Radiotherapy could increase the efficacy of immunotherapy in non-small cell lung cancer

Abstract

Background: In non-small cell lung cancer (NSCLC), immunotherapy is a treatment option in patients without targetable mutations in second and later lines. Nevertheless, there is no validated test that can predict immunotherapy response. Material and Methods: Our study aimed to investigate the effect of radiotherapy (RT) on survival in patients with NSCLC receiving immunotherapy after first-line chemotherapy. Twenty-five patients diagnosed with NSCLC and received immunotherapy after at least one previous chemotherapy line were included in our study. Results: The median age of the patients was 61.7 (26.6-81.2) years. 19 (76%) patients were male. 11 (44%) of the patients had received immunotherapy in the second-line and 14 (66%) in ≥3 lines. Patients had received a median of 5 cycles (1-27) of immunotherapy. RT to immunotherapy interval was 6.4 months (1.0-11.8). Partial response was observed in 12 patients, stable disease in 8 patients, progression in 1 patient, and hyperprogression in 4 patients. Median progression-free survival (PFS) was 4.4 months (95% CI; 3.2-5.6), and median overall survival (OS) was 16.4 months (95% CI; 5.6-27.3). 14 (56%) of the patients had received RT. RT was administered to 12 patients before immunotherapy, and two patients received RT to bones during immunotherapy. The patients who received RT had statistically longer PFS (4.9 vs 3.9 months, p=0.012) and OS (18.7 vs 7.3 months, p=0.023) comparing those without RT. Conclusions: Our findings showed that RT significantly improved the survival in patients who received immunotherapy, pointing that RT may have an influential role in immunotherapy response.

Keywords

• Immunotherapy
• radiotherapy
• efficacy
• non-small cell lung cancer.

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424. doi: 10.3322/ caac.21492.
2. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non- small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83:584-94. doi: 10.4065/83.5.584.
3. National Comprehensive Cancer Network. Non–small cell lung cancer (Version 5.2021). Available at: https://www.nccn.org/ professionals/physician_gls/pdf/nscl.pdf. Accessed June 20, 2021.
4. Wang C, Thudium KB, Han M, Wang XT, Huang H,Feingersh D, Garcia C, Wu Y, Kuhne M, Srinivasan M, Singh S, Wong S, Garner N, Leblanc H, Bunch RT, Blanset D, Selby MJ, Korman AJ. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non- human primates. Cancer Immunol Res. 2014;2:846-56. doi: 10.1158/2326-6066.CIR-14-0040.
5. Fessas P, Lee H, Ikemizu S, Janowitz T. A molecular and preclinical comparison of the PD-1–targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab. Semin Oncol. 2017;44:136-40. doi: 10.1053/j.seminoncol.2017.06.002.
6. Chen DS, Irving BA, Hodi FS. Molecular pathways: next- generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-7. doi: 10.1158/1078-0432.CCR-12-1362.
7. Gettinger S, Herbst RS. B7-H1/PD-1 blockade therapy in non– small cell lung cancer: current status and future direction. Cancer J. 2014;20:281-9. doi: 10.1097/PPO.0000000000000063.
8. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, , Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatiaet S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-65. doi: 10.1056/ NEJMoa1200694.

9. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-54. doi: 10.1056/ NEJMoa1200690.
10. Herbst RS, Soria J-C, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HEK, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563- 7. doi:10.1038/nature14011.
11. Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, Reck M, Van Schil PE, Hellmann MD, Peters S. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv192-iv237. doi:10.1093/annonc/mdy275.
12. Mole R. Whole body irradiation—radiobiology or medicine? Br J Radiol. 1953;26:234-41.
13. Theelen WSME, Peulen HMU, Lalezari F, van der Noort V, de Vries JF, Aerts JGJV, Dumoulin DW, Bahce I, Niemeijer ALN, de Langen AJ, Monkhorst K, Baas P. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non- Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019;5:1276-82. doi:10.1001/jamaoncol.2019.1478.
14. Kato S, Goodman A, Walavalkar V, Sharabi A, Kurzrock R. Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clin Cancer Res. 2017;23:4242-50. doi: 10.1158/1078-0432.CCR-16- 3133.
15. Formenti SC, Demaria S. Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys. 2012;84:879-80. doi:10.1016/j.ijrobp.2012.06.020.
16. Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol. 2015;1:1325-32. doi:10.1001/jamaoncol.2015.2756.
17. Schaue D, Comin-Anduix B, Ribas A, Zhang L, Goodglick L, Sayre JW, Debucquoy A, Haustermans K, McBride WH. T-cell responses to survivin in cancer patients undergoing radiation therapy. Clin Cancer Res. 2008;14:4883-90. doi:10.1158/1078- 0432.CCR-07-4462.
18. Vanpouille-Box C, Diamond JM, Pilones KA, Zavadil J, Babb JS, Formenti SC, Barcellos-Hoff MH, Demaria S. TGFβ is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res. 2015;75:2232-42. doi: 10.1158/0008- 5472.CAN-14-3511.
19. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687-95. doi: 10.1172/JCI67313.
20. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, Stratford IJ, Poon E, Morrow M, Stewart R, Jones H, Wilkinson RW, Honeychurch J, Illidge TM. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74:5458-68. doi: 10.1158/0008-5472.CAN-14-1258.
21. Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009;10:718-26. doi: 10.1016/ S1470-2045(09)70082-8.
22. Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, Formenti SC. 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;11:728-34.
23. Gong X, Li X, Jiang T, Xie H, Zhu Z, Zhou F, Zhou C. Combined radiotherapy and anti–PD-L1 antibody synergistically enhances antitumor effect in non–small cell lung cancer. J Thorac Oncol. 2017;12:1085-97. https://doi.org/10.1016/j.jtho.2017.04.014.
24. Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, Garon EB, Lee P. 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;18:895-903. doi: 10.1016/S1470-2045(17)30380-7.
25. Norum J, Nieder C. Tobacco smoking and cessation and PD- L1 inhibitors in non-small cell lung cancer (NSCLC): a review of the literature. ESMO open. 2018;3:e000406. doi: 10.1136/ esmoopen-2018-000406.
26. Bozorgmehr F, Hommertgen A, Krisam J, Lasitschka F, Kuon J, Maenz M, Huber PE, König L, Kieser M, Debus J, Thomas M, Rieken S. Fostering efficacy of anti-PD-1-treatment: Nivolumab plus radiotherapy in advanced non-small cell lung cancer-study protocol of the FORCE trial. BMC Cancer. 2019 Nov 8;19(1):1074. doi: 10.1186/s12885-019-6205-0.
27. Tang C, Wang X, Soh H, Seyedin S, Cortez MA, Krishnan S, Massarelli E, Hong D, Naing A, Diab A, Gomez D, Ye H, Heymach J, Komaki R, Allison JP, Sharma P, Welsh JW. Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res. 2014;2:831-8. doi: 10.1158/2326-6066.CIR-14-0069.
28. Sarihan S. Immunoterapi ve radyoterapi kombinasyonu. Uludag Universitesi Tip Fakultesi Dergisi. 2020;46:225-35. doi: 10.32708/uutfd.710919.
29. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:255- 65. doi: 10.1016/S0140-6736(16)32517-X.
30. Herbst RS, Baas P, Kim D-W, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro Jr G, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540-50. doi: 10.1016/S0140-6736(15)01281-7.
31. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Frontera OA, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med. 2015;373:123-35. doi: 10.1056/ NEJMoa1504627.
32. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CN, Rizvi N, Crinò L, Blumenschein Jr GR, Antonia SJ, Dorange C, Harbison CT, Finckenstein GF, Brahmeret JR. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. 2015;373:1627-39, doi: 10.1056/ NEJMoa1507643.
33. Martinov T, Fife BT. Fractionated radiotherapy combined with PD-1 pathway blockade promotes CD8 T cell-mediated tumor clearance for the treatment of advanced malignancies. Ann Transl Med. 2016;4:82. doi: 10.3978/j.issn.2305-5839.2016.01.13.