The evidence supporting this protocol is provided by a randomised, double-blind, active-controlled (experimental vaccine gp100), phase III, multicentre study (MDX010-20) involving 676 patients comparing ipilimumab plus gp100; ipilimumab alone or gp100 alone in patients with unresectable metastatic melanoma. All patients were HLA-A*0201 positive and had previously received chemotherapy or IL-2. Exclusion criteria included ocular melanoma, a history of autoimmune disease, use of immunosuppressants or long-term corticosteroid use and untreated brain metastases.r
Between September 2004 and August 2008, 403 patients were randomised to receive ipilimumab 3 mg/kg plus gp100, 137 patients were randomised to receive ipilimumab 3 mg/kg alone and 136 patients were randomised to receive gp100 alone. Treatment was administered once every 3 weeks for a total of 4 doses.r
61% of patients randomised to ipilimumab-containing arms received all 4 doses. Patients with confirmed partial or complete response or stable disease for three months or more after completion of the 12 week induction period were allowed to receive reinduction with their original treatment if they subsequently had disease progression. Assessment of tumour response was conducted at weeks 12 and 24, and every 3 months thereafter.
The primary endpoint was overall survival in the ipilimumab plus gp100 arm vs. gp100 alone arm. Key secondary endpoints were overall survival in the ipilimumab plus gp100 arm vs. ipilimumab monotherapy arm; and with ipilimumab monotherapy arm vs. gp100 alone arm. Other secondary endpoints included best overall response rate up to week 24, the duration of response and progression-free survival.r
Long-term follow-up on smaller studies have been reported and shows that ipilimumab induces durable and potentially curative tumour regression in a small percentage of patients with metastatic melanoma.r
A pooled analysis of long-term survival data from phase II and phase III trials has added to the evidence supporting the durability of long-term survival in a proportion of ipilimumab-treated patients with advanced melanoma.r
Efficacy
In the ipilimumab alone group, 9 of 15 patients maintained an objective response for at least 2 years (26.5 to 44.2 months ongoing) and in the ipilimumab plus gp100 group 4 of 23 (17.4%) maintained an objective response for at least 2 years (27.9 to 44.4 months ongoing). Neither of the 2 patients in the gp100 group who had a partial response maintained the response for 2 years. Responses to ipilimumab continued to improve beyond week 24. Among 31 patients given reinduction therapy with ipilimumab a partial or complete response or stable disease was achieved by 21.The effect of ipilimumab on overall survival was independent of age, sex, baseline LDH, metastasis stage of disease and previous IL-2 therapy.r
The phase III trial limited enrolment to patients who were HLA-A*0201 positive because of the use of the gp100 vaccine. Retrospective analysis of 453 previously treated patients treated with ipilimumab in four phase II trials compared patients who were HLA-A*0201 positive with those who were HLA-A*0201 negative. In this analysis, ipilimumab had similar activity regardless of HLA type.r
Kaplan-Meier curve of (A) Overall survival and (B) Progression-free survivalr
© New England Journal of Medicine 2010
© New England Journal of Medicine 2010
Response/time to eventr |
Ipilimumab plus gp100
(n=403) |
Ipilimumab alone
(n=137) |
Gp100 alone
(n=136) |
Total no. of deaths |
306 |
100 |
119 |
Median overall survival |
10.0 months |
10.1 months |
6.4 months |
Comparison with gp100 alone |
HR 0.68 (0.55-0.85); p<0.001 |
HR 0.66 (0.51- 0.87); p=0.003 |
|
Comparison with ipilimumab alone |
HR 1.04 (0.83-1.30); p=0.76 |
|
|
Disease control rate |
20.1%
p=0.02 (compared to ipilimumab alone) |
28.5%
p<0.001 (compared to gp100 alone) |
11.0% |
Best overall response rate |
5.7%
p=0.04 (compared to ipilimumab alone) |
10.9%
p=0.001 (compared to gp100 alone) |
1.5% |
Median duration of response |
11.5 months |
NR |
NR |
NR: not reported
A primary analysis pooled overall survival data for 1861 patients from ten prospective and two retrospective studies of ipilimumab; this included two phase III trials. Patients were either previously treated (n=1257) or treatment naïve (n=604), and the majority of patients received ipilimumab 3 mg/kg (n=965) or ipilimumab 10 mg/kg (n=706).r The primary analysis demonstrated a median overall survival of 11.4 months (95% CI, 10.7 to 12.1 months), with a 3 year survival rate estimated to be 22% (95% CI, 20% to 24%). The primary analysis included 254 patients who were still alive at least 3 years after receiving their first dose of ipilimumab. The Kaplan-Meier overall survival curve showed that a plateau began around year 3 and extended up to year 10 in some patients.r
Kaplan-Meier curve of overall survival datar
© Journal of Clinical Oncology 2015
Toxicity
Immune related adverse events occurred in approximately 60% of patients treated with ipilimumab. Grade 3 to 4 toxicity was seen in 10-15% of those treated with ipilimumab compared to only 3% of those on gp100 alone. Immune related adverse events all occurred in the induction and reinduction periods but often did not occur until several weeks into treatment. The most common immune related side effects were those affecting the gastrointestinal tract and skin. In all, 7 deaths (out of a total of 14 attributed to the study drug) were related to immune toxicity. 6 of these were associated with gastrointestinal toxicity. One of these deaths was attributed to Guillain-Barre syndrome.r
Adverse eventsr
Ipilimumab 3 mg/kg |
All grades
(%) |
Grade 3/4
(%) |
Fatigue |
42 |
7 |
Diarrhoea
|
33 |
5 |
Decreased appetite |
27 |
1.5 |
Vomiting |
24 |
2 |
Abdominal pain |
15 |
1.5 |
Dyspnoea |
14.5 |
4 |
Immune-related event |
Pruritus |
24 |
0 |
Rash |
19 |
1 |
Diarrhoea |
27.5 |
5 |
Colitis
|
8 |
5 |
Endocrine |
8 |
4 |
Hepatic |
4 |
0 |