Transcript A Clinical Trial

Improved Survival with Ipilimumab
in Patients with Metastatic
Melanoma
Melanoma
… the lymphatic system.
Melanin is a natural pigment formed in the body by specialized cells called melanocytes.
Melanin provides pigmentation for the iris, skin, hair – as well as other parts of the body.
Melanoma is a cancer whose primary cells are melanocytes.
Source: http://www.cancer.umn.edu/cancerinfo/NCI/CDR62713.html
Melanoma is a cancer of the melanocytes. Melanocytes become increasing deranged,
becoming dysfunctional, atypical and eventually malignant. Malignant cells are
characterized in terms of excessive reproduction, invasion and spread.
Cancer is typically staged from 0 to 4, depending on the locality of the cancer and
degree of malignancy of the cancer cells.
Stage 0 – Locally contained in the upper layers of the skin.
Stage I – The cancer penetrates more deeply into the upper layers of the skin and is
poised to spread more deeply.
Stage II: The cancer penetrates into the middle layers of the skin, the dermis, and is
poised to spread further.
Stage III: The cancer
has spread beyond
the skin to the lymph
nodes. The lymphatic
system gives access to
other parts of the
body.
Stage IV: The cancer has
spread to other organ
systems.
gp100: melanoma antigen
Glyco-protein gp100 is a protein expressed by melanoma cells – gp100 is an antigen – it can
provoke an immune response. In particular, there is interest in training the immune system
to aggressively react to gp100 via gp100-based vaccines.
gp100:209-217(210M) peptide vaccine
A synthetic peptide cancer vaccine consisting of amino acid residues 209 through 217 of the
glycoprotein 100 (gp100) melanoma antigen, with a methionine substitution at position 210
designed to improve immunogenicity. Vaccination with gp100:209-217(210M) peptide may
stimulate the host immune system to mount a cytotoxic T lymphocyte (CTL) response
against tumor cells expressing gp100.
http://www.cancer.gov/drugdictionary/?CdrID=476335
The purpose of this type of vaccine is to train the patient’s immune system to recognize
cancer cells as a threat, and to stimulate an immune response to the cancer.
ipilimumab (ih-pih-LIH-myoo-mab)
A monoclonal antibody being studied in the treatment of certain types of cancer. Ipilimumab
is made in the laboratory and binds to the molecule CTLA-4 on T cells (a type of white blood
cell). Ipilimumab may block CTLA-4 and help the immune system kill cancer cells. Also called
MDX-010.
Source: http://www.cancer.gov/dictionary/?CdrID=535555
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) limits the therapeutic potency of
cancer vaccines by decreasing T-cell function, which is critical in melanoma immunity.
Source: http://www.medscape.com/viewarticle/511624_2
The idea is that ipilimumab enhances the function of vaccines by blocking the ability of CTLA4 to interfere with T-cell function.
The study focused on people with stage III/IV melanoma, whose cancer was inoperable.
“Patients were randomly assigned, in a 3:1:1 ratio, to treatment with an induction course of
ipilimumab, at a dose of 3 mg per kilogram of body weight, plus a gp100 peptide vaccine;
ipilimumab plus gp100 placebo; or gp100 plus ipilimumab placebo — all administered once
every 3 weeks for four treatments. ”
Under a double-blinded design, the treatment groups involved three treatments:
Vaccine (gp100) plus CTLA-4 Blocker(ipilimumab)
Vaccine (gp100) plus PlaceboCTLA-4 Blocker(ipilimumab)
PlaceboVaccine (gp100) plus CTLA-4 Blocker(ipilimumab)
Enrolled subjects, having given informed consent, are randomly assigned to a single
treatment group. In a double-blinded study, neither the subjects nor the clinical personnel
know the individual treatment assignments.
Primary Endpoint: Overall Survival Time
The basic standard of benefit considered was overall survival – there are two measures of
overall survival.
Survival Rate: By the end of the study, what proportion of each treatment group survived?
Survival Time: Among the subjects who died during the study, what was the distribution of
time-to-death?
An alternative to Overall Survival is Progression Free Survival, which considers time in
stage rather than survival time. Some treatments may give patients more time at less
severe stages of disease without extending overall survival time.
“Survival was defined as the time from randomization to death from any cause, and
progression-free survival as the time from randomization to documented disease
progression or death. ”
Other endpoints include safety and toxicity. The treatments themselves may have side
effects and toxicity, up to and including severe/fatal risks.
hazard ratio
A measure of how often a particular event happens in one group compared to how
often it happens in another group, over time.
In cancer research, hazard ratios are often used in clinical trials to measure survival at
any point in time in a group of patients who have been given a specific treatment
compared to a control group given another treatment or a placebo.
A hazard ratio of one means that there is no difference in survival between the two
groups.
A hazard ratio of greater than one or less than one means that survival was better in
one of the groups.
Source: http://www.cancer.gov/dictionary/?CdrID=618612
Safety Considerations: Adverse Events
“Adverse events were graded according to the National Cancer Institute's Common
Terminology Criteria for Adverse Events, version 3.0. An immune-related adverse event
was defined as an adverse event that was associated with exposure to the study drug
and that was consistent with an immune phenomenon. Protocol guidelines for the
management of immune-related adverse events included the administration of
corticosteroids (orally or intravenously), a delay in a scheduled dose, or discontinuation
of therapy. Assigned doses were delayed in the case of nondermatologic immunerelated adverse events of grade 2 or higher until the event improved to grade 1 or
lower; if the event did not improve to grade 1 or lower, treatment was discontinued
permanently. Monitoring of adverse events continued for at least 70 days after the last
dose of study drugs had been administered or until any ongoing event resolved or
stabilized. All patients, including those with low-grade changes in bowel frequency or
stool consistency, were followed closely. A data and safety monitoring committee
provided independent oversight of safety and the risk–benefit ratio. ”
Safety Considerations: Stopping Rules
“During the study enrollment, the following stopping rule was in place: if 10% or more of the
patients in any study treatment group, evaluated cumulatively every 3 months, had a
nondermatologic-related toxic adverse event of grade 3 or higher that was attributable to the
investigational agents and that could not be alleviated or controlled by appropriate care or
corticosteroid therapy within 14 days after the initiation of supportive care or corticosteroid
therapy, assignment of patients to that study group would be suspended until the sponsor and
the data and safety monitoring committee had reviewed the events and determined the
appropriate course of action. “
Figure 1. Kaplan-Meier Curves for Overall Survival and Progression-free Survival in the Intentionto-Treat Population.
The median follow-up for overall survival (Panel A) in the ipilimumab (Ipi)-plus-glycoprotein 100
(gp100) group was 21.0 months, and the median overall survival was 10.0 months (95% CI, 8.5
to 11.5);
in the ipilimumab-alone group, the median follow-up was 27.8 months, and the median overall
survival, 10.1 months (95% CI, 8.0 to 13.8); and in the gp100-alone group, the median follow-up
was 17.2 months, and the median overall survival, 6.4 months (95% CI, 5.5 to 8.7).
The median progression-free survival (Panel B) was 2.76 months (95% CI, 2.73 to 2.79) in the
ipilimumab-plus-gp100 group, 2.86 months (95% CI, 2.76 to 3.02) in the ipilimumab-alone
group, and 2.76 months (95% CI, 2.73 to 2.83) in the gp100-alone group.
The rates of progression-free survival at week 12 were 49.1% (95% CI, 44.1 to 53.9) in the
ipilimumab-plus-gp100 group, 57.7% (95% CI, 48.9 to 65.5) in the ipilimumab-alone group, and
48.5% (95% CI, 39.6 to 56.7) in the gp100-alone group.
Kaplan-Meier Curves for Overall Survival and Progression-free Survival in the Intention-to-Treat
Population
Hodi F et al. N Engl J Med 2010;10.1056/NEJMoa1003466
Figure 2. Subgroup Analyses of Overall Survival.
The pre-specified analyses of overall survival among subgroups of patients, as defined by
baseline demographic characteristics and stratification factors (metastasis [M] stage, classified
according to the tumor-node-metastasis [TNM] categorization for melanoma of the American
Joint Committee on Cancer; and receipt or nonreceipt of interleukin-2 therapy), showed that
hazard ratios were lower than 1 (indicating a lower risk of death) for each subgroup in the
ipilimumab (Ipi)-plus-glycoprotein 100 (gp100) group as compared with the gp100-alone group
(Panel A) and
for each subgroup in the ipilimumab-alone group as compared with the gp100-alone group
(Panel B).
Hazard ratios were estimated with the use of unstratified Cox proportional-hazards models.
Horizontal lines represent 95% confidence intervals. LDH denotes lactate dehydrogenase, and
ULN the upper limit of the normal range.
Subgroup Analyses of Overall Survival
Hodi F et al. N Engl J Med 2010;10.1056/NEJMoa1003466
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
F. Stephen Hodi, M.D., Steven J. O'Day, M.D., David F. McDermott, M.D., Robert W. Weber, M.D., Jeffrey A.
Sosman, M.D., John B. Haanen, M.D., Rene Gonzalez, M.D., Caroline Robert, M.D., Ph.D., Dirk
Schadendorf, M.D., Jessica C. Hassel, M.D., Wallace Akerley, M.D., Alfons J.M. van den Eertwegh, M.D.,
Ph.D., Jose Lutzky, M.D., Paul Lorigan, M.D., Julia M. Vaubel, M.D., Gerald P. Linette, M.D., Ph.D., David
Hogg, M.D., Christian H. Ottensmeier, M.D., Ph.D., Celeste Lebbé, M.D., Christian Peschel, M.D., Ian Quirt,
M.D., Joseph I. Clark, M.D., Jedd D. Wolchok, M.D., Ph.D., Jeffrey S. Weber, M.D., Ph.D., Jason Tian, Ph.D.,
Michael J. Yellin, M.D., Geoffrey M. Nichol, M.D., Axel Hoos, M.D., Ph.D., and Walter J. Urba, M.D., Ph.D.
Published at www.nejm.org June 5, 2010
(10.1056/NEJMoa1003466)
ABSTRACT
Background An improvement in overall survival among patients with metastatic melanoma
has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic Tlymphocyte–associated antigen 4 to potentiate an antitumor T-cell response —
administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared
with gp100 alone in patients with previously treated metastatic melanoma.
Methods
A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma,
whose disease had progressed while they were receiving therapy for metastatic disease,
were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients),
ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram
of body weight, was administered with or without gp100 every 3 weeks for up to four
treatments (induction). Eligible patients could receive reinduction therapy. The primary end
point was overall survival.
Results
The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100,
as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death,
0.68; P<0.001).
The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in
the comparison with gp100 alone, 0.66; P=0.003).
No difference in overall survival was detected between the ipilimumab groups (hazard ratio with
ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in
10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone.
There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immunerelated adverse events.
Conclusions
Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved
overall survival in patients with previously treated metastatic melanoma.
Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate
treatment. (ClinicalTrials.gov number, NCT00094653 [ClinicalTrials.gov] .)