Download PDF
Semin Respir Crit Care Med 2020; 41(03): 360-368
DOI: 10.1055/s-0039-3399578
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Immunotherapy and Radiation Therapy for Non-Small Cell Lung Cancer—A Stimulating Partnership

Ritchell van Dams
1   Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California
,
Ye Yuan
1   Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California
,
Clifford G. Robinson
2   Department of Radiation Oncology, Washington University School of Medicine in St. Louis, St. Louis, Missouri
,
Percy Lee
3   Thoracic Radiation Oncology, Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
› Author Affiliations
Further Information

Publication History

Publication Date:
25 May 2020 (online)

    Permissions and Reprints

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.

Keywords

non-small cell lung cancer - NSCLC - SBRT - Immunotherapy - biologics
 

  • 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
    PubMed
  • 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
    PubMed
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMed
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 17 Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22 (01) 329-360
    CrossrefPubMedGoogle Scholar
  • 18 Girardi M, Oppenheim DE, Steele CR. , et al. Regulation of cutaneous malignancy by γδ T cells. J Immunol 2018; 200 (09) 3031-3035
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 22 Khong HT, Restifo NP. Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat Immunol 2002; 3 (11) 999-1005
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 25 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12 (04) 252-264
    CrossrefPubMedGoogle Scholar
  • 26 Ribas A. Releasing the brakes on cancer immunotherapy. N Engl J Med 2015; 373 (16) 1490-1492
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 30 Eriksson D, Stigbrand T. Radiation-induced cell death mechanisms. Tumour Biol 2010; 31 (04) 363-372
    CrossrefPubMedGoogle Scholar
  • 31 Galluzzi L, Maiuri MC, Vitale I. , et al. Cell death modalities: classification and pathophysiological implications. Cell Death Differ 2007; 14 (07) 1237-1243
    CrossrefPubMedGoogle Scholar
  • 32 Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol 2015; 25 (01) 11-17
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 34 Park SS, Dong H, Liu X. , et al. PD-1 restrains radiotherapy-induced abscopal effect. Cancer Immunol Res 2015; 3 (06) 610-619
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 38 Demaria S, Formenti SC. Radiation as an immunological adjuvant: current evidence on dose and fractionation. Front Oncol 2012; 2: 153
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 44 Timmerman RD, Forster KM, Chinsoo Cho L. Extracranial stereotactic radiation delivery. Semin Radiat Oncol 2005; 15 (03) 202-207
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMed
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar