Keywords
melanoma - squamous cell carcinoma - basal cell carcinoma - immunotherapy - PD-1
The development of immunotherapy (namely, checkpoint inhibitors targeting the programmed
death protein-1 [PD-1]/programmed death legand-1 [PDL-1] pathway) and targeted molecular
therapies in the last decade has dramatically changed the landscape for cancer therapeutics.
Within cutaneous oncology, the advent of immune checkpoint inhibitors has revolutionized
the treatment paradigms for locally advanced or metastatic melanoma, Merkel's cell
carcinoma (MCC), and cutaneous squamous cell carcinoma (cSCC). In addition, insights
into the molecular pathways of carcinogenesis have paved the way for development of
multiple nonimmunologic targeted therapies including inhibitors of BRAF and MEK for
melanomas harboring mutations in BRAF V600E/V600K and NRAS and inhibitors of the hedgehog
signaling pathway that is constitutively activated in both familial and sporadic forms
of basal cell carcinoma (BCC). In this article, we will briefly review the currently
approved targeted and immunotherapy-based treatments for locally advanced and metastatic
melanoma, MCC, cSCC, and BCC and discuss various combinations of approved therapies,
as well as novel therapeutic candidates that are currently in clinical trials.
Melanoma
Currently Approved BRAF and MEK Inhibitors
Vemurafenib is a small molecule inhibitor of the BRAF serine/threonine protein kinase
that is found to be mutated in 40 to 60% of cutaneous melanomas (BRAF V600E/V600K)
and was approved in 2011 for unresectable and metastatic melanoma harboring BRAF driver
mutations.[1] Dabrafenib is another BRAF inhibitor approved shortly after in 2013 for the treatment
of late-stage BRAF-mutant melanoma.[2] Development of resistance and rapid progression of disease has been observed with
BRAF monotherapy due to compensatory MEK1/MEK 2 upregulation, leading to the approval
of concurrent MEK inhibitors such as trametinib, cobimetinib, and bimimetanib for
use in combination with BRAF inhibitors.[2]
[3]
[4] Currently approved combinations include dabrafenib/trametenib, vemurafenib/cometinib,
and encorafenib/binimetanib.[5]
Currently Approved Immune Checkpoint Inhibitors
Ipilimumab is a monoclonal antibody directed against the cytotoxic T-lymphocyte associated
protein-4 (CTLA-4) T-cell receptor (TCR), and was approved in 2015 for adjuvant therapy
of stage-III melanoma.[6] CTLA-4 is constitutively expressed on regulatory T-cells, as well as conventional
T-cells after activation, and via interaction with B71/2 on antigen presenting cells
leads to a downregulation of the immune response allowing tumor proliferation.[7] The phase-III EORTC (European Organisation for Research and Treatment of Cancer)
trial of ipilimumab 10 mg/kg compared with placebo leading to its approval showed
significant improvement in recurrence-free survival (RFS) of 40.8% in the ipilumimab
group versus 30.3% for placebo at the most recent 5-year follow-up; however, there
was a high incidence (41.6%) of immune-related grade-3 and -4 events.[8] More recent trials have evaluated a lower-dose regimen of 3 mg/kg, showing a decreased
rate of grade 3 or higher toxicity (36.4 vs. 57%) and no difference in RFS at 3-year
follow up.[9] However, with the introduction of immune checkpoint inhibitors targeting the PD-1
axis associated with improved efficacy and lower toxicity, adjuvant ipilimumab has
fallen out of favor.[5]
PD-1 (also known as CD279) is a transmembrane protein receptor predominantly expressed
on memory T cells, as well as B cells, monocytes, natural killer (NK) and dendritic
cells that has an important role in regulating the immune response and maintaining
self-tolerance through apoptosis of antigen-specific T-cells and upregulation of regulatory
T-cells when activated by binding to its ligands PDL-1 (B7-H1) and PDL-2 (B7-DC).[10] PDL-2 is primarily expressed on antigen-presenting cells (APCs), dendritic cells,
and macrophages.[10] PDL-1 is expressed on multiple cell types including antigen-presenting cells, dendritic
cells, B cells, monocytes, epithelial cells, as well as multiple types of cancer cells,
including melanoma, lung, renal, and ovarian carcinomas, thus contributing to the
ability of tumor cells in these immunologically active cancers to evade the immune
system via activation of the PD-1/PDL-1 axis.[11]
Pembrolizumab and nivolumab are monoclonal antibodies against PD-1, and were approved
in 2014 for unresectable or metastatic melanoma.[12] Nivolumab was also approved in combination with ipilimumab for unresectable BRAF-wildtype
melanoma in 2015, and approval of anti-PD-1 agents as for adjuvant treatment of stage-III
melanoma following complete resection was granted for nivolumab in 2017 and pembrolizumab
in 2019.
There are currently three commercially available PDL-1 inhibitors on the market, all
of which are currently in clinical trials for melanoma (as detailed in below sections):
atezolizumab, durvalumab, and avelumab.[12] Atezolizumab was approved in 2016 for advanced urothelial carcinoma, and in 2019
for both advanced non–small-cell lung cancer (NSCLC), as well as advanced triple-negative
breast carcinoma expressing PDL-1 (as demonstrated by the PD-L1 IHC22C3 pharmDx assay)
in combination with paclitaxel. Durvalumab was approved in 2017 for advanced and metastatic
urothelial carcinoma, and avelumab was approved in 2017 for metastatic MCC.
Clinical Trials of Anti-PDL-1 Agents as Monotherapy in Melanoma
Avelumab is currently in phase I (JAVELIN solid tumor trial, NCT01772004) for unresectable
stage-IIIC/IV cutaneous and ocular melanoma that had progressed after at least one
prior therapy for metastatic disease, and phase 1B results were reported in early
2019.[13] The overall response rate was 21.6% (7.8% of patients with complete response and
13.8% with a partial response). The mean progression-free survival (PFS) was 3.1 months,
and mean overall survival (OS) time was 17.2 months. No grade-4 treatment-related
adverse events (TRAEs) or deaths occurred, and the rate of grade-3 TRAEs was 7.8%.[13]
Atezolizumab is slated to begin a phase-I trial (not yet recruiting) as a neoadjuvant
agent prior to surgery for resectable stage IB–IIC melanoma meeting criteria for a
sentinel lymph node biopsy (SLNB; NCT04020809).
Combination and Sequential Trials with Immunotherapy and Targeted Therapy
For patients with unresectable or metastatic BRAF-positive melanoma, the current therapeutic
options include targeted therapies (BRAF/MEK inhibitor combinations), as well as anti-PD-1
immunotherapies. While the addition of MEK inhibitors improved the durability of clinical
responses to BRAF inhibition, development of resistance remains an issue and the response
durations achieved with targeted therapy combinations are shorter than those achieved
with systemic immunotherapeutic agents.[14] The potential utility of combination trials is being investigated, as targeted agents
induce higher initial response rates but lack durability, while the clinical response
to PD-1 immunotherapy is often slower at onset but more durable.[15] In addition, preclinical studies have demonstrated increased CD8 + T lymphocyte
infiltration in the tumor microenvironment and synergistic antitumor effects with
a combination of BRAF/MEK inhibition and anti-PD-1 agents.[16] As a result, many of the current clinical trials for unresectable BRAF-mutant melanoma
are examining various combinations of PD-1 or PDL-1 inhibitors with one or more targeted
(BRAF/MEK) therapies.[17]
The initial study to evaluate a combination of a BRAF inhibitor (vemurafenib) with
immunotherapy (ipilimumab) in 2013 was halted in phase I due to development of severe
liver toxicity (NCT01400051).[18] Owing in part to the toxicity observed with ipilimumab in combination with BRAF
inhibitors, newer combination studies have focused on PD-1/PDL-1 inhibitors. Phase-Ib
results were reported from a combination trial of atezolizumab (anti-PDL-1) and vemurafenib
in 2015, demonstrating an overall response rate of 76% (58% partial response and 17%
complete response) with median duration of response 20.9 months and no severe adverse
events observed (NCT01646442).[19]
Multiple recent clinical trials are examining a triple combination regimen with anti
PD-1/PDL-1 agent, BRAF inhibitor, and a MEK inhibitor. The anti-PDL-1 durvalumab was
evaluated in combination with dabrafenib and trametenib in a phase-I trial of patients
with advanced BRAF-mutant melanoma that completed in 2018 (NCT02027961).[20] The overall response rate was 69%, and dose-limiting toxicity (reversible grade
3 thrombocytopenia) was observed in one out of 26 patients on the triple therapy regimen.
Phase-I data were reported in 2017 from the KEYNOTE-022 study of pembrolizumab, dabrafenib,
and trametenib in 15 patients with BRAF-mutant stage III/IV melanoma.[21] The overall response rate was 67%, and dose-limiting toxicities (grades 3 and 4
increase in aminotransferases and grade-4 neutropenia) were reported in 3 of 15 patients
and resolved after drug discontinuation. Phase II of KEYNOTE-022 compared dabrafenib,
trametenib, and pembrolizumab to dabrafenib and trametenib in a total of 120 patients
with BRAF-positive melanoma (60 per arm; NCT02130466).[22] The triple therapy arm had significantly higher rates of grade 3 to 5 treatment
related adverse events (58 vs. 27%) and premature discontinuation due to TRAEs was
40% in the triple therapy arm compared with 20% for the dabrafenib/trametenib arm.
The mean PFS was 16.0 months in the triple therapy group compared with 10.3 months
in the dabrafenib/trametenib cohort, which was nonsignificant due to failure to meet
one of the parameters for significance (hazard ratio < 0.66) and the median response
duration was 18.7 months in the triple therapy group compared with 12.5 months for
the dabrafenib/trametenib group.[22]
The IMPemBra trial is a phase-II study comparing pembrolizumab monotherapy to pembrolizumab
plus intermittent short-term targeted treatment with dabrafenib and trametenib for
1, 2, or 6 weeks to evaluate safety and tolerability (NCT02625337).[23] Preliminary results have demonstrated increased overall response rates in the short-term
BRAF/MEK cohorts compared with pembrolizumab monotherapy (objective response rate
[ORR] at 18 weeks was 57% in the pembrolizumab monotherapy group, 71% in the cohort
receiving dabrafenib and trametenib × 1 week, and 83% in the cohort receiving dabrafenib/trametenib × 2
weeks).
The ongoing COMBI-I trial is a phase-III study evaluating dabrafenib and trametenib
with and without the PD-1 inhibitor spartalizumab (NCT02967692).[24] The COMBI-I study is comprised of three distinct groups: a safety run-in, biomarker
analysis with collection of tumor samples for immunohistochemistry, and a randomized
double blind placebo-controlled phase to assess efficacy and safety of the dabrafenib
and trametenib with and without spartalizumab. Preliminary results reported in 2018
described grade 3/4 adverse events occurring in 22% of patients but none led to treatment
discontinuation. Significant increases in intratumoral CD8+ lymphocyte infiltration
were observed after 2 to 3 weeks of therapy in eight out of nine patients, and the
results of the PDL-1 expression and peripheral blood analysis will be reported at
a later date. All seven patients evaluated at week 12 demonstrated an unconfirmed
partial response, with no patients experiencing disease progression[24]
A phase-II trial of dabrafenib, trametenib, and the PD-1 inhibitor nivolumab is ongoing
in patients with unresectable stage III and mestastatic stage IV BRAF-mutant melanomas
(NCT02910700).[25] Preliminary results have been reported in 14 patients thus far, with 3 patients
(21%) requiring drug discontinuation due to severe adverse events (one case of grade
3 immune-mediated hepatitis and two cases of immune-mediated nephritis). Eleven patients
have been assessed for response thus far, with 10 patients (91%) showing a partial
response and 1 patient experiencing disease progression.[25]
A triple combination of the PDL-1 inhibitor atezolizumab, vemurafenib, and cobimetanib
has been assessed in a recent phase Ib open-label study (NCT01656442).[26]
[27] Enrolled patients had a 28-day lead-in phase with cobimetanib + vemurafenib followed
by addition of atezolizumab. The confirmed ORR in 39 patients was 71.8%. The median
response duration was 17.4 months, with ongoing response in 39.3% of patients after
29.9 months of follow-up.[26] Toxicity of the triple combination was reported with 66% of patients on triple therapy
having grade 3/4 TRAEs including elevations in liver transaminases, hypophosphatemia,
and hyponatremia.[26] In addition, a phase-III study (NEO-VC) of atezolizumab, vemurafenib, and cobimetanib
is currently enrolling (NCT02303951).
In summary, combination therapy trials with BRAF/MEK and immunotherapy suggest potential
synergistic effects with increased intratumoral CD8+ lymphocytes but long-term data
on OS, PFS, and durability of responses achieved are not yet available. In addition,
combinations of immunotherapy and targeted therapy may increase toxicity of treatment
and optimal combinations of therapeutic agents, as well as dosing schedules are unknown
at the present time, but hopefully optimal treatment strategies may become more evident
as results begin to emerge from the ongoing phase-II and phase-III combination trials.
Sequencing of Targeted Therapy and Immunotherapy
As discussed above, combination studies of targeted therapies with anti-CTLA-4 or
anti PD-1/PDL-1 agents may provide increased efficacy but increased toxicity of these
combination regimens are a limiting factor. As such, utilizing the targeted therapies
and immunotherapies in sequence as opposed to in combination is an area of active
investigation, with the goal of potentially harnessing some of the benefits of combination
therapy while minimizing toxicity.
There are currently two active clinical trials investigating the optimal sequencing
of targeted therapy and immunotherapy agents.[17] DREAM-SEQ (NCT02224781) is a phase-III trial in which patients are randomized to
receive either ipilimumab + nivolumab or dabrafenib + trametenib, then cross over
to the other treatment arm at disease progression. The SECOMBIT (NCT02631447) study
is a phase-II trial composed of the following three cohorts: encorafenib/binimetanib
followed by ipilimumab/nivolumab (arm A), ipilimumab/nivolumab followed by encorafenib/binimetnib
(arm B), and a “sandwich” arm treated first with encorafenib/binimetanib × 8 weeks,
ipilimumab/nivolumab until disease progression followed by repeat encorafenib/binimetanib.
While data on optimal therapeutic sequencing from randomized controlled trials are
pending, several previous retrospective studies have compared the outcomes of sequenced
therapy with BRAF/MEK inhibition before or after immunotherapy. A multicenter retrospective
study evaluated 274 patients with BRAF-mutant metastatic melanoma and compared outcomes
between those who received first-line immunotherapy (high-dose interleukin-2, ipilimumab,
nivolumab, or adoptive T-cell therapy) followed by targeted treatment (with trametinib
monotherapy, vemurafenib monotherapy, or combined dabrafenib/trametenib) versus the
reverse order.[28] No significant difference in response to targeted therapy was observed whether it
was first or second-line; however, for ipilimumab a decreased response was observed
in patients receiving ipilimumab after targeted therapy.[28] Likewise, in a retrospective analysis of a 93-patient cohort from the ipilimumab
expanded access program, superior outcomes were observed in patients who were treated
with front-line ipilimumab followed by single-agent vemurafenib or dabrafenib (median
OS, 14.5 months) compared with patients initially treated with BRAF inhibition followed
by ipilimumab (median OS, 9.9 months).[29] A more recent retrospective study in 114 patients compared the ORR, OS, and PFS
in patients treated with either anti-PD-1 agents or BRAF inhibitors first.[30] It was noted that patients who progressed on PD-1 inhibitors had worse outcomes
after transitioning to subsequent BRAF inhibitors compared with patients who had not
received anti-PD-1 agents (median OS, 10.6 vs. 40.3 months; median PFS, 5.0 vs. 7.4
months). A similar phenomenon was observed in patients who started anti-PD-1 after
progressing on BRAF inhibitor therapy, with poorer outcomes compared with patients
who had not been treated with prior BRAF inhibitors (median OS, 8.2 vs 27.6 months;
median PFS, 2.8 vs. 10.6 months). The conclusion was that either front-line BRAF inhibitors
or anti-PD-1 agents may be effective, regardless of treatment sequence, but there
may be a “shared responder” phenotype between BRAF inhibitors and PD-1 agents with
a poor response to one modality predicting a less than optimal response to the other.[30]
Intratumoral Immunotherapy
Intratumoral Immunotherapy
Involving direct injection of agents to promote tumor cell lysis, the goal of intratumoral
immunotherapy is to promote both local and systemic antitumor immune responses while
minimizing systemic toxicities.[31] Talimogene laherparepvec (T-VEC) is a genetically modified herpes-simplex type 1
virus that was the first oncolytic virus approved for unresectable (stage IIIB, IIIC,
or IV) melanoma in 2015. T-VEC was engineered and a gene allowing replication in healthy
cells (infected cell protein 34.5, ICP34.5) was removed, and granulocyte colony-stimulating
factor (G-CSF) was added to stimulate the local immune response (recruitment of dendritic
cells and presentation of tumor antigens to cytotoxic T-cells) upon tumor cell lysis
to promote a systemic antitumor immune response.
Currently there are multiple trials examining T-VEC in combination with systemic anti-PD-1
agents, as well as investigating additional novel oncolytic viral candidates (CAVATEK
and HF clone 10 [HF-10]), both as monotherapy, as well as in combination with immune
checkpoint inhibitors for advanced and metastatic melanoma. In addition, there are
multiple nonviral oncolytic agents in clinical trials including PV-10 (rose Bengal),
SD-101 (toll-like receptor [TLR]-9 agonist), tilsotomod (TLR-9 agonist), and CMP-001
(TLR 7/8 agonist) which are reviewed briefly below.
Oncolytic Viral Therapies
Oncolytic Viral Therapies
T-VEC in Combination with Systemic Immunotherapy
T-VEC is currently being studied with both systemic ipilimumab, as well as pembrolizumab
for unresectable and metastatic melanoma. A recent phase-II trial compared T-VEC plus
iplilimumab to ipilimumab monotherapy in unresectable stage IIIB-IV melanoma (NCT01740297).[32] The ORR was 39% in the combination arm compared to18% for ipilimumab monotherapy,
and responses of visceral lesions that had not been injected were seen in 52% of the
combination arm compared with 23% of the ipilumumab monotherapy group. Grade 3 and
higher adverse events were observed more frequently in the combination arm than for
ipilimumab alone (45 vs. 35%) but overall the combination was well tolerated. T-VEC
has also been evaluated in combination with pembrolizumab in a phase-Ib trial in which
patients received local intratumor T-VEC injection (4 × 106 plaque forming units/mL) at week 1 and began pembrolizumab at week 3 coinciding with
the second T-VEC injection.[33] Biopsies were taken of injected tumors at baseline and at week 3 prior to the second
T-VEC injection and before pembrolizumab commenced. The overall response rate was
62% (with 33% of patients having a complete response), and immunohistochemical analysis
of tumors demonstrated increased CD8+ lymphocyte infiltration, as well as elevated
PDL-1, and interferon (IFN)-γ expression after the initial T-VEC injection in patients
who responded to combination therapy, suggesting that T-VEC may alter the tumor microenvironment
to improve the efficacy of PD-1 inhibition.[33] A phase-III trial of T-VEC and pembrolizumab is currently underway (NCT02263508).
Coxsackievirus A21
Coxsackievirus A21 (CAVATEK; Merck & Co.) is an unaltered coxsackie virus that preferentially
infects cells that express increased levels of intercellular adhesion molecules (ICAMs)
on their cell surface.[34] In the phase-II open-label CAVATEK in melanoma (CALM) study (NCT01227551), 57 patients
with stage IIIC-IV melanoma were treated with intratumoral injection of CAVATEK on
days 1, 3, 5, and 8 followed by a fifth injection 2 weeks later (day 22) and additional
injections every 3 weeks (up to a maximum of 10 injections or confirmed disease progression).
At 6 months, the ORR was 28% and no grade 3 or 4 adverse events were reported.[35]
CAVATEK was studied in combination with ipilimumab in the phase-Ib study titled melanoma
intertumoral CAVATEK and ipilimumab (MITCI; NCT02307149).[36] The 2017 interim results report in 18 evaluable patients showed an overall response
rate of 50%, and notably the response rate was higher in patients who had not been
previously treated with a checkpoint inhibitor in the past (60%) compared with 38%
in patients who had been previously treated with checkpoint inhibitors. However, responses
were seen in patients who had developed progressive disease on previous checkpoint
inhibitor therapy. In addition, CAVATEK is currently in phase-I trials in combination
with pembrolizumab (NCT02307149) and results have not yet been reported.
HF-10 (spontaneously mutated HSV-1)
HF-10 (Takara Bio Inc.) is a herpes simplex type 1 (HSV-1) virus containing spontaneous
mutations (not genetically engineered) that is spontaneously mutated and acts as a
potent oncolytic agent.[37] A phase-II trial in combination with ipilimumab has been completed in 44 patients
with stage IIIB-IV melanoma (NCT02272855).[38] The overall response rate at 24 weeks was 41%, with complete responses occurring
in 16% of patients. At 24 weeks, 42.9% of responses had been maintained without progression.
HF-10 is also being evaluated in a phase-II trial with nivolumab for unresectable
stage IIIB-IV melanoma (NCT03259425).
Nonviral Oncolytics
PV-10 (Rose Bengal Disodium)
PV-10 (Provectus Biopahrmaceuticals Inc.) is a an injectable form of rose Bengal disodium
(a xanthene dye) that accumulates in lysosomes after intratumoral injection leading
to tumor lysis, and it has received orphan drug designation from the U. S. Food and
Drug Administration (FDA) for investigation in melanoma, as well as hepatocellular
carcinoma.[39] A phase-II study of PV-10 was recently completed in 80 patients with refractory
metastatic melanoma (NCT005211053). The overall response rate was 51%, with a complete
response being observed in 26% of patients. The main side effects were injection site
tenderness and itching, and no grade 4 or 5 adverse events were observed.[40] Intralesional PV-10 is also being evaluated in a phase Ib/II study in combination
with pembrolizumab (NCT02557321), as well as a phase-III study, comparing intralesional
PV-10, intralesional T-VEC, and systemic chemotherapy with dacarbazine or temozolamide
in BRAF-wildtype melanoma who have failed at least one checkpoint inhibitor or are
not candidates for checkpoint inhibitor therapy (NCT02288897).
Toll-Like Receptor Agonists
An important component of immunity, TLRs are transmembrane receptors expressed on
a variety of leukocytes including dendritic cells, macrophages, NK cells, T-cells,
and B-cells in addition to epithelial and endothelial cells[41] that are involved in recognition of highly conserved antigens (such as those derived
from bacteria, fungi, and viruses) and initiating the innate and adaptive immune responses.
TLR agonists have shown potential utility in cancer treatment, by triggering T-cell
responses that can lead to antitumor effects.[42]
[43] Several TLR agonists have been studied in melanoma, including SD-101 (a TLR-9 agonist),
tilsotolimod (also known as IMO-2125, a TLR-9 agonist), and NKTR-262 (a TLR 7/8 agonist).[31] SD-101 (Dynavax Technologies) has been evaluated in a phase-Ib trial in conjunction
with pembrolizumab for unresectable and metastatic melanoma (NCT02521870). Patients
naïve to previous PD-1/PDL-1 therapy had a significantly better overall response rate
than those who had previously had treatment with another PD-1/PDL-1 agent (ORR, 88
vs. 15%). In addition, immunohistochemical analysis of tumors was performed and an
increase in CD8+ T cells, NK cells, dendritic cells, and B-cells was observed in both
the PD-1 naïve and previously treated cohorts.[44] Tilsotolimod IMO-2125 (Idera Pharmaceuticals) has been evaluated in combination
with ipilimumab in a phase I/II study in patients with PD-1 refractory metastatic
melanoma, and demonstrated an overall response rate of 38% (NCT02644967).[45] In addition, tilsotolimod is also being evaluated in combination with ipilimumab
for metastatic PD-1 refractory melanoma in the phase-III ILLUMINATE-301 study (NCT03445533).
Finally, NKTR-262 is a TLR 7/8 agonist that is currently being evaluated in the phase
I/II REVEAL trial in advanced melanoma, MCC, colorectal cancer, urothelial carcinoma,
and sarcoma in combination with NKTR-214 (a systemic CD-122 agonist) with or without
nivolumab (NCT03435640).
Merkel Cell Carcinoma
Similarly to melanoma, the systemic treatment of MCC has changed dramatically with
the development of anti-PD-1/PDL-1 immunotherapies.[46] Avelumab and pembrolizumab are currently approved for metastatic MCC, and current
trials are evaluating pembrolizumab, nivolumab, and ipilimumab (in combination with
nivolumab) for the treatment of unresectable and metastatic MCC. There are also trials
of multiple “next-generation” checkpoint inhibitors targeting the PD-1/PDL-1 axis
including antibodies to T-cell immunoglobulin and mucin containing domain 3 (TIM-3),
lymphocyte-activation gene-3 (LAG-3), and T cell immunoreceptor with Ig and immunoreceptor
tyrosine-based inhibition motif (ITIM) domains (TIGIT). T-VEC (alone and in combination
with nivolumab or radiation therapy) is also being evaluated in MCC, as are several
TLR agonists either alone or combined with other immunotherapies. Finally, other immune-mediated
treatment mechanisms including adoptive T-cell transfer, cell therapy with innate
immune cells, and costimulatory T-cell agonists are in the early phases of trials
for MCC.
Pembrolizumab
The phase II KEYNOTE-017 trial (NCT02267603) evaluated the use of pembrolizumab monotherapy
in patients with stage IIIB/IV MCC who had not previously had systemic therapy for
their disease.[47] Results reported in 2018 from 49 patients demonstrated an overall response rate
of 56% (32% partial and 24% complete responses) with a median follow-up of 14.9 months.
Based on these results, the FDA granted pembrolizumab approval for recurrent or metastatic
MCC in 2018, and phase-III trials are currently ongoing to assess pembrolizumab as
first-line therapy in advanced MCC (NCT03783078).
Nivolumab
The PD-1 inhibitor nivolumab is currently in phase I/II trials as monotherapy for
advanced MCC (CheckMate 358, NCT02488759), and demonstrated an overall response rate
of 64%, as well as PFS of 75% at 6 months.[48] In addition, the ongoing CheckMate 358 study is also investigating nivolumab in
combination for metastatic MCC (phase II), as well as neoadjuvant therapy in resectable
disease and in combination with daratumumab (anti-CD38 antibody, phase I) for unresectable
or metastatic disease. There are several additional trials of nivolumab in the recruiting
phase for MCC, including phase II in combination with ipilimumab and stereotactic
radiation for metastatic MCC (NCT03071406), a phase-II trial of nivolumab or ipilimumab
compared with placebo following resection of MCC (ADMEC-O, NCT03271372), as well as
nivolumab + radiation therapy versus nivolumab, and ipilimumab following resection
of MCC (NCT03798639).
‘Next-Generation” Checkpoint Inhibitors
‘Next-Generation” Checkpoint Inhibitors
In addition to the inhibitory effect that PD-1/PDL-1 interaction has on the immune
response, the tumor microenvironment contains several other inhibitory factors expressed
by T-cells including LAG-3 and TIGIT.[46]
LAG-3
LAG-3 expression may be increased in activated CD8+ and CD4+ T-cells in the setting
of chronic infections or malignancy, functioning analogous to PD-1 and suppressing
the immune response.[49] A monoclonal antibody to LAG-3 (INCAGNN02385) is currently being investigated in
a phase-I study of advanced tumors including MCC (NCT03538028), and in one of the
arms of the CheckMate 358 study evaluating a combination of nivolumab and relatamib
(anti-LAG-3 antibody).
TIM-3
TIM-3 is expressed by CD8+ T-cells within the tumor microenvironment and has been
shown to promote T-cell exhaustion, representing a potential target for immunotherapeutic
agents based on restoration of cytotoxicity following TIM-3 blockade in vitro.[50] A monoclonal antibody against TIM-3 (INCAGN02390) is currently in phase-I trials
for advanced tumors including MCC (NCT03652077).
TIGIT
TIGIT is a coinhibitory receptor expressed on T-cells and NK cells, and binding to
its ligand (CD155) results in dampening of immune response in a manner analogous to
PD-1.[51] An anti-TIGIT antibody (AB154) is currently in phase-I trials both alone and in
combination with a novel andi-PD1 antibody (AB154) in advanced tumors including MCC
(NCT03628677).
T-VEC
T-VEC is currently in phase-I trials for locally advanced MCC (NCT03458117), as well
as phase-II studies in combination with radiation therapy for unresectable stages
III/IV MCC (NCT02819843), as well as nivolumab (NCT02978625).
Toll-Like Receptor Agonists
Intratumoral injection of TLRs is currently being investigated as adjuvant agents
along with checkpoint inhibitors in MCC. AST-008 is a TLR-9 agonist in phase-I/II
trials in combination with pembrolizumab (NCT0364785). Another phase-I/II study is
evaluating NKTR262 (A TLR 7/8 agonist) in combination with nivolumab and systemic
NKTR214 (a CD122 agonist) in locally advanced and metastatic MCC (NCT03435640). Finally,
polyICLC (polyiosinic-polycytidylic acid with polylysine and carboxymethylcellulose,
a TLR-3 agonist) is being investigated in phase-I/II trials in combination with durvalumab
(anti-PDL-1 antibody) and tremilumimab (anti-CTLA-4 antibody; (NCT02643303).
Adoptive T-Cell Immunotherapy
Adoptive T-Cell Immunotherapy
Adoptive T-cell immunotherapy involves the extraction of T-cells followed by subsequent
selection and expansion of T-cells against a specific antigen, followed by reinfusion
into the patient, and is being investigated as an adjuvant agent in the treatment
of MCC using T-cells specific to the Merkel's cell polyomavirus (MCPyV).[52] A phase-I/II trial is evaluating adoptive T-cell therapy plus interferon versus
avelumab and radiation therapy in MCPyV-positive unresectable MCC (NCT02584829), and
another phase-I/II trial of MCPyV-specific autologous T-cells in combination with
avelumab and radiation therapy is slated to begin recruiting (NCT03747484).
T-Cell Costimulation
T-cell activation involves binding of the TCR to a major histocompatibility complex
(MHC) on the antigen presenting cell (APC) in addition to a second signal provided
by interaction of costimulatory molecules on the T-cell and APC, and agonists for
these costimulatory molecules are an additional adjuvant therapy in development for
multiple cancers.[53] CD27, OX40, 4 to 1 BB, and glucocorticoid-induced tumor necrosis factor (TNF) receptor-related
protein (GITR) are all members of the TNF receptor superfamily and represent costimulatory
ligands currently under investigation.[54] A phase-I trial is investigating INCAGN01949 (an anti-OX40 agonistic antibody) in
combination with nivolumab, ipilimumab, or both in the treatment of unresectable stage
III/IV MCC (NCT03241173). INCAGN01876 is an anti-GITR agonistic antibody currently
in two phase-I/II trials for MCC; in combination with nivolumab, ipilimumab, or both
(NCT03126110) and in combination with pembrolizumab and epacadostat (inhibitor of
indoleamine 2,3 dioxygenase 1 [IDO-1], which acts to suppress effector T-cell function;
NCT03277352). In addition, ABBV-368 (an OX40 agonist) is under investigation in combination
with ABBV-181 (an anti-PD-1 antibody) in a phase-I trial (NCT03071757).
Innate Immune Cell Therapy
Innate Immune Cell Therapy
Increased NK cells within the Merkel's cell tumor microenvironment has been shown
to be associated with better prognosis in MCPyV-associated tumors,[55] and infusions of activated NK-92 (aNK) cells are being studied both alone and in
combination with other agents in MCC. Infusions of Neukoplast (QUILT-3.009 NK cell
line) are currently being evaluated in a phase-I single-arm open trial for unresectable
stage III-IV MCC (NCT02465957).
Cutaneous Squamous Cell Carcinoma
Cutaneous Squamous Cell Carcinoma
Prior to the development of immune checkpoint inhibitors, treatment options for unresectable
or metastatic cSCC and systemic treatments were limited to traditional chemotherapy
(mainly with platinum-based agents, 5-flurouracil derivatives, doxorubicin, bleomycin,
and taxanes)[56] and agents targeting the epidermal growth factor receptor (EGFR) such as cetuximab,
erlotinib, and gefitinib.[57] In 2018, cemiplimab became the first anti-PD-1 agent approved for metastatic and
unresectable cSCC.[58] Currently, there are clinical trials investigating cemiplimab as neoadjuvant therapy
(either intratumoral or systemic) for recurrent cSCC prior to surgery, as well as
an adjuvant agent after surgery, and radiation therapy in high-risk cSCC. In addition,
there are multiple clinical trials of other anti-PD-1 agents for first-line treatment
of unresectable or metastatic cSCC including pembrolizumab, nivolumab, avelumab, and
cosibelimab (CK-301) which is an investigational anti-PDL-1 monoclonal antibody.
Cemiplimab
The approval of cemiplimab in 2018 for metastatic or unresectable cSCC was based on
results from a phase-II study, demonstrating a 47% overall response rate and a response
duration exceeding 6 months in 57% of patients who responded to cemiplimab (NCT02760498).
In addition, cemiplimab was overall well-tolerated with the most common adverse events
being diarrhea, fatigue, and nausea, and 7% of patients needed to discontinue cempilimab
due to a TRAE.[59] Systemic cemiplimab is being evaluated as neoadjuvant therapy prior to surgical
resection in stage II-IV cSCC (NCT04154943). Neoadjuvant intralesional cempiplimab
is currently being studied in a phase-I trial for recurrent cSCC prior to surgical
resection (NCT03889912). In addition, cempiplimab is being evaluated as adjuvant treatment
after surgery and radiation for high-risk cSCC compared with placebo (NCT03969004).
Other Anti-PD-1/PDL-1 Agents (Pembrolizumab, Nivolumab, Avelumab, and Cosibelimab/CK-301)
Other Anti-PD-1/PDL-1 Agents (Pembrolizumab, Nivolumab, Avelumab, and Cosibelimab/CK-301)
Pembrolizumab and nivolumab were both approved in 2017 for the first-line treatment
of unresectable or metastatic head and neck SCC; however, neither the phase-III study
of nivolumab (Checkmate 041) nor the phase-Ib trial of pembrolizumab (KEYNOTE-012)
evaluated any patients with cSCC.[60]
[61] However, case series of both pembrolizumab and nivolumab have shown promising results
in cSCC not amenable to surgical resection and both drugs are currently being evaluated
in multiple clinical trials.[62]
[63]
Pembrolizumab monotherapy is currently being evaluated as first-line treatment for
advanced cSCC in four phase-II studies including the KEYNOTE-629 trial (NCT03284424),
the CARSKIN trial (NCT02883556) and two additional trials in unresectable or metastatic
cSCC (NCT02964559 and NCT02721732). Pembrolizumab is also being studied in combination
with an intratumoral TLR-9 agonist (AST-008) in a phase-1b/II trial for advanced cSCC
(NCT03684785), as well as an adjuvant agent compared with placebo, following resection
of locally advanced cSCC (KEYNOTE-630, NCT03833167). In addition, a phase-I trial
of pembrolizumab and the MG1-MAGEA3 vaccine (a genetically modified form of the Maraba
virus which acts as an oncolytic, coupled with the melanoma antigen family A3 [MAGE-3]
antigen that is overexpressed in many tumor types including cSCC) is slated to begin
recruiting (NCT03773744).[64]
First-line nivolumab is currently being studied in two phase-II trials in locally
advanced and metastatic cSCC (NCT03834233 and NCT04204837). Nivolumab is also being
evaluated for unresectable and metastatic cSCC in kidney transplant patients in a
phase-I trial (NCT03816332) given in conjunction with tacrolimus and prednisone, and
patients who have progressive disease on nivolumab will be treated with combination
nivolumab and ipilimumab.
There are currently two phase-II studies evaluating the anti-PDL-1 antibody avelumab
in unresectable and metastatic cSCC: with and without the anti-EGFR antibody cetuximab
(NCT03944941) and in combination with radical radiotherapy (NCT03737721).
Cosibelimab (CK-301) is an investigational anti PDL-1 monoclonal antibody, and is
currently being evaluated in a phase-I trial in multiple types of advanced and metastatic
cancers including cSCC, MCC, urothelial carcinoma, and both small-cell and non–small-cell
lung adenocarcinoma (NCT03212404).
Basal Cell Carcinoma
While the vast majority of BCC tumors can be treated primarily with surgery and have
an excellent prognosis, approximately 1% of patients develop advanced disease, defined
as either locally advanced BCC (laBCC) or metastatic BCC (mBCC). Though the incidence
of mBCC is extremely rare (0.0028–0.5%), it is associated with a median survival of
approximately 8 months when nodal metastases are present.[65] Approximately 85% of BCCs have mutations in the hedgehog signaling cascade, a pathway
critical for cell proliferation and differentiation in embryogenesis, and the treatment
of advanced and metastatic BCC has been revolutionized by the introduction of targeted
agents inhibiting this pathway.[65]
[66] Vismodegib is an inhibitor of the SMO receptor involved in the hedgehog pathway
and was approved for advanced BCC in 2012. The approval of vismodegib was based on
ERIVANCE, a multicenter, single-arm, two-cohort phase-2 trial that assessed the efficacy
and safety of vismodegib in patients with laBCC. In this study, 104 patients with
laBCC and mBCC were treated with vismodegib 150 mg daily. At 39 months, investigator-assessed
ORR was 60.3% in the laBCC group and 48.5% in the mBCC group. Median duration of response
was 26.2 months in laBCC and 14.8 months in mBCC, demonstrating the durability of
response of this treatment option.[67] Sonidegib is another orally dosed SMO inhibitor that is structurally distinct from
vismodegib, and was approved in 2015 for locally advanced BCC. In the double-blind
phase-2 BOLT trial, patients with laBCC or mBCC were randomized to either 200 or 800 mg
of sonidegib daily. No additional efficacy was found between the two doses and in
the 200-mg group, the ORR performed by central review was 56.1% for laBCC and 7.7%
for mBCC at 30-month follow-up, with the 200-mg group also exhibiting a better safety
profile.[68]
To date, there are no head-to-head randomized controlled trials comparing vismodegib
to sonidegib. In a meta-analysis of 1,102 patients, vismodegib and sonidegib demonstrated
a similar overall response rate (RR) for laBCC (69 vs. 57%, respectively), whereas
the complete RR differed drastically (31 vs. 3%, respectively). For metastatic disease,
the overall RR of vismodegib was 2.7-fold higher than that of sonidegib (39 vs. 15%,
respectively).[69] However, there is a need for future head-to-head clinical trials to further compare
the efficacy and safety profiles of these two agents.
Current areas of research in BCC include the use of SMO inhibitors as neoadjuvant
agents prior to surgical resection of locally advanced BCC, topical SMO inhibitors
(patidegib) for prevention and treatment of BCCs in the setting of BCC nevus syndrome
(BCCNS) resulting from Patched-1 mutations, as well as to treat and prevent high-frequency
BCCs in patients who do not have BCCNS, investigation of novel SMO inhibitors, as
well as alternative targets for inhibition within the hedgehog pathway.
Novel Smoothened Inhibitors
Taladegib is an investigational oral SMO inhibitor that recently completed a phase
dose-finding I clinical trial for advanced BCC (NCT01226485). Data from the phase-I
study reported an overall response rate of 46.8% (in both patients who had previous
hedgehog pathway inhibitors as well as hedgehog-naïve patients) with an acceptable
safety profile.[70] Phase-II trials are planned at doses below the maximum tolerated dose (MTD) of 400 mg
daily that was identified in the phase-I study.
Neoadjuvant Smoothened Inhibitors
Neoadjuvant SMO inhibitors for laBCC have been investigated, specifically for BCCs
at high risk for functional or aesthetic compromise with surgery in an effort to decrease
the size of the defect required for tumor clearance. Current evidence for their use
in the neoadjuvant setting is not well established, based primarily on open-label
studies and case series. In an open-label study in 15 patients, vismodegib 150 mg
daily was used for 3 to 6 months in the neoadjuvant setting, with a reduction of surgical
defect size by 27% (95% confidence interval [CI]: −45.7 to −7.9%, p = 0.006). Four patients were not able to continue vismodegib longer than 3 months
due to side effects, and 1 patient out of 11 evaluable patients had recurrence after
a mean follow-up of 11.5 months.[71] However, it is important to note that systemic SMO inhibitors do not always reduce
tumor volume in a concentric fashion from the periphery, and may result in a tumor
that effectively has “skip” lesions and reduce the accuracy of microscopically controlled
excision methods such as Mohs’ surgery. Larger randomized placebo-controlled studies
will be required to investigate the efficacy of neoadjuvant SMO inhibitors for advanced
BCC.
Topical Smoothened Inhibitors
With more than one quarter of patients discontinuing treatment due to side effects,
the use of topical SMO inhibitors is currently being explored. In a double-blind,
vehicle-controlled, intraindividual study, 8 nevoid BCC patients with 27 BCCs were
randomized to twice daily treatment of either 0.75% sonidegib cream (n = 13) or vehicle (n = 14). In the topical sonidegib group, three lesions demonstrated a complete response,
and nine had a partial response (PR); only one PR was noted in the placebo group.[72] Topical patidegib is currently being studied for its ability to decrease BCC disease
burden in the setting of BCCNS (phase III, NCT03703310) as well as in non-BCCNS high-frequency
BCCS (phase II, NCT04155190).
Alternative Targets in the Hedgehog Pathway
Alternative Targets in the Hedgehog Pathway
In addition to side effects, resistance to SMO inhibitors raises a major concern,
as approximately 5 to 10% of patients demonstrate resistance with eventual lack of
response and progression of disease.[65] The use of additional therapies directed at alternative downstream targets of the
hedgehog signaling pathway have been considered for cases of resistance. Iraconazole,
an FDA-approved antifungal, inhibits the hedgehog pathway by blocking SMO migration
and has been shown to inhibit GLI expression in cells with vismodegib-resistant mutations. A clinical trial investigating
the use of oral SUBA-itraconazole (SUBA-Cap) for BCCNS is currently in phase II (NCT02354261).
Topical itraconazole is also in a phase-I study for non-BCCNS patients with BCC (NCT02735356).
Additionally, direct inhibition of GLI transcription factors, terminal effectors in the hedgehog pathway, may also be a
promising target in the treatment of laBCCs. Arsenic trioxide (ATO) is a chemotherapeutic
agent that directly binds GLI1 and GLI2, preventing the accumulation of GLI in the primary cilium, an essential step in downstream hedgehog signaling.[73] While combination therapies targeting more than one component of the hedgehog pathway
may be more effective in combating resistance, future clinical studies are necessary
for further confirmation.
Immunotherapy (PD-1 Inhibitors)
Immunotherapy (PD-1 Inhibitors)
Pembrolizumab is currently in phase-II clinical trials for advanced BCC in combination
with vismodegib (NCT02690948). Phase-I results were recently reported in which 16
patients were assigned to either pembrolizumab monotherapy versus pembrolizumab with
oral vismodegib. Although not randomized, the authors concluded that the overall response
rate of the pembrolizumab–vismodegib combination group was not subjectively superior
compared with the pembrolizumab monotherapy group but merits further investigation
in larger randomized controlled trials.[74] Cepilimumab monotherapy is currently in phase-II trials for in patients with BCC
that had either progressed on or been intolerant prior hedgehog inhibitor therapy
(NCT03132636) and results have not yet been published.[75] However, a case report in one patient with metastatic BCC resistant to hedgehog
inhibitors had a partial response with cepilimumab, and PFS was 32 weeks.[76] Nivolumab has not been studied in clinical trials but has shown a partial response
in a case report of one patient with metastatic BCC refractory to hedgehog inhibitors
and a PFS time of 116 weeks.[77]
Conclusion
The development of immunotherapeutic agents targeting the PD-1/PDL-1 axis has dramatically
altered the treatment of and improved survival outcomes of many cancers that previously
had limited therapeutic options in advanced stages, including melanoma, MCC, and cSCC.
Numerous other treatments have emerged for melanoma, including the development of
targeted agents against the BRAF/MEK pathway, as well intratumoral oncolytic agents,
which are being investigated both alone and in combination with immunotherapy. Trials
exploring various combinations and administration sequences of approved targeted therapies
and immune-based treatments are underway in melanoma in an effort to help improve
efficacy while minimizing toxicity. In addition, the treatment of advanced and metastatic
BCC has been significantly improved by the development of targeted inhibitors of the
hedgehog signaling pathway, and future directions include investigation of PD-1 inhibitors
as a means to augment response and potentially treat BCCs that are resistant to hedgehog
inhibitors. With multiple late-stage clinical trials underway, the next several years
will provide valuable data on safety, efficacy, and durability of responses achieved
by these recently approved targeted and immune-based therapies, as well as hopefully
provide insight into the optimal treatment combinations, and regimens for advanced
melanoma and non-melanoma skin cancers.
