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DOI: 10.1055/s-0039-3399578
Immunotherapy and Radiation Therapy for Non-Small Cell Lung Cancer—A Stimulating Partnership
Publication History
Publication Date:
25 May 2020 (online)
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Abstract
Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer and the leading cause of cancer-related death. Although durable local control rates are high after surgical resection or definitive radiotherapy for early-stage disease, a substantial proportion of these patients eventually experience regional and/or distant failure and succumb to their metastatic disease. The discovery of immunotherapeutics and targeted biologics has revolutionized the treatment of locally advanced and metastatic disease, improving progression-free and overall survival when incorporated with the current standards of care. Notably, post-hoc analyses and early clinical trials provide a growing body of evidence to support a synergistic effect between radiation and immunotherapy for the treatment of NSCLC from early-stage to metastatic disease. Radiotherapy appears to be capable of not only potentiating the effect of immunotherapy in targeted lesions, but also eliciting an antitumor response in distant lesions without any direct exposure to radiation. This review explores the biologic basis of immunotherapy, targeted biologics, and radiotherapy as well as the preclinical and clinical data that support the combined use of radioimmunotherapy for early-stage, locally advanced, and metastatic NSCLC.
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References
- 1 American Cancer Society. . Cancer facts & figures 2018 . Available at: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2018.html . Accessed April 5, 2019
- 2 National Cancer Institute. . SEER cancer stat facts: lung and bronchus cancer. Available at: https://seer.cancer.gov/statfacts/html/lungb.html . Accessed April 5, 2019
- 3 Aberle DR, Adams AM, Berg CD. , et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365 (05) 395-409
- 4 National Comprehensive Cancer Network. . Non-small cell lung cancer (version 3. 2019). Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf . Accessed March 28, 2019
- 5 Curran Jr WJ, Paulus R, Langer CJ. , et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 2011; 103 (19) 1452-1460
- 6 Aupérin A, Le Péchoux C, Rolland E. , et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010; 28 (13) 2181-2190
- 7 Antonia SJ, Villegas A, Daniel D. , et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018; 379 (24) 2342-2350
- 8 Reck M, Rodríguez-Abreu D, Robinson AG. , et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016; 375 (19) 1823-1833
- 9 Gandhi L, Rodríguez-Abreu D, Gadgeel S. , et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378 (22) 2078-2092
- 10 Theelen W, H.Peulen@Nki.Nl NF Lalezari F. , et al. Randomized phase II study of pembrolizumab after stereotactic body radiotherapy (SBRT) versus pembrolizumab alone in patients with advanced non-small cell lung cancer: the PEMBRO-RT study. J Clinic Oncol 2018; 36 (15 Suppl): 9023
- 11 Palma DA, Olson R, Harrow S. , et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet 2019; 393 (10185): 2051-2058
- 12 Soria J-C, Ohe Y, Vansteenkiste J. , et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378 (02) 113-125
- 13 Sandler A, Gray R, Perry MC. , et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355 (24) 2542-2550
- 14 Spigel DR, Hainsworth JD, Yardley DA. , et al. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol 2010; 28 (01) 43-48
- 15 Socinski MA, Stinchcombe TE, Moore DT. , et al. Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small-cell lung cancer: results of a phase I/II trial. J Clin Oncol 2012; 30 (32) 3953-3959
- 16 Wozniak AJ, Moon J, Thomas Jr CR. , et al. A pilot trial of cisplatin/etoposide/radiotherapy followed by consolidation docetaxel and the combination of bevacizumab (NSC-704865) in patients with inoperable locally advanced stage III non-small-cell lung cancer: SWOG S0533. Clin Lung Cancer 2015; 16 (05) 340-347
- 17 Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22 (01) 329-360
- 18 Girardi M, Oppenheim DE, Steele CR. , et al. Regulation of cutaneous malignancy by γδ T cells. J Immunol 2018; 200 (09) 3031-3035
- 19 Smyth MJ, Crowe NY, Godfrey DI. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol 2001; 13 (04) 459-463
- 20 Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol 2010; 28 (01) 367-388
- 21 Formenti SC, Demaria S. Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys 2012; 84 (04) 879-880
- 22 Khong HT, Restifo NP. Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat Immunol 2002; 3 (11) 999-1005
- 23 Sakaguchi S, Sakaguchi N, Shimizu J. , et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001; 182 (01) 18-32
- 24 Rosenthal R, Cadieux EL, Salgado R. , et al; TRACERx consortium. Neoantigen-directed immune escape in lung cancer evolution. Nature 2019; 567 (7749): 479-485
- 25 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12 (04) 252-264
- 26 Ribas A. Releasing the brakes on cancer immunotherapy. N Engl J Med 2015; 373 (16) 1490-1492
- 27 Zou W, Wolchok JD, Chen L. PD-L1 (B7–H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med 2016; 8 (328) 328rv4
- 28 Lynch TJ, Bondarenko I, Luft A. , et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 2012; 30 (17) 2046-2054
- 29 Carbone DP, Reck M, Paz-Ares L. , et al; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017; 376 (25) 2415-2426
- 30 Eriksson D, Stigbrand T. Radiation-induced cell death mechanisms. Tumour Biol 2010; 31 (04) 363-372
- 31 Galluzzi L, Maiuri MC, Vitale I. , et al. Cell death modalities: classification and pathophysiological implications. Cell Death Differ 2007; 14 (07) 1237-1243
- 32 Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol 2015; 25 (01) 11-17
- 33 Demaria S, Kawashima N, Yang AM. , et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 2005; 11 (2, Pt 1): 728-734
- 34 Park SS, Dong H, Liu X. , et al. PD-1 restrains radiotherapy-induced abscopal effect. Cancer Immunol Res 2015; 3 (06) 610-619
- 35 Twyman-Saint Victor C, Rech AJ, Maity A. , et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520 (7547): 373-377
- 36 Filatenkov A, Baker J, Mueller AM. , et al. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin Cancer Res 2015; 21 (16) 3727-3739
- 37 Dewan MZ, Galloway AE, Kawashima N. , et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009; 15 (17) 5379-5388
- 38 Demaria S, Formenti SC. Radiation as an immunological adjuvant: current evidence on dose and fractionation. Front Oncol 2012; 2: 153
- 39 Ginsberg RJ, Rubinstein LV. ; Lung Cancer Study Group. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Ann Thorac Surg 1995; 60 (03) 615-622 , discussion 622–623
- 40 Wang L, Hayes S, Paskalev K. , et al. Dosimetric comparison of stereotactic body radiotherapy using 4D CT and multiphase CT images for treatment planning of lung cancer: evaluation of the impact on daily dose coverage. Radiother Oncol 2009; 91 (03) 314-324
- 41 Underberg RWM, Lagerwaard FJ, Cuijpers JP, Slotman BJ, van Sörnsen de Koste JR, Senan S. Four-dimensional CT scans for treatment planning in stereotactic radiotherapy for stage I lung cancer. Int J Radiat Oncol Biol Phys 2004; 60 (04) 1283-1290
- 42 Jang SS, Huh GJ, Park SY, Yang PS, Cho EY. The impact of respiratory gating on lung dosimetry in stereotactic body radiotherapy for lung cancer. Phys Med 2014; 30 (06) 682-689
- 43 Yin F-F, Wang Z, Yoo S. , et al. Integration of cone-beam CT in stereotactic body radiation therapy. Technol Cancer Res Treat 2008; 7 (02) 133-139
- 44 Timmerman RD, Forster KM, Chinsoo Cho L. Extracranial stereotactic radiation delivery. Semin Radiat Oncol 2005; 15 (03) 202-207
- 45 Rauschenbach BM, Mackowiak L, Malhotra HK. A dosimetric comparison of three-dimensional conformal radiotherapy, volumetric-modulated arc therapy, and dynamic conformal arc therapy in the treatment of non-small cell lung cancer using stereotactic body radiotherapy. J Appl Clin Med Phys 2014; 15 (05) 4898
- 46 Lee P, Loo Jr BW, Biswas T. , et al. Local control after stereotactic body radiation therapy for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2019 (e-pub ahead of print). doi:10.1016/j.ijrobp.2019.03.04
- 47 Timmerman R, Paulus R, Galvin J. , et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010; 303 (11) 1070-1076
- 48 Timmerman RD, Hu C, Michalski J. , et al. Long-term results of RTOG 0236: a phase II trial of stereotactic body radiation therapy (SBRT) in the treatment of patients with medically inoperable stage I non-small cell lung cancer. Int J Radiat Oncol 2014; 90 (01) S30
- 49 Nyman J, Hallqvist A, Lund J-Å. , et al. SPACE - A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC. Radiother Oncol 2016; 121 (01) 1-8
- 50 Ball D, Mai GT, Vinod S. , et al; TROG 09.02 CHISEL investigators. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol 2019; 20 (04) 494-503
- 51 Onishi H, Shirato H, Nagata Y. , et al. Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery?. Int J Radiat Oncol Biol Phys 2011; 81 (05) 1352-1358
- 52 Timmerman RD, Paulus R, Pass HI. , et al. Stereotactic body radiation therapy for operable early-stage lung cancer findings from the NRG oncology RTOG 0618 trial. JAMA Oncol 2018; 4 (09) 1263-1266
- 53 Zheng X, Schipper M, Kidwell K. , et al. Survival outcome after stereotactic body radiation therapy and surgery for stage I non-small cell lung cancer: a meta-analysis. Int J Radiat Oncol Biol Phys 2014; 90 (03) 603-611
- 54 Chang JY, Senan S, Paul MA. , et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol 2015; 16 (06) 630-637
- 55 Pignon J-P, Tribodet H, Scagliotti GV. , et al; LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26 (21) 3552-3559
- 56 Le Chevalier T, Dunant A, Arriagada R. , et al. Long-term results of the International Adjuvant Lung Cancer Trial (IALT) evaluating adjuvant cisplatin-based chemotherapy in resected non-small cell lung cancer (NSCLC). J Clin Oncol 2008; 26 (15) 7507-7507
- 57 Douillard J-Y, Rosell R, De Lena M, Riggi M, Hurteloup P, Mahe M-A. ; Adjuvant Navelbine International Trialist Association. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys 2008; 72 (03) 695-701
- 58 Burdett S, Stewart L. ; PORT Meta-analysis Group. Postoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data meta-analysis. Lung Cancer 2005; 47 (01) 81-83
- 59 Roth JA, Fossella F, Komaki R. , et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 1994; 86 (09) 673-680
- 60 Rosell R, Gómez-Codina J, Camps C. , et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994; 330 (03) 153-158
- 61 Rusch VW, Giroux DJ, Kraut MJ. , et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007; 25 (03) 313-318
- 62 Tsujino K, Kurata T, Yamamoto S. , et al. Is consolidation chemotherapy after concurrent chemo-radiotherapy beneficial for patients with locally advanced non-small-cell lung cancer? A pooled analysis of the literature. J Thorac Oncol 2013; 8 (09) 1181-1189
- 63 Albain KS, Swann RS, Rusch VW. , et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009; 374 (9687): 379-386
- 64 Gray JE, Villegas AE, Daniel DB. , et al. Three-year overall survival update from the PACIFIC trial. J Clinic Oncol 2019; 37 (15 Suppl): 8526
- 65 Antonia SJ, Villegas A, Daniel D. , et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017; 377 (20) 1919-1929
- 66 Topalian SL, Hodi FS, Brahmer JR. , et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366 (26) 2443-2454
- 67 Garon EB, Rizvi NA, Hui R. , et al; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372 (21) 2018-2028
- 68 Shaverdian N, Lisberg AE, Bornazyan K. , et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 2017; 18 (07) 895-903
- 69 Lisberg A, Garon EB. Does platinum-based chemotherapy still have a role in first-line treatment of advanced non-small-cell lung cancer?. J Clin Oncol 2019; 37 (07) 529-536
- 70 Mok TSK, Wu YL, Kudaba I. , et al; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019; 393 (10183): 1819-1830
- 71 FDA. . FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS ≥1%). Available at: https://www.fda.gov/drugs/fda-expands-pembrolizumab-indication-first-line-treatment-nsclc-tps-1 . Published 2019 . Accessed April 29, 2019
- 72 Formenti SC, Rudqvist N-P, Golden E. , et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med 2018; 24 (12) 1845-1851
- 73 Gomez DR, Tang C, Zhang J. , et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non–small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol 2019; 37 (18) 1558-1565