Highlights
- •Patients may develop very early irAEs following combination immunotherapy.
- •Whether these are more difficult to manage or impact cancer outcome are unknown.
- •We studied hyperacute toxicity (grade 2+ toxicity within 21 days of first dose).
- •IrAEs were varied, often severe and further toxicities were common.
- •Efficacy was similar to trials, but greater immunosuppression had inferior outcomes.
Abstract
Background
Combination ipilimumab and nivolumab is approved for several malignancies. Toxicity
most often occurs 6–10 weeks into treatment. Whether very early toxicity is harder
to manage or influences efficacy is unknown.
Methods
Consecutive metastatic melanoma patients who developed hyperacute toxicity, defined
as Grade 2+ irAE within 21 days of receiving ipilimumab + anti-PD-1 were retrospectively
identified from nine centres.
Results
A total of 82 patients developed hyperacute toxicity (estimated incidence 9%), at
a median 10 days (range 1–21). Toxicities included colitis (N = 23), rash (17), hepatitis
(9), endocrine (9), pneumonitis (6) and neurotoxicity (4) and were G2 (38%), G3 (52%),
G4 (6%) and G5 (2% myocarditis). Fifty-nine percent required treatment beyond oral
steroids, including IV steroids (28%), infliximab and other immunosuppression (30%).
A total of 29% patients developed an additional hyperacute toxicity and 26% another
toxicity >21 days after treatment commencement but before further immunotherapy. The
objective response rate (ORR) was 54%, and after a median 11.6 mo follow-up, median
PFS was 7.4 mo. Increasing levels of immunosuppression was associated with a reduced
PFS (12-month PFS 62% no immunosuppression versus 49% oral steroids versus 33% IV
steroids versus 20% further immunosuppressants, p = 0.006). There was no significant
difference in ORR or PFS by duration of immunosuppression.
Conclusions
Hyperacute toxicities from combination immunotherapy have a wide spectrum and can
be severe. Many patients require significant immunosuppression for prolonged durations
and remain at risk of further severe toxicity. Melanoma outcomes in such patients
appear similar to those of trial populations, although greater immunosuppression requirements
may be associated with inferior outcomes.
Keywords
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Article info
Publication history
Published online: June 25, 2021
Accepted:
April 29,
2021
Received in revised form:
March 14,
2021
Received:
January 4,
2021
Identification
Copyright
© 2021 Elsevier Ltd. All rights reserved.
