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 Abeloff’s
Clinical
Oncology
Issue 2 - 2015
Immunotherapy for Melanoma
Mark Diamond, MD, PhD, Tara Gangadhar, MD, and Lynn M. Schuchter, MD
Recent advances in immunotherapy and molecularly targeted
therapy have dramatically altered the outlook for patients with
advanced melanoma. Emerging from an increased understanding of T-cell regulatory pathways, a novel class of antibody-based
therapeutics termed immune checkpoint inhibitors has been developed with the potential to induce durable disease control as
well as complete tumor regressions in a subset of patients that
previously had few therapeutic options. Ipilimumab, a monoclonal antibody (mAb) directed against cytotoxic T-lymphocyteassociated antigen 4 (CTLA-4) and the prototype immune checkpoint inhibitor, was the first therapy to demonstrate improved
overall survival in patients with unresectable or metastatic melanoma and achieved FDA approval for this indication in 2011.1
Since then, second-generation checkpoint inhibitors including
pembrolizumab and nivolumab, which target the programmed
cell death protein-1 (PD-1) pathway also expressed on T cells,2
have shown immense promise in clinical trials, leading to their
approval in late 2014. Herein, we review the current landscape of
immunotherapy for melanoma, with a focus on the checkpoint
inhibitors, and highlight some of the ongoing areas of investigation related to their use.
Rationale and Early Approaches
The foundation for immunotherapy lies in the ability of the immune system to recognize cancer cells on the basis of genetic
and epigenetic changes that accumulate during cancer development.3 Compared with other human cancers, malignant melanoma exhibits a particularly high prevalence of somatic mutations,
including a characteristic mutational signature likely related
to ultraviolet light exposure.4 Naturally occurring immune responses to melanoma are, in fact, often detected in patients3; and
although the presence of tumor-infiltrating lymphocytes (TILs)
in primary melanoma or lymph node metastases was found to
indicate a better prognosis,5-7 an association between TILs and
survival was not clear in patients with metastatic disease.8 The
progression of cancer despite a host immune response implies
the presence of immune evasion or immunosuppressive mechanisms acquired during the process of cancer development,9 and
avoiding
immune
destruction has been
identified as a “hallmark of cancer.”10 Early attempts to reinvigorate a host immune
response to cancer
have involved strategies such as therapeutic cancer vaccines,
cytokine administration, and immune
cell–based therapies.
Whereas vaccine approaches can induce
detectable immune
responses, they have
been largely ineffective at altering tumor growth,11 perhaps due to the dominance
of cancer-induced immunosuppressive pathways.
One approach that demonstrated efficacy in a subset
of patients is high-dose intravenous administration of
interleukin-2 (IL-2), a potent T-cell growth factor, and this
therapy was approved for use in metastatic melanoma in
1998. The overall response rate (RR) with high-dose IL-2 treatment was 16%, with a 6% complete RR and durable responses
observed.12 However, given the potential for substantial toxicity, this therapy is limited to carefully selected patients
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Division of Hematology–Oncology, Department of Medicine,
University of Pennsylvania, Philadelphia, Pennsylania
Copyright © 2015 Elsevier, Inc.
This material was supported by an educational grant from Bristol-Myers Squibb.
1
2
Immunotherapy for Melanoma
with good performance status and adequate cardiopulmonary function. IL-2 therapy should be administered
by experienced clinicians at established cancer treatment
centers. Dose-related toxicities of IL-2, some of which result from a capillary leak syndrome, include hypotension,
renal dysfunction with oliguria, respiratory failure, fever,
chills, diarrhea, and vomiting. Although most of the side
effects are self-limiting and resolve after discontinuation of
therapy, intensive supportive care is often required. Highdose IL-2 has been combined with a gp100 vaccine therapy.
One study evaluated IL-2 with gp100 vaccine compared to
IL-2 alone in a randomized phase III clinical trial, and RRs
were significantly improved in the combined IL-2 and gp100
vaccine arm (16% vs. 6%; P = 0.03) as well as longer progression-free survival (PFS) in favor of the combination.13
a hyporesponsiveness originally described in the setting of
chronic viral infection20 but also noted in TILs from patients
with melanoma.21,22 Antibody blockade of the PD-1/PD-L1 axis
is therefore intended to reinvigorate such exhausted T cells
(Figure 2B), and several antibodies have been developed for
clinical use, including approved agents pembrolizumab and
nivolumab (both humanized IgG4 mAbs to PD-1) and the antiPD-L1 mAbs BMS-936559 and MPDL-3280A, which are not approved but have demonstrated efficacy in early phase trials.23,24
Notably, given hematopoietic cell expression of PD-1, both pembrolizumab and nivolumab are nondepleting IgG4 isotype mAbs.
In addition to the CTLA-4 and PD-1 pathways, antibodies targeting other inhibitory T-cell receptors (e.g., LAG-3 and TIM-3) or
stimulatory receptors promoting T-cell activation (e.g., OX40 and
4-1BB) are in various stages of clinical development.
Immune Checkpoint Inhibition
CTLA-4 Blockade
More recently, interventions aimed at reversing cancerassociated immunosuppressive mechanisms have led to the
approval of promising new immunotherapeutic agents such as
the checkpoint inhibitors (Figure 1). This treatment strategy
involves the therapeutic manipulation of inhibitory signaling
pathways that normally function to maintain T-cell homeostasis
and prevent autoimmunity.14 CTLA-4 is one such inhibitory receptor that is induced on activated T cells and provides negative
feedback by binding to its ligands CD80 and CD86 (also known
as B7.1 and B7.2) on antigen-presenting cells (APCs), outcompeting the costimulatory receptor CD28, which also shares these
ligands but binds with lower affinity. Early studies in animal
models identified the ability of CTLA-4 blockade to promote antitumor immunity15 and led to the eventual clinical development
of ipilimumab, a fully human immunoglobulin G (IgG)1 mAb, as
well as a second blocking anti–CTLA-4 mAb tremelimumab (human IgG2 isotype). Although their precise mechanism of action
in patients is not completely understood, studies in mice indicate that CTLA-4 blockade both enhances effector T-cell function
and inhibits immunosuppressive T regulatory cells (Treg) (which
constitutively express high levels of CTLA-4),16 possibly through
Treg depletion from the tumor microenvironment via antibodydependent cell-mediated cytotoxicity (ADCC)17 (Figure 2A).
A second inhibitory pathway on T cells involves PD-1, a receptor expressed on antigen-stimulated T cells, which upon binding to its ligands programmed cell death-ligand 1(PD-L1) and
PD-L2 (also known as B7-H1 and B7-DC) leads to impairment
in effector T-cell functions including cytotoxicity, cytokine production, and proliferation.18 PD-L1 is expressed broadly in the
parenchymal cells of many tissues as well as on hematopoietic
cells, whereas PD-L2 expression is confined to APCs. The PD-1
receptor is believed to operate in the maintenance of peripheral
immune tolerance and to limit excessive tissue damage during
acute infection. Importantly, this pathway can be co-opted by
tumors to suppress antitumor immunity through tumor cell
expression of PD-L1.19 Chronic antigen exposure, as in the
case of chronic infection or cancer, can lead to elevated PD-1
expression and the development of a state of T-cell “exhaustion,”
Ipilimumab, a monoclonal antibody that blocks the CTLA-4 receptor, was approved by the FDA in 2011 based on the results
of two large randomized clinical trials, both of which demonstrated an improvement in overall survival in the ipilimumabcontaining arm. In the first study, 676 patients with metastatic
melanoma who were previously treated were randomized to one
of three arms in a 3:1:1 ratio; ipilimumab plus peptide vaccine
(gp100), ipilimumab alone, or peptide vaccine alone.25 The median overall survival was 10.0 and 10.1 months in the ipilimumabcontaining arms compared with 6.4 months in the peptide alone
arm (hazard ratio [HR], 0.68; P < 0.003). The objective RR was
significantly improved in the groups of patients who received
ipilimumab compared with the peptide vaccine alone arm (5.7%
and 10.9% vs. 1.5%, respectively). In a second phase III clinical
trial, 502 patients with previously untreated metastatic melanoma were randomized to ipilimumab (10 mg/kg) plus dacarbazine
(850 mg/m2, IV) or dacarbazine plus placebo, with an observed
improvement in overall survival with ipilimumab (11.2 months
vs. 9.1 months), as well as higher survival rates in the ipilimumab group at 1 year (47.3% vs. 36.3%) and at 3 years (20.8%
vs. 12.2%) (HR for death, 0.72; P < 0.001).26 Although objective
responses were low (15.2% vs. 10.3%), the duration of response
was 19.3 months for the ipilimumab arm versus 8.1 months for
dacarbazine. The FDA-approved dose and schedule for ipilimumab is 3 mg/kg IV every 3 weeks for 4 cycles of treatment
without maintenance. A second CTLA-4–blocking agent, tremelimumab, has also been tested in clinical trials with observed
responses; however, a randomized phase III trial did not demonstrate an improvement in overall survival with tremelimumab
compared with standard chemotherapy.27
Data regarding efficacy of CTLA-4 blockade in treating central nervous system (CNS) disease are more limited because
patients with active untreated brain metastases were excluded
from phase III trials of ipilimumab. However, retrospective analyses of phase II data28 and a small prospective phase II study
of patients with progressive brain metastases29 suggest activity
in this patient population, particularly in those with asymptomatic metastases not requiring corticosteroid treatment. Notably,
Figure 1. T
imeline of milestones in melanoma immunotherapy. Some of the key scientific and clinical advances leading to recent gains in the
treatment of advanced melanoma patients are indicated. Since 2010, two classes of immune checkpoint inhibitors that target the T-cell
inhibitory receptors CTLA-4 (ipilimumab) and PD-1 (pembrolizumab and nivolumab), as well as targeted therapies including BRAF inhibitors
(vemurafenib and dabrafenib) and a MEK inhibitor (trametinib), have achieved FDA approval. CTLA-4 = cytotoxic T-lymphocyte-associated
antigen 4; HD = high-dose; IFN = interferon; IL = interleukin; PD-1 = programmed cell death protein-1; TIL = tumor-infiltrating lymphocyte.
Immunotherapy for Melanoma
3
4
there was no increase in immune-related adverse events or unexpected toxicities observed in this study population.29 Limited
data are also available regarding the activity of ipilimumab in
advanced mucosal and uveal melanoma, although retrospective
analyses indicate activity.30-33 Randomized prospective trials to
further evaluate the checkpoint inhibitors in these relatively rare
subsets of melanoma patients are ongoing.
PD-1/PD-L1 Blockade
Several PD-1– and PD-L1–blocking agents have demonstrated
clinical activity with pembrolizumab and nivolumab, both gaining FDA approval in the United States in late 2014. An earlyphase study of nivolumab demonstrated objective responses
in various solid tumors, including melanoma.34 Subsequent
trials confirmed activity in melanoma, and the drug gained
initial FDA approval as second- or third-line therapy in patients
who had prior ipilimumab treatment, and if BRAF v600 mutant,
prior BRAF-directed therapy. The initial approval of nivolumab
was based on an objective RR of 32% (4 complete responses
and 34 partial responses) and durability of response in the first
120 patients who were treated with nivolumab and had a minimum 6 months’ follow-up from a randomized, open-label trial
of nivolumab 3 mg/kg intravenously every 2 weeks or investigator’s choice of chemotherapy in patients with prior ipilimumab treatment (CheckMate-037 trial). Eighty-seven percent
of patients had durable responses ranging from greater than
2.6 months to greater than 10 months. Subsequently, in a clinical trial conducted outside of the United States, nivolumab
has also demonstrated improved activity when compared with
dacarbazine in 418 previously untreated patients who had
metastatic melanoma without a BRAF mutation.35
Patients with advanced melanoma initially were enrolled in
a phase I clinical trial of pembrolizumab for patients with advanced solid tumors (KEYNOTE-001) in late 2011. When initial
efficacy data were first reported in abstract form in 2012 for patients with melanoma, the study protocol had been amended to
add additional cohorts of melanoma patients. Data from the first
135 patients enrolled in KEYNOTE-001 were published in 2013,
with a centrally confirmed Response Evaluation Criteria In Solid
Tumors (RECIST) objective RR of 38% and no difference in the
RRs of those patients who had and had not received prior ipilimumab. Responses were very durable with 42 of the 52 responding
patients (81%) still receiving treatment at the time of analysis.36
Data from the 173 ipilimumab-refractory patients enrolled on
randomized expansion cohorts of KEYNOTE-001 were published
in 2014 with no difference in RRs for patients randomized to
receive pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg
every 3 weeks. The centrally confirmed objective RR was 26%
in both dose cohorts of ipilimumab-refractory patients.37 Similarly to nivolumab, pembrolizumab gained initial FDA approval
as second- or third-line therapy in patients with prior ipilimumab
treatment and if they were BRAF V600 mutant and had prior
BRAF-directed therapy.
Overall, the objective RR from all 411 patients with advanced
melanoma treated with pembrolizumab for all cohorts of the
KEYNOTE-001 trial was 34%, with some amount of tumor shrinkage in 72% of patients. Responses were observed in patients with
Immunotherapy for Melanoma
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, lactate dehydrogenase (LDH) level elevated or normal
and brain metastasis present or absent. Responses were observed
in all subsets of patients, regardless of their M stage, BRAF mutation status, prior BRAF/MEK inhibitor treatment, prior ipilimumab treatment, or prior chemotherapy.38
PD-L1 blockade has also demonstrated clinical activity in melanoma and other tumor types,23,24 with clinical trials involving
different agents in progress. A summary of selected published
clinical trials of checkpoint inhibitors is shown in Table 1.
Immune-Related Toxicity
Managing immune therapy-related toxicity presents a unique
challenge; as more immune therapy approaches gain approval,
clinicians must have a high level of understanding of the common toxicities, mechanism of immune-mediated toxicity, and
management. Although immune-mediated adverse effects are
common, severe toxicity is uncommon with CTLA-4 blockade and
even rarer with PD-1 blockade. Immune-related adverse effects
usually are reversible, although early recognition and intervention are essential, along with patient education and close monitoring. Skin-related adverse events including rash and pruritus
can occur early in treatment with either CTLA-4 or PD-1 blockade. Liver and gastrointestinal events with ipilimumab typically
occur 6 to 7 weeks after starting treatment, whereas endocrinopathies usually are observed 9 weeks after initial ipilimumab administration.39 However, endocrinopathies with ipilimumab can
also occur in a delayed manner, including delayed hypothyroidism or hypophysitis resulting in adrenal insufficiency, which can
present with vague symptoms of nausea, fevers, and fatigue, or
can present with adrenal crisis including hypotension. Follow-up
for delayed toxicity should be continued after the last dose of ipilimumab and may also occur while patients are on subsequent
therapies, including PD-1 blockade. In general, mild ipilimumabrelated toxicities can be managed with increased monitoring and
supportive care. Moderate toxicity requires dose interruption,
increased monitoring and initiation of high-dose corticosteroids,
and severe toxicity requires permanent discontinuation of ipilimumab, increased monitoring, and initiation of corticosteroids.40
Endocrinopathies can be managed with hormone replacement
therapy according to the endocrinopathy observed, including
possible replacement with levothyroxine for hypothyroidism
or low-dose hydrocortisone for adrenal insufficiency. Clinicians
should have a high index of suspicion for hypophysitis-related
adrenal insufficiency in patients presenting with vague symptoms. Low adrenocorticotropic hormone (ACTH) and cortisol
levels can be diagnostic with excellent clinical responses after
starting low-dose replacement therapy; referral to an endocrinologist should be considered as well.
Severe treatment-related adverse events are much less frequent with PD-1 blockade compared with ipilimumab. Toxicity led to discontinuation of pembrolizumab in only 4% of the
411 melanoma patients treated on the KEYNOTE-001. No specific grade 3 or 4 adverse events occurred in more than 2% of
patients; 2% of patients experienced grade 3 or 4 fatigue; and
in less than 1% of patients, grade 3 or 4 pruritus, rash, diarrhea,
nausea, headache, hypothyroidism, decreased appetite, dyspnea
Immunotherapy for Melanoma
Figure 2. Immunostimulatory mechanisms of CTLA-4 and PD-1/PD-L1 blockade. A simplified schematic is presented
depicting the proposed mechanisms of action of immune checkpoint inhibitors. (A) The cytotoxic
T-lymphocyte-associated antigen 4 (CTLA-4) is an inhibitory receptor that is upregulated as a negative
feedback mechanism after T-cell receptor (TCR) stimulation of naïve or resting T cells by peptide in the
context of major histocompatibility complex (MHC) molecules. CTLA-4 binds its ligands (CD80 and CD86)
on antigen-presenting cells (APCs) and out competes the costimulatory receptor CD28, leading to inhibition
of the T-cell response. CTLA-4 blockade with the monoclonal antibody (mAb) ipilimumab therefore enhances
antitumor immunity by augmenting T-cell function. In addition, anti-CTLA-4 monoclonal antibodies (mAbs)
inhibit the suppressive activity of T regulatory cells (Treg) through CTLA-4 engagement and/or intratumoral
Treg depletion by antibody-dependent cell-mediated cytotoxicity (ADCC). (B) Antigen-stimulated T effector
(Teff) cells express programmed cell death protein 1 (PD-1), an inhibitory receptor that mediates its effects
on binding to its ligands PD-L1 (expressed on parenchymal cells, hematopoietic cells, and some tumors) or
PD-L2 (expressed on APCs), and is important in the maintenance of peripheral tolerance. PD-1 engagement
down regulates T cell effector functions including cytokine production, proliferation, and tumor cell
cytotoxicity. Tumor or immune cells expressing high levels of PD-L1 (possibly in response to inflammatory
cytokines such as interferon gamma, IFNγ) or PD-L2 (on APCs) can thus inhibit antitumor immunity, and
PD-1 blockade with mAbs pembrolizumab or nivolumab (or anti-PD-L1 agents currently in clinical trials) can
reinvigorate an immune response. Ag = antigen.
5
6
Immunotherapy for Melanoma
Table 1. Selected Published Clinical Trials of Immune Checkpoint Inhibitors in Melanoma
Immune
Target
Study Drug (Ref)
Phase Setting
Regimen
N
Primary
Endpoint
CTLA-4
Ipilimumab
III
2nd line
Ipi (3 mg/kg) + gp100
vs. ipi alone vs. gp100
alone (3:1:1 ratio)
674
OS
Median OS 10.0 (ipi + gp100) vs.
10.1 (ipi) vs. 6.4 (gp100) mo
HR for death (ipi alone vs. gp100)
0.66, P = 0.003
Ipilimumab26
III
1st line
Ipi (10 mg/kg) + DTIC vs.
ipi alone (1:1 ratio)
502
OS
Median OS 11.2 (ipi + DTIC) vs.
9.1 (DTIC) mo
HR for death 0.72, P < 0.001
Tremelimumab27
III
1st line
Treme (15 mg/kg) vs.
chemo (physician
choice) (1:1 ratio)
655
OS
Median OS 12.6 (treme) vs. 10.7
(chemo) mo
HR for death 0.88, P = 0.127
Nivolumab34,88
(BMS-936558)
I
At least 2nd line
Nivo dose escalation
(0.1–10 mg/kg)
107
Safety,
secondary
endpoint
ORR
ORR 31% (all doses)
ORR 41% (7 of 17 pts) at 3 mg/kg
dose level
Median OS 16.8 mo
Nivolumab35
III
1st line
Nivo (3 mg/kg) vs. DTIC
(1:1 ratio)
418
OS,
OS at 1 yr 72.9% (nivo) vs. 42.1%
secondary
(DTIC)
endpoints HR for death 0.42, P < 0.001
PFS, ORR Median PFS 5.1 (nivo) vs. 2.2
(DTIC) mo
ORR 40% (nivo) vs. 13.9% (DTIC)
Pembrolizumab36
(MK-3475,
lambrolizumab)
I
1st line or above
(both ipi-naïve
or treated)
Pembro (2 or 10 mg/kg)
135
Safety,
ORR 38% (all cohorts)
secondary ORR 52% in 10 mg/kg q2 wk
endpoint
cohort
ORR
Similar activity in ipi-naïve and ipipretreated patients
Pembrolizumab37
I
At least 2nd line
(all ipi-treated)
Pembro (2 vs. 10 mg/kg, 173
randomized in 1:1 ratio)
ORR,
secondary
endpoints
PFS, OS
BMS-93655923
I
At least 2nd line
BMS-936559 dose
escalation (0.3–
10 mg/kg)
55*
Safety,
ORR 17% (all doses)
secondary Additional 27% of patients with SD
endpoint
(lasting at least 24 wk)
ORR
MPDL-3280A24
I
Check-point
inhibitor-naïve
MPDL-3280A dose
escalation (0.01–
20 mg/kg)
45*
Safety,
ORR 26% (for cohorts receiving
secondary
≥ 1 mg/kg)
endpoint
ORR
PD-1
PD-L1
25
Results
ORR 26% in both treatment groups
No significant difference between
dose levels in median PFS or OS
*Subset of melanoma patients in study.
CTLA-4 = cytotoxic T-lymphocyte-associated antigen 4; DTIC = dacarbazine; HR = hazard ratio; ORR = objective response rate;
OS = overall survival; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death-ligand 1;PFS = progression-free
survival; SD = stable disease.
or increased alanine transaminase (ALT) developed. Eight percent of patients treated with pembrolizumab experienced hypothyroidism of any grade. Similarly, grade 1 or 2 hypothyroidism
occurred in 8% of patients receiving nivolumab on the CheckMate-037 study; nivolumab was discontinued due to adverse reactions in 9% of patients. In general, the drug was also well tolerated. More common mild toxicities include arthralgias as well.
Of note, rare events of treatment related pneumonitis have been
observed with both nivolumab and pembrolizumab. A summary
of common toxicities and principles related to their management
are shown in Table 2.
Response Kinetics and Heterogeneity
Collective experience with the immune checkpoint inhibitors
in patients with advanced melanoma has demonstrated considerable heterogeneity in response kinetics as well as patterns of
response. Compared with conventional cytotoxic chemotherapy
or targeted agents, responses to the checkpoint inhibitors can be
7
Immunotherapy for Melanoma
Table 2. Toxicities of Approved Checkpoint Inhibitors and General Management
Drug
(Approved Dose)
Most Frequent Toxicities
(Any Grade)*
Ipilimumab
(3 mg/kg q3 wk x
4 doses)
Immune-related (14.5%): colitis
Immune-related (61%):
(5.3%), diarrhea (4.6%),
diarrhea (28%), pruritus
endocrinopathy (3.8%),
(24%), rash (19%), colitis
Mild: Continue immunotherapy with
dermatologic (1.5%)
(8%), endocrinopathy (8%),
increased monitoring, supportive
hepatotoxicity (4%), vitiligo (2%) Other: fatigue (6.9%), dyspnea
care
(3.9%), anemia (3.1%), headache
Other: fatigue (42%), nausea
(2.3%), nausea (2.3%), vomiting
(35%), decreased appetite (27%),
Moderate: Withhold therapy with
(2.3%), constipation (2.3%),
vomiting (24%), constipation
frequent monitoring, supportive
decreased appetite (1.5%)
(21%), cough (16%), abdominal
care or appropriate medical
Death (1.5%, colon perforation,
pain (15%), dyspnea (15%),
interventions, can resume therapy
liver failure)25
headache (15%), pyrexia (12%),
after resolution or improvement to
anemia (12%)25
mild, if progression to severe (see
Fatigue (33%), pruritus (26%),
Immune-related (2%):
below)
rash (18%), arthralgia (12%),
endocrinopathy (1.1%),
diarrhea (11%), vitiligo (9%),
pneumonitis (1.1%)
Severe: Permanently discontinue
cough (9%), decreased appetite
Other: fatigue (5.6%), anemia
therapy, appropriate medical
(9%), endocrinopathy (9%),
(1.1%), muscle weakness
evaluation and intervention as
37
dyspnea (8%), nausea (8%),
(1.1%)
indicated, including systemic
chills (8%), myalgia (6%),
corticosteroids (1–2 mg/kg
asthenia (6%), elevated ALT (5%),
prednisone daily, or equivalent),
headache (5%), constipation
can consider additional
37
(5%), peripheral edema (5%)
immunosuppression (infliximab
Fatigue (20%), pruritus (17%),
Any AE (5.8%): diarrhea (1%),
for colitis, mycophenolate for
nausea (17%), diarrhea (16%),
endocrinopathy (1%), elevated
hepatotoxicity), continue steroids
rash (15%), vitiligo (11%),
ALT (1%), colitis (0.5%), rash
until resolution or improvement to
constipation (11%), asthenia
(0.5%), pruritus (0.5%), elevated
mild with long taper
(10%), pyrexia (7%), vomiting
AST (0.5%), vomiting (0.5%)35
(6%), erythema (6%), arthralgia
(6%), decreased appetite (5%)35
Pembrolizumab
(2 mg/kg q3 wk)
Nivolumab
(3 mg/kg q2 wk)
Severe Toxicity
(Grade ≥ 3)
Recommended Management
(By Grade of AE)
*Toxicity profile for approved dose level (based on indicated reference).
AE = adverse event; ALT = alanine transaminase; AST = aspartate aminotransferase.
delayed, which is consistent with their immunologic mechanism
of action. In addition, several distinct response patterns have been
observed, including tumor regression after initial radiographic evidence of progression, or a reduction in total tumor burden in the
presence of new lesions. Given these unique response patterns,
withdrawal of therapy due to early progressive disease based on
conventional response criteria may not be appropriate. Rather,
continuation of therapy can be considered in the face of clinically insignificant disease progression, until follow-up imaging
confirms progression. Another unique characteristic of immunotherapy involves the potential for extremely durable responses,
and long-term survival beyond 5 years has been seen in a subset of
patients treated with ipilimumab from the initial phase II trials.41
Prolonged stable disease also has been observed in a substantial
subset of patients and likely reflects treatment-associated antitumor activity. Notably, in the case of ipilimumab, both therapeutic
responses as well as autoimmune toxicity can occur after completion of induction therapy, suggesting persistent alterations in the
T-cell compartment.
The recognition that responses to immunotherapy might not
be optimally assessed by conventional metrics such as RECIST
or modified World Health Organization (mWHO) criteria has led
to development of an adaptation termed the immune-related response criteria (irRC).42 In this assessment schema, both index
lesions and measurable new lesions are considered in calculating total tumor burden. Unlike traditional criteria, new lesions
do not define progressive disease or preclude a partial response
in irRC, but instead are incorporated into calculations of total
tumor burden while established thresholds regarding change in
tumor burden (from mWHO criteria) are maintained for defining complete response (CR), partial response (PR), stable disease
(SD), or progressive disease (PD). The irRC thus accommodates
the distinct response patterns seen with immunotherapies that
are rarely encountered with other modalities. For example, in
an analysis of patients treated with ipilimumab in early phase
clinical trials, almost 10% of patients (22 of 227) initially characterized as having PD by WHO criteria were found to have objective responses (irPR and irSD) based on evaluation using irRC.42
Similarly, analysis of patients treated with pembrolizumab in a
phase I expansion cohort revealed that 19% of those with PD
based on RECIST criteria were progression free at 6 months as
per irRC.37 Furthermore, patients with PD based on RECIST but
non-PD based on irRC had favorable overall survival outcomes
compared with those patients with PD as determined by both
criteria.43 Conventional response criteria may, therefore, underestimate the therapeutic efficacy of immunotherapy, and work
is ongoing to provide additional validation of the irRC in prospective clinical trials.
8
Predictive Biomarkers
An important area of ongoing investigation involves the identification of biomarkers to predict favorable responses to immunotherapy. Initial descriptive studies have suggested correlations
between ipilimumab activity and increase in absolute lymphocyte count in peripheral blood after two cycles,44 expression of
T-cell activation markers such as the inducible T-cell costimulator (ICOS),45 elevated expression of inflammatory genes within
the tumor microenvironment,46 and levels of circulating immunosuppressive myeloid-derived suppressor cells (MDSCs).47 Additional work examining T-cell repertoires by high-throughput
sequencing of rearranged TCRβ chains in melanoma patients
treated with tremelimumab showed that maintenance of highfrequency clonotypes at baseline was associated with improved
overall survival,48 suggesting that responders to CTLA-4 blockade may have significant preexisting antitumor T-cell responses.
A recent study took a genetic approach to assess the relationship between a tumor’s mutational landscape and benefit from
CTLA-4 blockade.49 Whole-exome sequencing was performed on
paired melanoma tumor samples and peripheral blood to identify nonsynonymous mutations present in individual melanomas, followed by use of a computational algorithm to examine
those peptides predicted to bind to major histocompatibility complex (MHC) class I molecules and serve as potential neoepitopes
recognized by CD8 T cells. In comparing cohorts of patients with
or without long-term benefit from CTLA-4 blockade (defined as
stable or decreased volume of disease for greater than 6 months),
researchers found that whereas high mutational load correlated
with clinical response, the presence of a shared neoepitope signature (i.e., characteristic tetrapeptides arising from melanoma
neoantigens and predicted to be presented to T cells) could more
accurately predict long-term clinical benefit from therapy. Although further validation is needed, this work documents the potential of tumor genomics to inform immunotherapy, especially
given advances in genome sequencing and neoepitope prediction algorithms.50,51
Some studies of PD-1/PD-L1 blockade have included assessments of intratumoral PD-L1 expression and suggested a correlation between PD-L1 expression and response to therapy,24,34,52-54
although in other studies a relationship was not clear.35,55 In addition to different methodologies used for immunohistochemical
staining, intrapatient heterogeneity of PD-L1 staining within different tumor lesions has been described.56 The relative importance of tumor cell versus infiltrating immune cell PD-L1 expression also remains unclear. Tumor cell PD-L1 expression (possibly
induced by infiltrating T-cell cytokine production) as a mechanism of immune evasion termed adaptive immune resistance has
been described based on both animal and human studies.14,19,57
Several recent studies, however, have demonstrated the predictive value of infiltrating immune cell but not tumor cell PD-L1
expression on outcomes with PD-L1 blockade in melanoma and
other malignancies.24,58 Another recent study looking at pre- and
post-treatment tumor samples in melanoma patients receiving pembrolizumab found that responders had higher baseline
CD8+ cell densities at the tumor-invasive margin.53 This study
also reported a correlation between clinical response and more
Immunotherapy for Melanoma
restricted TCRβ chain usage in pretreatment samples, indicating
a more clonal T-cell population, possibly reflecting preexisting
tumor antigen-specific immune responses. Work is ongoing to
prospectively validate some of the aforementioned response biomarkers and to assess their clinical utility.
Sequencing of Therapy
As advances in both immunotherapy and targeted therapy have
expanded therapeutic options in advanced melanoma, the question of optimal sequencing of therapy frequently arises, particularly in patients with BRAF V600-mutant melanoma. In general,
immunotherapy offers the potential for durable responses, but
RRs are relatively low and responses can take months to manifest; whereas targeted BRAF/MEK inhibitors display relatively
high RRs and a rapid onset of action (days to weeks), but relapse
rates are high with a median time to progression of 5-7 months
for BRAF inhibitor monotherapy59-61 or 9-11 months for combined
BRAF and MEK inhibition.62-64 Considerations for choosing an
initial therapy in a patient with BRAF V600-mutant melanoma
generally have included disease burden, performance status,
and presence of symptomatic disease or impending organ compromise. Specifically, patients with symptomatic disease or high
tumor burden often are initiated on a BRAF inhibitor given the
higher likelihood of a rapid response, whereas asymptomatic patients with lower disease burden are perhaps better candidates
for checkpoint inhibitors. Although no prospective randomized
controlled trials have evaluated this issue, retrospective data support the above outlined approach. One retrospective study of patients treated with BRAF inhibitor therapy either before or after
immunotherapy (ipilimumab or IL-2) showed similar responses
to targeted therapy (RR, median PFS, and overall survival [OS])
in both circumstances.65 Outcomes generally were poor, however, with little benefit of immunotherapy if initiated after progression on targeted therapy.65 Another retrospective analysis of
patients treated with pembrolizumab identified baseline tumor
size as an independent predictor of response to therapy, finding superior objective response rate (ORR) and OS in patients
with lower tumor burden at initiation of PD-1 blockade, although
patients with larger baseline tumor size also derived benefit.66
Prospective trials are needed to determine optimal sequencing
of therapy in BRAF-mutant melanoma and whether sequential
treatment regimens (e.g., BRAF inhibitor lead-in to immunotherapy) might have synergistic effects (as discussed further below).
With a growing armamentarium of FDA-approved immunologic agents, further study will also be needed to guide choice and
sequence of different immunotherapies. Currently, ipilimumab
and IL-2 are approved for use in the first-line setting, whereas
PD-1 blocking agents (pembrolizumab and nivolumab) are approved in 2nd- or 3rd-line therapy, after ipilimumab and BRAF
inhibition (if applicable). Although data are limited, the efficacy
of PD-1 blockade after progression on prior ipilimumab has been
established36,37; and additionally, retrospective analysis of patients treated with ipilimumab revealed no association between
activity of CTLA-4 blockade and prior response to high-dose
IL-2.67 These findings support the idea that escape from immunosurveillance can occur through distinct pathways and that
9
Immunotherapy for Melanoma
response to a particular immunotherapy is dictated by the biology of an individual patient’s tumor. Further investigation aimed
at identifying mechanisms of resistance to therapy or testing
combinatorial strategies blocking multiple pathways simultaneously is ongoing.
Combination Approaches
With the success of checkpoint inhibitors as monotherapy, a
multitude of trials have been initiated to test these agents in
combination, when administered concurrently with other immunomodulatory agents or targeted BRAF/MEK inhibitors, or in
conjunction with other treatment modalities such as radiotherapy. Approaches combining two immunotherapies with different
mechanisms of action, or an immunotherapy along with agents
that promote immunogenic tumor cell death might be expected
to act synergistically. In early phase trials, concurrent CTLA-4
and PD-1 blockade have indeed shown potential for rapid and
deep responses that may be greater in magnitude than either
individually, although at a cost of more frequent autoimmune
toxicity.55 In this phase I study, cohorts of patients were treated
concurrently with ipilimumab and nivolumab at several dose
levels, and an objective RR of 40% was seen across all cohorts.
Among those receiving the maximum doses associated with
acceptable toxicity (ipilimumab at 3 mg/kg and nivolumab at
1 mg/kg), objective responses were observed in 53% of patients
(9 of 17), which included 3 complete responses and tumor
shrinkage of at least 80% in all responders. Grade 3 or 4 treatment-related adverse events occurred in approximately 50% of
patients (most common being elevated lipase and aminotransferase levels), although toxicities were manageable and generally
reversible with immunosuppression or hormone replacement
for endocrinopathies. Although comparisons to historic controls
suggest synergy with combination therapy, larger phase III trials
are ongoing to test this hypothesis.
Another recent study tested the combination of ipilimumab
and the granulocyte-macrophage colony-stimulating factor
(GM-CSF) sargramostim,68 arising from preclinical work that
demonstrated synergy between CTLA-4 blockade and GM-CSF–
secreting tumor cell vaccines.69 In this phase II trial, 245 patients were randomized to receive ipilimumab (10 mg/kg every
3 weeks) and sargramostim (250 µg SC daily for the first 2 weeks
of each cycle) or ipilimumab alone, both for 4 cycles of induction followed by maintenance every 12 weeks.68 Interim analysis
after a median follow up of 13.3 months showed that patients
treated with the combination of ipilimumab plus sargramostim
had improved overall survival compared with those treated with
ipilimumab alone (median OS 17.5 vs. 12.7 months, 1-year OS
68.9% vs. 52.9%, P = 0.01 for both comparisons) as well as lower
toxicity in the combination cohort (grade 3–5 adverse events in
44.9% vs. 58.3%, P = 0.04), which included a significant reduction in gastrointestinal and pulmonary toxicities. Larger studies
with longer follow-up (and testing of the combination with currently approved ipilimumab dosing) are needed to confirm these
results. But these findings further support the feasibility of combination immunotherapy, and trials investigating checkpoint
blockade with other cytokines, vaccination strategies, adoptive
cellular therapies, or in combination with immunomodulatory
small molecules such as indoleamine 2,3-dioxygenase (IDO) inhibitors, are currently ongoing.
There has also been considerable interest in testing the combination of checkpoint blockade and BRAF inhibition, as each has
proven efficacy individually and the combination offers the promise of high RRs along with durable disease control. Initial studies, however, have revealed dose-limiting hepatic toxicities.70 In a
phase I trial of concurrent vemurafenib and ipilimumab, patients
received a 1-month run-in period of vemurafenib alone (either at
approved 960 mg twice daily dose or a lower dose of 720 mg twice
daily) followed by ipilimumab (at 3 mg/kg every 3 weeks) with
concurrent vemurafenib. In both of these cohorts (occurring in
6 of the first 10 patients), grade 3 elevations in aminotransferase levels unexpectedly were observed within 2 to 5 weeks of
the initial ipilimumab infusion, accompanied in some cases by
elevations in total bilirubin levels. These hepatic toxicities were
reversible with temporary discontinuation of therapy or steroid
administration but led to termination of this study. Whether concurrent therapy at modified dosing schedules, with other BRAF inhibitors or combination BRAF/MEK inhibition, or upon sequential
administration (i.e., BRAF inhibitor followed by checkpoint blockade) might be beneficial without toxicity are subjects of ongoing
investigation. Data indicating that BRAF inhibitors can increase
the immunogenicity of melanoma (by upregulating expression of
melanocyte differentiation antigens), enhance T-cell infiltration,
and decrease immunosuppressive cytokine production provide
further rationale for pursuing this approach.71,72
The use of radiotherapy (RT) to potentiate the effects of checkpoint blockade is also the subject of ongoing clinical trials. The
abscopal effect, a rare phenomenon of tumor regression at sites
removed from the radiation field, has been described in various
malignancies, including melanoma, and is likely mediated by
an immunologic mechanism.73-75 Case reports and a case series
have documented abscopal effects in the setting of palliative RT
after melanoma progression on ipilimumab,76,77 and serial immunologic assessments of one such patient revealed enhanced
antitumor responses after RT.76 Retrospective analyses indicate
that the combination of ipilimumab and RT is safe,78 and clinical
trials are underway to test efficacy using different RT approaches
and target lesions including both brain metastases and lesions
outside the CNS.79 Because it is recognized increasingly that certain conventional chemotherapeutics can elicit immunogenic
cell death and promote induction of antitumor responses,80 the
combination of chemotherapy and checkpoint blockade is also
being explored in clinical trials, in some cases using metronomic
dosing rather than bolus administration to minimize immunosuppressive effects.81 Finally, checkpoint blockade in combination with antiangiogenic agents such as bevacizumab is currently
being investigated, and results from a phase I trial show that the
combination can be administered safely.82
Adoptive Cell Therapy
Adoptive cell therapy (ACT) involves infusing autologous T cells
to mediate an antitumor response. Different approaches to ACT
have been investigated, including infusion of ex vivo expanded
10
Immunotherapy for Melanoma
TILs, which has efficacy in melanoma,83 and the use of genetically modified T cells including chimeric antigen receptor (CAR)
T cells, which primarily has been investigated in hematologic
malignancies to date.84 TILs can be extracted from a resected tumor and expanded ex vivo, typically using a growth factor such
as high-dose IL2, and the expanded T cells are then reinfused intravenously into the patient after administration of nonmyeloablative lymphodepleting chemotherapy (to eliminate Treg cells).
An analysis of three clinical trials of TIL therapy in patients
with melanoma showed objective RRs of up to 72%. Complete
responses occurred in 20 of 93 patients (22%), all of whom maintained their response for over 3 years.85 Toxicities generally are
associated with the chemotherapy treatment; given the potential for severe toxicity, TIL therapy trials are an option in highly
selected melanoma patients.
Immunotherapy in the Adjuvant Setting
Currently, the only FDA-approved adjuvant therapy for melanoma is interferon (IFN) alfa. On the basis of the potent immunologic effects of interferon and its modest activity in patients
with metastatic melanoma, numerous studies with this drug have
been conducted in the postoperative adjuvant setting. The FDA
recommended approval for IFN alfa-2b in 1995 based on study
E1684 conducted by the ECOG. Pegylated IFN, which provides
weekly dosing, has also been developed for adjuvant therapy for
melanoma and is FDA approved. A series of randomized clinical trials, exploring a variety of schedules and doses have been
completed. Adjuvant immunotherapy with IFN prolongs diseasefree survival and overall survival in selected patients based on
meta-analysis.86 Overall, the decision regarding the use of adjuvant IFN should be made carefully, and it involves a thorough
conversation between the patient and physician that includes review of risks and benefits, as well as potential contraindications
to treatment with IFN.
Several alternative approaches are being evaluated to improve on the results with high-dose IFN in the adjuvant setting,
including ipilimumab. Two large randomized phase III studies
have completed accrual (Table 3).
The first study is EORTC 18071, in which 951 patients with
stage III melanoma were randomized to high-dose ipilimumab
(10 mg/kg every 3 weeks for 4 doses, then every 3 months for
3 years) versus placebo. The primary endpoint of the study is
relapse-free survival. The preliminary results were presented at
ASCO 2014.87 Toxicity associated with high-dose ipilimumab was
substantial, with the majority of patients experiencing immune
adverse events. There were 5 treatment-related deaths on the ipilimumab arm. Due to toxicity, a little more than 25% of patients
remained on therapy beyond 1 year. In terms of efficacy, relapsefree survival was significantly improved with ipilimumab compared with placebo (median 26 months vs. 17 months, 3-year
relapse-free survival 46.5 vs. 34.8%, HR 0.75, 95% confidence
interval [CI] 0.64–0.90). Results for overall survival will require
longer follow-up.
In a second study, ECOG 1609, patients with high risk stage
III melanoma were randomized to one of three arms for 1 year:
high dose ipilimumab (10 mg/kg), standard dose ipilimumab
(3 mg/kg), or standard high-dose IFN. The role of maintenance
ipilimumab is also explored in this study. The co-primary endpoints are overall survival and relapse-free survival. Accrual was
completed in 2014, with results expected in 2 to 3 years. Finally,
neoadjuvant or preoperative studies of immune check point inhibitors are also ongoing, with ipilimumab and with PD-1 inhibitors. These clinical trials allow for the collection of substantial
tumor tissue to better understand the immunomodulatory effects
of these agents.
Conclusion
Immunotherapeutic approaches to the treatment of melanoma
have been investigated for decades, albeit with limited success,
with few agents achieving approval by the FDA. However, in recent years, with deeper insight into our understanding of the
immune system, new approaches that focus on immune check-
Table 3. Ongoing Adjuvant Immunotherapy Trials in High-Risk Melanoma
Study
Phase
Primary
Endpoints
Status and Preliminary
Results
Ipilimumab
(10 mg/kg q3 wk x 4,
q3 mo x 3 yr) vs. placebo
(1:1 randomization)
RFS
Median RFS 26 (ipi) vs.
17 (PBO) mo, 3-yr RFS
46.5% (ipi) vs. 34.8%
(PBO), HR 0.75 (95%
CI 0.64-0.90,
P = 0.0013)
OS results pending
52% of patients
discontinued treatment
due to AEs, 5 deaths
(1.1%) in ipi group87
Ipilimumab 10 mg/kg
(q3 wk x 4, q3 mo x 4) vs.
ipilimumab 3 mg/kg
(same schedule) vs.
high-dose IFN
RFS, OS
Accrual completed 2014
Results pending
N
Patient Population
Regimen
EORTC 18071
III
(NCT00636168)
951
Resected stage III
(excluding LN metastasis
≤ 1 mm or in-transit
metastasis)
ECOG 1609
III
(NCT01274338)
1500
Resected stage III (IIIB or
IIIC) or IV (M1a or M1b)
AE = adverse event; CI = confidence interval; IFN = interferon; HR = hazard ratio; LN = lymph node; OS = overall survival;
PBO = placebo; RFS = relapse-free survival.
Immunotherapy for Melanoma
points such as CTLA-4, PD-1 and PD-L1 have produced durable
long-term responses, truly clinically meaningful responses, with
modest toxicity. Ongoing studies will define the subset of patients most likely to derive benefit through biomarker development. Important ongoing studies will define the optimal combination strategies, both with other immunotherapies and with
molecularly targeted therapies. Understanding the role of these
new agents in the adjuvant setting is also a priority area of investigation. Overall, the success with these new treatments challenges our long-held belief that advanced melanoma is largely
incurable. In particular, the long-term survivors following ipilimumab and with anti-PD-1 blockade raises the possibility that
more patients with advanced melanoma may be cured.
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