sun-damaged (CSD) skin. 4–7 It is now clear that
based on its association with CSD skin, melanoma can be subclassified into CSD or non-CSD melanoma. CSD and non-CSD melanoma
have distinct clinico-pathological characteristics
and are associated with different driver mutations. CSD melanomas typically arise in older
patients on sun-exposed areas (head/neck,
dorsal surfaces of distal extremities) and are
associated with particular driver mutations
(BRAF non-V600E, NRAS, NF1, or KIT) and
genetic signatures of UV-induced DNA damage
(G > T [UVA] or C > T [UVB]) transitions. Conversely, non-CSD melanomas typically arise in
younger (< 55 years) patients on intermittently
sun-exposed areas (trunk, proximal extremities) and are associated with BRAF V600E/K
driver mutations and often lack genetic signatures of UV mutagenesis.
Identification of driver mutations in compo-
nents of the MAPK pathway, including BRAF
and NRAS, facilitated the development of tar-
geted inhibitors. The BRAF inhibitors vemu-
rafenib and dabrafenib have been shown in
pivotal phase 3 studies to significantly improve
overall and progression-free survival in patients
with metastatic melanoma compared with che-
motherapy and garnered regulatory approval
(vemurafenib, BRIM- 3; 8, 9 dabrafenib, BREAK-
310). Concomitant MEK and BRAF inhibition
extends the duration of benefit by preventing
downstream kinase activation in the MAPK
pathway. Notably, concomitant MEK inhibition
alters the side-effect profile of BRAF inhibi-
tors, with reduced incidence of keratoacantho-
mas and cutaneous squamous cell carcinomas
that are attributable to on-target, off-tumor
effects of BRAF inhibitors. Combined BRAF
and MEK inhibition (vemurafenib/cobimetinib
and dabrafenib/trametinib) further improved
overall and progression-free survival compared
to single-agent BRAF inhibition in phase 3 stud-
ies (COMBI-d, 11 COMBI-v, 12 and coBRIM13).
Although often deep, the responses seen with
the use of targeted kinase inhibitors are not
often durable, with the vast majority of patients
progressing after 12 to 15 months of therapy.
In parallel, work primarily done in murine
models of chronic viral infection uncovered the
role played by co-inhibitory or co-excitatory immune checkpoints in mediating T-cell immune
responses. These efforts clarified that tumor-mediated immune suppression primarily occurs
through enhancement of inhibitory signals via
the negative T-cell immune checkpoints CTLA-
4 or PD- 1. 14, 15 Blockade of negative T-cell immune checkpoints resulted in activation of the
adaptive immune system, resulting in durable
anti-tumor responses as demonstrated in studies
of the CTLA- 4 inhibitor ipilimumab (CA184-
02016 and CA184-02417) and the PD- 1 inhibitors
nivolumab (CA209-003, 18 CheckMate 037, 19 and
CheckMate 06620) and pembrolizumab (KEY-
NOTE-00121 and KEYNOTE-00622). Compared
to the deep but short-lived responses seen with
targeted kinase inhibitors, patients treated with
CTLA- 4 or PD- 1 immune checkpoint blockade
often developed durable responses that persisted even after completion of therapy. Combined
CTLA- 4 and PD- 1 blockade results in greater
magnitude of response with proportionately
increased toxicity. 23–25
IMMUNOTHERAPY
CTLA- 4 AND PD- 1 IMMUNE CHECKPOINT INHIBITORS
The novel success of immunotherapy in recent decades is largely attributable to improved
understanding of adaptive immune physiology,
specifically T-cell activation and regulation. T-cell
activation requires 2 independent signaling
events: it is initiated upon recognition of the
antigen-MHC class II-receptor complex on
antigen-presenting cells (APC), and requires a
secondary co-stimulatory interaction of CD80/
CD86 (B7.1/B7.2) on APCs and CD28 molecule on T-cells; without this second event,
T-cells enter an anergic state. 30–32 Upon successful
signaling and co-stimulation, newly activated
