Immunotherapy rechallenge should be carried out with close follow-up to look-out for recurrent symptoms. The patient’s tumour status should be assessed before restarting therapy; immunotherapy should not be resumed if there is a high probability of toxicity recurrence.

Considering retreatment following recovery from an immune-related adverse event (irAE) is a common clinical scenario, however, close follow-up should be performed to look-out for recurrent symptoms.

Principles of Immunotherapy Rechallenge

The immunotherapy should be permanently discontinued if the toxicity returns on resuming immunotherapy. The patient’s tumour status should be assessed before restarting therapy and the patient should be educated regarding the risk/benefits of resuming immunotherapy. If an objective response was achieved to immune checkpoint inhibitor (ICI) therapy, there is a high probability of toxicity recurrence and hence immunotherapy should not be resumed.

The NCCN clinical practice guidelines lists out the following points when considering immunotherapy rechallenge after irAE:

• If a patient experiences moderate or severe irAE with a particular class of immunotherapy, then permanent discontinuation of that particular class is advised.
• In cases where the grade 2 irAEs are resolved to ≤ grade 1, resumption of immunotherapy can be considered.
• Organ-specific specialist should be consulted prior to resuming immunotherapy after an immunotherapy hold due to irAEs.

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Organ-specific recommendations for immunotherapy rechallenge after a hold

Skin

In cases with maculopapular rash or pruritus, rechallenge can be considered once skin condition is mild/localised (≤ grade 1) with only topical interventions indicated. Immunotherapy should be permanently discontinued in severe bullous skin diseases such as Stevens Johnson syndrome (SJS); TEN (Lyell's disease).

Gastrointestinal

In cases with grade 2-3 colitis due to PD-1/PD-L1 inhibitors, immunotherapy can be restarted after the symptoms have resolved to ≤ grade 1. In cases where the steroids cannot be completely tapered off, immunotherapy can be resumed while the patient is still on ≤10 mg prednisone equivalent daily.

CTLA-4 agents should be discontinued in serious or life-threatening irAEs. Attempts to make up for the missed dose due to irAE are not recommended.

Liver

In cases with transaminitis without elevated bilirubin (grade 2 irAE), immunotherapy can be resumed after the ALT/AST return to baseline, and steroids (if used) tapered to ≤10 mg prednisone equivalent daily. However, in cases with serious or life-threatening hepatitis, immunotherapy should be permanently discontinued.

Pancreas

In cases with symptomatic grade 2 pancreatitis, immunotherapy can be restarted if there is no evidence of pancreatitis ± improvement in amylase and lipase. In cases with severe pancreatitis (grade 3-4), it is recommended to discontinue therapy.

Endocrine

Therapy discontinuation is not required for hypothyroidism; however, immunotherapy should be halted in hypothyroidism cases with symptoms which resemble Graves’s disease. The therapy can be resumed after symptoms and thyroid function tests improve.

In cases with primary adrenal insufficiency, immunotherapy can be resumed after appropriate replacement endocrine therapy is initiated.

Immunotherapy can be continued, in cases with hypophysitis (without symptomatic pituitary swelling) due to TSH deficiency or gonad stimulating hormones. The replacement endocrine therapy should, however, be regulated. When hypophysitis occurs with pituitary swelling, the immunotherapy should be halted until the symptoms resolve.

In cases of Type 1 diabetes with diabetic ketoacidosis (DKA), the immunotherapy can be resumed after DKA and glucose levels are stabilised.

Lung

Immunotherapy should be kept on hold in progressive grade 1 pneumonitis; therapy can be resumed once it resolves to ≤ grade 1 and steroid therapy is stopped. In cases with severe pneumonitis, immunotherapy should be permanently discontinued.

Kidney

Immunotherapy should be kept on hold in grade 1-2 renal irAE. Therapy can be resumed once resolved to ≤ grade 1. Concomitant administration of steroid should be considered if creatinine is stable. In cases with severe proteinuria, immunotherapy should be permanently discontinued.

Eye

Immunotherapy should be kept on hold in cases with grade 2 irAE; therapy can be resumed once it resolves to ≤ grade 1, after consultation with an ophthalmologist. In cases with severe uveitis or episcleritis, immunotherapy should be permanently discontinued.

Nervous system

Therapy can be resumed, after considering steroid responsiveness, for moderate (grade 2) AE in myasthenia gravis. In peripheral neuropathy, immunotherapy should be kept on hold for grade 1-2 AE and therapy can be resumed once it resolves to ≤ grade 1 or the patient has well-controlled isolated painful sensory neuropathy. For mild to moderate AEs in aseptic meningitis, therapy can be resumed if symptoms resolve to grade 0.

Immunotherapy should be permanently discontinued in below cases:

• Moderate to severe encephalitis
• Myasthenia gravis; grade 3-4 AE
• Any grade Guillain–Barré syndrome
• Any grade transverse myelitis

Cardiovascular

For grade 1 myocarditis, immunotherapy can be resumed after resolution of symptoms; permanent discontinuation is recommended in grade 2-4 myocarditis.

Musculoskeletal

For inflammatory arthritis with moderate to severe AEs, immunotherapy can be resumed after the symptoms are effectively managed. Immunotherapy should be permanently discontinued in cases with severe inflammatory arthritis.