NcXHF

NEOADJUVANT THERAPY OF MELANOMA
TABLE 1. Neoadjuvant Studies of Resectable Locoegional Metastases of Cutaneous Melanoma
Study
No. of
Patients Design
Buzaid et al 19 64 Phase II
single
arm
Gibbs et al 20 48 Phase II
single
arm
Shah et al 18 19 Phase II
single
arm
Moschos 20 Phase II
et al 30 single
arm
Tarhini 33 Phase I/II
et al 35 single
arm
Primary
Objective Regimen Important Findings
Tumor response 2–4 (3-week) cycles; days 1–4: 20 mg/m 2 IV cisplatin,
1.5 mg/m 2 IV vinblastine, 9 MIU/m 2 /d continuous
IV IL-2; day 1 only: 800 mg/m 2 IV dacarbazine;
days 1–5: 5 MU/m 2 SC IFN alfa-2a
Tumor response 2 (3-week) cycles; days 1–4: 20 mg/m 2 IV cisplatin,
1.6 mg/m 2 IV vinblastine, 9 MIU/m 2 /d continuous
IV IL-2; day 1 only: 800 mg/m 2 IV dacarbazine;
days 1–5: 5 MU/m 2 SC IFN alfa-2a
Tumor response 2 (8-week) cycles 75 mg/m 2 /d temozolomide for 6
weeks then 2 weeks off
Tumor response
Safety,
biomarker
20 MU/m 2 IV IFN alfa-2b 5 days a week for 4 weeks
before surgery (induction)
20 MU/m 2 SC IFN alfa-2b 3 days a week for 48
weeks starting after surgery (maintenance)
10 mg/kg IV ipilimumab every 3 weeks for 2 doses,
bracketing surgery
High tumor response rates in phase II studies
but eventually abandoned, with the failure of
biochemotherapy to deliver survival benefits
in randomized trials of metastatic disease
The observed clinical activity was not different
from what is known in metastatic melanoma
Promising clinical activity. HDI upregulated pSTAT1
and TAP2 and downregulated pSTAT3.
Significant increases in endotumoral CD11c
and CD3 cells were noted after HDI. Phospho-
ERK1/2 was downregulated by HDI in tumor
cells but not in lymphocytes
Promising clinical activity. Ipilimumab led to
potentiation of type I CD4 and CD8 tumorspecific
T cells, downregulation of MDSC, and
an increase of CD8 TIL and T-cell memory
(CD45RO ). An immune-related gene expression
signature was significantly associated
with clinical benefit
Abbreviations: IV, intravenously; IL, interleukin; SC, subcutaneously; IFN, interferon; HDI, high-dose IFN alfa; MDSC, myeloid-derived suppressor cells; TIL, tumor-infiltrating lymphocytes.
with high-risk, locoregionally advanced disease. 5,10 Spontaneous
regression has been reported in melanoma, which suggests
a role for host immunity that is indirectly supported by
the presence of lymphoid infıltrates at primary melanoma
sites associated with tumor regression. 25 Host cellular immune
response within melanoma has potential disease prognostic
and immunotherapeutic predictive signifıcance. T-cell
infıltrates are prognostic of disease outcome in primary melanoma
and in melanoma that is metastatic to regional
nodes. 25-28 Furthermore, T-cell infıltrates within regional
nodal metastasis are signifıcantly associated with benefıt
from neoadjuvant IFN alfa therapy. 26,29,30 Further, evidence
supports a difference in the quality of the host immune response
of patients with earlier (operable) and more advanced
(inoperable) melanoma. Although T-helper type 1 (Th1)
–type CD4 antitumor T-cell function appears critical to the
induction and maintenance of antitumor cytotoxic T-lymphocyte
responses in vivo, and although Th2- or Th3/T regulatory-type
CD4 T-cell responses may subvert Th1-type cell-mediated
immunity and provide a microenvironment conducive to
disease progression, patients with advanced melanoma or renal
cell carcinoma have displayed strong tumor antigenspecifıc
Th2-type polarization. Conversely, normal donors
and patients who were disease free after therapy demonstrated
either a weak mixed Th1-/Th2-type or a strongly polarized
Th1-type response to the same epitopes. 31 Therefore,
factors of host immune tolerance that seem to impede immunotherapeutic
benefıts in advanced disease may be less pronounced
in the high-risk, operable setting. In patients with
earlier-stage melanoma, the host may be more susceptible to immunologic
interventions that may potentiate an antitumor
T-cell response and create lasting immunity.
Neoadjuvant HDI was investigated in patients who had
melanoma with palpable regional lymph node metastases
presenting either with clinical AJCC stage IIIB to IIIC disease
(TanyN2b,2c,3) or with recurrent regional lymphadenopathy.
Patients underwent surgical biopsy at study entry and
then received standard intravenous HDI (20 million units/m 2
on 5 days per week) for 4 weeks followed by complete lymphadenectomy
and standard maintenance subcutaneous HDI
(10 million units/m 2 3 times per week) for 48 weeks. Biopsy
samples were obtained before and after intravenous HDI.
Twenty patients were enrolled, and biopsy samples were informative
for 17. Eleven patients (55%) demonstrated a clinical
response, and three patients (15%) had a pCR. At a
median follow-up of 18.5 months, 10 patients had no evidence
of recurrent disease. By comparison, in the setting of
inoperable metastatic disease, response rates of less than 20%
were reported, although a number of patients had durable
responses that ranged from 26 months to more than 30
months. 32 In the context of this neoadjuvant study, HDI was
found to upregulate pSTAT1, whereas it downregulates
pSTAT3 and total STAT3 levels in both tumor cells and lymphocytes.
Higher pSTAT1/pSTAT3 ratios in tumor cells before
treatment were associated with longer overall survival
(p 0.032). The pSTAT1/pSTAT3 ratios were augmented by
HDI both in melanoma cells (p 0.005) and in lymphocytes
(p 0.022). Of the immunologic mediators and markers
tested, TAP2 (but not TAP1 and major histocompatibility
complex [MHC] classes I/II) was augmented by HDI. 33 In
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