BACKGROUND/AIM: The aim of this study was to investigate possible association between adverse events of nivolumab therapy and the effectiveness of treatment in patients with non-small cell lung cancer (NSCLC). Focusing on serious adverse events (i.e., those of grade ≥3), we evaluated overall survival (OS), progression-free survival (PFS), as well as objective response rate (ORR) to treatment. PATIENTS AND METHODS: We retrospectively analyzed a set of patients from the TULUNG database of NSCLC treated with nivolumab in eight oncology centers. We evaluated OS data based upon this set. To reduce possible bias, we further evaluated a subgroup of patients treated at the University Hospital in Pilsen, where the occurrence of adverse events, PFS, and ORR were independently examined by two experienced physicians. Survival statistics were evaluated using the Kaplan-Meier method and Cox analysis. RESULTS: We observed significantly greater OS, PFS, and ORR in the group of patients experiencing adverse events upon nivolumab treatment versus in those patients without such events. Although the univariable model analyzing the data set of all patients demonstrated higher OS in patients with serious adverse events, only a nonsignificant trend was observed in the Cox multivariable model. In a subgroup of patients with PFS and ORR evaluation, we did observe significant, favorable effects for patients having had serious adverse effects. CONCLUSION: Patients experiencing severe adverse events show a tendency toward better OS, PFS, and ORR compared to patients without or having only mild adverse events with nivolumab treatment.

BMS Czech Republic Prague Czech Republic

Department of Oncology 1st Faculty of Medicine Prague Charles University Prague Czech Republic

Department of Pneumology 2nd Faculty of Medicine and Motol University Hospital Charles University Prague Czech Republic

Department of Pneumology 3rd Faculty of Medicine and Bulovka University Hospital Charles University Prague Czech Republic

Department of Pneumology and Phthisiology Charles University Faculty of Medicine in Pilsen University Hospital in Pilsen Pilsen Czech Republic

Department of Pneumology and Phthisiology Charles University Faculty of Medicine in Pilsen University Hospital in Pilsen Pilsen Czech Republic;

Department of Pneumology Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czech Republic

Department of Respiratory Diseases Faculty of Medicine Masaryk University Brno Czech Republic

Department of Respiratory Medicine Faculty of Medicine Palacky University Olomouc Czech Republic

Department of Respiratory Medicine Thomayer Hospital Prague Czech Republic

Institute of Biostatistics and Analyses Ltd Brno Czech Republic

Laboratory of Cancer Treatment and Tissue Regeneration Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

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Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A, Bruno DS, Chang JY, Chirieac LR, D’Amico TA, Dilling TJ, Dowell J, Gettinger S, Gubens MA, Hegde A, Hennon M, Lackner RP, Lanuti M, Leal TA, Lin J, Loo BW Jr, Lovly CM, Martins RG, Massarelli E, Morgensztern D, Ng T, Otterson GA, Patel SP, Riely GJ, Schild SE, Shapiro TA, Singh AP, Stevenson J, Tam A, Yanagawa J, Yang SC, Gregory KM, Hughes M. NCCN guidelines insights: Non-small cell lung cancer, version 2.2021. J Natl Compr Canc Netw. 2021;19(3):254–266. doi: 10.6004/jnccn.2021.0013. PubMed DOI

Bassanelli M, Sioletic S, Martini M, Giacinti S, Viterbo A, Staddon A, Liberati F, Ceribelli A. Heterogeneity of PD-L1 expression and relationship with biology of NSCLC. Anticancer Res. 2018;38(7):3789–3796. doi: 10.21873/anticanres.12662. PubMed DOI

Fiala O, Pesek M, Finek J, Krejci J, Ricar J, Bortlicek Z, Benesova L, Minarik M. Skin rash as useful marker of erlotinib efficacy in NSCLC and its impact on clinical practice. Neoplasma. 2012;60(01):26–32. doi: 10.4149/neo_2013_004. PubMed DOI

Assi H, Wilson KS. Immune toxicities and long remission duration after ipilimumab therapy for metastatic melanoma: two illustrative cases. Curr Oncol. 2013;20(2):e165–e169. doi: 10.3747/co.20.1265. PubMed DOI PMC

Booka E, Kikuchi H, Haneda R, Soneda W, Kawata S, Murakami T, Matsumoto T, Hiramatsu Y, Takeuchi H. Impact of immune-related adverse events on nivolumab efficacy in patients with upper gastrointestinal cancer. In Vivo. 2021;35(4):2321–2326. doi: 10.21873/invivo.12506. PubMed DOI PMC

Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in resected and unresectable metastatic melanoma: Characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016;22(4):886–894. doi: 10.1158/1078-0432.CCR-15-1136. PubMed DOI PMC

Ishihara H, Takagi T, Kondo T, Homma C, Tachibana H, Fukuda H, Yoshida K, Iizuka J, Kobayashi H, Okumi M, Ishida H, Tanabe K. Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. Urol Oncol. 2019;37(6):355.e21–355.e29. doi: 10.1016/j.urolonc.2019.03.003. PubMed DOI

Maeda T, Yoshino K, Nagai K, Oaku S, Kato M, Hiura A, Hata H. Development of endocrine immune-related adverse events and improved survival in advanced melanoma patients treated with nivolumab monotherapy. Eur J Cancer. 2019;115:13–16. doi: 10.1016/j.ejca.2019.04.005. PubMed DOI

Kobayashi K, Iikura Y, Hiraide M, Yokokawa T, Aoyama T, Shikibu S, Hashimoto K, Suzuki K, Sato H, Sugiyama E, Tajima M, Hama T. Association between immune-related adverse events and clinical outcome following nivolumab treatment in patients with metastatic renal cell carcinoma. In Vivo. 2020;34(5):2647–2652. doi: 10.21873/invivo.12083. PubMed DOI PMC

Hussaini S, Chehade R, Boldt RG, Raphael J, Blanchette P, Maleki Vareki S, Fernandes R. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors - A systematic review and meta-analysis. Cancer Treat Rev. 2021;92:102134. doi: 10.1016/j.ctrv.2020.102134. PubMed DOI

Zhao Z, Wang X, Qu J, Zuo W, Tang Y, Zhu H, Chen X. Immune-related adverse events associated with outcomes in patients with NSCLC treated with anti-PD-1 inhibitors: A systematic review and meta-analysis. Front Oncol. 2021;11:708195. doi: 10.3389/fonc.2021.708195. PubMed DOI PMC

Haratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato R, Kaneda H, Hasegawa Y, Tanaka K, Takeda M, Nakagawa K. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol. 2018;4(3):374–378. doi: 10.1001/jamaoncol.2017.2925. PubMed DOI PMC

Ricciuti B, Genova C, De Giglio A, Bassanelli M, Dal Bello MG, Metro G, Brambilla M, Baglivo S, Grossi F, Chiari R. Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis. J Cancer Res Clin Oncol. 2019;145(2):479–485. doi: 10.1007/s00432-018-2805-3. PubMed DOI PMC

Sato K, Akamatsu H, Murakami E, Sasaki S, Kanai K, Hayata A, Tokudome N, Akamatsu K, Koh Y, Ueda H, Nakanishi M, Yamamoto N. Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab. Lung Cancer. 2018;115:71–74. doi: 10.1016/j.lungcan.2017.11.019. PubMed DOI

Toi Y, Sugawara S, Kawashima Y, Aiba T, Kawana S, Saito R, Tsurumi K, Suzuki K, Shimizu H, Sugisaka J, Ono H, Domeki Y, Terayama K, Nakamura A, Yamanda S, Kimura Y, Honda Y. Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab. Oncologist. 2018;23(11):1358–1365. doi: 10.1634/theoncologist.2017-0384. PubMed DOI PMC

Guezour N, Soussi G, Brosseau S, Abbar B, Naltet C, Vauchier C, Poté N, Hachon L, Namour C, Khalil A, Trédaniel J, Zalcman G, Gounant V. Grade 3-4 immune-related adverse events induced by immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) patients are correlated with better outcome: A real-life observational study. Cancers (Basel) 2022;14(16):3878. doi: 10.3390/cancers14163878. PubMed DOI PMC

Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45(2):228–247. doi: 10.1016/j.ejca.2008.10.026. PubMed DOI

Bisschop C, Wind TT, Blank CU, Koornstra RH, Kapiteijn E, Van Den Eertwegh AJ, De Groot JWB, Jalving M, Hospers GA. Association between pembrolizumab-related adverse events and treatment outcome in advanced melanoma: results from the dutch expanded access program. J Immunother. 2019;42(6):208–214. doi: 10.1097/CJI.0000000000000271. PubMed DOI

Shankar B, Zhang J, Naqash AR, Forde PM, Feliciano JL, Marrone KA, Ettinger DS, Hann CL, Brahmer JR, Ricciuti B, Owen D, Toi Y, Walker P, Otterson GA, Patel SH, Sugawara S, Naidoo J. Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer. JAMA Oncol. 2020;6(12):1952–1956. doi: 10.1001/jamaoncol.2020.5012. PubMed DOI PMC

Wang W, Gu X, Wang L, Pu X, Feng H, Xu C, Lou G, Shao L, Xu Y, Wang Q, Wang S, Gao W, Zhang Y, Song Z. The prognostic impact of mild and severe immune-related adverse events in non-small cell lung cancer treated with immune checkpoint inhibitors: a multicenter retrospective study. Cancer Immunol Immunother. 2022;71(7):1693–1703. doi: 10.1007/s00262-021-03115-y. PubMed DOI PMC

Xing P, Zhang F, Wang G, Xu Y, Li C, Wang S, Guo Y, Cai S, Wang Y, Li J. Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO+IPI: a systematic review and meta-analysis. J Immunother Cancer. 2019;7(1):341. doi: 10.1186/s40425-019-0779-6. PubMed DOI PMC

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 CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–1639. doi: 10.1056/NEJMoa1507643. PubMed DOI PMC

Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, 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(2):123–135. doi: 10.1056/NEJMoa1504627. PubMed DOI PMC

Owen DH, Wei L, Bertino EM, Edd T, Villalona-Calero MA, He K, Shields PG, Carbone DP, Otterson GA. Incidence, risk factors, and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer. Clin Lung Cancer. 2018;19(6):e893–e900. doi: 10.1016/j.cllc.2018.08.008. PubMed DOI PMC

Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60. doi: 10.1016/j.ctrv.2016.02.001. PubMed DOI