Patterns of immune-related adverse events in patients treated with immune checkpoint inhibitors: a Brazilian real-world analysis

ABSTRACT

Objectives: To report real-world data of a cohort of patients treated with immune-checkpoint inhibitors in Brazil, with focus in immune-related adverse events.

Material and Methods: In this retrospective study, we analyzed a cohort of patients with metastatic solid tumors treated at an oncology reference center with at least one dose of immune-checkpoint inhibitors (given as monotherapy or in combination with other agents). The safety profile was characterized through the incidence of adverse events, management and hospitalization.

Results: We included 185 patients. Immune-related adverse events were observed in 92 of the 185 study patients (49.7%), including 16 patients (8.6%) with such events of grade 3 or 4, and 28 patients (15.1%) requiring systemic corticosteroid therapy. Thyroid disorders (20%), rash (17.8%), pruritus (11.4%) and colitis (11.4%) were the most frequent immune-related adverse events. Five (2.7%) patients discontinued immune-checkpoint inhibitors and 15 (7.0%) were hospitalized due to immune-related adverse events. Development of immune-related adverse events and immune-checkpoint inhibitors used in the firstline setting were associated with prolonged progression-free survival and overall survival in the multivariate analysis. Moreover, age <75 years old and ECOG score 0 or 1 were positively associated with overall survival in the multivariate analysis.

Conclusion: This study based upon a Brazilian “real-world” data confirms the toxicity profile of immune-checkpoint inhibitors seen in clinical trials. In accordance with previous retrospective analyses, development of immune-related adverse events was associated with survival outcome of immune-checkpoint inhibitors treatment in patients with metastatic solid cancers.

RESUMO

Objetivos: Relatar dados do mundo real de uma coorte de pacientes tratados com inibidores de checkpoint imunológico no Brasil, com foco em eventos adversos relacionados ao sistema imunológico.

Material e Métodos: Neste estudo retrospectivo, analisamos uma coorte de pacientes com tumores sólidos metastáticos tratados em um centro de referência em oncologia com pelo menos uma dose de inibidores de checkpoint imunológico (administrados em monoterapia ou em combinação com outros agentes). O perfil de segurança foi caracterizado pela incidência de eventos adversos, manejo e hospitalização.

Resultados: Incluímos 185 pacientes. Eventos adversos relacionados ao sistema imunológico foram observados em 92 dos 185 pacientes do estudo (49,7%), incluindo 16 pacientes (8,6%) com tais eventos de grau 3 ou 4, e 28 pacientes (15,1%) necessitando de terapia com corticosteroides sistêmicos. Distúrbios da tireoide (20%), erupção cutânea (17,8%), prurido (11,4%) e colite (11,4%) foram os eventos adversos relacionados ao sistema imunológico mais frequentes. Cinco (2,7%) pacientes descontinuaram os inibidores de checkpoint imunológico e 15 (7,0%) foram hospitalizados devido a eventos adversos relacionados ao sistema imunológico. O desenvolvimento de eventos adversos relacionados ao sistema imunológico e inibidores de checkpoint imunológico usados no cenário de primeira linha foram associados a sobrevida livre de progressão prolongada e sobrevida global na análise multivariada. Além disso, idade <75 anos e pontuação ECOG 0 ou 1 foram positivamente associadas à sobrevida global na análise multivariada.

Conclusão: Este estudo baseado em dados brasileiros do “mundo real” confirma o perfil de toxicidade dos inibidores do checkpoint imunológico observado em ensaios clínicos. De acordo com análises retrospectivas anteriores, o desenvolvimento de eventos adversos relacionados ao sistema imunológico foi associado ao resultado de sobrevida do tratamento com inibidores de checkpoint imunológico em pacientes com cânceres sólidos metastáticos.

Keywords:

Brazil - Immunotherapy - Immune checkpoint inhibitors - Toxicity

Descritores:

Brasil - Imunoterapia - Inibidores do checkpoint imunológico - Toxicidade

Publikationsverlauf

Eingereicht: 08. August 2022

Angenommen: 23. September 2022

Artikel online veröffentlicht:
29. Dezember 2022

• REFERENCES

• 1 Conforti F, Pala L, Bagnardi V, Pas T, Martinetti M, Viale G. et al. Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis. Lancet Oncol 2018; Jun; 19 (06) 737-746
• 2 Garon EB, Hellmann MD, Rizvi NA, Carcereny E, Leighl NB, Ahn MJ. et al. Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J Clin Oncol 2019; Oct; 37 (28) 2518-2527
• 3 Rangachari D, Costa DB. From hope to reality: durable overall survival with immune checkpoint inhibitors for advanced lung cancer. J Clin Oncol 2019; Oct; 37 (28) 2511-2513
• 4 Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M. et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019; Sep; 16 (09) 563-580
• 5 Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018; Jan; 378 (02) 158-1668
• 6 Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel- Vinay S. et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016; 54: 139-148
• 7 Skribek M, Rounis K, Afshar S, Grundberg O, Friesland S, Tsakonas G. et al. Effect of corticosteroids on the outcome of patients with advanced non– small cell lung cancer treated with immune-checkpoint inhibitors. Eur J Cancer 2021; Mar; 145 (07) 245-254
• 8 Bjørnhart B, Hansen KH, Jørgensen TL, Herrstedt J, Schytte T. Efficacy and safety of immune checkpoint inhibitors in a Danish real life non-small cell lung cancer population: a retrospective cohort study. Acta Oncol 2019; Jul; 58 (07) 953-961
• 9 Corbaux P, Maillet D, Boespflug A, Locatelli-Sanchez M, Perier-Muzet M, Duruisseaux M. et al. Older and younger patients treated with immune checkpoint inhibitors have similar outcomes in real-life setting. Eur J Cancer 2019; Nov; 121: 192-201
• 10 Shimozaki K, Sukawa Y, Beppu N, Kurihara I, Suzuki S, Mizuno R. et al. Multiple immune-related adverse events and anti-tumor efficacy: real- world data on various solid tumors. Cancer Manag Res 2020; Jun; 12: 4585-4593
• 11 Nice L, Bycroft R, Wu X, Rai SN, Figg L, Bhandari S. et al. Assessment of hospitalization rates for immune-related adverse events with immune checkpoint inhibitors. J Oncol Pharm Pract 2021; Oct; 27 (07) 1736-1742
• 12 Schmerling RA, Buzaid AC, Haddad CK, Schutz FAB, Kater FR, Pimenta J. et al. Immune manifestations with checkpoint inhibitors in a single Brazilian center: experience and literature review. Future Sci OA 2021; Jan; 7 (01) FSO655
• 13 Shi Y, Fang J, Zhou C, Liu A, Wang Y, Meng Q. et al. Immune checkpoint inhibitor-related adverse events in lung cancer: real-world incidence and management practices of 1905 patients in China.. Thorac Cancer 2022; Feb; 13 (03) 412-422
• 14 Ahern E, Allen MJ, Schmidt A, Lwin Z, Hughes BGM. Retrospective analysis of hospital admissions due to immune checkpoint inhibitor-induced immune-related adverse events (irAE). Asia Pac J Clin Oncol 2021; Apr; 17 (02) e109-e116
• 15 Schweizer C, Schubert P, Rutzner S, Eckstein M, Haderlein M, Lettmaier S. et al. Prospective evaluation of the prognostic value of immune-related adverse events in patients with non-melanoma solid tumour treated with PD-1/PD-L1 inhibitors alone and in combination with radiotherapy. Eur J Cancer 2020; Nov; 140: 55-62
• 16 Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R. et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol 2019; Apr; 30 (04) 582-588
• 17 Grossi F, Genova C, Crinò L, Delmonte A, Turci D, Signorelli D. et al. Real-life results from the overall population and key subgroups within the Italian cohort of nivolumab expanded access program in non-squamous non–small cell lung cancer. Eur J Cancer 2019; Dec; 123: 72-80
• 18 Maillet D, Corbaux P, Stelmes JJ, Dalle S, Locatelli-Sanchez M, Perier- Muzet M. et al. Association between immune-related adverse events and long-term survival outcomes in patients treated with immune checkpoint inhibitors. Eur J Cancer 2020; Jun; 132: 61-70
• 19 Eggermont AMM, Kicinski M, Blank CU, Mandala M, Long GV, Atkinson V. et al. Association between immune-related adverse events and recurrence-free survival among patients with stage iii melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial. JAMA Oncol 2020; Apr; 6 (04) 519-527
• 20 Haratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato R. et al. Association of immune-related adverse events with nivolumab efficacy in non-small cell lung cancer. JAMA Oncol 2018; Mar; 4 (03) 374-378
• 21 Kono Y, Choda Y, Nakagawa M, Miyahara K, Ishida M, Kubota T. et al. Association between immune-related adverse events and the prognosis of patients with advanced gastric cancer treated with nivolumab. Target Oncol 2021; Mar; 16 (02) 237-248
• 22 Dousset L, Pacaud A, Barnetche T, Kostine M, Dutriaux C, Pham-Ledard A. et al. Analysis of tumor response and clinical factors associated with vitiligo in patients receiving anti-programmed cell death-1 therapies for melanoma: a cross-sectional study. JAAD Int 2021; Dec; 5: 112-120
• 23 Teulings HE, Limpens J, Jansen SN, Zwinderman AH, Reitsma JB, Spuls PI. et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol 2015; Mar; 33 (07) 773-781
• 24 Maher VE, Fernandes LL, Weinstock C, Tang S, Agarwal S, Brave M. et al. Analysis of the association between adverse events and outcome in patients receiving a programmed death protein 1 or programmed death ligand 1 antibody.. J Clin Oncol 2019; 37 (30) 2730-2737