Immune-Related Toxicity and Time to Treatment Failure With Nivolumab Plus Ipilimumab in Advanced Melanoma


Key Points

  • Overall, 39% of patients with advanced melanoma received all four doses of nivolumab plus ipilimumab.
  • Clinically significant immune-related adverse events occurred in 91% of patients.

As reported in JAMA Oncology by Shoushtari et al, a single-center experience has shown a very high rate of clinically significant immune-related adverse events with nivolumab (Opdivo) plus ipilimumab (Yervoy) for advanced melanoma. Their findings suggest that the full course of four doses of combined therapy is generally not tolerated and may not be necessary to achieve clinical benefit.

Study Details

The study involved a prospective cohort of 64 patients in the CheckMate 218 expanded-access protocol enrolled between December 2014 and January 2016 at Memorial Sloan Kettering Cancer Center. Patients received nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg every 3 weeks for up to 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks or off-protocol pembrolizumab (Keytruda) at 2 mg/kg every 3 weeks until unacceptable toxic effects, disease progression, or complete response.

Clinically significant immune-related adverse events were defined as Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher or any immune-related adverse events requiring systemic steroids; as noted by the investigators, clinical trials assessing this combination, and other immune checkpoint inhibitors, have assessed toxicity using CTCAE, which may underestimate the incidence of clinically significant immune-related adverse events. Time to treatment failure was the interval between initiating therapy and the earliest of clinical disease progression, new locally directed or systemic treatment other than anti–programmed cell death protein 1 (PD-1) monotherapy, or death.

Treatment Course and Time to Failure

Overall, 25 patients (39%) received all 4 doses of nivolumab plus ipilimumab. Of the remaining 39 patients, 11 (17%) received 3 doses, 20 (31%) received 2 doses, and 8 (13%) received 1 dose; among these patients, 31 (80%) received fewer than 4 doses due to toxicity. Among the patients who received fewer than 4 doses due to toxicity, 17 (54%) received anti–PD-1 monotherapy (median of 4 doses). A total of 31 patients (48%) received no maintenance anti–PD-1 therapy.

Among the 50 patients free of treatment failure at 12 weeks, there was no significant difference in the time to treatment failure between those who did (n = 34) and those who did not have treatment modified due to toxic effects (P = .95). The estimated 1-year treatment failure rate was 25% in each group.

Immune-Related Adverse Events

Overall, 58 patients (91%) had a clinically significant immune-related adverse event (median of 2 per patient), 46 (72%) required systemic steroids, and 16 (25%) required infliximab (Remicade) or mycophenolate for steroid-refractory immune-related events. Seven patients (11%) developed hyperglycemia, 32 (50%) had an emergency department visit, and 23 (36%) required hospital admission related to an immune-related adverse event. Among 31 patients stopping the combination treatment early due to toxic effects, 4 (13%) developed a new clinically significant immune-related event > 16 weeks after the last treatment.

The investigators concluded: “We observed a 91% incidence of clinically significant immune-related [adverse events] leading to frequent emergency department visits, hospitalizations, and systemic immunosuppression. Immuno-oncology trials should routinely report these metrics. Most patients do not tolerate four doses of [nivolumab plus ipilimumab]; however, four doses may not be required for clinical benefit.”

The study was supported by Bristol-Myers Squibb and the Memorial Sloan Kettering Cancer Center.

Alexander N. Shoushtari, MD, of the Memorial Sloan Kettering Cancer Center, is the corresponding author of the JAMA Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.