Front Line Applications and Future Directions of Immunotherapy in Small-Cell Lung Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Rationale for Immunotherapy in Small-Cell Lung Cancer
3. Immune Checkpoint Inhibitors
4. Extensive-Stage Small-Cell Lung Cancer
5. Limited-Stage Small-Cell Lung Cancer
6. Predictive Biomarkers
7. Other Immunotherapeutic Approaches
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Byers, L.; Rudin, C.M. Small cell lung cancer: Where do we go from here? Cancer 2015, 121, 664–672. [Google Scholar] [CrossRef] [PubMed]
- Rudin, C.M.; Ismaila, N.; Hann, C.L.; Malhotra, N.; Movsas, B.; Norris, K.; Pietanza, M.C.; Ramalingam, S.S.; Turrisi, A.T.; Giaccone, G. Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline. J. Clin. Oncol. 2015, 33, 4106–4111. [Google Scholar] [CrossRef] [PubMed]
- Dómine, M.; Morán, T.; Isla, D.; Martí, J.L.; Sullivan, I.; Provencio, M.; Olmedo, M.E.; Ponce, S.; Blasco, A.; Cobo, M. SEOM clinical guidelines for the treatment of small-cell lung cancer (SCLC) (2019). Clin. Transl. Oncol. 2020, 22, 245–255. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Van Meerbeeck, J.P.; Fennell, D.A.; De Ruysscher, D. Small-cell lung cancer. Lancet 2011, 378, 1741–1755. [Google Scholar] [CrossRef]
- Lally, B.E.; Urbanic, J.J.; Blackstock, A.W.; Miller, A.A.; Perry, M.C. Small Cell Lung Cancer: Have We Made Any Progress Over the Last 25 Years? Oncologist 2007, 12, 1096–1104. [Google Scholar] [CrossRef]
- Oze, I.; Hotta, K.; Kiura, K.; Ochi, N.; Takigawa, N.; Fujiwara, Y.; Tabata, M.; Tanimoto, M. Twenty-Seven Years of Phase III Trials for Patients with Extensive Disease Small-Cell Lung Cancer: Disappointing Results. PLoS ONE 2009, 4, e7835. [Google Scholar] [CrossRef]
- Horn, L.; Mansfield, A.S.; Szczęsna, A.; Havel, L.; Krzakowski, M.; Hochmair, M.J.; Huemer, F.; Losonczy, G.; Johnson, M.L.; Nishio, M.; et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 379, 2220–2229. [Google Scholar] [CrossRef]
- Paz-Ares, L.; Dvorkin, M.; Chen, Y.; Reinmuth, N.; Hotta, K.; Trukhin, D.; Statsenko, G.; Hochmair, M.J.; Özgüroğlu, M.; Ji, J.H.; et al. 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 2019, 394, 1929–1939. [Google Scholar] [CrossRef]
- Esposito, G.; Palumbo, G.; Carillio, G.; Manzo, A.; Montanino, A.; Sforza, V.; Costanzo, R.; Sandomenico, C.; La Manna, C.; Martucci, N.; et al. Immunotherapy in Small Cell Lung Cancer. Cancers 2020, 12, 2522. [Google Scholar] [CrossRef]
- Iams, W.T.; Porter, J.; Horn, L. Immunotherapeutic approaches for small-cell lung cancer. Nat. Rev. Clin. Oncol. 2020, 17, 300–312. [Google Scholar] [CrossRef]
- Ragavan, M.; Das, M. Systemic Therapy of Extensive Stage Small Cell Lung Cancer in the Era of Immunotherapy. Curr. Treat. Options Oncol. 2020, 21, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Pujol, J.-L.; Greillier, L.; Audigier-Valette, C.; Moro-Sibilot, D.; Uwer, L.; Hureaux, J.; Guisier, F.; Carmier, D.; Madelaine, J.; Otto, J.; et al. A Randomized Non-Comparative Phase II Study of Anti-Programmed Cell Death-Ligand 1 Atezolizumab or Chemotherapy as Second-Line Therapy in Patients with Small Cell Lung Cancer: Results From the IFCT-1603 Trial. J. Thorac. Oncol. 2019, 14, 903–913. [Google Scholar] [CrossRef] [PubMed]
- Reck, M.; Vicente, D.; Ciuleanu, T.; Gettinger, S.; Peters, S.; Horn, L.; Audigier-Valette, C.; Pardo, N.; Juan-Vidal, O.; Cheng, Y.; et al. Efficacy and safety of nivolumab (nivo) monotherapy versus chemotherapy (chemo) in recurrent small cell lung cancer (SCLC): Results from CheckMate 331. Ann. Oncol. 2018, 29, x43. [Google Scholar] [CrossRef]
- Bristol Myers Squibb. Bristol Myers Squibb Statement on Opdivo (nivolumab) Small Cell Lung Cancer U.S. Indication. Available online: https://news.bms.com/news/details/2020/Bristol-Myers-Squibb-Statement-on-Opdivo-nivolumab-Small-Cell-Lung-Cancer-US-Indication/default.aspx (accessed on 19 January 2021).
- National Comprehensive Guidelines (NCCN). NCCN Clinical Practice Guidelines in Oncology, Small Cell Lung Cancer, Ver-sion 2.2021. Available online: https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf (accessed on 19 January 2021).
- Doyle, A.; Martin, W.J.; Funa, K.; Gazdar, A.; Carney, D.; Martin, S.E.; Linnoila, I.; Cuttitta, F.; Mulshine, J.; Bunn, P. Markedly decreased expression of class I histocompatibility antigens, protein, and mRNA in human small-cell lung cancer. J. Exp. Med. 1985, 161, 1135–1151. [Google Scholar] [CrossRef] [Green Version]
- Seliger, B. Strategies of Tumor Immune Evasion. BioDrugs 2005, 19, 347–354. [Google Scholar] [CrossRef]
- Efremova, M.; Finotello, F.; Rieder, D.; Trajanoski, Z. Neoantigens Generated by Individual Mutations and Their Role in Cancer Immunity and Immunotherapy. Front. Immunol. 2017, 8, 1679. [Google Scholar] [CrossRef] [Green Version]
- Sabari, J.K.; Lok, B.H.; Laird, J.H.; Poirier, J.T.; Rudin, J.K.S.J.T.P.C.M. Unravelling the biology of SCLC: Implications for therapy. Nat. Rev. Clin. Oncol. 2017, 14, 549–561. [Google Scholar] [CrossRef]
- Yarchoan, M.; Johnson, B.A.; Lutz, E.R.; Laheru, D.A.; Jaffee, E.M. Targeting neoantigens to augment antitumour immunity. Nat. Rev. Cancer 2017, 17, 209–222. [Google Scholar] [CrossRef]
- George, J.; Lim, J.S.; Jang, S.J.; Cun, Y.; Ozretić, L.; Kong, G.; Leenders, F.; Lu, X.; Fernández-Cuesta, L.; Bosco, G.; et al. Comprehensive genomic profiles of small cell lung cancer. Nat. Cell Biol. 2015, 524, 47–53. [Google Scholar] [CrossRef]
- Peifer, M.; Fernández-Cuesta, L.; Sos, M.L.; George, J.; Seidel, D.; Kasper, L.H.; Plenker, D.; Leenders, F.; Sun, R.; Zander, T.; et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat. Genet. 2012, 44, 1104–1110. [Google Scholar] [CrossRef]
- Govindan, R.; Page, N.; Morgensztern, D.; Read, W.; Tierney, R.; Vlahiotis, A.; Spitznagel, E.L.; 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, 4539–4544. [Google Scholar] [CrossRef] [PubMed]
- Hiura, T.; Kagamu, H.; Miura, S.; Ishida, A.; Tanaka, H.; Tanaka, J.; Gejyo, F.; Yoshizawa, H. Both Regulatory T Cells and Antitumor Effector T Cells Are Primed in the Same Draining Lymph Nodes during Tumor Progression. J. Immunol. 2005, 175, 5058–5066. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Onizuka, S.; Tawara, I.; Shimizu, J.; Sakaguchi, S.; Fujita, T.; Nakayama, E. Tumor rejection by in vivo administration of an-ti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res. 1999, 59, 3128–3133. [Google Scholar] [PubMed]
- Shimizu, J.; Yamazaki, S.; Sakaguchi, S. Induction of tumor immunity by removing CD25+CD4+ T cells: A common basis be-tween tumor immunity and autoimmunity. J. Immun. 1999, 163, 5211–5218. [Google Scholar]
- Koyama, K.; Kagamu, H.; Miura, S.; Hiura, T.; Miyabayashi, T.; Itoh, R.; Kuriyama, H.; Tanaka, H.; Tanaka, J.; Yoshizawa, H.; et al. Reciprocal CD4+ T-Cell Balance of Effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ Regulatory T Cells in Small Cell Lung Cancer Reflects Disease Stage. Clin. Cancer Res. 2008, 14, 6770–6779. [Google Scholar] [CrossRef] [Green Version]
- Eerola, A.K.; Soini, Y.; Pääkkö, P. A high number of tumor-infiltrating lymphocytes are associated with a small tumor size, low tumor stage, and a favorable prognosis in operated small cell lung carcinoma. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2000, 6, 1875–1881. [Google Scholar]
- Muppa, P.; Terra, S.B.S.P.; Sharma, A.; Mansfield, A.S.; Aubry, M.-C.; Bhinge, K.; Asiedu, M.K.; De Andrade, M.; Janaki, N.; Murphy, S.J.; et al. Immune Cell Infiltration May Be a Key Determinant of Long-Term Survival in Small Cell Lung Cancer. J. Thorac. Oncol. 2019, 14, 1286–1295. [Google Scholar] [CrossRef] [Green Version]
- Wang, W.; Hodkinson, P.; McLaren, F.; MacKean, M.J.; Williams, L.; Howie, S.E.M.; Wallace, W.A.; Sethi, T. Histologic Assessment of Tumor-Associated CD45 + Cell Numbers Is an Independent Predictor of Prognosis in Small Cell Lung Cancer. Chest 2013, 143, 146–151. [Google Scholar] [CrossRef]
- He, Y.; Rozeboom, L.; Rivard, C.J.; Ellison, K.; Dziadziuszko, R.; Yu, H.; Zhou, C.; Hirsch, F.R. MHC class II expression in lung cancer. Lung Cancer 2017, 112, 75–80. [Google Scholar] [CrossRef]
- Schalper, K.A.; Carvajal-Hausdorf, D.E.; McLaughlin, J.F.; Altan, M.; Chiang, A.C.; Velcheti, V.; Kaftan, E.; Zhang, J.; Lu, L.; Rimm, D.L.; 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, 8566. [Google Scholar] [CrossRef]
- Maddison, P.; Newsom-Davis, J.; Mills, K.R.; Souhami, R.L. Favourable prognosis in Lambert-Eaton myasthenic syndrome and small-cell lung carcinoma. Lancet 1999, 353, 117–118. [Google Scholar] [CrossRef]
- Iams, W.T.; Shiuan, E.; Meador, C.B.; Roth, M.; Bordeaux, J.; Vaupel, C.; Boyd, K.L.; Summitt, I.B.; Wang, L.L.; Schneider, J.T.; et al. Improved Prognosis and Increased Tumor-Infiltrating Lymphocytes in Patients Who Have SCLC With Neurologic Paraneoplastic Syndromes. J. Thorac. Oncol. 2019, 14, 1970–1981. [Google Scholar] [CrossRef] [PubMed]
- Fife, B.T.; Bluestone, J.A. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol. Rev. 2008, 224, 166–182. [Google Scholar] [CrossRef] [PubMed]
- Iwai, Y.; Ishida, M.; Tanaka, Y.; Okazaki, T.; Honjo, T.; Minato, N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci. USA 2002, 99, 12293–12297. [Google Scholar] [CrossRef] [Green Version]
- Reck, M.; Liu, S.; Mansfield, A.; Mok, T.; Scherpereel, A.; Reinmuth, N.; Garassino, M.; De Carpeno, J.; Califano, R.; Nishio, M.; et al. IMpower133: Updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Ann. Oncol. 2019, 30, v710–v711. [Google Scholar] [CrossRef]
- Paz-Ares, L.G.; Dvorkin, M.; Chen, Y.; Reinmuth, N.; Hotta, K.; Trukhin, D.; Statsenko, G.; Hochmair, M.; Özgüroğlu, M.; Ji, J.H.; et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): Updated results from the phase III CASPIAN study. J. Clin. Oncol. 2020, 38, 9002. [Google Scholar] [CrossRef]
- Leal, T.; Wang, Y.; Dowlati, A.; Lewis, D.A.; Chen, Y.; Mohindra, A.R.; Razaq, M.; Ahuja, H.G.; Liu, J.; King, D.M.; et al. Randomized phase II clinical trial of cisplatin/carboplatin and etoposide (CE) alone or in combination with nivolumab as frontline therapy for extensive-stage small cell lung cancer (ES-SCLC): ECOG-ACRIN EA5161. J. Clin. Oncol. 2020, 38, 9000. [Google Scholar] [CrossRef]
- Rudin, C.M.; Awad, M.M.; Navarro, A.; Gottfried, M.; Peters, S.; Csőszi, T.; Cheema, P.K.; Rodriguez-Abreu, D.; Wollner, M.; Yang, J.C.-H.; et al. Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J. Clin. Oncol. 2020, 38, 2369–2379. [Google Scholar] [CrossRef]
- Reck, M.; Bondarenko, I.; Luft, A.; Serwatowski, P.; Barlesi, F.; Chacko, R.; Sebastian, M.; Lu, H.; Cuillerot, J.-M.; Lynch, T.J. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: Results from a randomized, double-blind, multicenter phase 2 trial. Ann. Oncol. 2012, 24, 75–83. [Google Scholar] [CrossRef]
- Reck, M.; Luft, A.; Szczesna, A.; Havel, L.; Kim, S.-W.; Akerley, W.; Pietanza, M.C.; Wu, Y.-L.; Zielinski, C.; Thomas, M.; et al. 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, 34, 3740–3748. [Google Scholar] [CrossRef]
- Faivre-Finn, C.; Snee, M.; Ashcroft, L.; Appel, W.; Barlesi, F.; Bhatnagar, A.; Bezjak, A.; Cardenal, F.; Fournel, P.; Harden, S.; et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): An open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017, 18, 1116–1125. [Google Scholar] [CrossRef] [Green Version]
- Pignon, J.-P.; Arriagada, R.; Ihde, D.C.; Johnson, D.H.; Perry, M.C.; Souhami, R.L.; Brodin, O.; Joss, R.A.; Kies, M.S.; Lebeau, B.; et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N. Engl. J. Med. 1992, 327, 1618–1624. [Google Scholar] [CrossRef] [PubMed]
- Warde, P.; Payne, D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J. Clin. Oncol. 1992, 10, 890–895. [Google Scholar] [CrossRef] [PubMed]
- Welsh, J.W.; Heymach, J.V.; Guo, C.; Menon, H.; Klein, K.; Cushman, T.R.; Verma, V.; Hess, K.R.; Shroff, G.; Tang, C.; et al. Phase 1/2 Trial of Pembrolizumab and Concurrent Chemoradiation Therapy for Limited-Stage SCLC. J. Thorac. Oncol. 2020, 15, 1919–1927. [Google Scholar] [CrossRef] [PubMed]
- Antonia, S.J.; Villegas, A.; Daniel, D.; Vicente, D.; Murakami, S.; Hui, R.; Kurata, T.; Chiappori, A.; Lee, K.H.; De Wit, M.; et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 2018, 379, 2342–2350. [Google Scholar] [CrossRef] [PubMed]
- Antonia, S.J.; Villegas, A.; Daniel, D.; Vicente, D.; Murakami, S.; Hui, R.; Yokoi, T.; Chiappori, A.; Lee, K.H.; De Wit, M.; et al. Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2017, 377, 1919–1929. [Google Scholar] [CrossRef] [PubMed]
- Reck, M.; Rodríguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csőszi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2016, 375, 1823–1833. [Google Scholar] [CrossRef] [Green Version]
- Lantuejoul, S.; Sound-Tsao, M.; Cooper, W.A.; Girard, N.; Hirsch, F.R.; Roden, A.C.; Lopez-Rios, F.; Jain, D.; Chou, T.-Y.; Motoi, N.; et al. PD-L1 Testing for Lung Cancer in 2019: Perspective From the IASLC Pathology Committee. J. Thorac. Oncol. 2020, 15, 499–519. [Google Scholar] [CrossRef]
- Ilie, M.; Long-Mira, E.; Bence, C.; Butori, C.; Lassalle, S.; Bouhlel, L.; Fazzalari, L.; Zahaf, K.; Lalvée, S.; Washetine, K.; et al. Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: A potential issue for anti-PD-L1 therapeutic strategies. Ann. Oncol. 2015, 27, 147–153. [Google Scholar] [CrossRef]
- Mansfield, A.S.; Aubry, M.C.; Moser, J.C.; Harrington, S.M.; Dronca, R.S.; Park, S.S.; Dong, H. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann. Oncol. 2016, 27, 1953–1958. [Google Scholar] [CrossRef]
- McLaughlin, J.K.; Han, G.; Schalper, K.A.; Carvajal-Hausdorf, D.; Pelekanou, V.; Rehman, J.; Velcheti, V.; Herbst, R.S.; Lorusso, P.M.; Rimm, D.L. Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non–Small-Cell Lung Cancer. JAMA Oncol. 2016, 2, 46–54. [Google Scholar] [CrossRef] [PubMed]
- Paz-Ares, L.; Goldman, J.; Garassino, M.; Dvorkin, M.; Trukhin, D.; Statsenko, G.; Hotta, K.; Ji, J.; Hochmair, M.; Voitko, O.; et al. PD-L1 expression, patterns of progression and patient-reported outcomes (PROs) with durvalumab plus platinum-etoposide in ES-SCLC: Results from CASPIAN. Ann. Oncol. 2019, 30, v928–v929. [Google Scholar] [CrossRef]
- Lin, H.; Wei, S.; Hurt, E.M.; Green, M.D.; Zhao, L.; Vatan, L.; Szeliga, W.; Herbst, R.; Harms, P.W.; Fecher, L.A.; et al. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression. J. Clin. Investig. 2018, 128, 805–815. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tang, H.; Liang, Y.; Anders, R.A.; Taube, J.M.; Qiu, X.; Mulgaonkar, A.; Liu, X.; Harrington, S.M.; Guo, J.; Xin, Y.; et al. PD-L1 on host cells is essential for PD-L1 blockade–mediated tumor regression. J. Clin. Investig. 2018, 128, 580–588. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schultheis, A.M.; Scheel, A.H.; Ozretić, L.; George, J.; Thomas, R.K.; Hagemann, T.; Zander, T.; Wolf, J.; Buettner, R. PD-L1 expression in small cell neuroendocrine carcinomas. Eur. J. Cancer 2015, 51, 421–426. [Google Scholar] [CrossRef] [Green Version]
- Kim, H.S.; Lee, J.H.; Nam, S.J.; Ock, C.-Y.; Moon, J.-W.; Yoo, C.W.; Lee, G.K.; Han, J.-Y. Association of PD-L1 Expression with Tumor-Infiltrating Immune Cells and Mutation Burden in High-Grade Neuroendocrine Carcinoma of the Lung. J. Thorac. Oncol. 2018, 13, 636–648. [Google Scholar] [CrossRef] [Green Version]
- Samstein, R.M.; Lee, C.-H.; Shoushtari, A.N.; Hellmann, M.D.; Shen, R.; Janjigian, Y.Y.; Barron, D.A.; Zehir, A.; Jordan, E.J.; Omuro, A.; et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 2019, 51, 202–206. [Google Scholar] [CrossRef]
- Gubin, M.M.; Zhang, X.; Schuster, H.; Caron, E.; Ward, J.P.; Noguchi, T.; Ivanova, Y.; Hundal, J.; Arthur, C.D.; Krebber, W.J.; et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014, 515, 577–581. [Google Scholar] [CrossRef]
- Ricciuti, B.; Kravets, S.; Dahlberg, S.E.; Umeton, R.; Albayrak, A.; Subegdjo, S.J.; Johnson, B.E.; Nishino, M.; Sholl, L.M.; Awad, M.M. Use of targeted next generation sequencing to characterize tumor mutational burden and efficacy of immune checkpoint inhibition in small cell lung cancer. J. Immunother. Cancer 2019, 7, 87. [Google Scholar] [CrossRef]
- Gandara, D.R.; Paul, S.M.; Kowanetz, M.; Schleifman, E.; Zou, W.; Li, Y.; Rittmeyer, A.; Fehrenbacher, L.; Otto, G.; Malboeuf, C.; et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat. Med. 2018, 24, 1441–1448. [Google Scholar] [CrossRef]
- Sadelain, M.; Brentjens, R.; Rivière, I. The Basic Principles of Chimeric Antigen Receptor Design. Cancer Discov. 2013, 3, 388–398. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Crossland, D.L.; Denning, W.L.; Ang, S.; Olivares, S.; Mi, T.; Switzer, K.; Singh, H.; Huls, H.; Gold, K.S.; Glisson, B.S.; et al. Antitumor activity of CD56-chimeric antigen receptor T cells in neuroblastoma and SCLC models. Oncogene 2018, 37, 3686–3697. [Google Scholar] [CrossRef] [PubMed]
- Weiskopf, K.; Jahchan, N.S.; Schnorr, P.J.; Cristea, S.; Ring, A.M.; Maute, R.L.; Volkmer, A.K.; Volkmer, J.-P.; Liu, J.; Lim, J.S.; et al. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J. Clin. Investig. 2016, 126, 2610–2620. [Google Scholar] [CrossRef] [PubMed]
- Owen, D.H.; Giffin, M.J.; Bailis, J.M.; Smit, M.-A.D.; Carbone, D.P.; He, K. DLL3: An emerging target in small cell lung cancer. J. Hematol. Oncol. 2019, 12, 1–8. [Google Scholar] [CrossRef]
- Leonetti, A.; Facchinetti, F.; Minari, R.; Cortellini, A.; Rolfo, C.D.; Giovannetti, E.; Tiseo, M. Notch pathway in small-cell lung cancer: From preclinical evidence to therapeutic challenges. Cell. Oncol. 2019, 42, 261–273. [Google Scholar] [CrossRef]
- Tanaka, K.; Isse, K.; Fujihira, T.; Takenoyama, M.; Saunders, L.; Bheddah, S.; Nakanishi, Y.; Okamoto, I. Prevalence of Delta-like protein 3 expression in patients with small cell lung cancer. Lung Cancer 2018, 115, 116–120. [Google Scholar] [CrossRef]
- Slaney, C.Y.; Wang, P.; Darcy, P.K.; Kershaw, M.H. CARs versus BiTEs: A Comparison between T Cell–Redirection Strategies for Cancer Treatment. Cancer Discov. 2018, 8, 924–934. [Google Scholar] [CrossRef] [Green Version]
- Saunders, L.R.; Bankovich, A.J.; Anderson, W.C.; Aujay, M.A.; Bheddah, S.; Black, K.; Desai, R.; Escarpe, P.A.; Hampl, J.; Laysang, A.; et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci. Transl. Med. 2015, 7, 302ra136. [Google Scholar] [CrossRef] [Green Version]
- Morgensztern, D.; Besse, B.; Greillier, L.; Santana-Davila, R.; Ready, N.; Hann, C.L.; Glisson, B.S.; Farago, A.F.; Dowlati, A.; Rudin, C.M.; et al. 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, 6958–6966. [Google Scholar] [CrossRef] [Green Version]
- Serzan, M.T.; Farid, S.; Liu, S.V. Drugs in development for small cell lung cancer. J. Thorac. Dis. 2020, 12, 6298–6307. [Google Scholar] [CrossRef]
- Calles, A.; Aguado, G.; Sandoval, C.; Álvarez, R. The role of immunotherapy in small cell lung cancer. Clin. Transl. Oncol. 2019, 21, 961–976. [Google Scholar] [CrossRef] [PubMed]
- Saltos, A.; Shafique, M.; Chiappori, A.A. Update on the Biology, Management, and Treatment of Small Cell Lung Cancer (SCLC). Front. Oncol. 2020, 10, 1074. [Google Scholar] [CrossRef] [PubMed]
- Schmidt, M.; Hagner, N.; Marco, A.; König-Merediz, S.A.; Schroff, M.; Wittig, B. Design and Structural Requirements of the Potent and Safe TLR-9 Agonistic Immunomodulator MGN1703. Nucleic Acid Ther. 2015, 25, 130–140. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thomas, M.; Ponce-Aix, S.; Navarro, A.; Riera-Knorrenschild, J.; Schmidt, M.; Wiegert, E.; Kapp, K.; Wittig, B.; Mauri, C.; Gómez, M.D.; et al. Immunotherapeutic maintenance treatment with toll-like receptor 9 agonist lefitolimod in patients with extensive-stage small-cell lung cancer: Results from the exploratory, controlled, randomized, international phase II IMPULSE study. Ann. Oncol. 2018, 29, 2076–2084. [Google Scholar] [CrossRef]
- Koyama, S.; Akbay, E.A.; Li, Y.Y.; Herter-Sprie, G.S.; Buczkowski, K.A.; Richards, W.G.; Gandhi, L.; Redig, A.J.; Rodig, S.J.; Asahina, H.; et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun. 2016, 7, 10501. [Google Scholar] [CrossRef] [PubMed]
- Qin, S.; Xu, L.; Yi, M.; Yu, S.; Wu, K.; Luo, S. Novel immune checkpoint targets: Moving beyond PD-1 and CTLA-4. Mol. Cancer 2019, 18, 1–14. [Google Scholar] [CrossRef]
- Friedlaender, A.; Addeo, A.; Banna, G. New emerging targets in cancer immunotherapy: The role of TIM3. ESMO Open 2019, 4, e000497. [Google Scholar] [CrossRef] [Green Version]
- Uboha, N.V.; Milhem, M.M.; Kovacs, C.; Amin, A.; Magley, A.; Das Purkayastha, D.; Piha-Paul, S.A. Phase II study of spartalizumab (PDR001) and LAG525 in advanced solid tumors and hematologic malignancies. J. Clin. Oncol. 2019, 37, 2553. [Google Scholar] [CrossRef]
- Chauvin, J.-M.; Zarour, H.M. TIGIT in cancer immunotherapy. J. Immunother. Cancer 2020, 8, e000957. [Google Scholar] [CrossRef]
- Wrangle, J.M.; Velcheti, V.; Patel, M.R.; Garrett-Mayer, E.; Hill, E.G.; Ravenel, J.G.; Miller, J.S.; Farhad, M.; Anderton, K.; Lindsey, K.; et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: A non-randomised, open-label, phase 1b trial. Lancet Oncol. 2018, 19, 694–704. [Google Scholar] [CrossRef]
- Thomas, A.; Vilimas, R.; Trindade, C.; Erwin-Cohen, R.; Roper, N.; Xi, L.; Krishnasamy, V.; Levy, E.; Mammen, A.; Nichols, S.; et al. Durvalumab in Combination with Olaparib in Patients with Relapsed SCLC: Results from a Phase II Study. J. Thorac. Oncol. 2019, 14, 1447–1457. [Google Scholar] [CrossRef] [PubMed]
- Cummings, A.L.; Kim, D.D.-Y.; Rosen, L.S.; Garon, E.B.; Wainberg, Z.A.; Slamon, D.J.; Goldman, J.W. A phase Ib/II study of niraparib plus temozolomide plus atezolizumab versus atezolizumab as maintenance therapy in extensive-stage small cell lung cancer (TRIO-US L-06). J. Clin. Oncol. 2020, 38, TPS9084. [Google Scholar] [CrossRef]
- Kim, C.; Liu, S.V.; Subramaniam, D.S.; Torres, T.; Loda, M.; Esposito, G.; Giaccone, G. Phase I study of the 177Lu-DOTA0-Tyr3-Octreotate (lutathera) in combination with nivolumab in patients with neuroendocrine tumors of the lung. J. Immunother. Cancer 2020, 8, e000980. [Google Scholar] [CrossRef] [PubMed]
Trial | Phase | No. of Patients | Treatment | FDA Approval | Primary Endpoint(s) (Met?) | PFS | OS | ORR (%) | Grade 3/4 Adverse Events (%) |
---|---|---|---|---|---|---|---|---|---|
IMpower133 (Horn et al.) | III | 403 | Atezolizumab + carboplatin/etoposide vs. carboplatin/etoposide | Yes | OS (yes) PFS (yes) | 5.2 vs. 4.3 months (HR 0.77, 95%CI 0.62–0.96, p = 0.02) | 12.3 vs. 10.3 months (HR 0.70, 95%CI 0.54–0.91, p = 0.007) | 60.2 vs. 64.4 | 56.6 vs. 56.1 |
CASPIAN * (Paz-Ares et al.) | III | 805 | Durvalumab + platinum/etoposide vs. platinum/etoposide | Yes | OS (yes) | 5.1 vs. 5.4 months (HR 0.78, 95% CI 0.65–0.94) | 13.0 vs. 10.3 months (HR 0.73, 95%CI 0.59–0.91, p = 0.0047) | 79 vs. 70 | 62 vs. 62 |
ECOG-ACRIN EA5161 (Leal et al.) | II | 160 | Nivolumab + platinum/etoposide vs. platinum/etoposide | No | PFS (yes) | 5.5 vs. 4.6 months (HR 0.65, 95%CI 0.46–0.91, p = 0.012) | 11.3 vs. 8.5 months (HR 0.67, 95%CI 0.46–0.98, p = 0.038) | 52.3 vs. 47.7 | 77 vs. 62 |
KEYNOTE-604 (Rudin et al.) | III | 453 | Pembrolizumab + platinum/etoposide vs. platinum/etoposide | No | OS (no) PFS (yes) | 4.5 vs. 4.3 months (HR 0.75, 95% CI 0.61–0.91, p = 0.0023) | 10.8 vs. 9.7 months (HR 0.80, 95%CI 0.64–0.98, p = 0.0164) | 70.6 vs. 61.8 | 76.7 vs. 74.9 |
CA184-156 (Reck et al.) | III | 1132 | Ipilimumab + platinum/etoposide vs. platinum/etoposide | No | OS (no) | 4.6 vs. 4.4 months (HR 0.85, 95%CI 0.75–0.97, p = 0.0161) | 11.0 vs. 10.9 months (HR 0.94, 95%CI 0.81–1.09, p = 0.3775) | 62 vs. 62 | 48 vs. 45 |
Trial | Phase | Status | Setting | Treatment | Primary Endpoint(s) | Target Enrolment | Start Date–Estimated Completion Date |
---|---|---|---|---|---|---|---|
Welsh et al. 2020 | I/II | Complete | Concurrent with CRT | Pembrolizumab + concurrent CRT | Safety: no grade 5 toxicity, pneumonitis 15%, esophagitis 42.5% * PFS was 19.7 months (95% CI 8.8–30.5) * OS was 39.5 months (95% CI 8.0–71.0) * ORR of 79% | 40 | Completed |
LU-005 (NCT03811002) | II/III | Ongoing | Concurrent with CRT | Atezolizumab + concurrent CRT vs. CRT | OS, PFS | 506 | 28 May 2019–28 December 2026 |
ACHILES (NCT03540420) | II | Ongoing | Maintenance after CRT | Atezolizumab vs. observation | 2-year survival | 212 | 31 July 2018–December 2026 |
ADRIATIC (NCT03703297) | III | Ongoing | Maintenance after CRT | Durvalumab vs. durvalumab + tremelimumab vs. placebo | OS, PFS | 724 | 27 September 2018–10 May 2024 |
STIMULI (NCT02046733) | II | Ongoing | Maintenance after CRT | Nivolumab + ipilimumab vs. observation | OS, PFS | 174 | 28 July 2014–January 2022 |
Type | Examples |
---|---|
CAR T cell therapy | AMG 119 (targeting DLL-3) |
Bispecific T cell engager | AMG 757 (targeting DLL-3) |
Antibody-drug conjugate | Rovalpituzumab tesirine (targeting DLL-3) |
Immunomodulators | Interleukin-2 Interferon Lefitolimod (TLR9 agonist) N-803 (interleukin-15 agonist) BNT411 (TLR7 agonist) |
Vaccine | Fucosyl GM-1 GD3 ganglioside Polysialic acid Dendritic cell-based p53 |
Immune checkpoint | TIM-3 LAG-3 TIGIT |
Small molecule | CDK4/6 inhibitor PARP inhibitor |
Alkylating agent | Lurbinectedin |
Other | Lutetium-labeled somatostatin analog |
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Wong, S.K.; Iams, W.T. Front Line Applications and Future Directions of Immunotherapy in Small-Cell Lung Cancer. Cancers 2021, 13, 506. https://doi.org/10.3390/cancers13030506
Wong SK, Iams WT. Front Line Applications and Future Directions of Immunotherapy in Small-Cell Lung Cancer. Cancers. 2021; 13(3):506. https://doi.org/10.3390/cancers13030506
Chicago/Turabian StyleWong, Selina K., and Wade T. Iams. 2021. "Front Line Applications and Future Directions of Immunotherapy in Small-Cell Lung Cancer" Cancers 13, no. 3: 506. https://doi.org/10.3390/cancers13030506