Research progress on application of the combination of radiotherapy and immune-checkpoint blockade in treatment of stage Ⅲ unresectable non-small cell lung cancer
Li Rutian1, Zhu Zhengfei2, Wang Lifeng1, Yan Jing1, Yan Yingtzu1, Liu Baorui1
1The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China; 2Department of Radiation Therapy,Cancer Hospital,Fudan University,Shanghai 200032,China
Abstract：Chemoradiation has been the standard treatment of stage Ⅲ unresectable non-small cell lung cancer (NSCLC) for a long period of time. However,the clinical efficacy of chemoradiation has not been significantly improved in recent two decades. In the past 2-3 years,the role of immune-checkpoint inhibitors in metastatic NSCLC has been persistently strengthened. Moreover,the synergistic effect between radiotherapy and immune-checkpoint blockade has been conformed in pre-clinical and clinical studies. Recent clinical trials have demonstrated that the combination of radiotherapy and immune-checkpoint blockade has been proven to be more effective in the treatment of stage Ⅲ unresectable NSCLC. In this article, the latest clinical studies since 2017 regarding the application value of this combined treatment of stage Ⅲ unresectable NSCLC were summarized.
Li Rutian,Zhu Zhengfei,Wang Lifeng et al. Research progress on application of the combination of radiotherapy and immune-checkpoint blockade in treatment of stage Ⅲ unresectable non-small cell lung cancer[J]. Chinese Journal of Radiation Oncology, 2019, 28(11): 872-875.
[1] NCCN. Clinical guidelines in oncology:non-small cell lung cancer[M].4 ed. Maryland:NCCN,2018. [2] Antonia SJ,Villegas A,Daniel D,et al. Durvalumab after chemoradiotherapy in stage Ⅲ non-small cell lung cancer[J]. N Engl J Med,2017,377(20):1919-1929. DOI:10.1056/NEJMoa1709937. [3] Durm GA,Althouse SK,Sadiq AA,et al. Phase Ⅱ trial of concurrent chemoradiation with consolidation pembrolizumab in patients with unresectable stage Ⅲ non-small cell lung cancer:hoosier cancer research network LUN 14-179,in 2018 ASCO annual meeting[C]. Chicago:ASCO,2018. [4] Liang J,Bi N,Wu S,et al. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage Ⅲ non-small cell lung cancer:a multicenter randomized phase Ⅲ trial[J]. Ann Oncol,2017,28(4):777-783. DOI:10.1093/annonc/mdx009. [5] Soria JC,Ohe Y,Vansteenkiste J,et al. Osimertinib in Untreated EGFR-mutated advanced non-small cell lung cancer[J]. N Engl J Med,2018,378(2):113-125. DOI:10.1056/NEJMoa1713137. [6] Camidge DR,Peters S,Mok T,et al. Updated efficacy and safety data from the global phase Ⅲ ALEX study of alectinib (ALC) vs. crizotinib (CZ) in untreated advanced ALK+ NSCLC,in 2018 ASCO annual meeting[C]. Chicago:ASCO,2018. [7] Hargadon KM,Johnson CE,Williams CJ. Immune checkpoint blockade therapy for cancer:an overview of FDA-approved immune checkpoint inhibitors[J]. Int Immunopharmacol,2018,62(1):29-39. DOI:10.1016/j.intim2018.06.001. [8] Peters SK,Kerr M,Stahel R. PD-1 blockade in advanced NSCLC:a focus on pembrolizumab[J]. Cancer Treat Rev,2018,62(1):39-49. DOI:10.1016/j.ctrv.2017.10.002. [9] Carbone DP,Reck M,Paz-Ares L,et al. First-line nivolumab in stage Ⅳ or recurrent non-small cell lung cancer[J]. N Engl J Med,2017,376(25):2415-2426. DOI:10.1056/NEJMoa1613493. [10] 朱鲁程,许雅思,夏冰,等. 肺癌放射敏感性标志物研究进展[J]. 中华放射肿瘤学杂志,2018,27(4):420-424. DOI:10.3760/cma.j.issn.1004-4221.2018.04.018. Zhu LC,Xu YS,Xia B,et al. Research progress on biomarkers in predicting radiosensitivity of non-small cell lung cancer[J]. Chin J Radiat Oncol,2018,27(4):420-424. DOI:10.3760/cma.j.issn.1004-4221.2018.04.018. [11] Deng L,Liang H,Burnette B,et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice[J]. J Clin Invest,2014,124(2):687-95. DOI:10.1172/JCI67313. [12] Dovedi SJ,Adlard AL,Lipowska-Bhalla G,et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade[J]. Cancer Res,2014,74(19):5458-6548. DOI:10.1158/0008-5472. CAN-14-1258. [13] Bernstein MB,Krishnan S,Hodge JW,et al. Immunotherapy and stereotactic ablative radiotherapy (ISABR):a curative approach?[J]. Nat Rev Clin Oncol,2016,13(8):516-524. DOI:10.1038/nrclinonc.2016.30. [14] 袁梦,门玉,惠周光. NSCLC放疗联合免疫治疗研究进展[J]. 中华放射肿瘤学杂志,2018,27(5):533-537. DOI:10.3760/cma.j.issn.1004-4221.2018.05.020. Yuan M,Men Y,Hui ZG. Research progress in radiotherapy combined with immunotherapy for non-small cell lung cancer[J]. Chin J Radiat Oncol,2018,27(5):533-537. DOI:10.3760/cma.j.issn.1004-4221.2018.05.020. [15] 张诗博,赵蔚,徐世东. 肺癌晚期免疫综合治疗的研究进展[J].癌症进展,2018,16(2):144-146. DOI:10.11877/j.issn.1672-1535.2018.16.02.04. Zhang Shibo, Zhao Wei, Xu Shidong. Advances in comprehensive immunotherapy for advanced lung cancer[J]. Oncol Prog,2018,16(2):144-146. DOI:10.11877/j.issn.1672-1535.2018.16.02.04. [16] Shaverdian NA,Lisberg E,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[J]. Lancet Oncol,2017,18(7):895-903. DOI:10.1016/s1470-2045(17)30380-7. [17] Antonia SJ, Villegas A, Daniel D,et al. Durvalumab after Chemoradiotherapy in Stage Ⅲ Non-Small-Cell Lung Cancer[J]. N Eng J Med,2017, 377(20):1919-1929. DOI:10.1056/NEJMoa1709937. [18] Antonia, S. J., A. Villegas, D. Daniel, et al., Overall Survival with Durvalumab after Chemoradiotherapy in Stage Ⅲ NSCLC. N Eng J Med, 2018. 379(24):2342-2350. DOI:10.1056/NEJMoa1809697. [19] Paz-Ares L,Villegas A,Daniel D,et al. Pacific:a double-blind,placebo-controlled phase Ⅲ study of durvalumab after chemoradiation therapy in patients with Stage Ⅲ,locally advanced,unresectable NSCLC,in 2017 ESMO[C]. Madrid:ESMO,2017. [20] Hui RM,Zguroglu O,Villegas A,et al. Time to deterioration of symptoms with durvalumab in stage Ⅲ,locally advanced,unresectable NSCLC:post-hoc analysis of PACIFIC patient-reported outcomes,in 2018 ELCC[C]. Geneva:ELCC,2018. [21] Doebele, R. et al. OA02.01 Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC)[J]. Journal of Thoracic Oncology, 2018, 13(10):S321-S322. DOI:10.1016/j.jtho.2018.08.239 [22] Gerber DE,Urbanic J,Langer C,et al. Treatment design and rationale for a randomized trial of cisplatin and etoposide plustThoracic radiotherapy followed by nivolumab or placebo for locally advanced non-small cell lung cancer (RTOG3505)[J]. Clin Lung Cancer,2017,18(3):333-339. DOI:10.1016/j.cllc.2016.10.009. [23] Hwang WL,Pike LRG,Royce TJ,et al. Safety of combining radiotherapy with immune-checkpoint inhibition[J]. Nat Rev Clin Oncol,2018,15(8):477-494. DOI:10.1038/s41571-018-0046-7. [24] Heinzerling L,Ott A,Hodi FS,et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy[J]. J Immunother Cancer,2016,4(1):50. DOI:10.1186/s40425-016-0152-y. [25] VarricchiG,Galdiero R,Marone G,et al. Cardiotoxicity of immune checkpoint inhibitors[J]. ESMO Open,2017,2(4):e000247. DOI:10.1136/esmoopen-2017-000247. [26] Peters SD,Ruysscher D,Dafni U,et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-RT regimen in unresectable locally advanced NSCLC:the ETOP NICOLAS phase Ⅱ trial.in 2018 ASCO[C]. Chicago:ASCO,2018. [27] Senan S,Brade A,Wang LH,et al. PROCLAIM:randomized phase Ⅲ trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small cell lung cancer[J]. J Clin Oncol,2016,34(9):953-962. DOI:10.1200/JCO.2015.64.8824. [28] Nakamura A,Inoue A,Morita S,et al. Phase Ⅲ study comparing gefitinib monotherapy (G) to combination therapy with gefitinib,carboplatin,and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009),in 2018 ASCO[C]. Chicago:ASCO,2018. [29] Faivre-Finn C. Efficacy and safety evaluation based on time from completion of radiotherapy to randomization with durvalumab or placebo in pts form PACIFIC,in 2018 ESMO[C]. Munich:ESMO,2018.
2019, Vol. 28 
