Highlights
- •Combined immune checkpoint blockade is very efficacious to treat advanced melanoma.
- •Immune-related adverse drug reactions (ADR) are more frequent and more severe.
- •Frequencies of immune-related ADR in certain organs classes are not yet fully captured.
- •ADR treatment approach for combined therapy is principally similar to monotherapies.
- •Closer patient monitoring and longer follow-up after combined therapy is recommended.
Abstract
Background
Combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in
numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab
in advanced melanoma as first-ever approved therapies for combined ICB. However, gains
in efficacy must be balanced against a higher frequency and severity of adverse drug
reactions (ADR). Because delays in diagnosis and management might result in symptom
worsening and further complications, clinicians shall be well trained to identify
ADR promptly and monitor patients adequately. This paper reviews safety data assessed
by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and provides
a literature overview on published case reports for rare ADR with suspected potential
underreporting. Incidences and kinetics of immune-related ADR are described. Recommendations
for the evaluation and management of ADR are convened by an interdisciplinary expert
panel focusing on rare but clinically important side effects arising from combined
ICB.
Pooled safety data from 1551 patients with advanced melanoma, treated either with
3 mg/kg ipilimumab plus 1 mg/kg nivolumab (N = 407), or nivolumab alone (N = 787), or ipilimumab alone (N = 357) demonstrate that immune-related ADR occur more frequently for the combination,
with a shorter time-to-onset, and tend to be more severe. The majority of events is
reversible after systemic use of glucocorticoids, notably methylprednisolone or equivalents;
in certain cases of long-lasting and refractory immune toxicities, non-steroidal immunosuppressants
may be used, once ICB is interrupted or terminated. Combined ICB has considerable
toxicities, therefore close monitoring and high experience in diagnosis and treatment
of ADR is necessary.
Graphical abstract
Graphical Abstract
Keywords
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Article Info
Publication History
Published online: May 18, 2017
Accepted:
May 6,
2017
Received in revised form:
May 5,
2017
Received:
March 10,
2017
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
