5.3 Adverse reactions to checkpoint inhibitors

Adverse reactions related to immunotherapy with checkpoint inhibitors:

  • Anti CTLA-4
  • Anti PD-1
  • Anti PD-L1

When checkpoint inhibitors are used to treat cancer, it is not only the cancer cells that are affected by the increased immunological response, but it also slows down the natural inhibition of the immune system. This can create an imbalance in immunological self-tolerance with the risk of developing autoimmune-related adverse events (irAEs).

There are some organ systems that are more frequently affected by irAEs (rash, diarrhoea, hyperthyroidism/hypothyroidism and fatigue) than others , but all organ systems can be affected.

The vast majority of irAEs are reversible if treated in time. It is therefore important to respond early and adequately to irAEs. It is essential that the patient is well-informed and instructed to contact the outpatient clinic if irAEs1are suspected.

Grading of irAEs

irAEs are graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5, see section on adverse reactions to targeted treatment.

Frequency of irAEs (monotherapy vs. combination therapy)

There are more severe irAEs (imAEs) (grade 3-4) with combination immunotherapy (anti-CTLA-4+anti-PD-1) than with monotherapy2.

ALL GRADES OF IRAES GRADE 3/4 IRAES
CTLA-4 inhibition 60% to 85% 10% to 27%
PD-1/PD-L1 inhibition 58% to 85% 7% to 20%
Combination of CTLA-4/PD-1 inhibition 95% 55%

Combination therapy with CTLA/PD-1 inhibitors poses the greatest risk

Characteristics of irAEs4

  1. Several irAEs may occur in the same patient at the same time or intermittently over time
  2. Can be anything from transient to serious and life-threatening
  3. irAEs can occur even after cessation of treatment (even months after)

Managing immune-related adverse reactions5

The overall strategy for the management of irAEs is listed below, depending on the severity of irAEs. Treatment with immunosuppressive therapy, in the form of corticosteroids, constitutes a cornerstone in the treatment of irAEs.

GRADE OUTPATIENT/HOSPITALISATION CORTICOSTEROID:
PREDNISOLONE		 OTHER
IMMUNOSUPPRESSIVES		 IMMUNOTHERAPY
1 Outpatient – – Continuing
2 Outpatient Topical or systemic
0.5–1 mg/kg		 – Interrupt temporarily and usually resume
treatment at grade 0–1
3 Hospitalisation Systemic, oral or IV
1–2 mg/kg		 Consider if no
response after 3–5 days of corticosteroid treatmentConsult with specialist		 Interrupt and discuss
resumption based on individual assessment of the patient
4 Hospitalisation Systemic, IV
1–2 mg/kg		 Consider if no
response after 3–5 days of corticosteroid treatmentConsult with specialist		 Discontinue
IV

IV = intravenous; p.o. = peroral.

Guidelines for the evaluation and treatment of IrAEs2,5,6,7

Many guidelines have been drawn up for the assessment and treatment of irAEs (ESMO, NCCN, ASCO, etc.). A Danish guideline has also been developed for which an app, MyMedCards, has been created and can be downloaded free of charge:

Prevention and treatment of irAEs8

There are several factors involved in preventing irAEs and treating irAEs adequately, including identifying possible risk factors, training of patient/carer and doctors/nurses. See below.

Reference

  1. Poskow et al, NEJM 2018
  2. Haanen JB et al, ann oncol, 2017;28;IV 119–141
  3. Brahmer JR et, JCO 2018
  4. Nagai et al, Int J Clin Oncol 2018
  5. Immunotherapy is cancer treatment with a completely new adverse reaction profile. Kondrup et al. The Danish medical journal, Ugeskrift for læger. 2017
  6. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
  7. Management of Immunotherapy-Related Toxicities, Version 1,2019; Thompson JA. J Natl Compr Canc Netw. 2019.)
  8. Champiat et al, Ann Oncol 2016
Explore this chapter menu