Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609
- Study type
- Clinical trial
- Study name
- E1609
- Phase
- Phase 3
- Design
- Three-arm randomised phase 3 trial (1:1:1 ratio) with central randomisation and a two-step hierarchical evaluation (first ipi3 versus HDI, then ipi10 versus HDI)
- Sample size
- 1,670 adult patients (ipi3: 523, HDI: 636, ipi10: 511)
- Source
- JCO · 2020
- Trial registration
- NCT01274338
In plain words
In this large study, people whose high-risk melanoma had been removed by surgery received one of three add-on treatments: ipilimumab at a dose of 3 or 10 mg per kg, or high-dose interferon. Ipilimumab at 3 mg per kg led to better survival than interferon and also caused fewer severe side effects. The 10 mg per kg dose was more toxic and was not significantly better than interferon.
Key results
Treatment arms and regimens
Induction: ipilimumab 3 mg/kg IV (90-minute infusion) on day 1 every 21 days for 4 cycles. Maintenance: from week 24, ipilimumab 3 mg/kg IV every 90 days for up to 4 cycles; in the absence of relapse or unacceptable toxicity.
Induction: ipilimumab 10 mg/kg IV (90-minute infusion) on day 1 every 21 days for 4 cycles. Maintenance: from week 24, ipilimumab 10 mg/kg IV every 90 days for up to 4 cycles; in the absence of relapse or unacceptable toxicity.
Induction: high-dose interferon alfa-2b IV on days 1 to 5, 8 to 12, 15 to 19 and 22 to 26 (4 weeks). Maintenance: interferon alfa-2b subcutaneously on days 1, 3 and 5 each week for 48 weeks. The exact interferon dose is not stated in the abstract or the trial registration.
Source of the regimen details: Abstract of the paper and ClinicalTrials.gov NCT01274338 (arm schedules; the interferon dose is not stated in these sources)
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Patients aged 18 years or older (with separate arms for ages 12 to 17) with resected stage IIIB, IIIC or IV cutaneous melanoma (M1a or M1b only with normal LDH; metastases to skin, subcutaneous tissue, distant lymph nodes or lung) per AJCC 7th edition, disease-free on PET-CT or CT and brain imaging within 4 weeks before randomisation (ClinicalTrials.gov).
Endpoints
Two co-primary endpoints: overall survival (OS) and relapse-free survival (RFS). Safety, adverse events leading to discontinuation and patterns of salvage treatment after relapse were also assessed.
Safety and side effects
Treatment-related adverse events of grade ≥ 3 occurred in 37% of the ipi3 group, 79% of the HDI group and 58% of the ipi10 group. Adverse events leading to discontinuation were seen in 35%, 20% and 54% of patients, respectively.
Clinical significance and place in guidelines
According to the abstract, ipilimumab at 3 mg/kg was the first adjuvant melanoma therapy to show a significant overall survival improvement versus an active control regimen, and the approved 10 mg/kg dose was more toxic and not superior to HDI. The place of these regimens in current guidelines and the status of drug approvals should be checked separately.
Limitations
The RFS improvement for ipi3 versus HDI was not statistically significant. After relapse, use of ipilimumab and ipilimumab/anti-PD-1 was significantly more frequent in the HDI arm, which may affect the overall survival comparison. The ipi10 versus HDI comparison did not reach statistical significance.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.