{"entity":{"id":"irae-rechallenge","kind":"protocol","name":"Restarting a checkpoint inhibitor after an immune-related side effect","aka":["immunotherapy rechallenge","ICI rechallenge","checkpoint inhibitor retreatment after irAE","resuming immunotherapy after toxicity","re-challenge after immune-related adverse event"],"tldr":"After an immunotherapy side effect has settled, your team may offer to restart the same treatment. About 3 in 10 people who restart have the same side effect again, and some side effects (such as heart or nerve inflammation, or very severe reactions) usually mean stopping for good. It is a shared decision that weighs the cancer benefit against the risk.","summary":"Rechallenge is considered once the toxicity has resolved to grade 1 or less and the patient needs no more than 10 mg prednisone a day (SITC 2021). SITC: after grade 2 irAEs, rechallenge may proceed once resolved or controlled on 10 mg/day or less (LE: 3); after grade 3 to 4, the decision is risk-adjusted (LE: 3). Factors against: severe or life-threatening irAEs, prolonged or multiple immunosuppressants, long prior treatment, and complete response or prolonged benefit. ASCO 2021 (abstract): consider resuming most grade 2 toxicities when grade 1 or less; permanently discontinue after grade 4, except endocrinopathies controlled by hormone replacement. ESE 2022: a controlled endocrinopathy is no contraindication (++00).\n\nOrgan rules in SITC: colitis needs a repeat endoscopy before resuming; pneumonitis after grade 2 only after complete resolution (LE: 4); myocarditis, Guillain-Barré syndrome and grade 3 to 4 myasthenia gravis lead to permanent or seriously considered permanent discontinuation. ADQI 2026 supports cautious rechallenge after kidney injury (recurrence under 20%).\n\nEvidence: a WHO pharmacovigilance cohort found the same irAE recurred in 28.8% of informative rechallenges, more often after colitis, hepatitis and pneumonitis and less often after adrenal events; two small SITC-cited series found 26 to 43% recurrence and 13 to 26% new irAEs.","asOf":"2026-11-11","links":[],"tags":["protocol","irae"],"related":["irae-colitis","irae-pneumonitis","irae-hepatitis","irae-myocarditis","irae-neurological","irae-nephritis","io-rechallenge-caution-rcc"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":[],"drugs":["pembrolizumab","nivolumab","ipilimumab","atezolizumab","durvalumab","cemiplimab","tremelimumab","avelumab","dostarlimab"],"companies":[],"institutions":["sitc","asco","esmo"],"pathways":[],"terms":["rechallenge","irae"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-asco-irae-guideline-jco-2021"],"journals":[],"dependsOn":[],"notes":[],"simple":"After a side effect from immunotherapy has settled, it may be possible to restart. Your team will talk through the benefits and risks with you.","domain":"immunotherapy-toxicity","setting":{"who":["doctor","patient-or-carer","multidisciplinary-team","nurse"],"where":["outpatient-clinic"]},"population":"Adults whose checkpoint inhibitor was paused for an immune-related adverse event that has since improved. Children are not addressed by these sources.","trigger":"An immune-related adverse event has improved to grade 1 or less and the patient's steroid dose is down to about 10 mg prednisone a day or less.","steps":[{"action":"Consider restarting once the side effect is grade 1 or less and the steroid dose is 10 mg prednisone a day or less","why":"Restarting while the inflammation is still active or on high-dose steroids risks a flare.","source":"sitc-2021","quote":"Once the toxicity has sufficiently resolved (generally to grade 1 symptoms or lower with ≤10 mg prednisone equivalents per day), patients may be re-challenged."},{"action":"After a grade 2 side effect, restart if it has resolved or is controlled on 10 mg prednisone a day or less","why":"Most moderate side effects can be managed if they return.","source":"sitc-2021","quote":"Unless otherwise specified, patients who have experienced grade 2 irAEs may be re-challenged with ICI therapy if their signs and symptoms have resolved or are controlled with ≤10 mg of prednisone (or equivalent) per day","grade":"LE: 3"},{"action":"After a grade 3 or 4 side effect, decide case by case, weighing the expected cancer benefit against the risk","why":"Severe side effects are more likely to return, but restarting may still be worthwhile for some.","source":"sitc-2021","quote":"The decision to re-challenge a patient who has experienced grade 3 or 4 irAEs should be risk-adjusted based on anticipated benefit with therapy versus the potential for toxicity","grade":"LE: 3"},{"action":"Weigh the factors against restarting: a severe or life-threatening side effect, long or multiple immunosuppressants, long prior treatment, and a complete or lasting response","why":"Someone whose cancer has already responded well may gain little from restarting and risk a lot.","source":"sitc-2021","quote":"Factors that may cause clinicians to lean away from re-challenge include severe or life-threatening irAEs, requirement for prolonged or multiple immunosuppressants, and a history of long-term ICI therapy and/or patients with complete responses or prolonged clinical benefit."},{"action":"Continue or restart treatment when an endocrine side effect is controlled with hormone replacement","why":"A hormone shortage that is replaced does not get worse with more immunotherapy.","source":"ese-2022","quote":"We recommend that a controlled endocrinopathy is not a contraindication for initiation and/or continuation of ICI therapy","grade":"++00"},{"action":"After colitis, repeat the endoscopy before restarting","why":"Bowel inflammation can persist without symptoms and is one of the side effects most likely to return.","source":"sitc-2021","quote":"Repeat endoscopy should be performed prior to resuming ICI therapy."},{"action":"After grade 2 pneumonitis, restart only once symptoms have completely resolved, with more frequent reviews","why":"Lung inflammation can recur and is among the commonest to come back.","source":"sitc-2021","quote":"If patients have experienced grade 2 pneumonitis, they may be re-challenged with ICIs upon complete resolution of symptoms. These patients should be monitored through more frequent consultations with their physician","grade":"LE: 4"},{"action":"Do not restart after Guillain-Barré syndrome, and seriously consider never restarting after myocarditis","why":"These side effects can be fatal if they return.","source":"sitc-2021","quote":"Patients diagnosed with Guillain-Barré syndrome should always permanently discontinue ICI therapy, and should receive IVIG or PLEX with corticosteroid therapy","grade":"LE: 1"},{"action":"Tell the patient that about 3 in 10 people have the same side effect again, more often after colitis, hepatitis or pneumonitis","why":"Knowing the size of the risk helps the patient decide and spot a recurrence early.","source":"vigibase-2020","quote":"This cohort study found a 28.8% recurrence rate of the same irAE associated with the discontinuation of ICI therapy after a rechallenge with the same ICI."},{"action":"After restarting, monitor closely for the side effect returning and treat it as before","why":"A recurrence caught early is easier to treat.","source":"sitc-2021","quote":"Close monitoring for recurrence of diarrhea or colitis symptoms is recommended after re-challenging patients with ICI therapy."}],"bestInClass":{"statement":"SITC 2021 (full text) gives the clearest rule: rechallenge after grade 2 once resolved or controlled on 10 mg prednisone a day or less (LE: 3), a risk-adjusted decision after grade 3 to 4 (LE: 3), and organ-specific exceptions. ASCO 2021 (abstract) is stricter at the top: permanent discontinuation after grade 4 in general, with controlled endocrinopathies the exception. ESE 2022 grades continuing through a controlled endocrinopathy ++00. ADQI 2026 supports cautious rechallenge after kidney injury. All rest on retrospective series and pharmacovigilance data; there are no randomised trials of rechallenge. ESMO 2022 could not be read.","sources":["sitc-2021","asco-2021","ese-2022","adqi-2026","vigibase-2020","esmo-2022"]},"variants":[{"name":"Permanent discontinuation after grade 4 (ASCO 2021)","differs":"Recommends permanent discontinuation after grade 4 toxicities in general, except endocrinopathies controlled by hormone replacement, where SITC leaves grade 3 to 4 as a risk-adjusted decision.","evidence":"Informal consensus of an expert panel after a systematic review; read as abstract only.","sources":["asco-2021"]},{"name":"Cautious rechallenge after kidney injury (ADQI 2026)","differs":"A nephrology consensus that supports rechallenge in selected patients after ICI-associated kidney injury, citing recurrence in fewer than 20%.","evidence":"Modified Delphi consensus; read as abstract only.","sources":["adqi-2026"]}],"grades":[{"claim":"Rechallenge after grade 2 once resolved or controlled on 10 mg prednisone a day or less","grade":"LE: 3","source":"sitc-2021"},{"claim":"Risk-adjusted rechallenge after grade 3 or 4","grade":"LE: 3","source":"sitc-2021"},{"claim":"Permanent discontinuation after grade 4, except controlled endocrinopathies","grade":"expert consensus","source":"asco-2021","quote":"In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement."},{"claim":"A controlled endocrinopathy is no contraindication to continuing","grade":"++00","source":"ese-2022"},{"claim":"Recurrence of the same irAE after rechallenge","grade":"observational (pharmacovigilance cohort)","source":"vigibase-2020","quote":"One hundred thirty recurrences (28.8%; 95% CI, 24.8-33.1) of the initial irAE were observed."}],"sources":[{"key":"sitc-2021","label":"Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events","publisher":"SITC, Journal for ImmunoTherapy of Cancer","year":2021,"url":"https://europepmc.org/article/PMC/PMC8237720","doi":"10.1136/jitc-2021-002435","gradingScheme":"Oxford Centre for Evidence-Based Medicine Levels of Evidence 2 (2016), printed after a recommendation as LE: 1 (systematic review) to LE: 5 (mechanism-based reasoning); a recommendation without an LE is expert consensus, approved by at least 75% of the voting panel.","read":"full-text","accessed":"2026-11-11"},{"key":"asco-2021","label":"Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update","publisher":"ASCO, Journal of Clinical Oncology","year":2021,"url":"https://europepmc.org/abstract/MED/34724392","doi":"10.1200/JCO.21.01440","gradingScheme":"The abstract states that, because high-quality evidence is scarce, the recommendations are based on expert consensus (informal consensus process).","read":"abstract","accessed":"2026-11-11"},{"key":"ese-2022","label":"Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline","publisher":"European Society of Endocrinology, European Journal of Endocrinology","year":2022,"url":"https://europepmc.org/article/PMC/PMC9641795","doi":"10.1530/EJE-22-0689","gradingScheme":"GRADE: quality of evidence printed as +000 (very low), ++00 (low), +++0 (moderate) or ++++ (strong); 'recommend' is a strong and 'suggest' a weak recommendation; recommendations not formally graded are marked good clinical practice.","read":"full-text","accessed":"2026-11-11"},{"key":"vigibase-2020","label":"Immune Checkpoint Inhibitor Rechallenge After Immune-Related Adverse Events in Patients With Cancer","publisher":"JAMA Oncology","year":2020,"url":"https://europepmc.org/abstract/MED/32297899","doi":"10.1001/jamaoncol.2020.0726","gradingScheme":"An observational pharmacovigilance cohort study (WHO VigiBase); not a guideline.","read":"abstract","accessed":"2026-11-11"},{"key":"adqi-2026","label":"Immune Checkpoint Inhibitor-Associated Acute Kidney Injury: A Report from the 34th Acute Disease Quality Initiative (ADQI) Consensus Conference","publisher":"Acute Disease Quality Initiative, Journal of the American Society of Nephrology","year":2026,"url":"https://europepmc.org/article/PMC/PMC13641466","doi":"10.1681/ASN.0000001232","gradingScheme":"Consensus statements reached by a modified Delphi method; the abstract does not give grades.","read":"abstract","accessed":"2026-11-11"},{"key":"esmo-2022","label":"Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","publisher":"ESMO, Annals of Oncology","year":2022,"url":"https://doi.org/10.1016/j.annonc.2022.10.001","doi":"10.1016/j.annonc.2022.10.001","read":"not-reachable","accessed":"2026-11-11"}],"upgrades":[],"gaps":["The ESMO 2022 guideline on toxicities from immunotherapy could not be read: Europe PMC holds no abstract and the publisher's page refused a script. Its grade-by-grade advice is not stated here and no step rests on it.","The ASCO 2021 guideline was read only as its abstract; its organ-by-organ resumption criteria are not compared here.","No randomised trial of rechallenge versus permanent discontinuation exists among the sources read; recurrence figures come from pharmacovigilance and small retrospective series, which may over- or under-count.","Whether switching to a different checkpoint inhibitor (for example from a combination to a PD-1 inhibitor alone) lowers the risk is not addressed by the sources read here."]},"route":"/protocols/irae-rechallenge/","neighbours":{"protocol":[{"id":"irae-haematological","kind":"protocol","name":"Blood side effects of checkpoint inhibitors: low platelets, haemolysis, neutropenia and marrow failure","route":"/protocols/irae-haematological/"},{"id":"irae-hepatitis","kind":"protocol","name":"Immune-mediated hepatitis from checkpoint inhibitors, by grade","route":"/protocols/irae-hepatitis/"},{"id":"irae-colitis","kind":"protocol","name":"Immune-related diarrhoea and colitis from checkpoint inhibitors, by grade","route":"/protocols/irae-colitis/"},{"id":"irae-myocarditis","kind":"protocol","name":"Immune-related myocarditis from checkpoint inhibitors","route":"/protocols/irae-myocarditis/"},{"id":"irae-pneumonitis","kind":"protocol","name":"Immune-related pneumonitis from checkpoint inhibitors, by grade","route":"/protocols/irae-pneumonitis/"},{"id":"irae-nephritis","kind":"protocol","name":"Kidney inflammation (immune-related nephritis) from checkpoint inhibitors","route":"/protocols/irae-nephritis/"},{"id":"irae-neurological","kind":"protocol","name":"Neurological side effects of checkpoint inhibitors: myasthenia gravis, Guillain-Barré syndrome, meningitis and encephalitis","route":"/protocols/irae-neurological/"},{"id":"irae-steroid-taper-and-pjp","kind":"protocol","name":"Steroid taper after immunotherapy side effects, with Pneumocystis prophylaxis and adrenal checks","route":"/protocols/irae-steroid-taper-and-pjp/"}],"pairing":[{"id":"io-rechallenge-caution-rcc","kind":"pairing","name":"Caution: PD-1 rechallenge after progression on immunotherapy (RCC)","route":"/pairings/io-rechallenge-caution-rcc/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}],"drug":[{"id":"atezolizumab","kind":"drug","name":"Atezolizumab","route":"/drugs/atezolizumab/"},{"id":"avelumab","kind":"drug","name":"Avelumab","route":"/drugs/avelumab/"},{"id":"cemiplimab","kind":"drug","name":"Cemiplimab","route":"/drugs/cemiplimab/"},{"id":"dostarlimab","kind":"drug","name":"Dostarlimab","route":"/drugs/dostarlimab/"},{"id":"durvalumab","kind":"drug","name":"Durvalumab","route":"/drugs/durvalumab/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"tremelimumab","kind":"drug","name":"Tremelimumab","route":"/drugs/tremelimumab/"}],"institution":[{"id":"asco","kind":"institution","name":"American Society of Clinical Oncology (ASCO)","route":"/institutions/asco/"},{"id":"esmo","kind":"institution","name":"European Society for Medical Oncology (ESMO)","route":"/institutions/esmo/"},{"id":"sitc","kind":"institution","name":"Society for Immunotherapy of Cancer","route":"/institutions/sitc/"}],"term":[{"id":"irae","kind":"term","name":"Immune-related adverse events (irAEs)","route":"/terms/irae/"},{"id":"rechallenge","kind":"term","name":"Rechallenge and retreatment","route":"/terms/rechallenge/"}],"paper":[{"id":"paper-asco-irae-guideline-jco-2021","kind":"paper","name":"ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors","route":"/key-papers/paper-asco-irae-guideline-jco-2021/"}]}}