The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

Dan L. Longo, M.D., Editor

Recent Advances in the Treatment

of Melanoma
Brendan D. Curti, M.D., and Mark B. Faries, M.D.​​

T
he frequency of melanoma continues to increase, yet the le- From the Earle A. Chiles Research Insti-
thality of advanced disease has decreased in the past 10 years.1 Insights tute, Providence Cancer Institute, Portland,
OR (B.D.C.); and Cedars–Sinai Medical
gained from studies of melanoma have led to a deeper understanding of Center and the Angeles Clinic and Re-
antitumor immune responses and have established immunotherapy as one of the search Institute, Los Angeles (M.B.F.).
main approaches to cancer treatment. A 2004 review of melanoma in the Journal Address reprint requests to Dr. Curti at the
Providence Cancer Institute, Providence
was prescient in describing checkpoint immunotherapy and BRAF-targeted therapy Portland Medical Center, 4805 NE Glisan
as representing future directions in treatment; these two approaches have revolu- St., Suite 2N82, Portland, OR 97213, or at
tionized treatment.2 In 2004, no systemic therapies for melanoma had been shown ­brendan​.­curti@​­providence​.­org.

to provide a survival benefit. Now, at least four regimens of immunotherapy and N Engl J Med 2021;384:2229-40.
three regimens of targeted therapy are known to increase overall survival and DOI: 10.1056/NEJMra2034861
Copyright © 2021 Massachusetts Medical Society.
disease-free survival (Fig. 1). This review highlights recent advances in the treat-
ment of melanoma, including changes in staging, surgical management, and ad-
vances in systemic therapy for high-risk and advanced melanoma.

Mel a nom a S taging

In the current (eighth) edition of the American Joint Committee on Cancer cancer
staging manual (AJCC-8), the melanoma staging system is based on data from
more than 46,000 patients who were treated with the use of contemporary surgical
methods, including sentinel lymph-node biopsy.3 The staging system retains the
traditional tumor–node–metastasis (TNM) categories and incorporates interac-
tions between categories in determining final stages. The inclusion of sentinel-
node status in the AJCC-8 melanoma staging system greatly improved prognostic
information because of the ability to discriminate between node-negative and
node-positive disease.3,4 Features of the primary melanoma site, including depth
of invasion, extent of ulceration, and mitotic rate, can be used to estimate the risk
of nodal metastasis.5 Future staging systems that do not require complete lymph-
node dissection are under development, since current standard practice is to avoid
that procedure in most patients.6

Mol ecul a r Fe at ur e s of Mel a nom a

Mutational analysis and gene-expression profiling are increasingly common in the
management of melanoma, but the AJCC-8 staging system does not include mo-
lecular characterization. Retrospective evaluations of gene-expression profiling
have shown promise in improving prognostic determinations and estimating the
probability of finding a positive sentinel node.7-9 Use of gene-expression profiling
signatures may aid in the selection of patients for sentinel-node biopsy or for ad-
juvant systemic therapy, though validation of such an approach will require addi-
tional prospective evaluation.10

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A FDA-Approved Melanoma Therapy

Checkpoint therapy Targeted therapy Other therapy

Talimogene laherparepvec

Advanced Metastatic Ipilimumab+nivolumab

Melanoma
Nivolumab

Pembrolizumab

Dabrafenib+trametinib Vemurafenib+
cobimetinib
Dabrafenib
Encorafenib+
Trametinib binimetinib
Vemurafenib Atezolizumab+
vemurafenib+
Dacarbazine Interleukin-2 Ipilimumab cobimetinib
70

75

80

85

90

95

00

05

10

15

20
19

19

19

19

19

19

20

20

20

20

20
Adjuvant Therapy Interferon alfa Pegylated interferon
after Surgery
Ipilimumab

Nivolumab

Dabrafenib+trametinib

Pembrolizumab

B 2-Year Overall Survival in Pivotal Clinical Trials

Chemotherapy Cytokine therapy Targeted therapy CTLA-4 blockade PD-1/PD-L1 blockade Oncolytic therapy
70

60
2-Yr Overall Survival (%)

50

40

30

20

10

0
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At

Figure 1. Approved Treatments for Melanoma and Associated Overall Survival at 2 Years.
Panel A shows the time course of Food and Drug Administration (FDA) approvals for systemic therapy, including
chemotherapy and cytokine, checkpoint, and targeted therapies for advanced melanoma and adjuvant therapy after
surgical resection. Panel B shows overall survival at 2 years in pivotal clinical trials of treatment for advanced mela-
noma. Atezo denotes atezolizumab, Bini binimetinib, Cobi cobimetinib, CTLA-4 cytotoxic T-lymphocyte antigen 4,
Dab dabrafenib, Enco encorafenib, Ipi ipilimumab, Nivo nivolumab, PD-1 programmed death 1, PD-L1 PD-1 ligand,
Pembro pembrolizumab, Tram trametinib, TVEC talimogene laherparepvec, and Vem vemurafenib.

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 Recent Advances in the Treatment of Melanoma

Molecular evaluation also reveals that mela-
noma is among the solid tumors with the high-
est mutational burden, which is hypothesized to
serve as a source of neoantigens for host im-
mune responses and may predict the response to
immunotherapy.11 Most mutations in melanoma
are passenger mutations, but several driver mu-
tations that can be targeted by drugs have revo-
lutionized treatment. Because of a BRAF muta-
tion, first described in 2002, BRAF has become
the main target of currently approved targeted
therapies.12 BRAF is a serine–threonine kinase
in the RAS–RAF–MEK–ERK pathway. Approxi-
mately 50% of melanomas have BRAF mutations
resulting in constitutive activation of MEK and
ERK signaling, providing a rationale for com-
bined BRAF and MEK inhibition. The other de-
scribed genomic subtypes are mutated RAS
(accounting for approximately 28% of cases),
mutated NF1 (approximately 14%), and triple
wild type, although these other subtypes have
not been as successfully targeted with therapy to
date.13 BRAF testing should be performed in
patients with stage III or IV melanoma at the
time of diagnosis.
Surgic a l T r e atmen t
More than 90% of patients with melanoma have
localized or regional disease, and the primary
treatment for such patients is surgical. Current
standard surgical approaches are now markedly
less invasive and associated with lower morbid-
ity than previous approaches yet have equivalent
or superior accuracy and effectiveness.
Historical approaches to surgical treatment
were radical, with excision of 5-cm margins at
the primary tumor site and elective prophylactic
removal of regional lymph nodes.14,15 Questions
about the necessity of such extensive surgery led
to prospective, randomized clinical trials exam-
ining less radical procedures (Fig. 2). Safety mar-
gins for primary tumor excision for thin melano-
mas (<2 mm) were narrowed first to 2 cm16,17 and
then to 1 cm.18 Trial data for intermediate-
thickness melanomas (1 to 4 mm) established
2-cm margins as safe,19 and the most recent
trials for thicker melanomas (>2 mm) have
shown 2-cm margins to be safe. The ongoing
20
that are stage T2b or higher, to determine wheth-
er further narrowing of the excision margin is safe.
Elective lymph-node dissection (removal of
regional lymph nodes in patients who have
melanoma with no clinically detectable regional
metastases), first proposed by Snow in the
1890s, is associated with clinically significant
complications. The role of elective lymph-node
dissection remained controversial until develop-
ment of the sentinel lymph-node biopsy rendered
the concept moot.21-25 With sentinel-node biopsy,
only nodes receiving direct lymphatic drainage
are removed, which averts full dissection in the
majority of patients. This approach reduces mor-
bidity, including lymphedema, and improves stag-
ing accuracy by allowing a more precise assess-
ment of nodal disease. Initially, all patients found
to have metastases on sentinel-node biopsy sub-
sequently underwent completion lymph-node dis-
section (removal of the remaining regional lymph
nodes after sentinel-node excision), although it
was not clear whether that additional procedure
was necessary. The German Dermatologic Coop-
erative Oncology Group sentinel lymph-node
trials (DeCOG-SLT)26 and the second Multicenter
Selective Lymphadenectomy Trial (MSLT-II)27
showed the safety of nodal observation, bring-
ing practice to the current standard.
At present, patients with more than a mini-
mal risk of nodal metastases undergo wide exci-
sions with 1- or 2-cm margins, depending on
tumor thickness, with lymphatic mapping and
sentinel-node biopsy. Most patients with sentinel-
node metastases can elect nodal observation, in-
cluding nodal ultrasonography, rather than com-
pletion nodal dissection. This change in practice
has not increased the risk of uncontrolled local
or regional recurrence and has substantially re-
duced the number of patients who undergo ex-
tensive surgery. Important unanswered questions
involve how to adequately select patients who
require sentinel-node biopsy. In the future, im-
proved predictive models incorporating clinico-
pathological variables and molecular markers may
be useful in providing answers to such questions.
T r e atmen t of A dva nced
Mel a nom a

Melanoma Margins Trial II (MelMarT-II; Clinical­ Checkpoint Immunotherapy

Trials.gov number, NCT03860883) is comparing The paradigm-changing advances in cancer im-
1-cm margins with 2-cm margins for melanomas munotherapy involve inhibitory receptors or check-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A Progress in Excision Margin Width Figure 2. Progress in Recommendations for Excision

Margin Width and Node Dissection in Primary Melanoma.
Historical: 5 cm
Panel A shows the evolution of recommended margin
widths for wide excision of primary melanoma. Margins
Tumor Clinical New Clinical New have narrowed within all thickness categories on the
Thickness Trial Margin Trial Margin basis of the results of randomized clinical trials. The
Melanoma Margins Trial II (MelMarT-II) clinical trial is
<2 mm Swedish
2 cm WHO #10 1 cm ongoing for patients with stage T2b or higher primary
French
melanomas and is evaluating 1-cm and 2-cm margin
widths. Panel B shows the proportions of patients with
1–4 mm Intergroup 2 cm
clinically localized melanoma who underwent immedi-
ate or early complete lymph-node dissection. Estimates
>2 mm 2 cm 1 cm are based on historical information from Snow14 and
Swedish
Ongoing on information from the National Cancer Database on
versus
3 cm MelMarT-II tumor thickness and the results of the Intergroup Mel-
United
Kingdom 2 cm anoma Surgical Trial and reflect avoidance of comple-
tion lymph-node dissection in patients with negative
sentinel lymph nodes (SLNs), as confirmed by the first
B Progress in Node Dissection Multicenter Selective Lymphadenectomy Trial (MSLT-I),
Historical Surgical Treatment Elective Lymph-Node Dissection and avoidance of immediate completion lymph-node
No dissection dissection in SLN-positive patients, as confirmed by
MSLT-II and the German Dermatologic Cooperative
Oncology Group SLN trial (DeCOG-SLT). WHO #10
denotes World Health Organization Melanoma Trial
Thin No. 10.
Dissection

Dissection and eradication of tumor cells in preclinical tu-

Thick
After MSLT-I After MSLT-II and DeCOG-SLT
Isolated nodal Multisite
Dissection recurrence recurrence
SLN-positive
Thin Thin
Node-negative SLN-negative
points, including cytotoxic T-lymphocyte antigen
4 (CTLA-4) and programmed death 1 (PD-1) pro-
tein, pioneered by Allison28 and Honjo.29 They
earned a Nobel prize for their achievements, and
translation of their basic science insights changed
the standard of care for melanoma and many
solid tumors. CTLA-4, which is up-regulated on
T cells as a result of T-cell receptor engagement
by tumor antigen during the interaction between
a T cell and an antigen-presenting cell, acts as a
negative regulator of T-cell activation in lym-
phoid tissues. CTLA-4 blockade with an antago-
nistic antibody results in improved T-cell function
mor models. The PD-1 pathway promotes T-cell
tolerization and is a marker of T-cell exhaustion
in chronically inflamed peripheral tissues, includ-
ing the tumor microenvironment. Promising
early results of trials using CTLA-4 blockade
with ipilimumab and PD-1 blockade with nivolu­
mab or pembrolizumab have been the catalysts
for more than a decade of clinical research in
checkpoint immunotherapy.27,28,30,31
The outcome for patients with advanced mela-
noma has been transformed with combined
checkpoint antibody therapy. Ipilimumab com-
bined with nivolumab has been associated with
a 53% response rate and is now the standard of
care for immunotherapy in most patients with
advanced melanoma.32 In a span of 3 years,
therapy for advanced melanoma changed from
ipilimumab monotherapy, with a 10% response
rate and an incremental survival benefit, to check-
point combination therapy, which has more than
a 50% response rate and a significant survival
benefit, with approximately 10% of patients re-
quiring no further melanoma therapy (Table 1).
Immune-mediated toxic effects are increased
with checkpoint combinations, but side effects
can be managed by means of dose delays, gluco-
corticoids, and anti–tumor necrosis factor anti-
bodies.39

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 Table 1. Combined Checkpoint Blockade (CTLA-4 plus PD-1) in Advanced, Unresectable Melanoma According to Clinical Trial.*

Variable CheckMate 20432,33 CheckMate 06934 CheckMate 06735,36 Zimmer et al.37 KEYNOTE-02938
Target group Concurrent therapy (no prior ipi) Known BRAF status Previously untreated Progression after nivo No prior therapy
Sequential therapy (prior ipi)
Regimens (mg/kg of body Group A: nivo 0.3 mg + ipi 3 mg Group A: ipi 3 mg + nivo 1 mg Group A: nivo 1 mg + ipi 3 mg Group A: ipi 3 mg Pembro 2 mg + ipi 1 mg
weight) Group B: nivo 1 mg + ipi 3 mg Group B: ipi 3 mg Group B: nivo 3 mg Group B: nivo 1 mg or 3 mg
Group C: nivo 3 mg + ipi 1 mg Group C: ipi 3 mg + ipi 1 mg or 3 mg
Group D: nivo 3 mg + ipi 3 mg
Group E/F: nivo 1 mg/nivo 3 mg
(after ipi)
Expansion: nivo 1 mg + ipi 3 mg
No. of patients Group A: 14 BRAFwt: group A, 72; Group A: 314 Group A: 47 153
Group B: 17 group B, 37 Group B: 316 Group B: 37
Group C: 16 BRAFmu: group A, 23; Group C: 315
Group D: 6 group B, 10
Group E/F: 33
Expansion: 41
Objective response rate Group A: 21 BRAFwt: group A, 61; Group A: 57.6 Group A: 16 61
(%) Group B: 53 group B, 11 Group B: 43.7 Group B: 21
Group C: 40 BRAFmu: group A, 52; Group C: 19.0
Group D: 50 group B, 10
Group E/F: 20
Expansion: NR
Survival Concurrent therapy (groups A Median PFS: group A, not 5-yr OS: 52% in group A, 44% 1-yr OS: 54% in group A, 1-yr PFS: 69%

n engl j med 384;23  nejm.org  June 10, 2021

through D): OS, 63% at 3 yr reached; group B, 4.4 mo in group B, 26% in group C 55% in group B 1-yr OS: 89%

The New England Journal of Medicine

Other findings 16 Patients receiving concur- CR: 22% for BRAFwt and 22% CR: 11.5%, 8.9%, and 2.2% Dual therapy not more effec- Grade 3–4 adverse events
rent therapy (30%) had a for BRAFmu with combined in groups A, B, and C, re- tive than ipi monotherapy in 45% of patients
profound (>80%) response; 4 therapy; response indepen- spectively after progression on anti– Response similar in PD-
Recent Advances in the Treatment of Melanoma

patients receiving sequential dent of PD-L1 status for Adverse events: 95.5%, 82.1%, PD-1 therapy L1–positive and PD-
therapy (13%) had a pro- dual-therapy group and 86.2%, respectively L1–negative patients

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

found response after ipi PFS better with dual therapy in
Grade 3–4 adverse events in 59% PD-L1–negative tumors
of patients

* BRAFwt denotes BRAF wild-type, BRAFmu BRAF-mutated, CR complete response, CTLA-4 cytotoxic T-lymphocyte antigen 4, ipi ipilimumab, nivo nivolumab, NR not reported, OS overall
survival, PD-1 programmed death 1, PD-L1 PD-1 ligand, pembro pembrolizumab, and PFS progression-free survival.

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2233
 The n e w e ng l a n d j o u r na l of m e dic i n e

Checkpoint immunotherapy can induce re- Administration (FDA) for the treatment of mela-
gression of melanoma in any organ, including the noma on the basis of a 48% response rate and a
brain. The combination of ipilimumab and nivolu­ 63% reduction in the risk of death, as compared
mab was shown to induce an intracranial re- with dacarbazine chemotherapy.45 Although the
sponse (defined as complete or partial regression initial response to vemurafenib was rapid and
or stable brain metastases for at least 6 months) clinically meaningful, progression-free survival
in 57% of patients with brain metastases mea- was only 5.3 months, which is indicative of the
suring up to 3 cm.40 The objective response at rapid development of resistance through mitogen-
other visceral sites was 56%. Similar intracranial activated protein (MAP) kinase reactivation with
and extracranial responses are achieved with monotherapy. Combined BRAF and MEK inhibi-
the use of BRAF-targeted therapy for melanomas tion addresses this mechanism of resistance and
expressing a BRAF V600E mutation.41 Surgery, is now the standard of care for targeted therapy
radiosurgery, and whole-brain irradiation remain in patients with melanoma. Treatment with dab-
important for controlling brain metastases, but rafenib and trametinib, vemurafenib and cobi-
as discussed above, medical therapy alone can be metinib, or encorafenib and binimetinib is asso-
effective in selected patients. ciated with prolonged progression-free and overall
Although checkpoint blockade improves sur- survival, as compared with BRAF inhibitor mono-
vival in a majority of patients, a minority have a therapy, with response rates exceeding 60% and
complete remission or cure. Many potential tumor- a complete response rate of 10 to 18% (Table 2).
mediated resistance mechanisms have been sug- No randomized, controlled trials have compared
gested, but acquired resistance to immunother- combined BRAF and MEK inhibition regimens
apy can occur through the Janus kinase (JAK1/2) to ascertain whether there are any differences in
cytokine signaling pathway or decreased beta2- response rate or survival.54 Combining atezolizu­
microglobulin expression.42,43 JAK1/2 mutations re- mab anti–PD-L1 immunotherapy with vemu-
duce expression of the PD-1 ligand (PD-L1), lessen rafenib and cobimetinib was recently shown to
the antiproliferative effects of interferons, and improve progression-free survival, as compared
lower tumor antigen presentation to immune cells. with combined targeted therapy.53
Truncating mutations of beta2-microglobulin re- BRAF plus MEK targeted therapy can achieve
sult in loss of major histocompatibility complex disease control that lasts for years, but the major
class 1 expression and decreased immune recog- limitation is the acquisition of resistance. In
nition. Although the time course and frequency of community practice, targeted therapy is usually
acquired resistance after PD-1 exposure are not offered as first-line treatment to symptomatic
known, prolonged exposure to anti–PD-1 anti- patients with a high tumor burden, since the
bodies may not be advisable in some patients. response may be more rapid than the response
The remarkable success of combination check- to immunotherapy. Ultimately, most patients with
point therapy has transformed melanoma treat- advanced, BRAF-mutated melanoma receive both
ment, but many questions remain. We do not targeted therapy and immunotherapy.
know the best sequence of immunotherapy and
targeted therapy in patients with BRAF-mutated Other Targeted Therapies
melanoma. Survival is significantly increased Mutations of KIT (encoding proto-oncogene re-
among patients with advanced melanoma, but ceptor tyrosine kinase) are most frequently located
the probability of a cure remains low. The use of
in exon 11 and activate intracellular MAP kinase
biomarkers to predict treatment response and and phosphatidylinositol 3-kinase (PI3K) path-
toxic effects has limited value. Other melanomaways.55 KIT mutations are typically found in
subtypes, including mucosal and uveal melano- mucosal and acral melanomas and chronically
mas, have proved less responsive to checkpoint sun-damaged skin, with frequencies of 39%,
inhibition, although early, encouraging results36%, and 28%, respectively.56 Tyrosine kinase
with combined CTLA-4 and PD-1 inhibition have inhibitors such as imatinib have activity in KIT-
been reported.44 mutated melanomas. Imatinib was associated
with a 53% response rate and progression-free
Therapy Targeting BRAF and MEK survival of 3.9 months among patients with KIT-
In 2011, vemurafenib became the first BRAF- mutated melanoma but failed to cause regression
targeted therapy approved by the Food and Drug in melanomas with KIT amplification.57 The mech-

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 Recent Advances in the Treatment of Melanoma

Table 2. Outcomes of Targeted Therapy According to Clinical Trial.*

Variable coBRIM46,47 COMBI-d48-50 COLUMBUS51,52 IMspire15053

Regimen Vem Vem + cobi Dab Dab + tram Enco Enco + bini Atezo + vem + cobi Vem + cobi
Objective response 45 68 55 68 52 64 66.3 65
rate (%)
Complete response 4 10 15 18 7.2 12.5 15.7 17.1
rate (%)
Median PFS (mo) 7.2 12.3 8.8 11.0 9.6 14.9 16.1 12.3
Survival at 2 yr (%) 41 48 43 52 NR 58 NR NR
Toxic effects leading to 7 14 7 11 16 15 13 16
discontinuation (%)
Median OS (mo) 17.4 22.3 18.7 25.1 23.5 33.6 NR NR

* Atezo denotes atezolizumab, bini binimetinib, cobi cobimetinib, dab dabrafenib, enco encorafenib, NR not reported, tram trametinib, and
vem vemurafenib.

anisms of resistance included the presence of
other driver mutations such as NRAS and ampli-
fication of the KIT copy number. Anti–PD-1
checkpoint immunotherapy has activity in mu-
cosal melanoma, with a 20% response rate, and
with the addition of anti–CTLA-4 immunother­
apy, the response rate increases to 37%, with a
median progression-free survival of 6 months,
although the incidence of KIT mutations was not
determined in the study population.58 Other
driver mutations that may give rise to targeted
agents for subgroups of patients with melanoma
are reviewed below in the discussion of future
directions.
Adjuvant and Neoadjuvant Therapy
For many years, adjuvant therapy was limited to
interferon alfa-2b, which offered improved relapse-
free survival but with clinically significant con-
stitutional toxic effects and an inconclusive sur-
vival benefit.59 Ipilimumab was the first agent
shown to improve relapse-free and overall sur-
vival,60 and these benefits have proved to be
durable.61 Comparisons of PD-1 blockade with
either ipilimumab or placebo (CheckMate 238 and
KEYNOTE-054) showed improvement in efficacy
and a reduction in toxic effects, making it the
current standard adjuvant therapy for patients
with resected stage III BRAF wild-type melano-
mas62,63 (Table 3). Anti–PD-1 therapy may also be
used in patients with resected stage IV melano-
ma, though recent data support the combination
of ipilimumab and nivolumab in such patients.64
Treatment with dabrafenib plus trametinib
was compared with placebo in a randomized,
double-blind study involving patients with stage
III melanoma.65 A 53% lower probability of recur-
rence and a 43% lower risk of death with com-
bined therapy than with placebo were reported.
Five-year follow-up showed that 52% of patients
remained recurrence-free in the combination
therapy group, as compared with 36% in the
placebo group.66 Combined BRAF and MEK in-
hibition is a standard adjuvant treatment option
for stage III BRAF-mutated melanomas.
Both PD-1 blockade and combined BRAF and
MEK inhibition have a clear benefit in resected
stage IIIB, stage IIIC, and stage IV melanomas.
No head-to-head comparisons of the two treat-
ments have been performed or are anticipated,
but the relative risk reductions appear to be simi-
lar and durable. Side-effect profiles are distinct,
with targeted therapy having more common but
more easily reversible toxic effects. Patients and
providers may select therapy on the basis of the
anticipated toxic effects or the route and sched-
ule of administration. The threshold for the risk
of recurrence — for example, in stage IIIA mela-
noma — that justifies adjuvant therapy is currently
unresolved. An ongoing phase 3 randomized trial
comparing checkpoint immunotherapy with sur-
veillance in stage IIB or IIC disease may change
the standard of care for the treatment of high-
risk, earlier-stage primary melanomas character-
ized by deep invasion or ulceration (NCT04099251).
Neoadjuvant treatment has not yet become
standard but is among the most intriguing areas
of ongoing investigation. A standardized format
for such studies has been proposed.67 Neoadjuvant
combined BRAF and MEK inhibition has been
compared with surgery alone in a randomized
phase 2 study.68 That trial was stopped early

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 The n e w e ng l a n d j o u r na l of m e dic i n e

because of significantly longer event-free survival

in the group assigned to neoadjuvant plus adju-

Grade 3–4 adverse events:

Dab + tram (435) vs. dual
vant targeted therapy (Table 4).

Stage IIIA,† IIIB, IIIC

COMBI-AD
Preclinical data and several small trials sug-

52% vs. 36% at 5 yr

86% vs. 77% at 3 yr

placebo (432)

41% vs. 14%

gest that checkpoint blockade may be more suc-
cessful before surgery than afterward.70 Although
rapid responses to anti–PD-1 therapy have been
observed in up to 30% of patients, even after a
single dose, some concern has been voiced re-
garding the risk of progression with monother-
Pembro (514) vs. placebo (505)

similar across BRAF status

apy.69 Combined blockade with standard doses

Influence of pembro on RFS

of ipilimumab (3 mg per kilogram of body
EORTC 1325

63.7% vs. 44.1% at 3 yr

weight) and nivolumab (1 mg per kilogram) has

Stage IIIA,† IIIB, IIIC

NR
been associated with higher response rates but
also clinically significant toxic effects. The
and stage
OpACIN-neo (Optimal Neo-adjuvant Combina-
tion Scheme of Ipilimumab and Nivolumab) trial
used a modified regimen (ipilimumab at a dose
of 1 mg per kilogram and nivolumab at a dose
of 3 mg per kilogram, with two doses adminis-
70.5% vs. 60.8% at 12 mo

Serious adverse events in

17.5% of patients vs.

tered preoperatively), which had a 57% response

Nivo (453) vs. ipi (453)
CheckMate 238

rate with moderate toxic effects.71 Ongoing trials,

Stage IIIB, IIIC, IV

including the Personalized Response-Driven Ad-

NR

juvant Therapy after OpACIN (PRADO) trial, may

40.4%

determine whether the extent of surgical exci-

sion after neoadjuvant treatment can be safely
reduced. As with adjuvant therapy, no random-
ized comparisons of targeted therapy and immu-
(511) vs. interferon (636)

72% vs. 70% vs. 63% at 5 yr

Ipi 3 mg (523) vs. ipi 10 mg

events grade ≥3: 38.2%

Median, 4.5 yr vs. 3.9 yr vs.

† In stage IIIA, nodal metastasis had to be more than 1 mm in the longest dimension.

notherapy as neoadjuvant treatments have been

Treatment-related adverse
Stage IIIB, IIIC, M1a, M1b

vs. 78.8% vs. 57.9%

performed. However, the extremely low rate of

ECOG 1609

observed recurrences after a major response to

checkpoint blockade (i.e., a substantial reduc-
tion in tumor burden in individual patients) has
2.5 yr

increased enthusiasm for this approach.

Vaccine Therapy
* NR denotes not reported, and RFS relapse-free survival.

Efforts to develop a melanoma vaccine have

Immune adverse events grade
Table 3. Adjuvant Therapies According to Clinical Trial.*

spanned more than 100 years. Although vaccina-

≥3 in 41.6% of patients
Ipi (475) vs. placebo (476)

tion has induced an immune response, there has

40.8% vs. 30.3% at 5 yr

65.4% vs. 54.4% at 5 yr

EORTC 18071
Stage IIIA,† IIIB, IIIC

been no correspondence between the immune

response and a clinical benefit. Clinical activity
receiving ipi

has been observed with intratumoral vaccina-

tion with the use of oncolytic virus. Talimogene
laherparepvec (TVEC) is a genetically modified
herpes simplex virus type 1 that is characterized
by decreased virulence and selective intratumoral
viral replication.72 A phase 3 randomized trial
Study groups (no.

comparing TVEC with granulocyte–macrophage

of patients)

Other findings
Eligible stages

colony-stimulating factor showed significantly

increased rates of durable and objective responses
Variable

with TVEC. The side-effect profile of TVEC was

RFS

OS

favorable, with the main effects limited to tran-

2236 n engl j med 384;23  nejm.org  June 10, 2021

The New England Journal of Medicine

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Copyright © 2021 Massachusetts Medical Society. All rights reserved.
 Table 4. Neoadjuvant Therapies According to Clinical Trial.*

Variable Amaria et al.68 Amaria et al.67 OpACIN NeoCombi Huang et al.69 OpACIN-Neo
Eligible clinical Stage III or IV (BRAF- Stage III or IV Stage III Stage III (BRAF-mutated) Stage III or IV Stage III
stages mutated)
Preoperative therapy Dab + tram for 8 wk (14) Nivo 3 mg (12) vs. ipi Ipi 3 mg + nivo 1 mg for Dab + tram for 12 wk (35) Single-dose pembro, 2 courses ipi 3 mg + nivo
(no. of patients) vs. none (7) 3 mg + nivo 1 mg 6 wk (10) vs. none (10) (single group) resection at 1 mg (30) vs. 2 courses
(11) for 12 wk 3 wk (30) ipi 1 mg + nivo 3 mg (30)
vs. 2 courses ipi 3 mg fol-
lowed by 2 courses nivo
3 mg (26)†
Postoperative Dab + tram vs. observa- Nivo 3 mg vs. ipi Ipi 3 mg + nivo 1 mg for Dab + tram for 40 wk Pembro for 1 yr None
therapy tion until recurrence 3 mg + nivo 1 mg for 6 wk vs. for 12 wk
24 wk
RFS Median, 19.7 mo vs. 2.9 Ipi + nivo, 90% at No relapse in neoadjuvant Median, 23 mo 100% among patients Not mature (no deaths from
mo 14.9 mo group at 25.6 mo with pCR or near melanoma in patients
pCR (30% of with pathological
patients) response)
Other findings Toxic effects did not delay Patients with a response Neoadjuvant therapy in- 49% pCR Potential mechanisms Pathological response in
planned surgery had increased TIL creased T-cell clones; of resistance 80% vs. 77% vs. 65%;

n engl j med 384;23  nejm.org  June 10, 2021

The New England Journal of Medicine

with higher clonal- 90% of patients had examined group 3 closed early
ity; 73% of patients grade ≥3 toxic effects because of toxicity
had grade ≥3 toxic
effects
Recent Advances in the Treatment of Melanoma

* The abbreviation pCR denotes pathological complete response, and TIL tumor-infiltrating lymphocytes.

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

† Two courses of therapy (one course every 3 wk) were administered for each treatment group.

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2237
 The n e w e ng l a n d j o u r na l
sient injection-site reactions, fatigue, and pyrexia.
TVEC can be a valuable therapeutic option for
patients with coexisting medical conditions for
whom the immune-mediated toxic effects of
checkpoint blockade may be unacceptable.
F u t ur e Dir ec t ions
Determining an effective sequence of targeted
and immune checkpoint therapy in patients with
BRAF-mutated, advanced melanoma is an active
area of research. One of the high-priority clinical
trials is Dabrafenib and Trametinib Followed by
Ipilimumab and Nivolumab or Ipilimumab and
Nivolumab Followed by Dabrafenib and Trametinib
in Treating Patients with Stage III–IV BRAFV600
Melanoma (NCT02224781), also known as
DREAMseq (Doublet, Randomized Evaluation in
Advanced Melanoma Sequencing). Another im-
portant sequencing trial is examining continua-
tion of combined BRAF and MEK inhibition with
the use of vemurafenib plus cobimetinib followed
by PD-L1 blockade with atezolizumab after ini-
tial BRAF and MEK inhibition or the reverse order
of therapies (ImmunoCobiVem; NCT02902029).
Finally, the SECOMBIT (Sequential Combo Im-
muno and Target Therapy) study is examining
encorafenib plus binimetinib followed by ipilimu­
mab plus nivolumab at the time of disease pro-
gression, the same therapies in reverse order,
and encorafenib plus binimetinib with a change
to ipilimumab and nivolumab after 8 weeks,
with a return to encorafenib plus binimetinib at
the time of disease progression (NCT02631447).
The best regimen after checkpoint progres-
sion has not been determined, but adoptive cel-
lular therapy with the use of tumor-infiltrating
lymphocytes (TIL) holds promise. The clinical
development of TIL started in the late 1980s.
Although the FDA has not approved TIL for the
treatment of melanoma, TIL used in conjunction
with conditioning chemotherapy and high-dose
interleukin-2 was associated with a 24% com-
plete response rate and a 55% overall response
rate among patients who had progressive mela-
noma after prior therapy.73 One of the challenges
for the clinical application of TIL is scaling up
the technology, since TIL has been used only in
a small number of highly specialized centers
that can also administer high-dose interleukin-2.
The infrastructure for centralized cell processing
has been established, and pivotal multicenter
clinical trials of TIL (Lifileucel, Iovance Biothera-
2238 n engl j med 384;23  nejm.org  June 10, 2021
The New England Journal of Medicine
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Copyright © 2021 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
peutics), administered with interleukin-2 and
sequential checkpoint immunotherapy in patients
with melanoma and other solid tumors, are un-
der way (NCT02360579).
Better treatment for metastatic uveal mela-
noma would be an important advance, since
checkpoint immunotherapy has activity but is
less effective in this melanoma subtype than in
melanoma of cutaneous origin.44 Mutations of
the regulatory guanine nucleotide–binding pro-
tein (G-protein) subunits αq and α11 of RAS,
known as GNAQ and GNA11, are present in 33%
and 39% of uveal melanomas, respectively. These
mutations influence signaling in the MAP kinase
and PI3K pathway and can be targeted by oral
agents.56 The MEK inhibitor selumetinib and the
protein kinase C inhibitor IDE196 have entered
clinical trials for stage IV uveal or cutaneous
melanomas with GNAQ mutations (NCT01143402
and NCT03947385). The melanocyte lineage pro-
tein gp100 is also under active clinical develop-
ment for the treatment of uveal melanoma. The
immunogenic peptide for gp100 is known in
HLA-A2.01 tissue type, and a bispecific antibody
called tebentafusp has been engineered to target
gp100 and CD3, inducing T cells to kill gp100-
expressing tumor cells. Phase 1 trial results
confirm the clinical and immunologic activity of
tebentafusp in metastatic uveal melanoma.74 A
randomized phase 3 study comparing tebentafusp
with immune checkpoint antibody therapy has
completed enrollment (NCT03070392), and the
results are expected in 2021.
C onclusions
Treatment and survival for patients with local-
ized or metastatic melanoma have improved
dramatically in the past 10 years. Initial surgical
treatment is more precise and less invasive, with
a lower morbidity. Systemic therapy has under-
gone remarkable changes. Particular areas of
research interest include improving the selection
and sequence of therapies that have the highest
probability of inducing a durable response, de-
fining the benefit of neoadjuvant therapy, and
developing treatments with a higher probability
of inducing complete and durable remission.
Integration of surgical and medical interven-
tions is likely to be key in improving long-term
outcomes for patients with melanoma.
Dr. Curti reports receiving data and safety monitoring board
fees from Merck and Eisai, grant support, paid to his institution,
 Recent Advances in the Treatment of Melanoma

and advisory board fees from Clinigen, grant support, paid to his
institution, from AstraZeneca and BMS, donated supplies from
Galectin Therapeutics, travel support from Agonox, advisory
board fees and travel support from Replimune, and advisory
board fees from Nektar Therapeutics; and Dr. Faries, receiving
advisory board fees from Novartis, Pulse Bioscience, Array Bio-
science, Bristol-Myers Squibb, Sanofi, Nektar Therapeutics, and
Merck. No other potential conflict of interest relevant to this
article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Walter Urba, M.D., Ph.D., for numerous helpful
suggestions, and Kathleen Chilton for assistance in the prepara-
tion of an earlier version of the manuscript.

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