Download the ESMO 2012 Abstract Book - Oxford Journals

Annals of Oncology
1113PD THE MELANOMA RISK LOCI AS DETERMINANTS
OF MELANOMA PROGNOSIS
J. Rendleman 1 , S. Shang 2 , C. Brocia 3 ,M.Ma 4 , R. Shapiro 4 , R. Berman 4 ,
A. Pavlick 4 , Y. Shao 2 , I. Osman 4 , T. Kirchhoff 3
1 Cancer Institute, NYU Medical Center, New York, NY, UNITED STATES OF
AMERICA, 2 Division of Biostatistics, NYU Medical Center, New York, NY,
UNITED STATES OF AMERICA, 3 Division of Epidemiology, Nyu Cancer Institute,
NYU Medical Center, New York, NY, UNITED STATES OF AMERICA,
4 Dermatology, NYU Medical Center, New York, NY, UNITED STATES OF AMERICA
Background: Genetic risk factors of human cancer emerge as promising markers of
clinical outcome. Recent melanoma genome-wide scans (GWAS) have identified loci
associated with disease risk, nevi or UV/pigmentation, but prognostic potential of these
variants is yet to be determined. In this study, we performed the first-to-date systematic
evaluation of the association between established melanoma risk loci and progression.
Methods: 891 melanoma patients prospectively accrued and followed up at NYU
Medical Center were studied. We examined the association of 108 melanoma
susceptibility single nucleotide polymorphisms (SNPs), selected or imputed from recent
GWAS on melanoma, nevi or pigmentation, with recurrence-free survival (RFS) and
overall survival (OS). The genotyping was performed using Sequenom I-plex. Univariate
and multivariate Cox PH model were used to test association between each SNP and
RFS and OS. Multivariate adjustments included age at diagnosis, gender, tumor stage,
histological subtype, thickness, ulceration status, and mitotic index. ROC curves were
used to measure utility of SNPs in predicting 3-year recurrence.
Results: Strong associations were observed from the multivariate analysis for
rs7538876 (RCC2) with RFS (HR = 1.48, 95% CI 1.20 – 1.83, p = 0.0002) and
rs9960018 (DLGAP1) with both RFS and OS (HR = 1.43, 95% CI = 1.07-1.91, p =
0.0159, HR = 1.52, 95% CI = 1.09-2.22, p = 0.0138, respectively). Subgroup analyses
for ulceration and tumor thickness have identified several SNPs which show
associations for RFS and OS among these different groups. In addition, we identified
the classifiers rs7538876 and rs9960018, that when combined with stage and
histological type, achieve a higher area under the ROC curve (AUC = 84%),
compared to the baseline (AUC = 78%), in predicting 3-year recurrence.
Conclusions: Our data revealed associations between specific melanoma
susceptibility variants and worse disease outcome. The strength of associations
observed for rs7538876 and rs9960018 suggest biological implication of these loci in
melanoma recurrence. The observed predictive patterns of associated variants with
clinical outcome provide the evidence for the potential utilization of genetic markers
in melanoma prognostication.
Disclosure: All authors have declared no conflicts of interest.
1114PD SKIN-TEST INFILTRATING LYMPHOCYTES PREDICT
CLINICAL OUTCOME OF DENDRITIC CELL BASED
VACCINATION IN METASTATIC MELANOMA
K. Bol1 , E. Aarntzen1 , W.R. Gerritsen1 , G. Schreibelt2 , J. Jacobs1 ,
W.J. Lesterhuis1 , M. van Rossum3 , C.J.A. Punt4 , C. Figdor2 , J. De Vries2 1
Medical Oncology/tumorimmunology Lab, Radboud University Nijmegen
Medical Centre, Nijmegen, NETHERLANDS, 2 Tumorimmunology Lab, Radboud
University Nijmegen Medical Center, Nijmegen, NETHERLANDS, 3 Dematology,
Radboud University Nijmegen Medical Center, Nijmegen, NETHERLANDS,
4
Department of Medical Oncology, Academic Medical Center, Amsterdam,
NETHERLANDS
Introduction: The identification of responding patients early during treatment would
greatly improve the efficacy of novel and costly immunotherapies. Bioassays which
accurately link preceding immune responses to clinical outcome are therefore needed.
The mainstay of immunotherapy is to induce, enhance or sustain TAA-specific effector
T cell immunity. Consequently, evaluation of the migratory-, antigen recognition-, as
well as the effector function of tumor-specific cellular responses is critical.
Methods: A large cohort of metastatic melanoma patients (n = 91) enrolled in dendritic
cell (DC)-based vaccination protocols was retrospectively analyzed for overall survival
(OS) in relation to skin-test infiltrating lymphocyte (SKIL) cultures characteristics.
Increasingly stringent criteria were defined identify long-term survivors.
Results: The presence of TAA-specific CD8 + T cells (criterion I: detection by
tetrameric MHC-peptide complexes) in SKIL cultures associated with improved OS;
14.1 versus 10.9 months, p = 0.055. Further analyses showed that the presence of
multiple specificities was highly predictive for long-term survival. Tumor recognition
by TAA-specific CD8+ T cells on peptide level (detected by specific production of
Thelper 1 (Th1) cytokines (criterion II; e.g. IFNg and/or IL-2) or cytotoxicity and no
Thelper 2 (Th2) cytokines) was strongly associated with improved OS; 14.2 versus
10.2 months, p = 0.003. Recognition of naturally processed antigen by specific
production of Th1 cytokines or cytotoxicity and no Th2 cytokines ((criterion III),
maximized the accuracy of the test; 24.1 versus 9.9 months, p = 0.001.
Conclusion: Our results demonstrate that analyzing SKIL cultures is a solid bioassay
to predict overall survival in metastatic melanoma patients. This bioassay is simple,
feasible and integrates multiple aspects of cellular functions needed for effective
immune responses.
Disclosure: All authors have declared no conflicts of interest.
1115PD A PHASE 2 RANDOMIZED STUDY OF RAMUCIRUMAB (IMC
1121B; RAM) WITH OR WITHOUT DACARBAZINE (DTIC)
IN PATIENTS (PTS) WITH METASTATIC MELANOMA (MM)
(CP12-0604/NCT00533702)
R. Carvajal 1 , J. Thompson 2 , M. Gordon 3 , K. Lewis 4 , A. Pavlick 5 , J. Wolchok 1 ,
P. Rojas 6 , J. Schwartz 7 , A. Bedikian 8
1 Melanoma-Sarcoma Division, Memorial Sloan-Kettering Cancer Center,
New York, NY, UNITED STATES OF AMERICA, 2 Medical L Oncology, Seattle
Cancer Care Alliance, Seattle, UNITED STATES OF AMERICA, 3 Pinnacle
Oncology Hematology, Oncology Research Associates, Scottsdale, AZ, UNITED
STATES OF AMERICA, 4 Medical Oncology, University of Colorado Denver,
Aurora, CO, UNITED STATES OF AMERICA, 5 Hematology-Oncology, New York
University, New York, NY, UNITED STATES OF AMERICA, 6 Biostatistics, ImClone
Systems, Bridgewater, NJ, UNITED STATES OF AMERICA, 7 Medical, ImClone
Systems, Bridgewater, NJ, UNITED STATES OF AMERICA, 8 Melanoma Medical
Oncology, MD Anderson Cancer Center, Houston, UNITED STATES OF AMERICA
Background: Vascular endothelial growth factor (VEGF)-mediated angiogenesis
contributes to MM pathogenesis. RAM is a fully human IgG1 recombinant monoclonal
antibody that inhibits VEGF receptor-2 (VEGFR-2) ligand binding and signaling. We
investigated RAM alone and in combination with DTIC in chemotherapy-naïve MM pts.
Methods: Eligible pts had stage IV cutaneous MM, ECOG PS 0-1, adequate
hematologic, hepatic, and renal function. Therapy (Rx) in Arm A: RAM (10 mg/kg)
+ DTIC (1000 mg/m 2 ); Arm B: RAM (10 mg/kg). Rx was every (q) 3 weeks (wk);
tumor assessments were q6 wk. The primary endpoint was progression-free survival
(PFS); other endpoints were safety, response, overall survival (OS).
Results: 106 pts were randomized; 102 received study Rx. Arm A (n = 52) median
(medn) age was 63, 71% male, 37% had elevated LDH, 23% stage M1c. Arm B (n =
50) medn age was 62, 76% male, 38% had elevated LDH, 36% stage M1c. Medn PFS
was 2.6 months (m) Arm A and 1.7m Arm B; 6m PFS rates were 31% and 18%; 12m
PFS rates were 24% and 16% on Arms A and B, respectively. There were 9 (17%)
partial responses (PR) & 19 (37%) with stable disease (SD); 2 (4%) PR & 21(42%)
SD on Arms A and B, respectively. Medn OS was 8.7m Arm A; 11m Arm
B. Nonhematologic adverse events (AEs) considered at least possibly related to RAM
included fatigue (50%; 4% Grade [G] ≥3), hypertension ([HTN] 21%; 15% G ≥3),
infusion-related reactions ([IRR] 8%; 0 G ≥3), proteinuria ([PU] 8%; 4% G ≥ 3),
headache ([HA] 10%; 2% G ≥3) on Arm A; fatigue (30%; 2% G ≥3), HTN (22%;
14% G ≥3), IRR (14%; 6% G ≥3), PU (12%; 2% G ≥3), HA (20%; 0 G ≥3) on Arm
B. IRR incidence was reduced following a recommendation for premedication after
37 pts received initial Rx. Hematologic AEs were neutropenia ([NP] 33%; 19% G
≥3), thrombocytopenia ([TP] 39%; 15% G ≥3), and anaemia ([A]14%; 4% G ≥3) on
Arm A; NP (0%), TP (6%; 0 G ≥3) and A (2%; 0 G ≥3) on Arm B.
Conclusions: RAM alone or in combination with DTIC was associated with
acceptable incidence of AEs in MM. Clinical activity was modest on both arms.
Although the study was not powered for definitive comparison between treatment
arms, PFS appeared greater in Arm A. Biomarker analysis is ongoing.
Disclosure: R. Carvajal: Cosulting, Novartis - money paid to me Consulting,
Morphotek - money paid to me Grants, NIH/NCI - money paid to me Grants,
FDA - money paid to me Grants, ASCO - money paid to me. J. Thompson: ImClone
provided funding to the University of Washington to support this research. K. Lewis:
Research Funding - ImClone. J. Wolchok: Consultant - Bristol Myers Squibb; Merck;
GlaxoSmithKline Research support - Bristol Myers Squibb and GlaxoSmithKline. P.
Rojas: I am an employee of Lilly and own Lilly stock. J. Schwartz: I am an employee
of Lilly and own Lilly stock. All other authors have declared no conflicts of interest.
1116PD FIVE-YEAR SURVIVAL RATES FOR PATIENTS (PTS) WITH
METASTATIC MELANOMA (MM) TREATED WITH
IPILIMUMAB (IPI) IN PHASE II TRIALS
C. Lebbe1 , J.S. Weber2 , M. Maio3 , B. Neyns4 , K. Harmankaya5 , K. Chin6 ,
D. Opatt McDowell7 , L. Cykowski8 , M.B. McHenry9 , J.D. Wolchok10 1 2
Saint-Louis Hospital, APHP University, Paris, FRANCE, Interdisciplinary
Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, FL,
UNITED STATES OF AMERICA, 3 Department of Oncology, Azienda Ospedaliera
Senese - Medical Oncology and Immunotherapy Unit, Siena, ITALY, 4 Medical
Oncology, Vrije Universiteit Brussel, Brussels, BELGIUM, 5 Department of General
Clinical Dermatology, Medical University of Vienna, Vienna, AUSTRIA, 6 Global
Clinical Research - Oncology, Bristol-Myers Squibb, Wallingford, CT, UNITED
STATES OF AMERICA, 7 Global Medical, Bristol-Myers Squibb, Lawrenceville,
NJ, UNITED STATES OF AMERICA, 8 Global Clinical Operations, Bristol-Myers
Squibb, Wallingford, CT, UNITED STATES OF AMERICA, 9 Global Biometrics
Sciences, Bristol-Myers Squibb, Wallingford, CT, UNITED STATES OF AMERICA,
10
Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, UNITED
STATES OF AMERICA
Purpose: Two phase III, randomized trials showed statistically significant
improvement in overall survival (OS) in MM pts treated with IPI and data from
phase II/III studies of IPI suggest the potential for prolonged survival (beyond 4 yrs)
in some pts with MM. Three phase I/II studies conducted at NCI demonstrated 5-yr
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds404 | ix363