Advances in Clinical and Experimental Medicine

Adv Clin Exp Med
Impact Factor (IF) – 1.227
Index Copernicus (ICV 2018) – 157.72
MNiSW – 40
Average rejection rate – 84.38%
ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download PDF

Advances in Clinical and Experimental Medicine

2018, vol. 27, nr 9, September, p. 1317–1323

doi: 10.17219/acem/70159

Publication type: review article

Language: English

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Creative Commons BY-NC-ND 3.0 Open Access

Advances in antibody therapeutics targeting small-cell lung cancer

Hongyang Lu1,2,A,B,C,D,E,F, Zhiming Jiang1,B,D

1 Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Hangzhou, China

2 Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China

Abstract

The proportion of small-cell lung cancer (SCLC) among all lung cancers decreased from 17.26% in 1986 to 12.95% in 2002. Chemotherapy is the key mode of treatment. However, novel therapeutic strategies and drugs are imperative, as the prognosis remains poor. In recent years, antibody therapies have shown promising prospects against malignancy. This review focuses on the advances in antibody therapies in SCLC. Although the results of pembrolizumab, nivolumab, ipilimumab, and rovalpituzumab tesirine are inspiring, all of the clinical trials on these drugs are phase I/II and have been verified for further phase III clinical trials. It was demonstrated that chemotherapy in combination with bevacizumab can improve the progression-free survival (PFS) in phase III trials. The insulin-like growth factor-1 receptor (IGF-1R) is associated with a poor prognosis in SCLC, while the anti-IGF-1R monoclonal antibody figitumumab has a potential therapeutic value. Tarextumab, an antibody that blocks both Notch2 and Notch3 signaling, in combination with etoposide and platinum (EP) in patients with untreated extensive-stage SCLC, proved to be well-tolerated and showed dosedependent anti-tumor activity. The therapeutic effect of sacituzumab govitecan, BW-2 and lorvotuzumab mertansine in SCLC warranted further evaluation. Bec2/BCG as an adjuvant vaccination in patients with limited-disease SCLC could not improve the survival, PFS, or quality of life. Thus, clinical studies are essential to confirm the anti-tumor efficacy of trastuzumab in SCLC.

Key words

small-cell lung cancer, antibody therapeutics, antibody-drug conjugate

References (41)

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.
  2. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–132.
  3. Govindan R, Page N, Morgensztern D, et al. Changing epide­miology of small-cell lung cancer in the United States over the last 30 years: Analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24:4539–4544.
  4. Horn L, Reck M, Spigel DR. The future of immunotherapy in the treatment of small cell lung cancer. Oncologist. 2016;21:910–921.
  5. Ott PA, Elez E, Hiret S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: Results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2017;35:3823–3829.
  6. Antonia SJ, López-Martin JA, Bendell J, 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. 2016;17:883–895.
  7. Berghoff AS, Ricken G, Wilhelm D, et al. Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC). J Neurooncol. 2016;130:19–29.
  8. Schalper KA, Carvajal-Hausdorf DE, McLaughlin JF, et al. Objective measurement and significance of PD-L1, B7-H3, B7-H4 and TILs in small cell lung cancer (SCLC). J Clin Oncol. 2016;34(Suppl abstr):8566.
  9. Miao L, Lu Y, Xu Y, et al. PD-L1 and c-MET expression and survival in patients with small cell lung cancer. Oncotarget. 2017;8:53978–53988.
  10. Takada K, Toyokawa G, Okamoto T, et al. An immunohistochemical analysis of PD-L1 protein expression in surgically resected small cell lung cancer using different antibodies and criteria. Anticancer Res. 2016;36:3409–3412.
  11. Roviello G, Generali D. Is there a place for bevacizumab in patients with extensive-stage small cell lung cancer? Curr Cancer Drug Targets.
  12. Ustuner Z, Saip P, Yasasever V, et al. Prognostic and predictive value of vascular endothelial growth factor and its soluble receptors, VEGFR-1 and VEGFR-2 levels in the sera of small cell lung cancer patients. Med Oncol. 2008;25:394–399.
  13. Pujol JL, Lavole A, Quoix E; French Cooperative Thoracic Intergroup IFCT: Randomized phase II–III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: Results from the IFCT-0802 trial. Ann Oncol. 2015;26:908–914.
  14. Tiseo M, Boni L, Ambrosio F, et al. 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. 2017;35:1281–1287.
  15. Petrioli R, Roviello G, Laera L, et al. Cisplatin, etoposide, and bevacizumab regimen followed by oral etoposide and bevacizumab maintenance treatment in patients with extensive-stage small cell lung cancer: A single-institution experience. Clin Lung Cancer. 2015;16: 229–234.
  16. Jalal S, Bedano P, Einhorn L, et al. Paclitaxel plus bevacizumab in patients with chemosensitive relapsed small cell lung cancer: A safety, feasibility, and efficacy study from the Hoosier Oncology Group. J Thorac Oncol. 2010;5:2008–2011.
  17. Mountzios G, Emmanouilidis C, Vardakis N, et al. Paclitaxel plus bevacizumab in patients with chemoresistant relapsed small cell lung cancer as salvage treatment: A phase II multicenter study of the Hellenic Oncology Research Group. Lung Cancer. 2012;77:146–150.
  18. Gately K, Collins I, Forde L, et al. A role for IGF-1R-targeted therapies in small-cell lung cancer? Clin Lung Cancer. 2011;12:38–42.
  19. Ferté C, Loriot Y, Clémenson C, et al. IGF-1R targeting increases the antitumor effects of DNA-damaging agents in SCLC model: An opportunity to increase the efficacy of standard therapy. Mol Cancer Ther. 2013;12:1213–1222.
  20. Cao H, Dong W, Shen H, et al. Combinational therapy enhances the effects of anti-IGF-1R mAb figitumumab to target small cell lung cancer. PLoS One. 2015;10:0135844.
  21. Previs RA, Coleman RL, Harris AL, Sood AK. Molecular pathways: Translational and therapeutic implications of the Notch signaling pathway in cancer. Clin Cancer Res. 2015; 21:955–961.
  22. Yen WC, Fischer MM, Axelrod F, et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin Cancer Res. 2015;21: 2084–2095.
  23. Chiang AC, Rudin CM, Spira AI, et al. Updated results of phase 1b study of tarextumab (TRXT, anti-Notch2/3) in combination with etoposide and platinum (EP) in patients (pts) with untreated extensive-stage small-cell lung cancer (ED-SCLC). J Clin Oncol. 2016;34(Suppl abstr):8564.
  24. Bao H, Chen X, Thomas S, et al. Evaluation of anti-cancer stem cell activity of the anti-DLL4 antibody MEDI0639 in a phase I clinical trial of SCLC. J Clin Oncol. 2016;34(Suppl abstr):20093.
  25. Gladkov O, Ramlau R, Serwatowski P, et al. Cyclophosphamide and tucotuzumab (huKS-IL2) following first-line chemotherapy in responding patients with extensive-disease small-cell lung cancer. Anticancer Drugs. 2015;26:1061–1068.
  26. Potti A, Willardson J, Forseen C, et al. Predictive role of HER-2/neu overexpression and clinical features at initial presentation in patients with extensive stage small cell lung carcinoma. Lung Cancer. 2002; 36:257–261.
  27. Canoz O, Ozkan M, Arsav V, et al. The role of c-erbB-2 expression on the survival of patients with small-cell lung cancer. Lung. 2006;184: 267–272.
  28. Yagishita S, Fujita Y, Kitazono S, et al. Chemotherapy-regulated microRNA-125-HER2 pathway as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in small cell lung cancer. Mol Cancer Ther. 2015;14:1414–1423.
  29. Minami T, Kijima T, Kohmo S, et al. Overcoming chemoresistance of small-cell lung cancer through stepwise HER2-targeted antibody-dependent cell-mediated cytotoxicity and VEGF-targeted antiangiogenesis. Sci Rep. 2013;3:2669.
  30. Kinehara Y, Minami T, Kijima T, et al. Favorable response to trastuzumab plus irinotecan combination therapy in two patients with HER2-positive relapsed small-cell lung cancer. Lung Cancer. 2015;87:321–325.
  31. Grant SC, Kris MG, Houghton AN, Chapman PB. Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus Calmette-Guérin. Clin Cancer Res. 1999;5:1319–1323.
  32. Giaccone G, Debruyne C, Felip E, et al. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study). J Clin Oncol. 2005;23:6854–6864.
  33. Bottomley A, Debruyne C, Felip E, et al. Symptom and quality of life results of an international randomised phase III study of adjuvant vaccination with Bec2/BCG in responding patients with limited disease small-cell lung cancer. Eur J Cancer. 2008;44:2178–2184.
  34. Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: A first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18(1):42–51.
  35. Gray JE, Heist RS, Starodub AN, et al. Therapy of small cell lung cancer (SCLC) with a topoisomerase-I-inhibiting antibody-drug conjugate (ADC) targeting Trop-2, sacituzumab govitecan. Clin Cancer Res. 2017;23:5711–5719.
  36. Ehrlich D, Wang B, Lu W, Dowling P, Yuan R. Intratumoral anti-HuD immunotoxin therapy for small cell lung cancer and neuroblastoma. J Hematol Oncol. 2014;7:91.
  37. Whiteman KR, Johnson HA, Mayo MF, et al. Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models. Mabs. 2014;6:556–566.
  38. Shah MH, Lorigan P, O’Brien ME, et al. Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors. Invest New Drugs. 2016;34:290–299.
  39. Fujiwara K, Koyama K, Suga K, et al. 90Y-labeled anti-ROBO1 monoclonal antibody exhibits antitumor activity against small cell lung cancer xenografts. PLoS One. 2015;10:e0125468.
  40. Chen S, Yu L, Jiang C, et al. Pivotal study of iodine-131-labeled chimeric tumor necrosis treatment radioimmunotherapy in patients with advanced lung cancer. J Clin Oncol. 2005;23:1538–1547.
  41. Krug LM, Milton DT, Jungbluth AA, et al. Targeting Lewis Y (Le(y)) in small cell lung cancer with a humanized monoclonal antibody, hu3S193: A pilot trial testing two dose levels. J Thorac Oncol. 2007;2: 947–952.