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Clinical Trial
. 2019 Jan 15;25(2):524-532.
doi: 10.1158/1078-0432.CCR-18-2258. Epub 2018 Nov 12.

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

Ahmad A Tarhini  1   2 , Sandra J Lee  3 , Xiaoxue Li  4 , Uma N M Rao  2 , Arun Nagarajan  5 , Mark R Albertini  6 , Jerry W Mitchell Jr  7 , Stuart J Wong  8 , Mark A Taylor  9 , Noel Laudi  10 , Phu V Truong  11 , Robert M Conry  12 , John M Kirkwood  2
Affiliations
Clinical Trial

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

Ahmad A Tarhini et al. Clin Cancer Res. .

Abstract

Purpose: Interferon-α 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-α (HDI) showed promising efficacy, supporting this hypothesis.

Patients and methods: E3611 followed a 2-by-2 factorial design (A: ipi10+HDI; B: ipi10; C: ipi3+HDI; 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 = 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-α or a higher dose of ipilimumab did not reach statistical significance and do not outweigh the added toxicity risks.

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Conflict of interest statement

Conflicts of Interest:

The rest of the authors declare no potential conflicts of interest relevant to the study.

Figures

Figure 1:
Figure 1:
E3611: Study Schema, phase II randomized trial of of ipilimumab at 3 mg/kg or 10 mg/kg alone or in combination with high dose interferon-α in advanced melanoma
Figure 2:
Figure 2:
E3611 Consort diagram. The 2 additional patients analyzed for toxicity but not efficacy were enrolled and treated on Arm C, but later found to be ineligible
Figure 3a:
Figure 3a:
Kaplan-Meier plots of progression-free survival (PFS) by treatment arm
Figure 3b:
Figure 3b:
Kaplan-Meier plots of progression-free survival (PFS) by HDI treatment status
Figure 3c:
Figure 3c:
Kaplan-Meier plot of progression-free survival (PFS) all patients
Figure 4:
Figure 4:
E3611: Kaplan-Meier plots of overall survival (OS) by treatment arm
See this image and copyright information in PMC

References

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    1. Hodi FS, et al., Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 2010. 363(8): p. 711–23. - PMC - PubMed

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