Skip to content

Immune-related adverse events in melanoma therapy

TL;DR — Immune-related adverse events are regimen-specific in both frequency and organ pattern: combination anti-CTLA-4 plus anti-PD-1 raises the relative risk of colitis (RR 3.56, 95% CI 1.56–8.12), pneumonitis (2.31, 1.54–3.45), hepatitis (2.54, 1.65–3.91) and hypothyroidism over monotherapy (Da 2019, PMID 32082164), and CheckMate 238 recorded grade 3/4 treatment-related events in 14.4% with nivolumab versus 45.9% with ipilimumab 10 mg/kg (Weber 2017, PMID 28891423). Fatal toxicity is rare but has a regimen-specific spectrum: of 613 fatal events reported to the WHO pharmacovigilance database 2009–2018, anti-CTLA-4 deaths were usually from colitis (135 of 193, 70%) while anti-PD-(L)1 fatalities were more often pneumonitis (Wang 2018, PMID 30242316). The specific harm that matters most for the stage II adjuvant decision is chronicity: among 387 patients receiving adjuvant anti-PD-1 for resected stage III–IV melanoma, 43.2% developed an event persisting beyond 12 weeks after therapy cessation, and 96.4% of those chronic events were grade 1–2 but most persisted to last follow-up (Patrinely 2021, PMID 33764387). Extended follow-up of 318 patients with at least 18 months' evaluable follow-up confirmed the pattern (Goodman 2023, PMID 37535354).

Frequency by regimen

Regimen Grade 3/4 treatment-related AEs Source
Nivolumab (adjuvant, stage III/IV) 14.4% Weber 2017, PMID 28891423
Ipilimumab 10 mg/kg (adjuvant, stage III/IV) 45.9% PMID 28891423
Nivolumab (adjuvant, stage IIB/C) 10.3% (vs 2.3% placebo) Kirkwood 2023, PMID 37845511
Nivolumab + relatlimab (advanced) 18.9% (vs 9.7% nivolumab) Tawbi 2022, PMID 34986285
Neoadjuvant ipilimumab 3 + nivolumab 1 (OpACIN-neo group A) 40% grade 3–4 immune-related within 12 weeks Rozeman 2019, PMID 31160251
Neoadjuvant ipilimumab 1 + nivolumab 3 (group B) 20% PMID 31160251
Neoadjuvant sequential ipilimumab then nivolumab (group C) 50% — accrual closed early by the DSMB PMID 31160251
Neoadjuvant nivolumab + relatlimab No grade 3–4 immune-related events in the neoadjuvant phase (n = 30) Amaria 2022, PMID 36289334
Neoadjuvant-adjuvant vs adjuvant-only pembrolizumab (S1801) 12% vs 14% Patel 2023, PMID 36856617

OpACIN-neo is the cleanest demonstration that schedule, not just drug combination, determines toxicity: three schedules of the same two agents produced grade 3–4 immune toxicity of 20%, 40% and 50% (PMID 31160251).

Organ pattern

Meta-analysis of 8 randomised trials and 2,716 patients gives any-grade incidences: colitis 14.5%, hypothyroidism 13.8%, hepatitis 10.4%, hypophysitis 10.0%, hyperthyroidism 9.3%, pneumonitis 4.6%; combination therapy significantly increased any-grade risk for colitis (RR 3.56, 1.56–8.12), pneumonitis (2.31, 1.54–3.45), hepatitis (2.54, 1.65–3.91) and hypothyroidism (2.17) (Da 2019, PMID 32082164). Pharmacovigilance data over a decade distinguish 25 types of event across 50,347 cases (single event in 84.9%), predominantly anti-PD-1 monotherapy (62.4%), with skin reactions the most reported (22.9%) followed by pneumonitis; the prescribing mix shifted markedly after 2020, with anti-CTLA-4 monotherapy almost vanishing (1.6% vs 47% before 2016) while combination use rose (20% vs 8.9%) (Gougis 2024, PMID 38560659).

Cutaneous events specifically have been quantified by systematic review and meta-analysis across checkpoint-containing regimens (PMID 38254829), as has neurotoxicity (PMID 40795646).

Fatal and near-fatal toxicity

Finding Detail
Global spectrum 613 fatal checkpoint-inhibitor toxic events reported to WHO Vigilyze 2009 – January 2018; anti-CTLA-4 deaths usually colitis (135/193, 70%), anti-PD-(L)1 fatalities often pneumonitis (Wang 2018, PMID 30242316)
Myocarditis and myositis French nationwide cohort of 172,363 checkpoint-treated adults 2012–2022: incidence of myotoxicity at 6 months 0.7–0.9% depending on case definition, with risk factors and lethality modelled (Salem 2026, PMID 40884033)
Mechanism α-myosin-specific T cells drive immunotherapy-related myocarditis (Axelrod 2022, PMID 36385524); immune responses in checkpoint myocarditis have been profiled across heart, blood and tumour (PMID 39506125)
Cardio-oncology guidance Heart Failure Association / ESC Council of Cardio-Oncology scientific statement on cardiovascular toxicities of cancer immune therapies (PMID 39087551)
Overlap syndromes Myocarditis–myositis–myasthenia gravis overlap has been systematically reviewed (PMID 39202282)

Fatal events are rare in absolute terms but concentrated early, and their organ distribution differs so sharply between anti-CTLA-4 and anti-PD-1 that a single "checkpoint toxicity" monitoring protocol is inappropriate (PMID 30242316).

Chronic and permanent toxicity — the decisive quantity for adjuvant decisions

Cohort Finding
387 patients, adjuvant anti-PD-1 for stage III–IV melanoma, 8 centres in the US and Australia, 2015–2020 (Patrinely 2021, PMID 33764387) Acute events in 69.0%, including 19.5% grade 3–5; one fatal myocarditis and one fatal neurotoxicity. Chronic events (persisting ≥12 weeks after cessation) in 43.2%; 96.4% of these were grade 1–2 and most persisted to last available follow-up
318 patients, 6 centres, 2015–2022, ≥18 months' evaluable follow-up (range 18.2–70.4 months) (Goodman 2023, PMID 37535354) Acute events during treatment in 63.7%, including 13.8% grade 3 or higher. Chronic events defined as persisting ≥3 months after cessation, with resolution versus persistence tracked over extended follow-up

Endocrinopathy is the archetype of permanent harm. The European Society of Endocrinology guideline concludes that with the exception of thyroiditis, most endocrine dysfunction after checkpoint therapy requires ongoing management, that baseline endocrine testing before each treatment cycle is needed, and that there is no clear evidence of benefit from high-dose glucocorticoids for endocrine toxicities except possibly severe thyroid eye disease and hypophysitis affecting the visual apparatus (Husebye 2022, PMID 36149449). Rare endocrine events have been separately catalogued (PMID 37046677), and general endocrine side-effects reviewed (PMID 27136136).

For a patient with resected stage IIB/IIC melanoma whose absolute recurrence-free-survival gain at 48 months is roughly 13 percentage points (71.3% vs 58.3%) (Luke 2025, PMID 40198940), a 43% chance of an adverse event persisting past treatment — mostly mild but mostly permanent — is the other side of the ledger. Neither trial reports that trade-off as a single decision quantity.

Management, and the corticosteroid question

ASCO's guideline update was developed by a multidisciplinary panel across eleven specialties from a systematic review of evidence published 2017–2021; 175 studies met eligibility, and because of the paucity of high-quality evidence the recommendations are based on expert consensus. In general, checkpoint therapy is continued with close monitoring for grade 1 toxicities, with exceptions for some neurological, haematological and cardiac events (Schneider 2021, PMID 34724392). A hospitalist-focused summary exists (PMID 37039096), and general management reviews predate the guideline (PMID 26874776).

Corticosteroid dose may not be a free parameter. Post-hoc analysis of individual patient data from the anti-PD-1 plus anti-CTLA-4 arms of six trials (CheckMate-067, -142, -214, -648, -743 and -9LA) included 834 of 1,959 patients who received immunosuppression for treatment-related adverse events; 100% received corticosteroids and 10% received second-line immunosuppressants. High corticosteroid peak dose was associated with worse progression-free survival after adjustment for age and sex (Verheijden 2024, PMID 39110922). The direction of causation is not established — sicker patients get more steroids — but it is the strongest available argument for steroid-sparing management.

Predicting who will develop an event

No validated predictor exists; several candidate signals have been reported and none has been prospectively validated as a selection tool.

Candidate Evidence
Sex and baseline blood counts In a multicentre prospective pan-cancer cohort of 145 patients, 52 (35.8%) experienced at least one immune-related event with a 1-year cumulative incidence of 41.6%; Fine–Gray competing-risk models identified female sex (HR 2.17) among the predictors, alongside baseline and early-change values of absolute neutrophil and lymphocyte counts and lymphocyte-related ratios (Teijeira 2023, PMID 38201577)
Baseline laboratory values In 105 patients receiving multiple checkpoint-inhibitor types at a single centre 2016–2020, lower relative lymphocyte count and higher albumin were among the parameters associated with events on logistic regression, with ROC-derived cut-offs (Bai 2021, PMID 34259422)
Comorbidity burden In 885 patients aged ≥65 receiving adjuvant anti-PD-1 in the Dutch Melanoma Treatment Registry, age was not associated with grade ≥3 events but increasing comorbidity count was (multivariable OR 1.83, 95% CI 0.99–3.40) (Özkan 2024, PMID 39368226)
Serum cytokines A composite cytokine score has been proposed for early identification of high-risk patients (PMID 41394871)
Body mass index Real-world analysis of BMI as a toxicity determinant (PMID 41278286)

All of these are candidate signals from single cohorts or pan-cancer populations, and none has been tested prospectively in melanoma as a basis for altering treatment. Given that the stage IIB/IIC adjuvant decision turns on a benefit–harm ratio (see adjuvant therapy), a validated toxicity predictor would change practice more than a marginal efficacy gain would.

The toxicity–efficacy association

Development of immune-related adverse events is associated with better outcomes, which complicates any attempt to treat toxicity purely as harm.

  • In 186 advanced melanoma patients on anti-PD-1, any-grade events occurred in 47% and grade ≥3 in 15%. In a landmark analysis excluding early deaths, median overall survival was 39 versus 23 months for any event versus none (HR 0.46, P = .001), and not reached versus 29 months for grade ≥3 events. In multivariable analysis grade ≥3 events remained associated with longer survival (HR 0.29, P = .024) alongside elevated LDH predicting worse survival (HR 2.34, P = .001) and each additional treatment cycle predicting better (HR 0.94, P < .001) (Suo 2020, PMID 32048768).
  • The general relationship between immune-related adverse events and antitumour efficacy has been reviewed (PMID 31730012).

The association is heavily confounded by exposure time — patients who live longer receive more cycles and have more opportunity to develop an event — and the 0.94-per-cycle hazard ratio in the same model is direct evidence of that confounding (PMID 32048768).

Interpretation rules for this page

  • Report the regimen and schedule, not the drug class. Grade 3–4 immune toxicity ranged 20–50% across three schedules of ipilimumab plus nivolumab (PMID 31160251).
  • Separate acute from chronic events. A 69% acute-event rate and a 43% chronic-event rate describe different harms (PMID 33764387).
  • Grade does not equal permanence. 96.4% of chronic events were grade 1–2, and most never resolved (PMID 33764387).
  • Fatal-toxicity spectra differ by agent — colitis for anti-CTLA-4, pneumonitis for anti-PD-(L)1 (PMID 30242316).
  • The toxicity–survival association is confounded by exposure duration (PMID 32048768).
  • Management guidance is consensus-based, not evidence-based (PMID 34724392), and high-dose steroids may reduce efficacy (PMID 39110922).
  • Endocrine events usually require lifelong replacement and steroids do not prevent that (PMID 36149449).

Open questions

  • What is the number needed to harm for permanent endocrinopathy per 100 patients treated with adjuvant anti-PD-1 in stage IIB/IIC, set against the recurrence-free-survival gain (PMID 33764387; PMID 40198940)?
  • Does high-dose corticosteroid treatment of immune-related events reduce antitumour efficacy causally, or is the association confounded (PMID 39110922)?
  • Can steroid-sparing immunosuppression (second-line agents were used in only 10% of one large post-hoc cohort) preserve efficacy (PMID 39110922)?
  • Why does the nivolumab–relatlimab combination produce so much less toxicity than ipilimumab-containing combinations at comparable efficacy (PMID 34986285; PMID 36289334)?
  • Is the toxicity–survival association causal, and would it change monitoring or dosing if it were (PMID 32048768)?
  • What proportion of chronic grade 1–2 events ever resolve with follow-up beyond five years (PMID 37535354)?

References

  1. Da L, et al. Organ-Specific Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor Monotherapy Versus Combination Therapy in Cancer: A Meta-Analysis of Randomized Controlled Trials. Frontiers in pharmacology. 2019;10:1671. PMID 32082164
  2. Weber J, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. The New England journal of medicine. 2017;377:1824-1835. PMID 28891423
  3. Wang DY, et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA oncology. 2018;4:1721-1728. PMID 30242316
  4. Patrinely JR Jr, et al. Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma. JAMA oncology. 2021;7:744-748. PMID 33764387
  5. Goodman RS, et al. Extended Follow-Up of Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-Risk Resected Melanoma. JAMA network open. 2023;6:e2327145. PMID 37535354
  6. Kirkwood JM, et al. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Nature medicine. 2023;29:2835-2843. PMID 37845511
  7. Tawbi HA, et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. The New England journal of medicine. 2022;386:24-34. PMID 34986285
  8. Rozeman EA, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. The Lancet. Oncology. 2019;20:948-960. PMID 31160251
  9. Amaria RN, et al. Neoadjuvant relatlimab and nivolumab in resectable melanoma. Nature. 2022;611:155-160. PMID 36289334
  10. Patel SP, et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. The New England journal of medicine. 2023;388:813-823. PMID 36856617
  11. Gougis P, et al. Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade-a worldwide perspective. EClinicalMedicine. 2024;70:102536. PMID 38560659
  12. Curkovic NB, et al. Incidence of Cutaneous Immune-Related Adverse Events and Outcomes in Immune Checkpoint Inhibitor-Containing Regimens: A Systematic Review and Meta-Analysis. Cancers. 2024;16. PMID 38254829
  13. Nielsen DL, et al. Immune checkpoint inhibitor-related neurotoxicity: Incidence and management. A systematic review and meta-analysis. Cancer treatment reviews. 2025;140:103011. PMID 40795646
  14. Salem JE, et al. Incidence and risk factors of immune checkpoint inhibitor myocardial and muscle toxicity: a French nationwide study. European heart journal. 2026;47:1014-1030. PMID 40884033
  15. Axelrod ML, et al. T cells specific for α-myosin drive immunotherapy-related myocarditis. Nature. 2022;611:818-826. PMID 36385524
  16. Blum SM, et al. Immune responses in checkpoint myocarditis across heart, blood and tumour. Nature. 2024;636:215-223. PMID 39506125
  17. Tocchetti CG, et al. Cardiovascular toxicities of immune therapies for cancer - a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology. European journal of heart failure. 2024;26:2055-2076. PMID 39087551
  18. Lipe DN, et al. Myocarditis, Myositis, and Myasthenia Gravis Overlap Syndrome Associated with Immune Checkpoint Inhibitors: A Systematic Review. Diagnostics (Basel, Switzerland). 2024;14. PMID 39202282
  19. Husebye ES, et al. Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline. European journal of endocrinology. 2022;187:G1-G21. PMID 36149449
  20. Mytareli C, et al. The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events. Cancers. 2023;15. PMID 37046677
  21. Torino F, et al. Endocrinological side-effects of immune checkpoint inhibitors. Current opinion in oncology. 2016;28:278-87. PMID 27136136
  22. Luke JJ, et al. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Long-term follow-up, crossover, and rechallenge with pembrolizumab in the phase III KEYNOTE-716 study. European journal of cancer (Oxford, England : 1990). 2025;220:115381. PMID 40198940
  23. Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;39:4073-4126. PMID 34724392
  24. Chitnis SD, et al. Clinical guideline highlights for the hospitalist: Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy. Journal of hospital medicine. 2023;18:1013-1016. PMID 37039096
  25. Spain L, et al. Management of toxicities of immune checkpoint inhibitors. Cancer treatment reviews. 2016;44:51-60. PMID 26874776
  26. Verheijden RJ, et al. Corticosteroids for Immune-Related Adverse Events and Checkpoint Inhibitor Efficacy: Analysis of Six Clinical Trials. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2024;42:3713-3724. PMID 39110922
  27. Teijeira L, et al. Baseline Circulating Blood Cell Counts and Ratios and Changes Therein for Predicting Immune-Related Adverse Events during Immune Checkpoint Inhibitor Therapy: A Multicenter, Prospective, Observational, Pan-Cancer Cohort Study with a Gender Perspective. Cancers. 2023;16. PMID 38201577
  28. Bai R, et al. Analysis of characteristics and predictive factors of immune checkpoint inhibitor-related adverse events. Cancer biology & medicine. 2021;18:1118-33. PMID 34259422
  29. Özkan A, et al. Adjuvant immunotherapy in older patients with stage III and resected stage IV melanoma: Toxicity and recurrence-free survival outcomes from the Dutch melanoma treatment registry. European journal of cancer (Oxford, England : 1990). 2024;212:115056. PMID 39368226
  30. Flatt N, et al. A composite score of serum cytokines enables early identification of patients at high risk for irAEs under immune checkpoint inhibition. Frontiers in immunology. 2025;16:1733357. PMID 41394871
  31. Spagnolo CC, et al. Immune checkpoint inhibitor-induced toxicity: a real-world analysis of the role of BMI. Frontiers in oncology. 2025;15:1659977. PMID 41278286
  32. Suo A, et al. Anti-PD1-Induced Immune-Related Adverse Events and Survival Outcomes in Advanced Melanoma. The oncologist. 2020;25:438-446. PMID 32048768
  33. Das S, et al. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. Journal for immunotherapy of cancer. 2019;7:306. PMID 31730012