Will neo-adjuvant immunotherapy become a new paradigm in the treatment of lung cancer patients

Nowadays neoadjuvant immunotherapy is one of the main research areas in oncology. This interest is supported by the success of check-point inhibitors in treatment of advanced and metastatic lung cancer. The postulate that neoadjuvant immunotherapy achieves tumor devitalization before surgery is confirmed by a morphological assessment of surgical material with a gradation of the antitumor effect. In addition to affecting directly to the tumor, it also affects at potential micrometastases. A morphological assessment  with a gradation of the antitumor effect (MPR – a major pathomorphological response, CPR – a complete pathomorphological response) provides a unique opportunity to identify predictors of effectiveness and adjust the treatment tactic. A major morphological response (MPR – less than 10% of viable tumor cells in the tumor tissue) is associated with better overall survival. Currently, there is evidence that the appointment of neoadjuvant immunotherapy in mono mode allows you to achieve MPR in 18–45%, and the use of a combination of immunotherapy with chemotherapy increases it to 32–92%. Neoadjuvant immunotherapy or combination with chemotherapy does not postpone surgical treatment but allows us to achieve the better result.

neoadjuvant immunotherapy, non-small cell lung cancer, checkpoint inhibitors

1. Eberhardt W.E., Mitchell A., Crowley J., Kondo H., Kim Y.T., Turrisi A. 3rd, Goldstraw P., RamiPorta R. The IASLC Lung Cancer Staging Project: proposals for the revision of the M descriptors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2015;10(11):1515-22. doi: 10.1097/JTO.0000000000000673.

2. Asamura H., Chansky K., Crowley J., Goldstraw P., Rusch V.W., Vansteenkiste J., et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;(10):1675–1684. doi: 10.1097/JTO.0000000000000678.

3. Rami-Porta R., Bolejack V., Crowley J., Ball D., Kim J., Lyons G., et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;(10):990–1003. doi: 10.1097/JTO.0000000000000559.

4. Hilaris B.S., Gomez J., Nori D., Anderson L.L., Martini N. Combined surgery, intraoperative brachytherapy, and postoperative external radiation in stage III non-small cell lung cancer. Cancer. 1985;(55):1226–1231. doi: 10.1002/1097-0142(19850315)55:6<1226::aidcncr2820550614>3.0.co;2-6.

5. Faber L.P., Kittle C.F., Warren W.H., Bonomi P.D., Taylor S.G. 4th, Reddy S., Lee M.S. Preoperative chemotherapy and irradiation for stage III non-small cell lung cancer. Ann Thorac Surg. 1989;(47):669–675; discussion 676-667. doi: 10.1016/0003-4975(89)90115-x.

6. Rosell R., Gomez-Codina J., Camps C., Maestre J., Padille J., Cantó A., 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):153–158. doi: 10.1056/NEJM199401203300301.

7. Roth J.A., Fossella F., Komaki R., Ryan M.B., Putnam J.B. Jr., Lee J.S., 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):673–680. doi: 10.1093/jnci/86.9.673.

8. Pisters K.M., Vallieres E., Crowley J.J., Franklin W.A., Bunn P.A. Jr, Ginsberg R.J., Putnam J.B. Jr., Chansky K., Gandara D. Surgery with or without preoperative paclitaxel and carboplatin in earlystage non–small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial. J Clin Oncol. 2010;(28):1843–1849. doi: 10.1200/JCO.2009.26.1685.

9. Felip E., Rosell R., Maestre J.A., RodríguezPaniagua J.M., Morán T., Astudillo J., Alonso G. et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-smallcell lung cancer. J Clin Oncol. 2010;(28):3138–3145. doi: 10.1200/JCO.2009.27.6204.

10. Scagliotti G.V., Pastorino U., Vansteenkiste J.F., Spaggiari L., Facciolo F., Orlowski T.M., et al. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non–smallcell lung cancer. J Clin Oncol. 2012;(30):172–178. doi: 10.1200/JCO.2010.33.7089.

11. Burdett S., Stewart L., Auperin A., Pignon J.P. Chemotherapy in non–small-cell lung cancer: an update of an individual patient data metaanalysis. J Clin Oncol. 2005; (23):924–925. author reply 925-926. doi: 10.1200/JCO.2008.17.7162.

12. Garon E.B., Hellmann M.D., Costa E.C., et al. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001. J Clin Oncol. 2019 (suppl; abstr LBA9015). doi: 10.1200/JCO.2019.37.18_suppl.LBA9015.

13. Brahmer J., Borghaei H., Ramalingam S.S., Horn L., Holgado E., Pluzanski A., Burgioet M. et al. Abstract CT195: Long-term survival outcomes with nivolumab (NIVO) in pts with previously treated advanced non-small cell lung cancer (NSCLC): Impact of early disease control and response. Conference: Proceedings: AACR Annual Meeting. 2019; March 29-April 3, 2019; Atlanta, GA. doi: 10.1158/1538-7445.AM2019-CT195.

14. Horn L., Gettinger S., Gordon M., Herbst R., Gandhi L., Felip E. et al. Safety and clinical activity of atezolizumab monotherapy in metastatic non-small-cell lung cancer: final results from a phase I study. European Journal of Cancer. 2018;(101):201-209. doi: 10.1016/j.ejca.2018.06.031.

15. Chen D.S., Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1-10. doi: 10.1016/j.immuni.2013.07.012.

16. Rusch V., Chaft J., Johnson B., Wistuba I., Kris M., Lee J. et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Initial results from a multicenter study (LCMC3). Journal of Clinical Oncology. 2018;36(15_suppl):8541-8541. doi: 10.1200/JCO.2018.36.15_suppl.8541.

17. Cascone T., William W.N., Weissferdt A., Leung C.H., Federico L., Haymaker C. et al. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study. J Clin Oncol. 2019;(37S):ASCO#8504. doi: 10.1200/JCO.2019.37.15_suppl.8504.

18. Forde P.M., Chaft J.E., Smith K.N., Anagnostou V., Cottrell T., Hellmann M., Zahurak M., Yang S. et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018;378(21):1976-1986. doi: 10.1056/NEJMoa1716078.

19. Chaft J.E., Rusch V., Ginsberg M.S., Paik P.K., Finley D.J., Kris M.G., et al. Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers. J Thorac Oncol. 2013;8(8):1084-1090. doi: 10.1097/JTO.0b013e31829923ec.

20. Provencio M., Nadal E., Insa A., García Campelo R., Huidobro G., Domine M. et al. WCLC 2018 Abstract OA01.05. Available at: https://adisinsight.springer.com/trials/700281155.

21. Shu C., Grigg C., Chiuzan C., Garofano R., Patel V., Hernandezet S. et al. Neoadjuvant atezolizumab + chemotherapy in resectable nonsmall cell lung cancer (NSCLC). Journal of Clinical Oncology. 2018;36(15_suppl):8532-8532. doi: 10.1200/JCO.2018.36.15_suppl.8532