2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Because of the specificity of the peptide vaccine for certain
histocompatibility receptor subtypes, enrollment was limited
to HLA-A*0201 patients. The study reported an objective
response rate of 16% for the combination compared with
6% for HD IL-2 alone. There were eight complete responses
(9%) in the combination arm, but only one (1%) among those
treated with IL-2 alone. There was a trend toward increased
overall survival (median 17.8 months vs. 11.1 months; p �
0.06), although the trial was not adequately powered to
assess this endpoint. The clinical significance of this finding
is uncertain, considering the relatively poor response rate
in patients treated with HD IL-2 alone, the current lack of
availability of the specific formulation of vaccine adjuvant
used in this trial, and the observations that this same
vaccine did not improve the efficacy of ipilimumab in a phase
III trial (see below).
Others have explored the efficacy of HD IL-2 in combination
with adoptive transfer of tumor derived–tumor reactive
T cells. These approaches have included preparative regimens
involving myeloablative chemotherapy with or without
total-body irradiation in order to delete host immune
cells and promote engraftment of adoptively transferred
tumor-reactive T cells. 14 Autologous hematopoietic progenitorcell
support was used in patients who received TBI. The
Surgery Branch of the National Cancer Institute recently
reported the combined results from three separate trials.
There were 52 objective responses in 93 patients (56%
response rate), including 20 (22%) complete responses. Complete
responses were ongoing at 37 months to 82 months in
19 of the 20 responders, and the 3- and 5-year actuarial
survival rates for patients achieving a complete response
were 100% and 93%, respectively. Efforts to confirm these
results at other centers, including in a proposed multicenter
trial, as well as to develop a more practical treatment
regimen are currently underway.
Ipilimumab
The CTLA-4 receptor on T lymphocytes is a negative
regulator of T-cell activation that blocks positive stimulatory
effects to these cells, mediated through their costimulatory
and antigen specific–T-cell receptors. The monoclonal antibodies
ipilimumab and tremelimumab bind to CTLA-4 and
thus prevent this feedback inhibition. Both have been studied
in patients with melanoma, with the most extensive data
and promising results being observed with ipilimumab.
Ipilimumab was studied in a placebo-controlled phase III
trial in which 676 patients with previously treated advanced
melanoma were randomly assigned in a 3:1:1 ratio to ipilimumab
plus gp100 peptide vaccine, ipilimumab alone or
gp100 vaccine alone. 15 Ipilimumab (3 mg/kg) and/or vaccine
were given every three weeks for four 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.
In this study, overall survival was significantly increased
in the two groups who received ipilimumab (median 10.0
months and 10.1 months vs. 6.4 months, in the ipilimumab
plus gp100, ipilimumab alone, and gp100 groups, hazard
ratios for death 0.68 and 0.66 compared with gp100 alone,
respectively). Treatment benefits appeared to be independent
of sex, age (� age 65 or � age 65), stage at presentation
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FLAHERTY, SOSMAN, AND ATKINS
(M0, M1a, and M1b compared with M1c), baseline lactate
dehydrogenase (LDH), or prior use of IL-2. Tumor response
rate was also significantly improved in both groups of
patients treated with ipilimumab compared with gp100
alone (5.7% and 10.9% vs. 1.5%, respectively). Further,
objective partial or complete responses were maintained for
at least 2 years in four of 23 (17%) patients treated with
ipilimumab plus gp100 and nine of 15 (60%) patients with
ipilimumab alone. Among 31 patients who initially received
ipilimumab either alone or with gp100 and then underwent
reinduction therapy with ipilimumab, six (21%) had an
objective response to retreatment, and 15 (48%) had stable
disease. Although this phase III trial limited enrollment to
patients who were HLA-A*0201 positive, a retrospective
analysis of four phase II trials involving ipilimumab alone
showed similar activity regardless of HLA type. Although
patients in this trial did not have tumor profiling for BRAF
mutations, limited unpublished data from Bristol-Myers
Squibb (BMS) suggests that the activity of ipilimumab is
independent of BRAF mutational status. As a consequence
of this study, ipilimumab was approved for the treatment of
all patients with advanced melanoma.
The presumed mechanism of action of ipilimumab is to
break down tolerance to tumor-associated antigens in the
melanoma. At the same time, this break down of tolerance
may result in autoimmune reactions against self-antigens. A
wide range of immune-mediated adverse events have been
observed. The most common, serious manifestations include
enterocolitis, hepatitis, dermatitis, and endocrinopathies. In
this trial using a 3 mg/kg dose of ipilimumab, immunerelated
adverse events occurred in approximately 60% of
patients treated with ipilimumab. Grade 3 or 4 toxicity was
seen in 10% to 15% of ipilimumab-treated patients, compared
to 3% of those receiving only gp100. These side effects
were typically not seen until 6 or more weeks into therapy.
A somewhat higher incidence of side effects was observed
with a dose of 10 mg/kg every 3 weeks in a randomized phase
II trial that assessed the effects of dose on activity and
toxicity. 16 Several investigators have suggested that the
development of immune-related toxicities correlated with
benefit from therapy.
Although patients with untreated brain metastases were
excluded from the phase III trial, other studies have observed
antitumor activity with ipilimumab for patients with
brain metastases. 17 Finally, data from phase II trials suggested
that a number of patients (up to 10% of those treated)
exhibited apparent disease progression after 12 weeks of
ipilimumab (with either larger lesions or new lesions),
followed by subsequent disease regression. The overall survival
outcome of these patients was similar to those exhibiting
a tumor response. This led to the establishment of
Immune-related Response Criteria that endeavored to capture
these patients in the subset of patients achieving
treatment benefit. 18
A second phase III trial involved previously untreated
patients who were randomly assigned to dacarbazine plus
either ipilimumab or placebo. 19 In this study, overall survival
was significantly increased in patients assigned to the
dacarbazine plus ipilimumab arm (median 11.2 months vs.
9.1 months). The overall incidence of grade 3 or 4 toxicity
was significantly higher with dacarbazine plus ipilimumab
(56% vs. 28%). In particular, hepatic toxicity was significantly
more common with the combination than with dacar-