phase 2 trial. J Thorac Oncol 2018; 13( 10): S351– S352
https://doi.org/10.1016/j.jtho.2018.08.308
20 YH Kim, M Mishima. Second-line chemotherapy for small-cell lung cancer (SCLC). Cancer Treat Rev 2011; 37( 2): 143– 150
https://doi.org/10.1016/j.ctrv.2010.05.004
21 D Simos, G Sajjady, M Sergi, MS Liew, R Califano, C Ho, N Leighl, S White, Y Summers, W Petrcich, P Wheatley-Price. Third-line chemotherapy in small-cell lung cancer: an international analysis. Clin Lung Cancer 2014; 15( 2): 110– 118
https://doi.org/10.1016/j.cllc.2013.11.003
22 MC Pietanza, K Kadota, K Huberman, CS Sima, JJ Fiore, DK Sumner, WD Travis, A Heguy, MS Ginsberg, AI Holodny, TA Chan, NA Rizvi, CG Azzoli, GJ Riely, MG Kris, LM Krug. Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. Clin Cancer Res 2012; 18( 4): 1138– 1145
https://doi.org/10.1158/1078-0432.CCR-11-2059
23 D Morgensztern, B Besse, L Greillier, R Santana-Davila, N Ready, CL Hann, BS Glisson, AF Farago, A Dowlati, CM Rudin, S Le Moulec, S Lally, S Yalamanchili, J Wolf, R Govindan, DP Carbone. Efficacy and safety of rovalpituzumab tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell lung cancer: results from the phase II TRINITY study. Clin Cancer Res 2019; 25( 23): 6958– 6966
https://doi.org/10.1158/1078-0432.CCR-19-1133
24 NE Ready, PA Ott, MD Hellmann, J Zugazagoitia, CL Hann, F de Braud, SJ Antonia, PA Ascierto, V Moreno, A Atmaca, S Salvagni, M Taylor, A Amin, DR Camidge, L Horn, E Calvo, A Li, WH Lin, MK Callahan, DR Spigel. Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort. J Thorac Oncol 2020; 15( 3): 426– 435
https://doi.org/10.1016/j.jtho.2019.10.004
25 B Han, K Li, Y Zhao, B Li, Y Cheng, J Zhou, Y Lu, Y Shi, Z Wang, L Jiang, Y Luo, Y Zhang, C Huang, Q Li, G Wu. Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer: a multicentre, randomised phase II trial (ALTER0302). Br J Cancer 2018; 118( 5): 654– 661
https://doi.org/10.1038/bjc.2017.478
26 D Wu, J Nie, W Hu, L Dai, J Zhang, X Chen, X Ma, G Tian, J Han, S Han, J Long, Y Wang, Z Zhang, J Fang. A phase II study of anlotinib in 45 patients with relapsed small cell lung cancer. Int J Cancer 2020; 147( 12): 3453– 3460
https://doi.org/10.1002/ijc.33161
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