What's New in SCLC? A Review

Bryan Oronsky, Tony R Reid, Arnold Oronsky, Corey A Carter, Bryan Oronsky, Tony R Reid, Arnold Oronsky, Corey A Carter

Abstract

A few years ago the answer to the question in the title of this review would have been, "unfortunately not much" or even "nothing", likely eliciting knowing nods of agreement from oncologists. For the last 3 decades, SCLC has been notorious for its lack of progress, as drug after drug, over 60 of them, in fact, including inhibitors of VEGF, IGFR, mTOR, EGFR and HGF has failed and fallen by the wayside due to little or no impact on PFS or OS, while SCLC's cousin, NSCLC, has notched success after success with a spate of targeted treatment and immunotherapy regulatory approvals. However, a paradigm shift or, more appropriately, a 'paradigm nudge' is quietly underway in extensive stage SCLC with a series of agents that in early clinical trials have shown the potential to 'lift the curse' in SCLC, heretofore referred to as "a graveyard for drug development". These agents, constituting the "best of what's new" in SCLC, and discussed in this review following a brief overview of the classification, epidemiology, prognosis and current treatment of SCLC, include checkpoint inhibitors, antibody-drug conjugates, PARP inhibitors, epigenetic inhibitor/innate immune activator, and an inhibitor of RNA polymerase II. Compared to NSCLC, the therapeutic options are still limited but with one or more successes to build momentum and drive long-overdue R&D and clinical investment the hope is that the approval floodgates may finally open.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Platinum sensitivity is classified as refractory, resistant, or sensitive, according to the time elapsed during a chemotherapy-free interval since finishing first-line treatment. Probability of re-treatment response is shown for each group of patients.
Figure 2
Figure 2
Standard treatment of ES-SCLC.

References

    1. Khanna P, Blais N, Gaudreau PO, Corrales-Rodriguez L. Immunotherapy Comes of Age in Lung Cancer. Clin Lung Cancer. 2017;18(1):13–22.
    1. Mamdani H, Induru R, Jalal SI. Novel therapies in small cell lung cancer. Transl Lung Cancer Res. 2015;4(5):533–544.
    1. Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, Spitznagel EL, Piccirillo J. 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(28):4539–4544.
    1. Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H. National Cancer Institute; 2010. SEER Cancer Statistics Review, 1975–2007. [, Ref Type: Internet Communication. Jan 22, 2017]
    1. Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ, Berns A. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell. 2003;4:181–189.
    1. Navada S, Lai P, Schwartz AG, Kalemkerian GP. Temporal trends in small cell lung cancer: Analysis of the national Surveillance, Epidemiology, and End Results database (abstract 7082) J Clin Oncol. 2006;24(18_suppl):7082-7082.
    1. Small Cell Lung Cancer Treatment (PDQQR): Health Professional Version. National Cancer Institute; 2015. Available at .
    1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
    1. Pokharel K, Gilbar P, Sorour N. Case Report: Small-cell lung cancer in a young, female, never-smoker. Lung Cancer Manage. 2015;4(4):159–162.
    1. Casciato DA, Territo MC. Lippincott Williams & Wilkins; 2009. Manual of Clinical Oncology. [Medical - 794 pages]
    1. Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 2015;16(4):e165–e172.
    1. Dela Cruz CS, Tanoue LT, Matthat RA. Lung Cancer: Epidemiology, Etiology, and Prevention. Clin Chest Med. 2011;32(4)
    1. Brennan SM, Gregory DL, Stillie A, Herschtal A, Mac Manus M, Ball DL. Should extrapulmonary small cell cancer be managed like small cell lung cancer? Cancer. 2010;116(4):888–895.
    1. Beltran H, Tagawa ST, Park K, MacDonald T, Milowsky MI, Mosquera JM, Rubin MA, Nanus DM. Challenges in recognizing treatment-related neuroendocrine prostate cancer. J Clin Oncol. 2012;30:e386–9.
    1. Allen J, Jahanzeb M. Extensive-stage small-cell lung cancer: evolution of systemic therapy and future directions. Clin Lung Cancer. 2008;9(5):262–270.
    1. Pelayo Alvarez M, Gallego Rubio O, Bonfill Cosp X, Agra Varela Y. Chemotherapy versus best supportive care for extensive small cell lung cancer. Cochrane Database Syst Rev. 2009;(4)
    1. Davies AM, Evans WK, Mackay JA, Shepherd FA. Treatment of recurrent small cell lung cancer. Hematol Oncol Clin North Am. 2004;18(2):387–416.
    1. Simos D, Sajjady G, Sergi M, Liew MS, Califano R, Ho C, Leighl N, White S, Summers Y, Petrcich W. Third-line chemotherapy in small-cell lung cancer: an international analysis. Clin Lung Cancer. 2014;15(2):110–118.
    1. Shepherd FA, Crowley J, Van Houtte P, Postmus PE, Carney D, Chansky K, Shaikh Z, Goldstraw P. International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol. 2007;2(12):1067–1077.
    1. Von Pawel J, Schiller J, Shepherd F, Fields SZ, Kleisbauer JP, Chrysson NG, Stewart DJ, Clark PI, Palmer MC, Depierre A. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small cell lung cancer. J Clin Oncol. 1999;17:658–667.
    1. Gazdar AF, Minna JD. Developing New, Rational Therapies for Recalcitrant Small Cell Lung Cancer. J Natl Cancer Inst. 2016;108(10) djw119, .
    1. Chan BA, Coward JI. Chemotherapy advances in small-cell lung cancer. J Thorac Dis. 2013;5(Suppl. 5):S565–78.
    1. Wagar SN, Morgensztern D. Treatment advances in small cell lung cancer (SCLC) Pharmacol Ther. 2017
    1. Mattern MR, Mong SM, Bartus HF, Mirabelli CK, Crooke ST, Johnson RK. Relationship between the intracellular effects of camptothecin and the inhibition of DNA topoisomerase I in cultured L1210 cells. Cancer Res. 1987;47:1793–1798.
    1. Ott PA, Elez Fernandez ME, Hiret S, Kim Dong-Wan, Moss RA, Winser T, Yuan S, Cheng JD, Piperdi B, Mehnert JM. Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028. J Clin Oncol. 2015;33(15_suppl):7502-7502.
    1. Hellmann MD, Antonia SJ, Ponce S, Ott PA, Calvo E, Taylor M, Ready N, Hann CL, De Braud F, Eder JP. World Conference on Lung Cancer. Abstract MA09.05. Presented December 6, 2016. 2016. Nivolumab alone or with ipilimumab in recurrent small cell lung cancer: 2-year survival and updated analyses from the CheckMate 032 trial.
    1. Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, Pietanza MC, Wu Y, Zielinski C, Thomas M. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol. 2016;25:3740–3748.
    1. Li Y, Li F, Jiang F, Lv X, Zhang R, Lu A, Zhang G. A Mini-Review for Cancer Immunother- apy: Molecular Understanding of PD-1/PD-L1 Pathway & amp;amp; Translational Blockade of Immune Checkpoints. Int J Mol Sci. 2016;17(7)
    1. Pietanza C. Safety, activity, and response durability assessment of single agent rovalpituzumab tesirine, a delta-like protein3 (DLL3)-targeted anibody drug conjugate (ADC), in small cell lung cancer (SCLC) [abstract LBA 7] Presented at the ECC 2015. 2015
    1. Starodub A, Camidge DR, Ronald J, Scheff RJ, Thomas SS, Guarino MJ, Masters GA, Kalinsky K, Gandhi L, Bardia A. Trop-2 as a therapeutic target for the antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132), in patients (pts) with previously treated metastatic small-cell lung cancer (mSCLC) J Clin Oncol. 2016;34:8559-8559. [abst 8559]
    1. Gray JE, Heist RS, Starodub AN, Camidge DS, Kio E, Masters G, Purcell WT, Guarino MJ, Misleh J, Schneider CJ, et al. CT155-Phase 2 study of sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate (ADC), in patients with pretreated metastatic small-cell lung cancer (mSCLC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT155. .
    1. Byers LA, Krug L, Waqar S, Dowlati A, Hann C, Chiappori A, Owonikoko T, Woo K, Bensman Y, Hurtado B. MA11.07 Improved Small Cell Lung Cancer (SCLC) Response Rates with Veliparib and Temozolomide: Results from a Phase II Trial. J Thorac Oncol. 2017;12(1):S406–S407.
    1. Soares DG, Machado MS, Rocca CJ, Poindessous V, Ouaret D, Sarasin A, Galmarini CM, Henriques JA, Escargueil AE, Larsen AK. Trabectedin and its C subunit modified analogue PM01183 attenuate nucleotide excision repair and show activity toward platinum-resistant cells. Mol Cancer Ther. 2010;10:1481–1489.
    1. Céspedes MV, Guillén MJ, López-Casas PP, Sarno F, Gallardo A, Alamo P, Cuevas C, Hidalgo M, Galmarini CM, Allavena P. Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models. Dis Model Mech. 2016;9(12):1461–1471.
    1. Forster M, Calvo E, Olmedo Garcia ME, Lopez Criado MP, Moreno V, Soto-Matos A, Holgado E, Brown NF, Flynn M, Boni V. Lurbinectedin(PM1183)with doxorubicin (DOX), an active treatment as second-line therapy in small cell lung cancer (SCLC). Presented at: 2015 ASCO Annual Meeting; May 29–June 2, 2015. Chicago, IL. 2015 Abstract 7509.
    1. Oronsky B, Scicinski J, Ning S, Peehl D, Oronsky A, Cabrales P, Bednarski M, Knox S. Rockets, radiosensitizers, and RRx-001:an origin story part I. Discov Med. 2016;21(115):173–180.
    1. Oronsky B, Paulmurugan R, Foygel K, Scicinski J, Knox SJ, Peehl D, Zhao H, Ning S, Cabrales P, Summers TA., Jr. Carter CA.RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials. Expert Opin Investig Drugs. 2017;26(1):109–119.
    1. Weiskopf K, Jahchan NS, Schnorr PJ, Cristea S, Ring AM, Maute RL, Volkmer AK, Volkmer JP, Liu J, Lim JS. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest. 2016;126(7):2610–2620.
    1. Oronsky B, Reid TR, Larson C, Carter CA, Brzezniak CE, Oronsky A, Cabrales P. RRx-001 protects against cisplatin-induced toxicities. J Cancer Res Clin Oncol. 2017
    1. Chute JP, Chen T, Feigal E, Simon R, Johnson BE. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol. 1999;17(6):1794–1801.
    1. Popat S, O'Brien M. Chemotherapy strategies in the treatment of small cell lung cancer. Anticancer Drugs. 2005;16:361–372.
    1. Bassiri K, Cairns L, McVie G, Seckl M. Highlights from the ecancer Future Horizons in Lung Cancer conference, 1–2 September 2016: Focusing on the future of treatment for NSCLC and SCLC. Ecancermedicalscience. 2017;11:729.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner