Impact of Immune-Related Adverse Events on Immune Checkpoint Inhibitors Treated Cancer Patients’ Survival: Single Center Experience and Literature Review

Simple Summary The widespread use of immune checkpoint inhibitors (ICI) came along with a new challenge for oncologists, immune-related adverse events (irAE). A positive correlation between irAE onset and ICI efficacy has been suggested. However, it remains unsettled. Whether the association exists and if it is affected by cancer type or ethnicity needs further investigation. This study provides additional evidence to support this association by using a retrospective, single-center cohort design to analyze survival outcomes and the development of irAEs of 155 patients. Overall, the study offers new insights into the potential use of irAEs as biomarkers for response and survival in solid tumor patients receiving ICIs, and highlights the need for further research in this area. Abstract Immune-related adverse events have emerged as a new challenge and its correlation with survival remains unclear. The goal of our study was to investigate the effect of irAE on survival outcomes in solid tumor patients receiving ICI treatment. This was a retrospective, single-center study at a university hospital involving patients with malignancy who received immune checkpoint inhibitors. Chart review was performed on each patient, noting any irAE, including new events or worsening of previous autoimmune condition after starting treatment with ICI. A total of 155 patients were included, 118 (76.1%) were male, with median age of 64 years. Median follow up time was 36 months. Seventy patients (45.2%) had at least one irAE. Of all irAE, nine (8.1%) were classified as grade 3 or higher according to the CTCAE version 5.0. There was one death secondary to pneumonitis. Median ICI cycles until first irAE onset was 4 (range: 2–99). The objective response rate was higher for patients who developed irAE (18.7% vs. 9.0%; p = 0.001), as was median overall survival (18 months (95% CI, 8.67–27.32) vs. 10 (95% CI, 3.48–16.52) months; p < 0.016) and progression free survival (10 months (95% CI, 5.44–14.56) vs. 3 months (95% CI, 1.94–4.05); p = 0.000). The risk of death in patients with irAE was 33% lower when compared to patients without such events (hazard ratio (HR): 0.67; 95% CI, 0.46–0.99; p = 0.043). Development of irAE predicted better outcomes, including OS in patients with advanced solid tumors treated with ICI. Further prospective studies are needed to explore and validate this prognostic value.

[1]  G. Middleton,et al.  Germline genetic variation and predicting immune checkpoint inhibitor induced toxicity , 2022, NPJ genomic medicine.

[2]  J. Koivunen,et al.  Association of Rare Immune-Related Adverse Events to Survival in Advanced Cancer Patients Treated with Immune Checkpoint Inhibitors: A Real-World Single-Center Cohort Study , 2022, Cancers.

[3]  J. Naidoo,et al.  Immune-related adverse events and the balancing act of immunotherapy , 2022, Nature communications.

[4]  Zhanjun Guo,et al.  Correlation Between Immune-Related Adverse Events and Prognosis in Hepatocellular Carcinoma Patients Treated With Immune Checkpoint Inhibitors , 2021, Frontiers in Immunology.

[5]  Zhuoli Zhang,et al.  Association of Immune Related Adverse Events With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Cancers: A Systemic Review and Meta-analysis , 2021, Frontiers in Oncology.

[6]  Tingting Liu,et al.  Comparative risk of serious and fatal treatment-related adverse events caused by 19 immune checkpoint inhibitors used in cancer treatment: a network meta-analysis , 2020, Therapeutic advances in medical oncology.

[7]  D. Schadendorf,et al.  Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo , 2020, JAMA oncology.

[8]  D. Gerber,et al.  Autoimmunity, Checkpoint Inhibitor Therapy and Immune-related Adverse Events: A Review. , 2020, Seminars in cancer biology.

[9]  Douglas B. Johnson,et al.  Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors , 2019, Journal of Immunotherapy for Cancer.

[10]  J. Naidoo,et al.  Lower Survival in Patients Who Develop Pneumonitis Following Immunotherapy for Lung Cancer. , 2019, Clinical lung cancer.

[11]  R. Gutzmer,et al.  Neurological Immune Related Adverse Events Associated with Nivolumab, Ipilimumab, and Pembrolizumab Therapy—Review of the Literature and Future Outlook , 2019, Journal of clinical medicine.

[12]  Namrata Singh,et al.  Immune-related adverse events in cancer patients treated with immune checkpoint inhibitors , 2019, Medicine.

[13]  S. Barni,et al.  Immune-related Adverse Events and Survival in Solid Tumors Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis , 2019, Journal of immunotherapy.

[14]  G. Coukos,et al.  Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance , 2019, Nature Reviews Clinical Oncology.

[15]  K. Goldberg,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. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  M. Lenardo,et al.  Development of immune checkpoint therapy for cancer , 2019, The Journal of experimental medicine.

[17]  R. Sullivan,et al.  Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis , 2018, JAMA oncology.

[18]  Ling-Long Tang,et al.  Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis , 2018, British Medical Journal.

[19]  K. Kerr,et al.  Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  K. Hargadon,et al.  Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. , 2018, International immunopharmacology.

[21]  Yeonseok Chung,et al.  Future prospects of immune checkpoint blockade in cancer: from response prediction to overcoming resistance , 2018, Experimental & Molecular Medicine.

[22]  Jedd D. Wolchok,et al.  Cancer immunotherapy using checkpoint blockade , 2018, Science.

[23]  M. Suarez‐Almazor,et al.  Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  Matthew D. Hellmann,et al.  Immune‐Related Adverse Events Associated with Immune Checkpoint Blockade , 2018, The New England journal of medicine.

[25]  Kaoru Tanaka,et al.  Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non–Small-Cell Lung Cancer , 2017, JAMA oncology.

[26]  W. Black,et al.  Racial and Ethnic Disparities in Early‐Stage Lung Cancer Survival , 2017, Chest.

[27]  D. Schadendorf,et al.  Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  Ana C Anderson,et al.  Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. , 2016, Immunity.

[29]  J. Wolchok,et al.  Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  M. Atkins,et al.  Toxicities of Immunotherapy for the Practitioner. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  G. Linette,et al.  Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. , 2015, The New England journal of medicine.

[32]  David C. Smith,et al.  Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  R. Vonderheide,et al.  Mitigating the toxic effects of anticancer immunotherapy , 2014, Nature Reviews Clinical Oncology.

[34]  P. Ascierto,et al.  Correlation between efficacy and toxicity in pts with pretreated advanced melanoma treated within the Italian cohort of the ipilimumab expanded access programme (EAP). , 2013 .

[35]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.