Hyperacute toxicity with combination ipilimumab and anti-PD1 immunotherapy

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.