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Anlotinib plus etoposide and cisplatin/carboplatin as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC): a single-arm, phase II study

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Abstract

Patients with extensive-stage small-cell lung cancer (ES-SCLC) have high relapse rates and poor prognosis. Anlotinib monotherapy has shown promising efficacy for patients with ES-SCLC and has a non-overlapping toxicity profile with chemotherapy. Therefore, the study aims to assess the efficacy and safety of the addition of anlotinib to platinum-chemotherapy as first-line therapy for patients with ES-SCLC. ES-SCLC patients without systemic chemotherapy and immunotherapy were recruited. Eligible patients received anlotinib (12 mg/day, on day 1–14) of a 21-day cycle, with concomitant etoposide (100 mg/m2, on day 1–3) plus cisplatin (75 mg/m2, on day 1) or carboplatin (AUC = 4–5, on day 1) for 4–6 cycles, followed by indefinite anlotinib maintenance therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS). Between Jan 15, 2019 and Dec 31, 2020, 25 patients were enrolled. At the data cut-off time (November 3, 2021), the median follow-up was 14.3 months. Median PFS was 10.3 months (95% CI: 6.0–14.5) and median OS was 17.1 months (95% CI: 11.1–19.3). The ORR and DCR were 90% and 100%, respectively. The most common grade 3 or worse treatment-related adverse events were neutropenia (50%), leukopenia (35%), thrombocytopenia (25%), fatigue (10%), nausea (10%), hyponatremia (10%), anemia (10%). One patient discontinued treatment due to treatment-related adverse events. No treatment-related death occurred. Anlotinib plus platinum–chemotherapy as first-line therapy for ES-SCLC has anti-tumor activity, and showed acceptable tolerability. These results provide a basis for future randomized controlled trials.

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Data availability

All data included in this study are available upon request by contact with the corresponding author.

Abbreviations

ES-SCLC:

Extensive-stage small-cell lung cancer

PFS:

Progression-free survival

ORR:

Objective response rate

DCR:

Disease control rate

OS:

Overall survival

mOS:

Median overall survival

NSCLC:

Non-small cell lung cancer

RECIST:

Response Evaluation Criteria in Solid Tumors

ECOG:

Eastern Cooperative Oncology Group

AEs:

Adverse events

NCI:

National Cancer Institute

MRI:

Magnetic resonance imaging

CTCAE:

Common Terminology Criteria for Adverse Events

SD:

Stable disease

PD:

Disease progression

CT:

Computed tomography

AEs:

Adverse events

DOR:

Duration of response

TRAEs:

Treatment- related AEs

TTP:

Time to progress

rhG-CSF:

Recombinant human granulocyte colony-stimulating factor

rhTPO:

Recombinant human thrombopoietin

TKI:

Tyrosine kinase inhibitor

References

  1. Facchinetti F, Di Maio M, Tiseo M (2020) Adding PD-1/PD-L1 inhibitors to chemotherapy for the first-line treatment of extensive Stage Small Cell Lung Cancer (SCLC): A meta-analysis of randomized trials. Cancers (Basel). https://doi.org/10.3390/cancers12092645

    Article  Google Scholar 

  2. Morabito A, Rolfo C (2021) Small cell lung cancer: A new era is beginning? Cancers (Basel). https://doi.org/10.3390/cancers13112646

    Article  Google Scholar 

  3. Rudin CM, Brambilla E, Faivre-Finn C, Sage J (2021) Small-cell lung cancer. Nat Rev Dis Primers 7:3. https://doi.org/10.1038/s41572-020-00235-0

    Article  PubMed  PubMed Central  Google Scholar 

  4. Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Ozguroglu M, Ji JH et al (2019) Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 394:1929–1939. https://doi.org/10.1016/S0140-6736(19)32222-6

    Article  CAS  PubMed  Google Scholar 

  5. Domine M, Moran T, Isla D, Marti JL, Sullivan I, Provencio M, Olmedo ME, Ponce S, Blasco A, Cobo M (2020) SEOM clinical guidelines for the treatment of small-cell lung cancer (SCLC) (2019). Clin Transl Oncol 22:245–255. https://doi.org/10.1007/s12094-020-02295-w

    Article  CAS  PubMed  Google Scholar 

  6. Sun A, Durocher-Allen LD, Ellis PM, Ung YC, Goffin JR, Ramchandar K, Darling G (2019) Initial management of small-cell lung cancer (limited- and extensive-stage) and the role of thoracic radiotherapy and first-line chemotherapy: a systematic review. Curr Oncol 26:e372–e384. https://doi.org/10.3747/co.26.4481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, D’Amico TA, DeCamp MM, Dilling TJ, Dobelbower M et al (2017) Non-small cell lung cancer, version 5.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 15:504–535. https://doi.org/10.6004/jnccn.2017.0050

    Article  PubMed  Google Scholar 

  8. Rudin CM, Ismaila N, Hann CL, Malhotra N, Movsas B, Norris K, Pietanza MC, Ramalingam SS, Turrisi AT 3rd, Giaccone G (2015) Treatment of small-cell lung cancer: American society of clinical oncology endorsement of the American college of chest physicians guideline. J Clin Oncol 33:4106–4111. https://doi.org/10.1200/JCO.2015.63.7918

    Article  CAS  PubMed  Google Scholar 

  9. Pietanza MC, Byers LA, Minna JD, Rudin CM (2015) Small cell lung cancer: will recent progress lead to improved outcomes? Clin Cancer Res 21:2244–2255. https://doi.org/10.1158/1078-0432.CCR-14-2958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhou T, Zhang Z, Luo F, Zhao Y, Hou X, Liu T, Wang K, Zhao H, Huang Y, Zhang L (2020) Comparison of first-line treatments for patients with extensive-stage small cell lung cancer: A systematic review and network meta-analysis. JAMA Netw Open 3:e2015748. https://doi.org/10.1001/jamanetworkopen.2020.15748

    Article  PubMed  PubMed Central  Google Scholar 

  11. Fruh M, De Ruysscher D, Popat S, Crino L, Peters S, Felip E, Group EGW (2013) Small-cell lung cancer (SCLC): ESMO Clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 24(Suppl 6):vi99–vi105. https://doi.org/10.1093/annonc/mdt178

  12. Liu SV, Reck M, Mansfield AS, Mok T, Scherpereel A, Reinmuth N, Garassino MC, De Castro CJ, Califano R, Nishio M et al (2021) Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol 39:619–630. https://doi.org/10.1200/JCO.20.01055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shen G, Zheng F, Ren D, Du F, Dong Q, Wang Z, Zhao F, Ahmad R, Zhao J (2018) Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol 11:120. https://doi.org/10.1186/s13045-018-0664-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Syed YY (2018) Anlotinib: First global approval. Drugs 78:1057–1062. https://doi.org/10.1007/s40265-018-0939-x

    Article  CAS  PubMed  Google Scholar 

  15. Sun Y, Du F, Gao M, Ji Q, Li Z, Zhang Y, Guo Z, Wang J, Chen X, Wang J et al (2018) Anlotinib for the treatment of patients with locally advanced or metastatic medullary thyroid cancer. Thyroid 28:1455–1461. https://doi.org/10.1089/thy.2018.0022

    Article  CAS  PubMed  Google Scholar 

  16. Zhou A-P, Bai Y, Song Y, Li H, Xie X, Ren X-B, Ye D, Liu J, Luo H, Bai X (2016) Anlotinib in metastatic renal cell carcinoma (mRCC) with a previous anti-VEGFR TKI: Preliminary results from a multicenter, phase II trial. Am Soc Clin Oncol

  17. Huang J, Xiao J, Fang W, Lu P, Fan Q, Shu Y, Feng JF, Zhang S, Ba Y, Liu Y (2019) Anlotinib in chemotherapy-refractory metastatic esophageal squamous cell carcinoma (ESCC): A randomized, double-blind, multicenter phase II trial. Am Soc Clin Oncol

  18. Xie C, Wan X, Quan H, Zheng M, Fu L, Li Y, Lou L (2018) Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci 109:1207–1219. https://doi.org/10.1111/cas.13536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liang L, Hui K, Hu C, Wen Y, Yang S, Zhu P, Wang L, Xia Y, Qiao Y, Sun W et al (2019) Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells. J Exp Clin Cancer Res 38:71. https://doi.org/10.1186/s13046-019-1093-3

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ruan X, Shi X, Dong Q, Yu Y, Hou X, Song X, Wei X, Chen L, Gao M (2019) Antitumor effects of anlotinib in thyroid cancer. Endocr Relat Cancer 26:153–164. https://doi.org/10.1530/ERC-17-0558

    Article  CAS  PubMed  Google Scholar 

  21. He Z, Zhou H, Wang J, Li D, Zhang X, Wang P, Ma T, Zhang Y, Tian C, Chen Y et al (2021) Apatinib with etoposide capsules as a third- or further-line therapy for extensive-stage small cell lung cancer: an open-label, multicenter, single-arm phase II trial. Transl Lung Cancer Res 10:889–899. https://doi.org/10.21037/tlcr-20-1235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cheng Y, Wang Q, Li K, Shi J, Liu Y, Wu L, Han B, Chen G, He J, Wang J (2019) Overall survival (OS) update in ALTER 1202: Anlotinib as third-line or further-line treatment in relapsed small-cell lung cancer (SCLC). Ann Oncol 30:v711

    Article  Google Scholar 

  23. Li Y, Sun Z, Sun W, Wang H, Zu J (2022) Effectiveness and Safety of anlotinib monotherapy for patients with extensive-stage small-cell lung cancer who progressed to chemotherapy: A real-world exploratory study. Clin Med Insights Oncol 16:11795549211067184. https://doi.org/10.1177/11795549211067184

    Article  PubMed  PubMed Central  Google Scholar 

  24. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Article  CAS  Google Scholar 

  25. Lara PN Jr, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, Jett J, Langer CJ, Kuebler JP, Dakhil SR et al (2009) Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 27:2530–2535. https://doi.org/10.1200/JCO.2008.20.1061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang S, Zimmermann S, Parikh K, Mansfield AS, Adjei AA (2019) Current diagnosis and management of small-cell lung cancer. Mayo Clin Proc 94:1599–1622. https://doi.org/10.1016/j.mayocp.2019.01.034

    Article  PubMed  Google Scholar 

  27. Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M et al (2018) First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 379:2220–2229. https://doi.org/10.1056/NEJMoa1809064

    Article  CAS  PubMed  Google Scholar 

  28. Montanino A, Manzo A, Carillio G, Palumbo G, Esposito G, Sforza V, Costanzo R, Sandomenico C, Botti G, Piccirillo MC et al (2021) Angiogenesis inhibitors in small cell lung cancer. Front Oncol. https://doi.org/10.3389/fonc.2021.655316

    Article  PubMed  PubMed Central  Google Scholar 

  29. Deng P, Hu C, Chen C, Cao L, Gu Q, An J, Qin L, Li M, He B, Jiang J et al (2022) Anlotinib plus platinum-etoposide as a first-line treatment for extensive-stage small cell lung cancer: A single-arm trial. Cancer Med n/a. https://doi.org/10.1002/cam4.4736

    Article  Google Scholar 

  30. Liu C, Liao J, Wu X, Zhao X, Sun S, Wang H, Hu Z, Zhang Y, Yu H, Wang J (2022) A phase II study of anlotinib combined with etoposide and platinum-based regimens in the first-line treatment of extensive-stage small cell lung cancer. Thorac Cancer 13:1463–1470. https://doi.org/10.1111/1759-7714.14414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Almquist D, Langlais B, Yu NY, Sio TTW, Savvides P, Yang P, Schild SE, Mansfield AS, Ernani V (2021) Chemoimmunotherapy for the treatment of extensive-stage small cell lung cancer (ES-SCLC) in patients with an Eastern Cooperative Group (ECOG) performance status (PS) of two or greater. J Clin Oncol 39:8569–8569. https://doi.org/10.1200/JCO.2021.39.15_suppl.8569

    Article  Google Scholar 

  32. Broderick JM, Hussey J, Kennedy MJ, O’ Donnell DM (2014) Patients over 65years are assigned lower ECOG PS scores than younger patients, although objectively measured physical activity is no different. J Geriatr Oncol 5:49–56. https://doi.org/10.1016/j.jgo.2013.07.010

    Article  PubMed  Google Scholar 

  33. Tiseo M, Boni L, Ambrosio F, Camerini A, Baldini E, Cinieri S, Brighenti M, Zanelli F, Defraia E, Chiari R et al (2017) Italian, multicenter, phase III, randomized study of cisplatin plus etoposide with or without bevacizumab as first-line treatment in extensive-disease small-cell lung cancer: The GOIRC-AIFA FARM6PMFJM Trial. J Clin Oncol 35:1281–1287. https://doi.org/10.1200/JCO.2016.69.4844

    Article  CAS  PubMed  Google Scholar 

  34. Sharma N, Pennell N, Nickolich M, Halmos B, Ma P, Mekhail T, Fu P, Dowlati A (2014) Phase II trial of Sorafenib in conjunction with chemotherapy and as maintenance therapy in extensive-stage small cell lung cancer. Invest New Drugs 32:362–368. https://doi.org/10.1007/s10637-013-0061-6

    Article  CAS  PubMed  Google Scholar 

  35. Lu S, Li L, Luo Y, Zhang L, Wu G, Chen Z, Huang C, Guo S, Zhang Y, Song X et al (2015) A multicenter, open-label, randomized phase II controlled study of rh-endostatin (Endostar) in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer. J Thorac Oncol 10:206–211. https://doi.org/10.1097/JTO.0000000000000343

    Article  CAS  PubMed  Google Scholar 

  36. Luo H, Zhang L, Yang B, Feng Y, Xiong Y, Zhang S, Li X, Qian C, Dong W, Dai N (2020) A randomized phase 2 trial of apatinib vs observation as maintenance treatment following first­line induction chemotherapy in extensive­ stage small cell lung cancer. Invest New Drugs 38:148–159. https://doi.org/10.1007/s10637-019-00828-x

    Article  CAS  PubMed  Google Scholar 

  37. Lin B, Song X, Yang D, Bai D, Yao Y, Lu N (2018) Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2, PDGFRbeta and FGFR1. Gene 654:77–86. https://doi.org/10.1016/j.gene.2018.02.026

    Article  CAS  PubMed  Google Scholar 

  38. Spigel DR, Townley PM, Waterhouse DM, Fang L, Adiguzel I, Huang JE, Karlin DA, Faoro L, Scappaticci FA, Socinski MA (2011) Randomized phase ii study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: Results from the SALUTE Trial. J Clin Oncol 29:2215–2222. https://doi.org/10.1200/jco.2010.29.3423

    Article  CAS  PubMed  Google Scholar 

  39. Reck M, Horn L, Novello S, Barlesi F, Albert I, Juhasz E, Kowalski D, Robinet G, Cadranel J, Bidoli P et al (2019) Phase II study of roniciclib in combination with cisplatin/etoposide or carboplatin/etoposide as first-line therapy in patients with extensive-disease small cell lung cancer. J Thorac Oncol 14:701–711. https://doi.org/10.1016/j.jtho.2019.01.010

    Article  CAS  PubMed  Google Scholar 

  40. Jiang S, Huang L, Zhen H, Jin P, Wang J, Hu Z (2021) Carboplatin versus cisplatin in combination with etoposide in the first-line treatment of small cell lung cancer: a pooled analysis. BMC Cancer 21:1308. https://doi.org/10.1186/s12885-021-09034-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gao Y, Liu P, Shi R (2020) Anlotinib as a molecular targeted therapy for tumors. Oncol Lett 20:1001–1014. https://doi.org/10.3892/ol.2020.11685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhou AP, Bai Y, Song Y, Luo H, Ren XB, Wang X, Shi B, Fu C, Cheng Y, Liu J et al (2019) Anlotinib versus sunitinib as first-line treatment for metastatic renal cell carcinoma: a randomized phase ii clinical trial. Oncologist 24:e702–e708. https://doi.org/10.1634/theoncologist.2018-0839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all participants and their families.

Funding

This study was supported by Technologies R & D Program of Henan Province (202102310456), and Medical Science and Technology Joint construction Project of Henan Province (LHGJ20210730).

Author information

Author notes

  1. Tiandong Kong, Lu Chen and Xiaoli Zhao contributed equally as first authors.

Authors and Affiliations

  1. Department of Medical Oncology, Cancer Hospital of Henan University& the Third People’s Hospital of Zhengzhou, Henan, China

    Tiandong Kong, Lu Chen, Xiaoli Zhao, Fangfang Duan & Hanli Zhou

  2. Department of Respiratory Medicine, the First Affiliated Hospital of Zhengzhou University, Henan, China

    Lei Wang

  3. Department of Pharmacy, Cancer Hospital of Henan University& the Third People’s Hospital of Zhengzhou, Henan, China

    Danna Liu

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  1. Tiandong Kong
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  2. Lu Chen
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Contributions

Tiandong kong and Danna Liu contributed to the study conception and design. Administrative support was provided by Lei Wang. Hanli Zhou and Fangfang Duan provided materials and samples, Data collection, analysis and interpretation were performed by Xiaoli Zhao, Lu Chen, and Tiandong Kong. All authors have read and approved the manuscript.

Corresponding authors

Correspondence to Lei Wang or Danna Liu.

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This study was conducted according to the "Declaration of Helsinki". Ethics approval is obtained from the medical ethics committee of the Third People's Hospital of Zhengzhou city.

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Kong, T., Chen, L., Zhao, X. et al. Anlotinib plus etoposide and cisplatin/carboplatin as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC): a single-arm, phase II study. Invest New Drugs 40, 1095–1105 (2022). https://doi.org/10.1007/s10637-022-01279-7

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