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9584 Background: In both previous 18- and 24-month follow-up reports from CheckMate 238, NIVO demonstrated significantly longer recurrence-free survival (RFS) than ipilimumab (IPI) in patients (pts) with resected stage IIIB/C or stage IV melanoma. Here we provide a more comprehensive analysis of treatment-related adverse events (TRAEs) for NIVO over discrete follow-up intervals and an investigation of the association of these AEs with efficacy (RFS). Methods: Eligible pts were aged ≥15 years and underwent complete resection of stage IIIB/C or IV melanoma. A total of 453 pts were treated with NIVO 3 mg/kg Q2W for up to 1 year. The primary endpoint was RFS. Pts were followed for safety for up to 100 days following their last dose; as of the previous 18-month database lock, all pts had been off study drug for > 100 days. Here safety data were analyzed within discrete time intervals: months 0–3 of treatment (0–3), months 3–12 of treatment (3–12), and from last dose to 100 days after last dose (+100). In addition, the association of TRAEs with RFS was investigated using the 24-month efficacy dataset, accounting for time-delay bias within the first 12 weeks after randomization. Results: The incidence of the first onset of TRAEs reported in ≥5% of pts was highest in the 0–3 time frame; the most common TRAEs with NIVO were fatigue (28% for 0–3 vs 6% for 3–12 vs 2% for +100), pruritus (16% vs 7% vs 1%), and diarrhea (15% vs 7% vs 2%). Most TRAEs with NIVO resolved within 3 months of occurrence, except for endocrine AEs, which could have required hormone supplementation, and skin AEs (median overall resolution time of 48 and 22 weeks, respectively). Similar results were observed in an analysis taking into account repeat occurrences of TRAEs over time. Analyses investigating the association of TRAEs with RFS are ongoing and will be presented. Conclusions: These results in pts with resected stage IIIB/C or IV melanoma are consistent with the established safety profile of NIVO. Based on the time periods analyzed, the majority of TRAEs with adjuvant NIVO occurred early during treatment, and patients had a reduced frequency of TRAEs after the treatment course. The majority of select TRAEs resolved within 3 months. Clinical trial information: NCT02388906.

9027 Background: While treatments exist that extend survival in advanced MEL, the quality of that survival is not often evaluated. There is a need for treatments that demonstrate increased survival...

TPS230 Background: CTLA-4 blockade by monoclonal antibodies (mAb) up-regulates host’s immune response(s) through the inhibition of negative signals delivered to T lymphocytes by the engagement with...

8574 Background: Mutations of NRAS and BRAF genes have been identified with high frequency in nevi, cutaneous melanomas, and melanoma metastases. Prevalence of such mutations during the disease pro...

e13029 Background: Cytolytic T lymphocytes (CTL) able to kill tumor cells are efficiently induced by Dendritic Cells (DC); however, immunosuppressive factors, as CD4+CD25+FoxP3+ T lymphocytes (T-re...

8543 Background: Impairment of p16CDKN2A protein expression has been demonstrated to contribute to melanoma progression as well as to correlate with a shorter overall survival. Toward the character...

8505 Background: In the largest adjuvant phase III study in stage II melanoma to date, EORTC 18961 assessed the efficacy and toxicity of ganglioside GM2-KLH/QS-21 vaccination versus observation (OBS). Methods: Patients (Pts) were observed or received vaccine sc once weekly weeks 1-4, every 3 months from week 12 for first 2 years and every 6 months during third year (total of 14 vaccinations). Stratification factors at randomization were: Breslow thickness, ulceration, being staged yes vs no by sentinel node or elective lymph node dissection, sex and institution. Relapse-free survival (RFS) was the prespecified primary endpoint; distant metastasis-free survival (DMFS) and overall survival (OS) were secondary endpoints. An intent-to-treat analysis was performed. Results: Between March 2002 and December 2005, 1,314 pts entered the trial. Patient demographics showed excellent balance for prognostic factors. The second interim analysis was performed when 267 RFS events were reported. For the primary endpoint, ...

TPS311 Background: Dendritic cells (DCs) play a central role in the induction of specific antigen recognition and tumor cell killing. Therapeutic vaccination with DCs is based on the potential for the in vitro cultivation and maturation of DC precursors from peripheral blood over a maximum of 7 days using GM-CSF and IL-4 in order to avoid the influence of immunosuppressive mechanisms present in tumor tissue. Among these, attention has recently focused on CD4+CD25+FoxP3+ T lymphocytes (T-regs). It has been seen that daily low-dose temozolomide (TMZ) induces lymphopenia, with a consequent reduction in T-regs (Su YB, J Clin Oncol, 2004). Furthermore, in a preliminary experience, we evaluated the expression of tumor endothelial marker 8 (TEM8) as a predictive marker of immunological and clinical response in mature DCs (mDCs) (Venanzi FM, Cancer Immunol Immunother, 2009). Following our experience of a vaccination trial using autologous mDCs pulsed with autologous tumor lysate (ATL) and keyhole limpet hemocyani...

e20009 Background: Dacarbazine (DTIC) is the standard treatment for metastatic melanoma. Temozolomide (TMZ) is a potentially attractive chemotherapeutic agent for this disease because of the oral route of administration and efficacy similar to that of dacarbazine. Cisplatin is active against melanoma and might counteract mechanisms of resistance to TMZ. Metronomic administration of TMZ might be another way to overcome resistance. Patients and Methods: We reviewed data of metastatic melanoma patients treated at our Institutions with cisplatin (75 mg/m2 every 28 days) plus TMZ (75 mg/m2/die from day 2 for 21 days). Our practice included such scheme for patients younger than 75 years, with a performance status not worse than 2, and adequate bone marrow, liver and renal function. Assessment of response was done every 3 cycles. Toxicity was graded according to NCI-CTC. Results: From August 2007 to September 2008, 33 patients were treated with a median age of 44 years (18–74); primary melanoma was ulcerated in 19 cases (58%); most frequent sites of metastases were lung (18 cases), brain and lymph nodes (11 cases each); 29 patients were treated as first-line and 4 as second-line. The median number of delivered cycles was 4 (range 2- 8). Toxicity was mild, with no grade 4 event reported. Nausea and vomiting were the most frequent and severe toxic effects: grade 3 in 2 cases each and grade 2 in 16 and 9 cases, respectively. Other toxicities included thrombocytopenia (2 case grade 3 and 3 cases grade 2), anemia (1 grade 3 and 4 grade 2), neutropenia, and fatigue (1 grade 3 each). Overall, 6 patients had a partial response (18.2%; 95% exact CI: 7.0–35.5) and 8 (24%) had a disease stabilization. With a median follow-up of 20 weeks (95% CI: 19–57), there were 19 progressions and a median progression-free survival of 24 weeks (95% CI:16-nr); 9 patients died with a median survival of 50 weeks (95% CI 43-nr). Conclusions: Results obtained in clinical practice with metronomic temozolomide plus cisplatin in the treatment of patients with metastatic melanoma are encouraging, in light of the negative prognostic features of treated patients. We are now planning a formal phase II study. [Table: see text]

9040 Background: T regulatory (Treg) cells are an immunoregulatory cell type which express high levels of surface CD25, CTLA-4, and GITR. Tregs have been shown to be present in tumor and tumor-draining lymph nodes, acting as an inhibitory population blocking effector cell function. Depletion or blockade of Tregs might be able to enhance antitumor immunity. Recent evidence has been reported about the possibility of High Dose Interferon (HDI) to act through an indirect immunomodulatory mechanism (Gogas, NEJM 2006; Moschos JCO 2006). We started a study to verify if iv HDI treatment in melanoma patients could be able to reduce the number of Treg cells in peripheral blood. Methods: Analysis was performed on melanoma pts referring to the National Cancer Institute of Naples since July 2006 and who addressed to Neoadjuvant or Adjuvant treatment with iv HDI (20 MUI/m2, 5 days per week) for 4 wks. Peripheral blood mononuclear cells (PBMC) were obtained from 22 consecutive melanoma pts. Blood draw was performed at days 0, 8, 15, 22 and 29. PBMC were thawed and labeled with anti-CD4 and anti-CD25hi (BD, San Diego, CA) and anti-FoxP3 (eBioscience, San Diego, CA). Labeled cells were analyzed using a FACScalibur (Becton Dickinson). Results: Fifteen (68.2%) out of 22 pts showed a decrease of Treg cells in peripheral blood. The average value at day 0 for circulating Treg (cTreg) was 2.7%. The average percentage at day 29 was 1.4%. The average reduction was 1,4 (50% reduction in the average value of cTreg). Statistical analysis showed an average decrease of 0.29% per week of treatment. Despite of this clear trend in reducing cTreg by HDI, statistical significance was not reached (probably due to the power of the study). Moreover, it has been observed great differences between the disease status, the prognosis (recurred/not recurred pts, alive/deceased) and an increased basal percentage of cTreg. Our preliminary data are consistent for an effect of HDI on reducing cTreg, although no conclusion about the role of such reduction in terms of response to treatment or as prognostic markers of better/worse disease can be inferred. Further data are awaited in order to verify if the Treg reduction after a HDI treatment may indeed contribute to the antitumor response. [Table: see text]

20028 Characterization of the different molecular mechanisms involved in development and progression of melanoma (referred to as melanomagenesis) could represent a potential tool to identify the mo...

9004 Background: EORTC 18961 assessed in the largest adjuvant phase III trial to date in stage II melanoma the efficacy and toxicity of Ganglioside GM2-KLH21 Vaccination (VAC) Treatment vs Observat...

18009 Background: Detection of circulating malignant cells (CMCs) through a reverse transcriptase-polymerase chain reaction (RT-PCR) assay seems to be a demonstration of systemic disease. We here evaluated the prognostic role of RT-PCR assays in serially-taken peripheral blood samples from patients with malignant melanoma (MM). Methods: One hundred forty-nine melanoma patients with disease stage ranging from I to III were consecutively collected in 1997. A multi-marker RT-PCR assay was used on peripheral blood samples obtained at time of diagnosis and every 6 months during the first two years of follow-up (total: 5 samples). Univariate and multivariate analyses were performed after 83 months of median follow-up. Results: Detection of at least one circulating mRNA marker was considered a signal of the presence of CMC (referred to as PCR-positive assay). A significant correlation was found between the rate of recurrences and the increasing number of PCR-positive assays (P = 0.007). Presence of CMC in a high number (≥2) of analysed blood samples was significantly correlated with a poor clinical outcome (disease-free survival: P = 0.019; overall survival: P = 0.034). Multivariate analysis revealed that presence of a PCR-positive status does play a role as independent prognostic factors for overall survival in melanoma patients, adding precision to the predictive power of the disease stage. Conclusions: Our findings indicated that serial RT-PCR assay may identify a high risk subset of melanoma patients with occult cancer cells constantly detected in blood circulation. Prolonged presence of CMCs seems to act as a surrogate marker of disease progression or a sign of more aggressive disease. No significant financial relationships to disclose.

8051 Background: The chemokine receptor CXCR4 was identified as an independent predictor of poor prognosis in primary melanoma. In melanoma metastases CXCR4 is also expressed and functional suggesting that CXCR4 has a role in the melanoma biology. Differential chemokine receptors expression by activated tumor specific CD8+ T cells can be associated with divergent clinical outcomes. Expression of CXCR3 by CD8+ T cells was reported to be associated with survival in melanoma patients with stage III disease. To further characterize the role of CXCR4 in the melanoma metastatization we analyzed Fine Needle Ago Biopsy (FNAB) from disease involved lymph nodes. Moreover, we are currently evaluating CD8+ subpopulation for the expression of CXCR4 during the follow up Methods: FNAB of suspicious disease involved lymphnodes. was performed and the cell suspension was analyzed by flow cytometry and .immunocytochemistry. Peripheral blood lymphocytes (PBL) was analyzed by flow cytometry Results: FNAB were performed on 25. suspicious lymphnodes. Out of 25 FNAB 19 were positive per melanoma cells (HMB45 positive). Concomitant expression of HMB45 and CXCR4 was detected in 15 out of 19 samples.with the percentage of cells CXCR4 positive being the large majority ( 40–100%) of the detected melanoma cells. Ongoing studies are further characterizing the biology of the CXCR4/HMB45 cells. The inhibition of this cells migrating through the lymphnode may interfere with the metastatization. In relation to the CD8+ subpopulation for the expression of CXCR4 during the follow up preliminary data at the time of diagnosis showed a correlation between the activated CD8 + lymphocytes (HLA-DR+) /CXCR4 + and the level of invasion of the lesion. Conclusion: Altoghether these evidences confirm a role of CXCR4 in melanoma biology and as therapeuthic target . No significant financial relationships to disclose.

9584 Background: Somatic mutations of the BRAF gene has been recently reported in about two thirds of patients with malignant melanoma (MM). We here defined the contribution of BRAF to melanoma sus...