Abstract
Background
Given the widespread use of immune checkpoint inhibitors (ICIs), newer immune related adverse events (irAEs) have come to light, including flare-ups of preexisting autoimmune disorders (AIDs) and delayed immune-related events. We aimed to identify the frequency and severity of new IRAEs, including AID flares in cancer patients treated with ICIs at our institution. We also studied the tolerability of ICIs upon rechallenge in patients with irAEs and hospital admissions due to irAEs in a community setting in rural Maine.
Methods
We conducted a retrospective chart review analysis of all patients with cancer who received anti-PDL1/PDL1 inhibitors nivolumab, pembrolizumab, atezolizumab, and durvalumab at our tertiary care center from November 2015 to March 2019. Demographic data, cancer type and stage, irAEs, hospital admissions due to irAEs, and drug treatment information was extracted.
Results
We included 465 patients who received ICIs, 115 (out of 465 25%) developed new irAEs. Preexisting AID were identified in 47 (out of 465) (10%), AID flares were observed in 12 patients (25% of 47). 17 (out of 47 36%) were on immunosuppression for underlying AID, 5 (out of 17, 29%) developed flares. Overall, 148 (32% of 465) irAEs occurred, as some patients had multiple toxicities. Majority were treated for Lung cancer (63%), followed by melanoma and genitourinary cancers. Due to irAE severity, treatment was permanently discontinued in 15% (out of 465) patients. Hospital admissions due to irAEs were required for 34 patients (7.3% of 465). ICI rechallenge was performed in 27 patients (6% of 465), and majority tolerated well.
Conclusion
Our study shows that ICIs were generally well tolerated and can be used safely even in patients with preexisting AIDs; it is encouraging to see majority tolerated rechallenge with ICIs well.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abdel-Wahab N, Shah M, Lopez-Olivo MA et al (2018) Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: a systematic review. Ann Intern Med 168(2):121–130. https://doi.org/10.7326/M17-2073
Abou SA, Xie W, Nassar AH et al (2020) Safety and efficacy of restarting immune checkpoint inhibitors after clinically significant immune-related adverse events in metastatic renal cell carcinoma. J Immunother Cancer 8:e000144. https://doi.org/10.1136/jitc-2019-000144
Ahern E, Allen MJ, Schmidt A et al (2020) Retrospective analysis of hospital admissions due to immune checkpoint inhibitor-induced immune-related adverse events (irAE). Asia Pac J Clin Oncol. https://doi.org/10.1111/ajco.13350
Balaji A, Zhang J, Wills B et al (2019) Immune-related adverse events requiring hospitalization: spectrum of toxicity, treatment, and outcomes. J Oncol Pract 15(9):e825–e834. https://doi.org/10.1200/JOP.18.00703
Borghaei H, Paz-Ares L, Horn L et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639. https://doi.org/10.1056/NEJMoa1507643
Brahmer J, Reckamp KL, Baas P et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135. https://doi.org/10.1056/NEJMoa1504627
Brahmer JR, Lacchetti C, Schneider BJ et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 36(17):1714–1768. https://doi.org/10.1200/JCO.2017.77.6385
Brown JA, Dorfman DM, Ma FR et al (2003) Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 170(3):1257–1266. https://doi.org/10.4049/jimmunol.170.3.1257
Calabrese L, Velcheti V (2017) Checkpoint immunotherapy: good for cancer therapy, bad for rheumatic diseases. Ann Rheum Dis 76(1):1–3. https://doi.org/10.1136/annrheumdis-2016-209782
Chuzi S, Tavora F, Cruz M et al (2017) Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor-related pneumonitis. Cancer Manag Res 9:207–213. https://doi.org/10.2147/CMAR.S136818
Cortellini A, Buti S, Santini D et al (2019) Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with anti-programmed death-1 immunotherapy: a real-world transverse study. Oncologist 24(6):e327–e337. https://doi.org/10.1634/theoncologist.2018-0618
Couey MA, Bell RB, Patel AA et al (2019) Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance. J Immunother Cancer 7:165. https://doi.org/10.1186/s40425-019-0645-6
Eggermont AMM, Blank CU, Mandala M et al (2018) Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378(19):1789–1801. https://doi.org/10.1056/NEJMoa1802357
Garassino MC, Cho BC, Kim JH et al (2018) Durvalumab as third-line or later treatment for advanced non-smallcell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol 19(4):521–536. https://doi.org/10.1016/S1470-2045(18)30144-X
Giaj Levra ML, Cotté FE, Corre R et al (2020) Immunotherapy rechallenge after nivolumab treatment in advanced non-small cell lung cancer in the real-world setting: a national data base analysis. Lung Cancer 140:99–106. https://doi.org/10.1016/j.lungcan.2019.12.017
Gong J, Chehrazi-Raffle A, Reddi S et al (2018) Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer 6(1):8. https://doi.org/10.1186/s40425-018-0316-z
Gutzmer R, Koop A, Meier F et al (2017) Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity. Eur J Cancer 75:24–32. https://doi.org/10.1016/j.ejca.2016.12.038
Haanen JBAG, Carbonnel F, Robert C et al (2018) Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 29(Suppl 4):iv264–iv266. https://doi.org/10.1093/annonc/mdx225
Haanen J, Ernstoff MS, Wang Y et al (2020) Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy. Ann Oncol 31(6):724–744. https://doi.org/10.1016/j.annonc.2020.03.285
Hellmann MD, Ciuleanu TE, Pluzanski A et al (2018) Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378(22):2093–2104. https://doi.org/10.1056/NEJMoa1801946
Herbst RS, Baas P, Kim DW et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027):1540–1550. https://doi.org/10.1016/S0140-6736(15)01281-7
Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. https://doi.org/10.1056/NEJMoa1003466
Johnson DB, Sullivan RJ, Ott PA et al (2016) Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol 2(2):234–240. https://doi.org/10.1001/jamaoncol.2015.4368
Kennedy LC, Bhatia S, Thompson JA, Grivas P (2019) Preexisting autoimmune disease: implications for immune checkpoint inhibitor therapy in solid tumors. J Natl Compr Canc Netw 17(6):750–757. https://doi.org/10.6004/jnccn.2019.7310 (PMID: 31200356)
Khoja L, Day D, Wei-Wu Chen T et al (2017) Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann Oncol 28(10):2377–2385. https://doi.org/10.1093/annonc/mdx286
Leonardi GC, Gainor JF, Altan M et al (2018) Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders. J Clin Oncol 36(19):1905–1912. https://doi.org/10.1200/JCO.2017.77.0305
Menzies AM, Johnson DB, Ramanujam S et al (2017) Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 28(2):368–376. https://doi.org/10.1093/annonc/mdw443
Motzer RJ, Escudier B, McDermott DF et al (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813. https://doi.org/10.1056/NEJMoa1510665
Motzer RJ, Tannir NM, McDermott DF et al (2018) Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378(14):1277–1290. https://doi.org/10.1056/NEJMoa1712126
Muchnik E, Loh KP, Strawderman M et al (2019) Immune checkpoint inhibitors in real-world treatment of older adults with non-small cell lung cancer. J Am Geriatr Soc 67(5):905–912. https://doi.org/10.1111/jgs.15750
Niki M, Nakaya A, Kurata T et al (2018) Immune checkpoint inhibitor re-challenge in patients with advanced nonsmall cell lung cancer. Oncotarget 9(64):32298–32304. https://doi.org/10.18632/oncotarget.25949
Pollack MH, Betof A, Dearden H et al (2018) Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol 29(1):250–255. https://doi.org/10.1093/annonc/mdx642
Puzanov I, Diab A, Abdallah K et al (2017) Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 5(1):95. https://doi.org/10.1186/s40425-017-0300-z
Remon J, Mezquita L, Corral J et al (2018) Immune-related adverse events with immune checkpoint inhibitors in thoracic malignancies: focusing on non-small cell lung cancer patients. J Thorac Dis 10(Suppl 13):S1516–S1533. https://doi.org/10.21037/jtd.2017.12.52
Rittmeyer A, Barlesi F, Waterkamp D et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389(10066):255–265. https://doi.org/10.1016/S0140-6736(16)32517-X
Robert C, Long GV, Brady B et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372(4):320–330. https://doi.org/10.1056/NEJMoa1412082
Santini FC, Rizvi H, Plodkowski AJ et al (2018) Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC. Cancer Immunol Res 6(9):1093–1099. https://doi.org/10.1158/2326-6066.CIR-17-0755
Sattar J, Kartolo A, Hopman WM, Lakoff JM, Baetz T (2019) The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population. J Geriatr Oncol 10(3):411–414. https://doi.org/10.1016/j.jgo.2018.07.015
Simonaggio A, Michot JM, Voisin AL et al (2019) Evaluation of readministration of immune checkpoint inhibitors after immune-related adverse events in patients with cancer. JAMA Oncol 5(9):1310–1317. https://doi.org/10.1001/jamaoncol.2019.1022
Tarhini A, Lo E, Minor DR (2010) Releasing the brake on the immune system: ipilimumab in melanoma and other tumors. Cancer Biother Radiopharm 25(6):601–613. https://doi.org/10.1089/cbr.2010.0865
Thompson JA, Schneider BJ, Brahmer J et al (2019) Management of Immunotherapy-related toxicities version 1.2019. J Natl Compr Cancer Netw 17(3):255–289. https://doi.org/10.6004/jnccn.2019.0013
Uemura M, Fa’ak F, Haymaker C et al (2016) A case report of Grover’s disease from immunotherapy-a skin toxicity induced by inhibition of CTLA-4 but not PD-1. J Immunother Cancer 4:55. https://doi.org/10.1186/s40425-016-0157-6
von Euw E, Chodon T, Attar N et al (2009) CTLA4 blockade increases Th17 cells in patients with metastatic melanoma. J Transl Med 7:35. https://doi.org/10.1186/1479-5876-7-35
Wolchok JD, Chiarion-Sileni V, Gonzalez R et al (2017) Overall Survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377(14):1345–1356. https://doi.org/10.1056/NEJMoa1709684
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
None.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Bhatlapenumarthi, V., Patwari, A. & Harb, A.J. Immune-related adverse events and immune checkpoint inhibitor tolerance on rechallenge in patients with irAEs: a single-center experience. J Cancer Res Clin Oncol 147, 2789–2800 (2021). https://doi.org/10.1007/s00432-021-03610-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-021-03610-w