Immediate red flag or clinically unstable?
Immediately assess for potentially life-threatening irAE presentations. Red flags include: chest pain, arrhythmia, syncope, or hemodynamic instability; new or rapidly worsening dyspnea, hypoxemia, or respiratory distress; new weakness, ptosis, dysphagia, respiratory muscle weakness, seizures, confusion, or focal neurologic deficit; severe abdominal pain, peritoneal signs, major GI bleeding, or severe dehydration; adrenal crisis, severe hypotension, diabetic ketoacidosis, or other acute endocrine decompensation; severe hepatitis with synthetic dysfunction; extensive blistering, mucosal involvement, or suspected severe cutaneous adverse reaction; rapidly progressive multisystem toxicity. Clinical severity may be more important than the numerical CTCAE grade in high-risk organ toxicities.
-
Emergency stabilization and high-risk irAE pathway
Hold ICI therapy immediately. Stabilize the patient and initiate urgent evaluation: airway, breathing, circulation, and hemodynamic support; hospitalization or monitored care when appropriate; targeted laboratory testing, ECG, imaging, and other urgent diagnostics according to the suspected organ toxicity; early organ-specific specialist involvement. Do not delay treatment of a potentially life-threatening irAE while awaiting complete diagnostic confirmation when clinical suspicion is high. Initiate organ-specific corticosteroid therapy and/or additional immunomodulatory treatment when indicated. High-risk cardiac, neurologic, pulmonary, severe GI, hepatic, hematologic, and severe cutaneous toxicities should move promptly to their organ-specific pathway.
-
Identify affected organ system(s) and grade severity
Identify all potentially involved organ systems and assess severity using current CTCAE criteria together with clinical judgment and organ-specific guidance. Determine whether toxicity is: single-organ or multisystem; mild and stable; clinically significant but not immediately life-threatening; severe, rapidly progressive, or life-threatening. Particular caution is required for cardiac, neurologic, neuromuscular, hematologic, pulmonary, and selected ocular toxicities, in which apparently modest symptoms may precede rapid deterioration. Evaluate for overlapping myocarditis–myositis–myasthenia-like syndromes when clinically suspected. Proceed to the appropriate grade-based pathway and the corresponding organ-specific algorithm.
-
Grade 1
Most grade 1 irAEs: continue ICI; provide symptomatic/supportive care; monitor closely for progression; repeat relevant laboratory or clinical assessment as appropriate. Important exception: do not apply a “continue ICI” rule automatically to potentially high-risk cardiac, neurologic, hematologic, neuromuscular, or selected other organ toxicities. Escalate promptly if symptoms or laboratory abnormalities worsen. Endocrine irAEs may require hormone replacement even when symptoms are mild.
-
Grade 2
For most grade 2 irAEs: temporarily hold ICI; initiate organ-specific diagnostic work-up; involve the appropriate specialist when indicated; provide supportive care. If systemic corticosteroids are indicated, a common starting approach is: Prednisone 0.5–1 mg/kg/day or equivalent depending on the organ toxicity and clinical severity. Not every grade 2 irAE requires corticosteroids. Endocrine toxicities, for example, are often managed primarily with hormone replacement. Reassess within the organ-specific timeframe and escalate if the patient deteriorates.
-
Clinical improvement within organ-specific reassessment window?
Reassess clinical symptoms, examination findings, and relevant laboratory or imaging parameters within the timeframe appropriate for the affected organ. Do not apply one reassessment interval to every irAE. For many severe irAEs, response should be apparent within approximately 48–72 hours. For life-threatening toxicities, failure to improve after approximately 1–3 days of appropriate therapy should prompt rapid treatment escalation. Some non-life-threatening toxicities may reasonably require a longer response window. Escalate earlier at any time if the patient is clinically deteriorating.
-
Improve, taper corticosteroids, and monitor
Once the irAE is clearly improving: transition from IV to oral corticosteroids when clinically appropriate; taper gradually; continue organ-specific clinical and laboratory monitoring; watch for recurrence during taper. For significant grade 2–3 inflammatory irAEs requiring systemic corticosteroids, tapering commonly occurs over at least 4–6 weeks, although duration must be individualized according to the organ involved and clinical course. During prolonged corticosteroid therapy: monitor glucose and blood pressure; assess infection risk; consider antimicrobial, gastrointestinal, and bone-protection strategies according to corticosteroid dose, duration, comorbidities, and local protocol. A recurrent flare during taper may require re-escalation and reassessment for steroid-dependent toxicity.
-
Recovered to Grade ≤1 or acceptable baseline?
Confirm that: symptoms have resolved to grade ≤1 or an acceptable stable baseline; relevant laboratory abnormalities are improving or stable; the patient no longer requires escalating immunosuppression; corticosteroid dose is sufficiently reduced for the specific toxicity and planned ICI strategy. Stable endocrine dysfunction controlled with hormone replacement may represent an acceptable baseline even if hormone replacement remains permanent. If clinically active toxicity persists, continue organ-specific follow-up and do not proceed automatically to rechallenge.
-
Rechallenge versus permanent discontinuation
Rechallenge is an individualized risk–benefit decision, not an automatic consequence of recovery. Consider: irAE type, grade, and severity; whether the event was life-threatening; speed and completeness of recovery; requirement for multiple or prolonged immunosuppressants; risk of irreversible organ injury; tumor response and current cancer status; available alternative anticancer therapies; anticipated benefit from further ICI; patient goals and preferences. For many grade 2 irAEs, rechallenge may be considered after recovery to grade ≤1 and when systemic corticosteroids are reduced to approximately prednisone ≤10 mg/day or equivalent. Rechallenge after grade 3 toxicity requires substantially greater caution and multidisciplinary review. Grade 4 toxicity generally warrants permanent ICI discontinuation, except selected endocrinopathies controlled with hormone replacement. Organ-specific rules override this general framework.
-
Chronic IrAE and endocrine replacement follow-Up
Recognize that some irAEs persist after ICI discontinuation or require long-term therapy. Distinguish: Chronic active irAE persistent immune-mediated inflammation requiring ongoing immunosuppression or other active therapy. Chronic inactive irAE persistent organ dysfunction without ongoing active inflammation, such as many endocrine deficiencies. Management may include: long-term specialty follow-up; steroid-sparing immunomodulatory treatment when appropriate; rehabilitation and supportive care; monitoring for late sequelae; permanent hormone replacement for selected endocrine irAEs. Do not maintain systemic corticosteroids solely to treat a stable endocrine hormone deficiency.
-
Steroid-refractory or steroid-dependent irAE
First confirm: correct diagnosis; adequate corticosteroid dose and route; adherence; exclusion of infection or another mimic; appropriate organ-specific reassessment. Steroid-refractory / steroid-unresponsive toxicity: inadequate clinical improvement despite appropriate corticosteroid therapy. Steroid-dependent toxicity: initial improvement occurs, but toxicity worsens or cannot be controlled during corticosteroid taper. Obtain urgent organ-specific specialist input and use organ-directed second-line immunosuppression rather than a one-size-fits-all approach. Examples include: infliximab or vedolizumab for selected immune-mediated colitis; mycophenolate mofetil for steroid-refractory immune-mediated hepatitis; IVIG and/or plasma exchange for selected severe neurologic or neuromuscular toxicities; other targeted immunomodulatory agents according to the affected organ and specialist guidance. Do not use infliximab as the default second-line agent for immune-mediated hepatitis.
-
Improve, taper corticosteroids, and monitor
Once the irAE is clearly improving: transition from IV to oral corticosteroids when clinically appropriate; taper gradually; continue organ-specific clinical and laboratory monitoring; watch for recurrence during taper. For significant grade 2–3 inflammatory irAEs requiring systemic corticosteroids, tapering commonly occurs over at least 4–6 weeks, although duration must be individualized according to the organ involved and clinical course. During prolonged corticosteroid therapy: monitor glucose and blood pressure; assess infection risk; consider antimicrobial, gastrointestinal, and bone-protection strategies according to corticosteroid dose, duration, comorbidities, and local protocol. A recurrent flare during taper may require re-escalation and reassessment for steroid-dependent toxicity.
-
Recovered to Grade ≤1 or acceptable baseline?
Confirm that: symptoms have resolved to grade ≤1 or an acceptable stable baseline; relevant laboratory abnormalities are improving or stable; the patient no longer requires escalating immunosuppression; corticosteroid dose is sufficiently reduced for the specific toxicity and planned ICI strategy. Stable endocrine dysfunction controlled with hormone replacement may represent an acceptable baseline even if hormone replacement remains permanent. If clinically active toxicity persists, continue organ-specific follow-up and do not proceed automatically to rechallenge.
-
Rechallenge versus permanent discontinuation
Rechallenge is an individualized risk–benefit decision, not an automatic consequence of recovery. Consider: irAE type, grade, and severity; whether the event was life-threatening; speed and completeness of recovery; requirement for multiple or prolonged immunosuppressants; risk of irreversible organ injury; tumor response and current cancer status; available alternative anticancer therapies; anticipated benefit from further ICI; patient goals and preferences. For many grade 2 irAEs, rechallenge may be considered after recovery to grade ≤1 and when systemic corticosteroids are reduced to approximately prednisone ≤10 mg/day or equivalent. Rechallenge after grade 3 toxicity requires substantially greater caution and multidisciplinary review. Grade 4 toxicity generally warrants permanent ICI discontinuation, except selected endocrinopathies controlled with hormone replacement. Organ-specific rules override this general framework.
-
Chronic IrAE and endocrine replacement follow-Up
Recognize that some irAEs persist after ICI discontinuation or require long-term therapy. Distinguish: Chronic active irAE persistent immune-mediated inflammation requiring ongoing immunosuppression or other active therapy. Chronic inactive irAE persistent organ dysfunction without ongoing active inflammation, such as many endocrine deficiencies. Management may include: long-term specialty follow-up; steroid-sparing immunomodulatory treatment when appropriate; rehabilitation and supportive care; monitoring for late sequelae; permanent hormone replacement for selected endocrine irAEs. Do not maintain systemic corticosteroids solely to treat a stable endocrine hormone deficiency.
-
Grade 3–4
Hold ICI and initiate urgent organ-specific management. Grade 3 toxicity consider hospitalization depending on organ system and clinical status; obtain urgent specialist input; for many active inflammatory irAEs, initiate prednisone or methylprednisolone 1–2 mg/kg/day or equivalent. Grade 4 toxicity usually requires hospitalization and intensive monitoring; generally warrants permanent ICI discontinuation. Major exception: selected endocrinopathies that are controlled with appropriate hormone replacement may not require permanent discontinuation. Some severe cardiac, neurologic, hematologic, pulmonary, or neuromuscular events may warrant permanent discontinuation even below grade 4.
-
Clinical improvement within organ-specific reassessment window?
Reassess clinical symptoms, examination findings, and relevant laboratory or imaging parameters within the timeframe appropriate for the affected organ. Do not apply one reassessment interval to every irAE. For many severe irAEs, response should be apparent within approximately 48–72 hours. For life-threatening toxicities, failure to improve after approximately 1–3 days of appropriate therapy should prompt rapid treatment escalation. Some non-life-threatening toxicities may reasonably require a longer response window. Escalate earlier at any time if the patient is clinically deteriorating.
-
Improve, taper corticosteroids, and monitor
Once the irAE is clearly improving: transition from IV to oral corticosteroids when clinically appropriate; taper gradually; continue organ-specific clinical and laboratory monitoring; watch for recurrence during taper. For significant grade 2–3 inflammatory irAEs requiring systemic corticosteroids, tapering commonly occurs over at least 4–6 weeks, although duration must be individualized according to the organ involved and clinical course. During prolonged corticosteroid therapy: monitor glucose and blood pressure; assess infection risk; consider antimicrobial, gastrointestinal, and bone-protection strategies according to corticosteroid dose, duration, comorbidities, and local protocol. A recurrent flare during taper may require re-escalation and reassessment for steroid-dependent toxicity.
-
Recovered to Grade ≤1 or acceptable baseline?
Confirm that: symptoms have resolved to grade ≤1 or an acceptable stable baseline; relevant laboratory abnormalities are improving or stable; the patient no longer requires escalating immunosuppression; corticosteroid dose is sufficiently reduced for the specific toxicity and planned ICI strategy. Stable endocrine dysfunction controlled with hormone replacement may represent an acceptable baseline even if hormone replacement remains permanent. If clinically active toxicity persists, continue organ-specific follow-up and do not proceed automatically to rechallenge.
-
Rechallenge versus permanent discontinuation
Rechallenge is an individualized risk–benefit decision, not an automatic consequence of recovery. Consider: irAE type, grade, and severity; whether the event was life-threatening; speed and completeness of recovery; requirement for multiple or prolonged immunosuppressants; risk of irreversible organ injury; tumor response and current cancer status; available alternative anticancer therapies; anticipated benefit from further ICI; patient goals and preferences. For many grade 2 irAEs, rechallenge may be considered after recovery to grade ≤1 and when systemic corticosteroids are reduced to approximately prednisone ≤10 mg/day or equivalent. Rechallenge after grade 3 toxicity requires substantially greater caution and multidisciplinary review. Grade 4 toxicity generally warrants permanent ICI discontinuation, except selected endocrinopathies controlled with hormone replacement. Organ-specific rules override this general framework.
-
Chronic IrAE and endocrine replacement follow-Up
Recognize that some irAEs persist after ICI discontinuation or require long-term therapy. Distinguish: Chronic active irAE persistent immune-mediated inflammation requiring ongoing immunosuppression or other active therapy. Chronic inactive irAE persistent organ dysfunction without ongoing active inflammation, such as many endocrine deficiencies. Management may include: long-term specialty follow-up; steroid-sparing immunomodulatory treatment when appropriate; rehabilitation and supportive care; monitoring for late sequelae; permanent hormone replacement for selected endocrine irAEs. Do not maintain systemic corticosteroids solely to treat a stable endocrine hormone deficiency.
-
Steroid-refractory or steroid-dependent irAE
First confirm: correct diagnosis; adequate corticosteroid dose and route; adherence; exclusion of infection or another mimic; appropriate organ-specific reassessment. Steroid-refractory / steroid-unresponsive toxicity: inadequate clinical improvement despite appropriate corticosteroid therapy. Steroid-dependent toxicity: initial improvement occurs, but toxicity worsens or cannot be controlled during corticosteroid taper. Obtain urgent organ-specific specialist input and use organ-directed second-line immunosuppression rather than a one-size-fits-all approach. Examples include: infliximab or vedolizumab for selected immune-mediated colitis; mycophenolate mofetil for steroid-refractory immune-mediated hepatitis; IVIG and/or plasma exchange for selected severe neurologic or neuromuscular toxicities; other targeted immunomodulatory agents according to the affected organ and specialist guidance. Do not use infliximab as the default second-line agent for immune-mediated hepatitis.
-
Improve, taper corticosteroids, and monitor
Once the irAE is clearly improving: transition from IV to oral corticosteroids when clinically appropriate; taper gradually; continue organ-specific clinical and laboratory monitoring; watch for recurrence during taper. For significant grade 2–3 inflammatory irAEs requiring systemic corticosteroids, tapering commonly occurs over at least 4–6 weeks, although duration must be individualized according to the organ involved and clinical course. During prolonged corticosteroid therapy: monitor glucose and blood pressure; assess infection risk; consider antimicrobial, gastrointestinal, and bone-protection strategies according to corticosteroid dose, duration, comorbidities, and local protocol. A recurrent flare during taper may require re-escalation and reassessment for steroid-dependent toxicity.
-
Recovered to Grade ≤1 or acceptable baseline?
Confirm that: symptoms have resolved to grade ≤1 or an acceptable stable baseline; relevant laboratory abnormalities are improving or stable; the patient no longer requires escalating immunosuppression; corticosteroid dose is sufficiently reduced for the specific toxicity and planned ICI strategy. Stable endocrine dysfunction controlled with hormone replacement may represent an acceptable baseline even if hormone replacement remains permanent. If clinically active toxicity persists, continue organ-specific follow-up and do not proceed automatically to rechallenge.
-
Rechallenge versus permanent discontinuation
Rechallenge is an individualized risk–benefit decision, not an automatic consequence of recovery. Consider: irAE type, grade, and severity; whether the event was life-threatening; speed and completeness of recovery; requirement for multiple or prolonged immunosuppressants; risk of irreversible organ injury; tumor response and current cancer status; available alternative anticancer therapies; anticipated benefit from further ICI; patient goals and preferences. For many grade 2 irAEs, rechallenge may be considered after recovery to grade ≤1 and when systemic corticosteroids are reduced to approximately prednisone ≤10 mg/day or equivalent. Rechallenge after grade 3 toxicity requires substantially greater caution and multidisciplinary review. Grade 4 toxicity generally warrants permanent ICI discontinuation, except selected endocrinopathies controlled with hormone replacement. Organ-specific rules override this general framework.
-
Chronic IrAE and endocrine replacement follow-Up
Recognize that some irAEs persist after ICI discontinuation or require long-term therapy. Distinguish: Chronic active irAE persistent immune-mediated inflammation requiring ongoing immunosuppression or other active therapy. Chronic inactive irAE persistent organ dysfunction without ongoing active inflammation, such as many endocrine deficiencies. Management may include: long-term specialty follow-up; steroid-sparing immunomodulatory treatment when appropriate; rehabilitation and supportive care; monitoring for late sequelae; permanent hormone replacement for selected endocrine irAEs. Do not maintain systemic corticosteroids solely to treat a stable endocrine hormone deficiency.
-
Organ-specific subalgorithms
Use the appropriate organ-specific pathway for detailed diagnostic work-up, treatment, escalation, and rechallenge guidance: Dermatologic Gastrointestinal / colitis Hepatic Pulmonary / pneumonitis Endocrine Cardiac Neurologic / neuromuscular Renal Rheumatologic / musculoskeletal Hematologic Ocular Organ-specific guidance supersedes the general master pathway when management differs.
-
Evaluate suspected irAE and exclude mimics
Evaluate the suspected irAE while actively excluding alternative etiologies. Consider: infection; cancer progression or organ involvement by malignancy; toxicity from chemotherapy, targeted therapy, radiation, or other medications; thromboembolic or vascular disease; metabolic abnormalities; endocrine causes; pre-existing autoimmune or organ-specific disease; other common non-treatment-related diagnoses. Use focused laboratory testing, imaging, cultures, endoscopy, biopsy, or specialist-directed testing according to the organ system involved. Do not assume every new symptom during ICI therapy is immune-mediated.
-
Identify affected organ system(s) and grade severity
Identify all potentially involved organ systems and assess severity using current CTCAE criteria together with clinical judgment and organ-specific guidance. Determine whether toxicity is: single-organ or multisystem; mild and stable; clinically significant but not immediately life-threatening; severe, rapidly progressive, or life-threatening. Particular caution is required for cardiac, neurologic, neuromuscular, hematologic, pulmonary, and selected ocular toxicities, in which apparently modest symptoms may precede rapid deterioration. Evaluate for overlapping myocarditis–myositis–myasthenia-like syndromes when clinically suspected. Proceed to the appropriate grade-based pathway and the corresponding organ-specific algorithm.
-
Grade 1
Most grade 1 irAEs: continue ICI; provide symptomatic/supportive care; monitor closely for progression; repeat relevant laboratory or clinical assessment as appropriate. Important exception: do not apply a “continue ICI” rule automatically to potentially high-risk cardiac, neurologic, hematologic, neuromuscular, or selected other organ toxicities. Escalate promptly if symptoms or laboratory abnormalities worsen. Endocrine irAEs may require hormone replacement even when symptoms are mild.
-
Grade 2
For most grade 2 irAEs: temporarily hold ICI; initiate organ-specific diagnostic work-up; involve the appropriate specialist when indicated; provide supportive care. If systemic corticosteroids are indicated, a common starting approach is: Prednisone 0.5–1 mg/kg/day or equivalent depending on the organ toxicity and clinical severity. Not every grade 2 irAE requires corticosteroids. Endocrine toxicities, for example, are often managed primarily with hormone replacement. Reassess within the organ-specific timeframe and escalate if the patient deteriorates.
-
Clinical improvement within organ-specific reassessment window?
Reassess clinical symptoms, examination findings, and relevant laboratory or imaging parameters within the timeframe appropriate for the affected organ. Do not apply one reassessment interval to every irAE. For many severe irAEs, response should be apparent within approximately 48–72 hours. For life-threatening toxicities, failure to improve after approximately 1–3 days of appropriate therapy should prompt rapid treatment escalation. Some non-life-threatening toxicities may reasonably require a longer response window. Escalate earlier at any time if the patient is clinically deteriorating.
-
Improve, taper corticosteroids, and monitor
Once the irAE is clearly improving: transition from IV to oral corticosteroids when clinically appropriate; taper gradually; continue organ-specific clinical and laboratory monitoring; watch for recurrence during taper. For significant grade 2–3 inflammatory irAEs requiring systemic corticosteroids, tapering commonly occurs over at least 4–6 weeks, although duration must be individualized according to the organ involved and clinical course. During prolonged corticosteroid therapy: monitor glucose and blood pressure; assess infection risk; consider antimicrobial, gastrointestinal, and bone-protection strategies according to corticosteroid dose, duration, comorbidities, and local protocol. A recurrent flare during taper may require re-escalation and reassessment for steroid-dependent toxicity.
-
Recovered to Grade ≤1 or acceptable baseline?
Confirm that: symptoms have resolved to grade ≤1 or an acceptable stable baseline; relevant laboratory abnormalities are improving or stable; the patient no longer requires escalating immunosuppression; corticosteroid dose is sufficiently reduced for the specific toxicity and planned ICI strategy. Stable endocrine dysfunction controlled with hormone replacement may represent an acceptable baseline even if hormone replacement remains permanent. If clinically active toxicity persists, continue organ-specific follow-up and do not proceed automatically to rechallenge.
-
Rechallenge versus permanent discontinuation
Rechallenge is an individualized risk–benefit decision, not an automatic consequence of recovery. Consider: irAE type, grade, and severity; whether the event was life-threatening; speed and completeness of recovery; requirement for multiple or prolonged immunosuppressants; risk of irreversible organ injury; tumor response and current cancer status; available alternative anticancer therapies; anticipated benefit from further ICI; patient goals and preferences. For many grade 2 irAEs, rechallenge may be considered after recovery to grade ≤1 and when systemic corticosteroids are reduced to approximately prednisone ≤10 mg/day or equivalent. Rechallenge after grade 3 toxicity requires substantially greater caution and multidisciplinary review. Grade 4 toxicity generally warrants permanent ICI discontinuation, except selected endocrinopathies controlled with hormone replacement. Organ-specific rules override this general framework.
-
Chronic IrAE and endocrine replacement follow-Up
Recognize that some irAEs persist after ICI discontinuation or require long-term therapy. Distinguish: Chronic active irAE persistent immune-mediated inflammation requiring ongoing immunosuppression or other active therapy. Chronic inactive irAE persistent organ dysfunction without ongoing active inflammation, such as many endocrine deficiencies. Management may include: long-term specialty follow-up; steroid-sparing immunomodulatory treatment when appropriate; rehabilitation and supportive care; monitoring for late sequelae; permanent hormone replacement for selected endocrine irAEs. Do not maintain systemic corticosteroids solely to treat a stable endocrine hormone deficiency.
-
Steroid-refractory or steroid-dependent irAE
First confirm: correct diagnosis; adequate corticosteroid dose and route; adherence; exclusion of infection or another mimic; appropriate organ-specific reassessment. Steroid-refractory / steroid-unresponsive toxicity: inadequate clinical improvement despite appropriate corticosteroid therapy. Steroid-dependent toxicity: initial improvement occurs, but toxicity worsens or cannot be controlled during corticosteroid taper. Obtain urgent organ-specific specialist input and use organ-directed second-line immunosuppression rather than a one-size-fits-all approach. Examples include: infliximab or vedolizumab for selected immune-mediated colitis; mycophenolate mofetil for steroid-refractory immune-mediated hepatitis; IVIG and/or plasma exchange for selected severe neurologic or neuromuscular toxicities; other targeted immunomodulatory agents according to the affected organ and specialist guidance. Do not use infliximab as the default second-line agent for immune-mediated hepatitis.
-
Improve, taper corticosteroids, and monitor
Once the irAE is clearly improving: transition from IV to oral corticosteroids when clinically appropriate; taper gradually; continue organ-specific clinical and laboratory monitoring; watch for recurrence during taper. For significant grade 2–3 inflammatory irAEs requiring systemic corticosteroids, tapering commonly occurs over at least 4–6 weeks, although duration must be individualized according to the organ involved and clinical course. During prolonged corticosteroid therapy: monitor glucose and blood pressure; assess infection risk; consider antimicrobial, gastrointestinal, and bone-protection strategies according to corticosteroid dose, duration, comorbidities, and local protocol. A recurrent flare during taper may require re-escalation and reassessment for steroid-dependent toxicity.
-
Recovered to Grade ≤1 or acceptable baseline?
Confirm that: symptoms have resolved to grade ≤1 or an acceptable stable baseline; relevant laboratory abnormalities are improving or stable; the patient no longer requires escalating immunosuppression; corticosteroid dose is sufficiently reduced for the specific toxicity and planned ICI strategy. Stable endocrine dysfunction controlled with hormone replacement may represent an acceptable baseline even if hormone replacement remains permanent. If clinically active toxicity persists, continue organ-specific follow-up and do not proceed automatically to rechallenge.
-
Rechallenge versus permanent discontinuation
Rechallenge is an individualized risk–benefit decision, not an automatic consequence of recovery. Consider: irAE type, grade, and severity; whether the event was life-threatening; speed and completeness of recovery; requirement for multiple or prolonged immunosuppressants; risk of irreversible organ injury; tumor response and current cancer status; available alternative anticancer therapies; anticipated benefit from further ICI; patient goals and preferences. For many grade 2 irAEs, rechallenge may be considered after recovery to grade ≤1 and when systemic corticosteroids are reduced to approximately prednisone ≤10 mg/day or equivalent. Rechallenge after grade 3 toxicity requires substantially greater caution and multidisciplinary review. Grade 4 toxicity generally warrants permanent ICI discontinuation, except selected endocrinopathies controlled with hormone replacement. Organ-specific rules override this general framework.
-
Chronic IrAE and endocrine replacement follow-Up
Recognize that some irAEs persist after ICI discontinuation or require long-term therapy. Distinguish: Chronic active irAE persistent immune-mediated inflammation requiring ongoing immunosuppression or other active therapy. Chronic inactive irAE persistent organ dysfunction without ongoing active inflammation, such as many endocrine deficiencies. Management may include: long-term specialty follow-up; steroid-sparing immunomodulatory treatment when appropriate; rehabilitation and supportive care; monitoring for late sequelae; permanent hormone replacement for selected endocrine irAEs. Do not maintain systemic corticosteroids solely to treat a stable endocrine hormone deficiency.
-
Grade 3–4
Hold ICI and initiate urgent organ-specific management. Grade 3 toxicity consider hospitalization depending on organ system and clinical status; obtain urgent specialist input; for many active inflammatory irAEs, initiate prednisone or methylprednisolone 1–2 mg/kg/day or equivalent. Grade 4 toxicity usually requires hospitalization and intensive monitoring; generally warrants permanent ICI discontinuation. Major exception: selected endocrinopathies that are controlled with appropriate hormone replacement may not require permanent discontinuation. Some severe cardiac, neurologic, hematologic, pulmonary, or neuromuscular events may warrant permanent discontinuation even below grade 4.
-
Clinical improvement within organ-specific reassessment window?
Reassess clinical symptoms, examination findings, and relevant laboratory or imaging parameters within the timeframe appropriate for the affected organ. Do not apply one reassessment interval to every irAE. For many severe irAEs, response should be apparent within approximately 48–72 hours. For life-threatening toxicities, failure to improve after approximately 1–3 days of appropriate therapy should prompt rapid treatment escalation. Some non-life-threatening toxicities may reasonably require a longer response window. Escalate earlier at any time if the patient is clinically deteriorating.
-
Improve, taper corticosteroids, and monitor
Once the irAE is clearly improving: transition from IV to oral corticosteroids when clinically appropriate; taper gradually; continue organ-specific clinical and laboratory monitoring; watch for recurrence during taper. For significant grade 2–3 inflammatory irAEs requiring systemic corticosteroids, tapering commonly occurs over at least 4–6 weeks, although duration must be individualized according to the organ involved and clinical course. During prolonged corticosteroid therapy: monitor glucose and blood pressure; assess infection risk; consider antimicrobial, gastrointestinal, and bone-protection strategies according to corticosteroid dose, duration, comorbidities, and local protocol. A recurrent flare during taper may require re-escalation and reassessment for steroid-dependent toxicity.
-
Recovered to Grade ≤1 or acceptable baseline?
Confirm that: symptoms have resolved to grade ≤1 or an acceptable stable baseline; relevant laboratory abnormalities are improving or stable; the patient no longer requires escalating immunosuppression; corticosteroid dose is sufficiently reduced for the specific toxicity and planned ICI strategy. Stable endocrine dysfunction controlled with hormone replacement may represent an acceptable baseline even if hormone replacement remains permanent. If clinically active toxicity persists, continue organ-specific follow-up and do not proceed automatically to rechallenge.
-
Rechallenge versus permanent discontinuation
Rechallenge is an individualized risk–benefit decision, not an automatic consequence of recovery. Consider: irAE type, grade, and severity; whether the event was life-threatening; speed and completeness of recovery; requirement for multiple or prolonged immunosuppressants; risk of irreversible organ injury; tumor response and current cancer status; available alternative anticancer therapies; anticipated benefit from further ICI; patient goals and preferences. For many grade 2 irAEs, rechallenge may be considered after recovery to grade ≤1 and when systemic corticosteroids are reduced to approximately prednisone ≤10 mg/day or equivalent. Rechallenge after grade 3 toxicity requires substantially greater caution and multidisciplinary review. Grade 4 toxicity generally warrants permanent ICI discontinuation, except selected endocrinopathies controlled with hormone replacement. Organ-specific rules override this general framework.
-
Chronic IrAE and endocrine replacement follow-Up
Recognize that some irAEs persist after ICI discontinuation or require long-term therapy. Distinguish: Chronic active irAE persistent immune-mediated inflammation requiring ongoing immunosuppression or other active therapy. Chronic inactive irAE persistent organ dysfunction without ongoing active inflammation, such as many endocrine deficiencies. Management may include: long-term specialty follow-up; steroid-sparing immunomodulatory treatment when appropriate; rehabilitation and supportive care; monitoring for late sequelae; permanent hormone replacement for selected endocrine irAEs. Do not maintain systemic corticosteroids solely to treat a stable endocrine hormone deficiency.
-
Steroid-refractory or steroid-dependent irAE
First confirm: correct diagnosis; adequate corticosteroid dose and route; adherence; exclusion of infection or another mimic; appropriate organ-specific reassessment. Steroid-refractory / steroid-unresponsive toxicity: inadequate clinical improvement despite appropriate corticosteroid therapy. Steroid-dependent toxicity: initial improvement occurs, but toxicity worsens or cannot be controlled during corticosteroid taper. Obtain urgent organ-specific specialist input and use organ-directed second-line immunosuppression rather than a one-size-fits-all approach. Examples include: infliximab or vedolizumab for selected immune-mediated colitis; mycophenolate mofetil for steroid-refractory immune-mediated hepatitis; IVIG and/or plasma exchange for selected severe neurologic or neuromuscular toxicities; other targeted immunomodulatory agents according to the affected organ and specialist guidance. Do not use infliximab as the default second-line agent for immune-mediated hepatitis.
-
Improve, taper corticosteroids, and monitor
Once the irAE is clearly improving: transition from IV to oral corticosteroids when clinically appropriate; taper gradually; continue organ-specific clinical and laboratory monitoring; watch for recurrence during taper. For significant grade 2–3 inflammatory irAEs requiring systemic corticosteroids, tapering commonly occurs over at least 4–6 weeks, although duration must be individualized according to the organ involved and clinical course. During prolonged corticosteroid therapy: monitor glucose and blood pressure; assess infection risk; consider antimicrobial, gastrointestinal, and bone-protection strategies according to corticosteroid dose, duration, comorbidities, and local protocol. A recurrent flare during taper may require re-escalation and reassessment for steroid-dependent toxicity.
-
Recovered to Grade ≤1 or acceptable baseline?
Confirm that: symptoms have resolved to grade ≤1 or an acceptable stable baseline; relevant laboratory abnormalities are improving or stable; the patient no longer requires escalating immunosuppression; corticosteroid dose is sufficiently reduced for the specific toxicity and planned ICI strategy. Stable endocrine dysfunction controlled with hormone replacement may represent an acceptable baseline even if hormone replacement remains permanent. If clinically active toxicity persists, continue organ-specific follow-up and do not proceed automatically to rechallenge.
-
Rechallenge versus permanent discontinuation
Rechallenge is an individualized risk–benefit decision, not an automatic consequence of recovery. Consider: irAE type, grade, and severity; whether the event was life-threatening; speed and completeness of recovery; requirement for multiple or prolonged immunosuppressants; risk of irreversible organ injury; tumor response and current cancer status; available alternative anticancer therapies; anticipated benefit from further ICI; patient goals and preferences. For many grade 2 irAEs, rechallenge may be considered after recovery to grade ≤1 and when systemic corticosteroids are reduced to approximately prednisone ≤10 mg/day or equivalent. Rechallenge after grade 3 toxicity requires substantially greater caution and multidisciplinary review. Grade 4 toxicity generally warrants permanent ICI discontinuation, except selected endocrinopathies controlled with hormone replacement. Organ-specific rules override this general framework.
-
Chronic IrAE and endocrine replacement follow-Up
Recognize that some irAEs persist after ICI discontinuation or require long-term therapy. Distinguish: Chronic active irAE persistent immune-mediated inflammation requiring ongoing immunosuppression or other active therapy. Chronic inactive irAE persistent organ dysfunction without ongoing active inflammation, such as many endocrine deficiencies. Management may include: long-term specialty follow-up; steroid-sparing immunomodulatory treatment when appropriate; rehabilitation and supportive care; monitoring for late sequelae; permanent hormone replacement for selected endocrine irAEs. Do not maintain systemic corticosteroids solely to treat a stable endocrine hormone deficiency.
-
Organ-specific subalgorithms
Use the appropriate organ-specific pathway for detailed diagnostic work-up, treatment, escalation, and rechallenge guidance: Dermatologic Gastrointestinal / colitis Hepatic Pulmonary / pneumonitis Endocrine Cardiac Neurologic / neuromuscular Renal Rheumatologic / musculoskeletal Hematologic Ocular Organ-specific guidance supersedes the general master pathway when management differs.