E3611—A Randomized Phase II Study of Ipilimumab at 3 or 10 mg/kg Alone or in Combination with High-Dose Interferon-α2b in Advanced Melanoma

Abstract

Purpose: Interferon-a favors a Th1 shift in immunity, and combining with ipilimumab (ipi) at 3 or 10 mg/kg may downregulate CTLA4-mediated suppressive effects, leading to more durable antitumor immune responses. A study of tremelimumab and high-dose interferon-a (HDI) showed promising efficacy, supporting this hypothesis. Patients and Methods: E3611 followed a 2-by-2 factorial design (A: ipi10þHDI; B: ipi10; C: ipi3þHDI; D: ipi3) to evaluate (i) no HDI versus HDI (across ipilimumab doses) and (ii) ipi3 versus ipi10 (across HDI status). We hypothesized that median progression-free survival (PFS) would improve from 3 to 6 months with HDI versus no HDI and with ipi10 versus ipi3. Results: For eligible and treated patients (N ¼ 81) at a median follow-up time of 29.8 months, median PFS was 4.4 months [95% confidence interval (CI), 2.7-8.2] when ipilimumab was used alone and 7.5 months (95% CI, 5.1-11.0) when HDI was added. Median PFS was 3.8 months (95% CI, 2.6-7.5) with 3 mg/kg ipilimumab and 6.5 months (95% CI, 5.1-13.5) with 10 mg/kg. By study arm, median PFS was 8.0 months (95% CI, 2.8-20.2) in arm A, 6.2 months (95% CI, 2.7-25.7) in B, 5.7 months (95% CI, 1.5-11.1) in C, and 2.8 months (95% CI, 2.6-5.7) in D. The differences in PFS and overall survival (OS) did not reach statistical significance. Adverse events were consistent with the known profiles of ipilimumab and HDI and significantly higher with HDI and ipi10. Conclusions: Although PFS was increased, the differences resulting from adding interferon-a or a higher dose of ipilimumab did not reach statistical significance and do not outweigh the added toxicity risks.

Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma

“…A recent phase II study in patients who received at least one previous treatment reported a nonstatistical dose effect on progression-free survival (PFS), but not OS. 18 In contrast, results from the study presented here showed a significant improvement in OS, but not PFS, with 10 mg/kg vs 3 mg/kg. 11 Taking these results together, further investigation is needed to answer the important question of potential ipilimumab efficacy and dose-dependency.…”

Immune checkpoint inhibitor‐associated pituitary‐adrenal dysfunction: A systematic review and meta‐analysis

“…In addition, 38 clinical trials with results from https://ClinicalTrials.gov were identified and included. Overall, we included a total of 160 clinical trials involving 40 432 patients in the meta‐analysis (Figure , Table ) . The trials include 37 phase 3 studies with 25 084 patients; 1 phase 2/3 study with 1033 patients; 66 phase 2 studies with 8529 patients; 11 phase 1/2 studies with 1263 patients; and 45 phase 1 studies with 4523 patients.…”

Interferon α in cancer immunoediting: From elimination to escape

“…Interestingly, the median overall survival of patients who received combination therapy was lower at 20.1 months (95% CI, 8.5‐33.6 months). In comparison, those who received ipilimumab alone reported median overall survival of 24.7 months (95% CI, 12.6‐35.7 months) . Although the data did not reach statistical significance, the modest improvement in clinical outcomes are in support of combination therapy of ipilimumab and recombinant IFNα‐2b.…”