Annual Meeting Proceedings Part 1 - American Society of Clinical ...

560s Melanoma/Skin Cancers
8580 General Poster Session (Board #36F), Sun, 8:00 AM-12:00 PM
A clinical and translational phase II trial of sequential axitinib and
carboplatin/paclitaxel in advanced melanoma. Presenting Author: Alain
Patrick Algazi, University of California, San Francisco, San Francisco, CA
Background: Several clinical trials adding VEGF signaling inhibitors to
chemotherapy have not demonstrated any benefit over chemotherapy alone
in advanced melanoma potentially due to decreased tumor cell proliferation
induced by VEGF blockade. We tested the hypothesis that sequential
administration of axitinib followed by carboplatin and paclitaxel may be
more effective than chemotherapy alone in metastatic melanoma. Methods:
We conducted a prospective phase II trial of this combination in previously
treated metastatic melanoma patients. Patients had an ECOG PS 0-1, and
normal organ function. Axitinib 5 mg PO bid was taken on days 1 through
14 of each 21-day treatment cycle, and carboplatin (AUC�5) with
paclitaxel (175 mg/m2 ) was administered on day 1 starting with cycle 2.
FLT-PET scans were performed on 6 patients to assess tumor cell
proliferation on days 1, 14, 17, and 20 of cycle 1. Results: Treatment has
been well tolerated. The most common grade 3 AEs have been neutropenia,
hypertension, and gastrointestinal events. Grade 4 non-hematologic AEs
have not been observed. 4 of 5 patients completing FLT-PET scans to date
showed increases (23% to 92%) in SUV values during the axitinib holiday.
The fifth patient had a single, minimally FLT avid lesion at baseline
(SUV�1.9). In 30 evaluable patients, there have been 4 confirmed PRs, 2
unconfirmed PRs, and 3 patients with 28.6, 29.3, and 29.5% decreases in
tumor size by RECIST. Overall, 19 patients have had SD and 5 have had PD
as the best response. With a median follow-up of 8.3 months and 17
patients still active, the median PFS is 6.9 months, and 23 patients (77%)
are still alive. 26 of 30 evaluable patients have been wild type for
BRAF-V600E/K mutations. Conclusions: Axitinib followed by carboplatin
and paclitaxel has been well tolerated and effective in a largely BRAF
wild-type metastatic melanoma population. Given the urgent need for
effective therapies in this population, this regimen warrants phase III
testing.
8582 General Poster Session (Board #36H), Sun, 8:00 AM-12:00 PM
Phase I trial of extended-dose anti-PD-1 antibody BMS-936558 with a
multipeptide vaccine for previously treated stage IV melanoma. Presenting
Author: Ragini Reiney Kudchadkar, H. Lee Moffitt Cancer Center &
Research Institute, Tampa, FL
Background: BMS-936558, a fully human IgG4 anti-PD-1 antibody, has
shown clinical activity in melanoma and renal cancer. Methods: 30 HLA
A*0201 positive patients with unresectable, previously treated stage IV
melanoma received MART-1/gp100/NY-ESO-1 peptides with adjuvant
Montanide ISA 51 injected subcutaneously with BMS-936558 at 1, 3 or
10 mg/kg intravenously every 2 weeks for 24 weeks, followed by BMS-
936558 alone every 3 months. No patient had prior ipilimumab. Endpoints
were toxicity, correlative studies of immunity measured by ELISPOT and
T-cell phenotype assays, and response by RECIST. Results: Median age was
62, with 14 men and 16 women. 73% of patients had M1c disease. One
patient had dose limiting optic neuritis; one patient had dose limiting grade
3 interstitial pneumonitis. Of 10 patients at 1 mg/kg, 2 had confirmed
partial responses (PR), both one year from initiation of study. 13 patients
were treated at the 3 mg/kg cohort; 3 patients did not complete more than 3
doses secondary to progressive disease and one withdrew consent. Of 12
evaluable patients, 3 had confirmed PRs and 2 unconfirmed PRs. In the 10
mg/kg cohort, thus far 6 patients completed one cycle with 2 unconfirmed
PRs and one patient stable. Only 2 of the 9 responders after one cycle have
progressed with a median follow-up of 7 months. 2/6 patients failing
BMS-936558 responded to ipilimumab. At week 12, patients in all cohorts
had decreased PD-1 on CD4 and CD8 T-cells (p�0.0001), increased CD4
CTLA-4 levels (p�0.01) and dose related decreases in CD8 T-cells whereas
CD4 T-cells increased (both p�0.05). ELISPOT assays showed that
patients at all doses had no increased responses in fresh PBMC to
MART-1/gp100, but showed dose related decreased responses to viral
(CMV, EBV, FLU) peptides over time (p�0.04). Conclusions: BMS-936558
in combination with a peptide vaccine is well tolerated at 1 and 3mg/kg.
Accural to the 10mg/kg cohort is on-going. Responses have been observed
at all dose levels. PD-1 levels on T-cells decreased, and CTLA-4 levels
increased in CD4 T cells in all cohorts. There was a dose-related decrease in
CD8 T-cells and in viral-specific T-cells. Further study of BM-936558 is
warranted to determine its optimal dose.
8581 General Poster Session (Board #36G), Sun, 8:00 AM-12:00 PM
Assessment of germ-line and somatic alterations in main candidate genes
among patients with multiple primary melanoma. Presenting Author:
Giuseppe Palmieri, Istituto di Chimica Biomolecolare, CNR, Sassari, Italy
Background: We have studied a series of patients with multiple primary
melanoma (MPM) for the involvement of the key-regulator genes in
susceptibility (CDKN2A) and pathogenesis (BRAF, cKIT, CyclinD1) of such
a disease. Methods: Genomic DNA from peripheral blood of 63 MPM
patients (54 cases with two primary melanomas, 8 with three, and 1 with
four) were screened for germline mutations in p16CDKN2A and p14CDKN2A genes by automated DNA sequencing. Melanoma families were identified
according to standardized criteria: 9 (14%) patients were classified as
familial cases. Paired synchronous and/or asynchronous MPM tissues
(N�100) from same patients (N�46) were analyzed for somatic mutations
in BRAF gene and FISH-based amplifications in cKIT and CyclynD1 genes.
Results: Overall, 6 (10%) different CDKN2A germline mutations were
identified: 5 in p16CDKN2A and1inp14CDKN2A . The age of onset was
significantly lower and the number of primary melanomas higher in patients
with mutations. CDKN2A mutations were significantly more frequent in
patients with familial history of melanoma (5/9; 56%) compared with
patients without (1/54; 2%) (P�0.001), and in patients with more than
two melanomas (3/9; 33%) compared with patients with only two melanomas
(3/54; 6%) (P�0.012). The debated A148T polymorphism was found
at low level (2/54; 4%) in our series. Regarding genetic alterations at
somatic level, BRAF mutations were identified in 36/100 (36%) primary
melanoma tissues, whereas amplification of cKIT and CyclinD1 genes was
observed in 2/88 (2%) and 10/88 (11%) analyzed tissue samples,
respectively. Considering all types of genetic events, paired samples
presented a poorly consistent distribution of somatic alterations in same
patients (52% consistency). Conclusions: Coexistence of MPM and familial
recurrence of melanoma as well as the presence of more than two
melanomas seem to be strong indications to address patients to CDKN2A
mutational screening. The low consistency in genetic patterns of primary
tumors from the same patients provide additional evidence that pathogenetic
mechanisms of melanomagenesis are heterogeneous and molecularly
different cell types may be generated in multiple primary melanoma.
8583 General Poster Session (Board #37A), Sun, 8:00 AM-12:00 PM
Surgery for patients receiving ipilimumab: Safety profile and immunological
insights. Presenting Author: David E. Gyorki, Memorial Sloan-Kettering
Cancer Center, New York, NY
Background: Ipilimumab (ipi), a monoclonal antibody blocking CTLA-4,
demonstrated survival benefit in metastatic melanoma in two randomized
controlled trials. With its approval by the FDA, the use of this immunotherapy
is increasing. The surgical safety of ipi has not been reported.
Methods: From our prospective database, we identified patients undergoing
surgery within 30 days of receiving a dose of ipi or on maintenance ipi
between October 2007 and August 2011. Surgical toxicity was graded 1-5
by the Clavien classification. In 10 patients matched blood and tumor
infiltrating lymphocytes were harvested. Phenotype of T cell subsets were
analyzed by flow cytometry. Results: 23 patients were identified who
underwent 34 operations a median of 27 weeks after initiation of ipi
(1-123 weeks). Indications for surgery were symptomatic, progressive, or
isolated persistent disease in 52%, 39% and 9% respectively. Subcutaneous
resections were the most frequent, followed by intra-abdominal and
nodal procedures (Table). Grade 1 wound complications were seen in 17%
of patients. One patient had a Grade 2 wound complication. No Grade 3-5
complications were seen. With a median follow up from starting ipi of 86
weeks, 3 patients have no evidence of disease, 10 are alive with disease
and 10 have died of disease. Analysis of the T cell infiltrate and peripheral
blood from 10 patients with progressive or symptomatic disease shows an
elevated % of CD4 � FOXP3 � T regulatory cells and a 2.8 fold reduction in
CD8 � / CD4 � FOXP3 � T regulatory ratio in the tumor compared to blood
(p�0.02). Conclusions: Results from this single-center experience suggest
that surgery is safe in patients receiving ipi. Immune modulation caused by
CTLA-4 blockade does not appear to impact wound healing, even in the
bowel. In carefully selected patients metastectomy may be appropriate for
breakthrough metastases. The high percentage of T regulatory cells and low
T effector cells in the progressive tumors suggests a mechanism of immune
escape.
Surgical indications.
Metastectomy site n (%)
Isolated
disease
Progressive
disease
Symptomatic
disease
Subcutaneous 12 (35%) 2 5 5
Intra abdominal 11 (32%) 0 7 4
Brain 5 (15%) 0 0 5
Nodal 3 (9%) 1 2 0
Other 3 (9%) 0 0 3
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