Search

e21042Background: Uveal and mucosal melanomas are rare subtypes with a mean age-adjusted incidence of 5.6 and 2.3 cases per million person-years. Metastatic uveal and mucosal patients (pts) tend to...

e20647Background: We previously reported a 59% disease control rate among EGFR wild-type (WT) patients in a phase II trial of the combination of rilotumumab (an HGF neutralizing antibody) and erlot...

e21031Background: PD-1 inhibitors have reported response rates of 34-40% in patients (pts) with advanced MEL. Landmark 1- and 2- year survival rates with Nivolumab (Nivo), Pembrolizumab (Pembro) an...

9501Background: Pre-clinical studies report a critical role of c-KIT mutations in some mucosal, acral, solar, and vulvovaginal melanomas. Clinical trials of KIT-directed therapy with imatinib and s...

e21032Background: With the recent FDA approval of ipilimumab, the treatment options available to patients with high risk resected melanoma has changed. Now, reasonable treatment choices include hig...

9539Background: Overall responses (OR) are reported in 34% of patients (pts) with advanced MEL treated with Pembro. Landmark survival is 66%/49% at 1-/2- years respectively. Pre-existing CD8+ T-cell infiltrates and IFN gene signature at tumor sites correlate with response to PD-1 blockade. To evaluate synergy between PD-1 blockade and Peg-IFN, we implemented a phase Ib study of Pembro/Peg-IFN combination with dose-seeking and dose-expansion phases in stage IV MEL. Methods: Pts with IV MEL were enrolled. Peg-IFN was dose-escalated using modified toxicity probability interval (mTPI) design in 3 cohorts (4 pts each) at 1,2 and 3 mcg/kg SC while Pembrolizumab was dosed at 2mg/kg q3weeks in all pts. Primary endpoints were safety and incidence of dose-limiting toxicities (DLTs). Secondary endpoints were OR rate (ORR), progression free and overall survival. Response was assessed every 12 weeks (RECIST 1.1). Sequential blood draws and tumor biopsies were collected. Here, we report on response observed in 24 pts t...

9585Background: Neoadjuvant ipilimumab (ipi) at 3 or 10 mg/kg in combination with high dose IFNα2b (HDI) for locally/regionally advanced or recurrent melanoma may improve the clinical outcomes of t...

e21022Background: Primary & secondary prevention have not reduced the rising melanoma mortality in the US and Europe. We reported STAT3 activation in A/DN and IFNa modulation of STAT3 in A/DN in me...

Background Immunotherapy using high dose interleukin-2 (HD IL2) in patients with renal cell carcinoma (RCC) and melanoma is associated with severe toxicities. The association between annual hospital volume of HD IL2 and inpatient mortality is not well studied. In this study we aim to quantify the impact of annual hospital volume of HD IL2 on inpatient mortality using National Inpatient Sample (NIS) data. Methods We did a cross-sectional study using NIS, one of the largest inpatient datasets in United States, from 2003 to 2011. Patients with melanoma and RCC receiving HD IL2 were identified by ICD9 procedure code 00.15. The primary outcome was inpatient mortality. Using Joinpoint regression, which detects change in trend of inpatient mortality with change in annual volume, the hospitals were classified in three volume categories (low: 1–40, medium: 41–120, high: >120). Multivariate logistic regression was used to identify predictors of inpatient mortality controlling for confounders. Results From 2003 to 2011, 29,532 patients with RCC or melanoma who received HD IL2 were identified, and 124 died during the hospitalization (0.4%). The hospitals with low, medium and high annual volume had significant difference in inpatient mortality (0.83%, 0.29% and 0.13% respectively, p = 0.0003). On multivariate analysis, low volume hospitals were associated with significantly higher odds of inpatient mortality (OR 6.1, 95% CI 1.6–23.2, p = 0.003) as compared to high volume hospitals. Additionally, the hospitals with annual volume of 1–20 had even higher rates (1.31% vs. 0.13%, p

Changes in the biomarkers of host suppressor immune response were evaluated in patients with melanoma enrolled in 2 trials. Two similar cohorts of patients participating in the 2 studies were evaluated. The first (IFN/treme) tested interferon (IFN)-α2b and tremelimumab in metastatic melanoma and reported a response rate of 24%, 6.4 months median progression-free survival, and 21 months median overall survival. The second [toll-like receptor 9 (TLR)/GM] tested vaccination with MART-1, gp100, tyrosinase given with TLR-9 agonist and granulocyte-macrophage colony-stimulating factor and reported 9% response rate, median progression-free survival of 1.9 months, and median overall survival of 13.4 months. We monitored circulating T regulatory cells (T-reg) and myeloid-derived suppressor cells (MDSC) utilizing multicolor flow cytometry. In "IFN/treme," changes in circulating T-reg and MDSC were compared between baseline, day 29 (end of IFN-α induction) and day 85 (1 course). The CD4(+)CD25hi(+)CD39(+) T-reg percentage was increased most at day 85 (P = 0.018) and less significantly at day 29 (P = 0.09). There was a decrease in the percentage of MDSC populations taken in aggregate, which was most significant for monocytic MDSC (HLA-DR(+) low/CD14(+)) at day 29 (P0.0001) and day 85 (P = 0.001). In "TLR-9/GM," changes in T-reg and MDSC were compared between baseline and day 50 (4 vaccinations) and day 90 (8 vaccinations). There were no significant changes in T-reg or MDSC, except for a trend towards decreased (HLA-DR(+) low/CD14(+)) MDSC at day 50 (P = 0.07). Therefore, IFN/treme significantly downregulated MDSC suggesting a role on the significant clinical activity observed in this trial. T-reg findings suggest that IFN/treme induced clinically significant antitumor responses by inhibiting CTLA4 suppressive effects on T effectors, and less so by affecting T-reg.

Among the IFNs, IFN-α2 has been the most broadly evaluated clinically. At the molecular level, IFN-α has multiple effects in a variety of malignancies that range from antiangiogenic to potent immunoregulatory, differentiation-inducing, antiproliferative, and proapoptotic effects. A multitude of IFN-α2 regimens that may be classified as low dose, intermediate dose, and high dose have been evaluated as adjuvant therapy in melanoma. A durable impact on both relapse-free and overall survival was seen only with the regimen utilizing high-dose IFN-α2b tested in the Eastern Cooperative Oncology Group and intergroup trials E1684, E1690, and E1694 as adjuvant therapy for high-risk surgically resected melanoma (stage IIB or III). Adjuvant pegylated IFN-α2b has also been evaluated at maximally tolerable doses compared with the observation group in the European Organization for Research and Treatment of Cancer trial 18991 and has shown relapse-free survival benefits in patients with microscopic nodal disease.

Patients with melanoma have experienced durable therapeutic benefits with immunotherapy, and high-dose (HD) interferon alfa-2b (IFN2b) for 1 year and pegylated (PEG) IFN2b for 5 years have received regulatory approval as adjuvant therapy. IFNhas been administered in low-, intermediate-, and high-dose regimens for patients with intermediateand high-risk melanoma (corresponding to the American Joint Committee stages II, III, or IV). A durable impact on both relapse-free (RFS) and overall survival (OS) has only been demonstrated with HD IFN2b as tested in Eastern Cooperative Oncology Group (ECOG) and Intergroup trials E1684, E1690, and E1694. All three trials demonstrated significant reduction in relapse rate, whereas significant improvement in overall survival (OS) was observed in two of these trials. Specifically, in E1684, median relapse-free survival (RFS) was 1.72 versus 0.98 years (P .0023; hazard ratio [HR], 0.61; P .0013). Median OS was 3.82 versus 2.78 years, P .0237 (HR 0.67, P .01) in favor of IFN treatment. Likewise, in E1694, improvement in RFS with IFN (HR, 0.68; P .0015) and OS (HR, 0.66; P .009) were observed, both in the eligible population and in the intent-to-treat analysis (ITT) for RFS (HR, 0.67) and OS (HR, 0.72). The one trial that did not show OS benefit was conducted partly before and partly after the US Food and Drug Administration approval of HD IFN2b and did not require removal of regional lymph nodes, unlike the pivotal E1684. Thus, patients assigned to observation in E1690 frequently experienced lymph node relapse and uniformly crossed over to receive HD IFN2b at relapse in regional lymph nodes. Retrospective analysis has shown that those who crossed over to HD IFN2b at nodal relapse (n 38) also demonstrated a large benefit, which seemed to confound the outcome such that an RFS benefit was seen but no OS benefit was. A pooled analysis of the two observation-controlled trials (E1684 and E1690) as updated through April 2001 showed that HD IFN2b maintained significant benefits in relapse prevention out to intervals of 20 years. However, this analysis excluded the E1694 trial in which GM2 conjugated to keyhole limpet hemocyanin and administered with QS-21 (GMK) vaccine served as control. Given that the larger of the two observation-controlled trials (E1690) did not show an OS benefit for HD IFN2b, the pooled analysis did not show compelling evidence of OS benefit. In addition, the median 12.6-year follow-up in E1684 introduces the strong possibility that competing causes of death led to the erosion of the OS benefits originally seen in this trial at the mature median follow-up of 6.9 years. Three large meta-analyses examined the survival benefits of adjuvant IFN, pooling data from randomized controlled trials testing IFN. The first meta-analysis of 12 randomized controlled trials estimated significant RFS benefit for IFN compared with observation (HR, 0.83; 95% CI, 0.77 to 0.90; P .001) and showed OS benefits that were less significant (HR, 0.93; 95% CI, 0.85 to 1.02; P .1) suggesting increased benefit with increasing dosage. The second meta-analysis (using individual cooperative group patient data from 13 randomized controlled trials) demonstrated significant benefits for IFNin lowering the risk of recurrence (odds ratio [OR], 0.87; 95% CI, 0.81 to 0.93; P .001) and of death (OR 0.90; 95% CI, 0.84 to 0.97; P .008) versus observation or vaccination. The latest meta-analysis included 14 randomized controlled trials and estimated significant reductions in the risk of recurrence (HR, 0.82; 95% CI, 0.77 to 0.87; P .001) and death (HR, 0.89; 95% CI, 0.83 to 0.96; P .002). In the article that accompanies this editorial, Eggermont et al present mature results of European Organisation for Research and Treatment of Cancer (EORTC) 18991. This randomized phase III trial was conducted in patients with resected stage III melanoma who were assigned to observation or PEG IFN2b treatment for 5 years, testing the hypothesis that long-term therapy with PEG IFN2b is necessary to optimize the effects of IFNon the basis of previous EORTC and French studies in which the authors concluded that RFS benefit is lost after discontinuation of treatment. These investigators also hypothesized that weekly self-administration of PEG IFN2b might improve the benefit–toxicity ratio to allow this prolonged therapy. Distant metastasis-free survival (DMFS) was originally the primary end point, but RFS was later adopted as the primary regulatory end point. Mirroring E1684, PEG IFN2b was administered in two phases: induction for 8 weeks followed by maintenance for up to 5 years. The trial was first reported in 2007 (at 3.8 years median follow-up), demonstrating significant improvement in RFS in favor of PEG IFN2b versus observation (HR, 0.82; P .011); no significant benefit to either DMFS or OS were observed. Subgroup analyses showed a lack of benefit in patients with gross nodal disease (N2) across all end points: RFS, DMFS, and OS. PEG IFN2b significantly improved RFS and DMFS (but not OS) in patients with microscopic nodal involvement (N1). JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 31 NOVEMBER 1 2012

The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology. These principles have been critical in the development of immunotherapy in the laboratory and in the implementation of immunotherapy in the clinic. This improved understanding of immunotherapy, enhanced by increased insights into the mechanism of tumor immune response and its evasion by tumors, now permits manipulation of this interaction and elucidates the therapeutic role of immunity in cancer. Also important, this improved understanding of immunotherapy and the mechanisms underlying immunity in cancer has fueled an expanding array of new therapeutic agents for a variety of cancers. Pegylated interferon-α2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an increased understanding of the principles of tumor biology and immunology have been translated successfully from the laboratory to the clinical setting. Principles that guide the development and application of immunotherapy include antibodies, cytokines, vaccines, and cellular therapies. The identification and further elucidation of the role of immunotherapy in different tumor types, and the development of strategies for combining immunotherapy with cytotoxic and molecularly targeted agents for future multimodal therapy for cancer will enable even greater progress and ultimately lead to improved outcomes for patients receiving cancer immunotherapy.

To the editor: Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) is currently considered the gold standard first-line therapy for chronic lymphocytic leukemia (CLL).[1][1] In an attempt to reduce the neutropenia and maintain the high response rate of standard-dose FCR

Purpose We tested the hypothesis that the combination of tremelimumab and interferon alfa-2b acting via different and possibly synergistic mechanisms would overcome tumor immune tolerance and lead to significant and durable clinical responses. Patients and Methods We conducted a phase II study in which patients were administered tremelimumab 15 mg/kg/course (three cycles [one cycle = 4 weeks]) intravenously every 12 weeks. High-dose interferon alfa-2b (HDI) was administered concurrently, including intravenous induction at 20 MU/m2/d for 5 d/wk for 4 weeks followed by maintenance at 10 MU/m2/d subcutaneously three times a week for 8 weeks per course. From course 2 onward, HDI maintenance was administered subcutaneously. Results Thirty-seven patients with American Joint Committee on Cancer stage IV (9M1a, 6M1b, and 22M1c) were enrolled. Two patients had previously treated brain metastases. Grades 3 and 4 toxicities included neutropenia (six patients; 17%), diarrhea/colitis (four patients; 11%), liver enzyme increase (four patients; 11%), rash (four patients; 11%), fatigue (15 patients; 40%), and anxiety/depression (five patients; 14%). Response data were available for 35 patients. The best objective response rate (RR; Response Evaluation Criteria in Solid Tumors) by intention to treat was 24% (90% CI, 13% to 36%; four complete responses [CRs] and five partial responses [PRs] that lasted 6, 6, > 12, > 14, > 18, 20, > 28, 30, and > 37 months, respectively). Fourteen patients (38%) had stable disease (SD) that lasted 1.5 to 21 months. The median progression-free survival was 6.4 months (95% CI, 3.3 to 12.1 months). The median overall survival (OS) was 21 months (95% CI, 9.5 to not reached). There was a weak association between therapy-induced autoimmunity and clinical benefits (CR/PR/SD; P = .0059), baseline C-reactive protein (CRP) less than or equal to 2.7× the upper limit of normal and clinical benefits (P = .0494) and improved probability of survival (P = .0032), and baseline lymphocyte count of at least 1,000/μL and response (CR/PR; P = .0183) and clinical benefits (CR/PR/SD; P = .0255). Biomarker associations were not significant after adjustment for multiple comparisons. Conclusion HDI can be administered combined with tremelimumab with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.

Biomarkers that are of interest in patients with melanoma may relate to the individual host or to the tumor, and may represent molecules or other factors that indicate genetic predisposition, prognosis, clinical course or therapeutic outcome. Biomarkers include clinical covariates, host proteomic/genomic markers and tumor proteomic/genomic markers that allow improved prognostic assessment and/or serve to predict and subclassify patients in relation to their disease and/or its therapy.

Clinically detectable regional lymph node melanoma metastasis (AJCC stage IIIB-C) carries a risk of relapse and death that approaches 70% at 5 years. Surgical management is the cornerstone of therapy, with postoperative adjuvant therapy utilizing high-dose interferon alfa-2b (HDI). Neoadjuvant chemotherapy or immunotherapy in addition to surgery has been demonstrated to improve outcome in the management of patients with a variety of solid tumors. In patients with melanoma, the characteristics of the host immune response differ between patients with earlier stage and those with more advanced stages of disease (and particularly between those with measurable active disease and those without measurable gross disease) providing rationale for neoadjuvant approaches with immunotherapy. Host immune tolerance is now understood to impede the results of therapy for advanced disease, but appears to be less an issue for patients with microscopic high-risk operable disease, where the host may be more susceptible to immunologic interventions. Phase II studies have shown that neoadjuvant biochemotherapy has limited activity in melanoma patients with local-regional metastases, where chemotherapy may potentially alter the effects of immunotherapeutic agents. Studies of neoadjuvant HDI therapy for high-risk melanoma patients with bulky regional stage IIIB-C lymphadenopathy have shown unexpectedly high clinical and pathologic response rates, without increased morbidity. Through the design of neoadjuvant trials utilizing promising emerging melanoma therapeutics in which it is possible to obtain biopsy samples before and after therapy, a greater understanding of the dynamic interaction between tumors and the immune system is possible. This should lead to the identification of new targets for the treatment of melanoma and aid the development of new immunotherapy that may have greater specificity and less toxicity. This will simplify the evaluation of promising new combinations of agents with HDI to build on the clinical, immunologic, and molecular effect of this therapy for patients with melanoma.

Nodal status in melanoma is a critically important prognostic factor for patient outcome. The survival rate drops to10% when melanoma has spread beyond the regional lymph nodes and includes visceral involvement. In general, the process of melanoma metastasis is progressive in that dissemination of melanoma from the primary site to the regional lymph nodes occurs prior to systemic disease. The goal of this review article is to describe melanoma as a clinical model to study cancer metastasis. A future challenge is to develop a molecular taxonomy to subgroup melanoma patients at various stages of tumor progression for more accurate targeted treatment.

Advanced melanoma has proven difficult to treat for many years, and no previous agent has shown improved survival in a phase 3 trial. The deepening understanding of tumor immunobiology and the complexity of the interactions between host T cells and cancer have led to novel treatment approaches. Among these, ipilimumab is a first-in-class T-cell potentiator that works by blocking cytotoxic T-lymphocyte antigen-4, a critical negative regulator of the antitumor T-cell response. From phase 1 studies, ipilimumab has shown encouraging activity in melanoma and other cancers, with unusual response patterns and mechanism-related, predictable toxicities that are medically manageable and mostly reversible but can sometimes be life threatening unless recognized and treated early. Early indications of a survival benefit in phase 2 studies have been confirmed recently in the first randomized phase 3 trial; the primary endpoint of the trial, overall survival (OS), was met with ipilimumab significantly prolonging median OS both as a single agent (10.1 months; p = 0.003) and combined with gp100 vaccine (10.0 months; p < 0.001) compared with vaccine control (6.4 months). Even more noteworthy was the improvement in long-term survival at 24 months from 13.7% (gp100 alone) to 21.6% and 23.5% for the combination and single ipilimumab, respectively. The addition of gp100 vaccine did not appear to impact OS since data for ipilimumab alone were similar to those for the combination with vaccine. Re-induction with ipilimumab in selected patients who progressed gave further clinical benefits. Ipilimumab has also shown promising activity in melanoma patients with brain metastases, and patients with non-small cell lung cancer, renal cell cancer, and castrate-resistant prostate cancer. Ipilimumab not only has a novel mechanism of action but demonstrates unique immune-related toxicities that require particular care in their recognition and treatment.

With an incidence that is increasing at 2–5% per year, cutaneous melanoma is an international scourge that disproportionately targets young individuals. Despite much research, the treatment of advanced disease is still quite challenging. Immunotherapy with high-dose interferon-α2b or interleukin-2 benefits a select group of patients in the adjuvant and metastatic settings, respectively, with significant attendant toxicity. Advances in the biology of malignant melanoma and the role of immunomodulatory therapy have produced advances that have stunned the field. In this paper, we review the data for the use of interferon-α2b in various dosing ranges, vaccine therapy, and the role of radiotherapy in the adjuvant setting for malignant melanoma. Recent trials in the metastatic setting using anticytoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody therapy and BRAF inhibitor therapy have demonstrated clear benefit with prolongation of survival. Trials investigating combinations of these novel agents with existing immunomodulators are at present underway.

Manganese superoxide dismutase (MnSOD) is a genetically engineered therapeutic DNA/liposome containing the human MnSOD transgene. Preclinical studies in mouse models have demonstrated that the expression of the human MnSOD transgene confers protection of normal tissues from ionizing irradiation damage. This is a phase I study of MnSOD plasmid liposome (PL) in combination with standard chemoradiation in surgically unresectable stage III non-small-cell lung cancer. Chemotherapy (carboplatin and paclitaxel) was given weekly (for 7 weeks), concurrently with radiation. MnSOD PL was swallowed twice a week (total 14 doses), at three dose levels: 0.3, 3, and 30 mg. Dose escalation followed a standard phase I design. Esophagoscopy was done at baseline, day 4, and 6 weeks after radiation with biopsies of the squamous lining cells. DNA was extracted and analyzed by PCR for the detection of the MnSOD transgene DNA. Ten patients with AJCC stage IIIA (three) and IIIB (seven) completed the course of therapy. Five had squamous histology, two adenocarcinoma, one large cell, and two not specified. Patients were treated in three cohorts at three dose levels of MnSOD PL: 0.3 (three patients), 3 (three patients), and 30 mg (four patients). The median dose of radiation was 77.7 Gy (range 63–79.10 Gy). Overall response rate for the standard chemoradiation regimen was 70% (n = 10). There were no dose-limiting toxicities reported in all three dosing tiers. It is concluded that the oral administration of MnSOD PL is feasible and safe. The phase II recommended dose is 30 mg.

Interferon alpha2b (IFN-alpha2b) at high dosage is critical to the reversal of signaling defects in T cells of melanoma patients, and to the durable effector (alpha DC1) polarization of dendritic cells. These immunoregulatory effects appear to be uniquely achieved with levels of IFN-alpha only attainable in vivo using the high-dose regimen of IFN-alpha2b (HDI). Three US cooperative group studies have evaluated the benefit of HDI as an adjuvant therapy for high-risk melanoma. All have demonstrated significant and durable reduction in the frequency of relapse, while the first and third trials have demonstrated significant improvements in the fractions of patients surviving compared with observation (E1684) or with a ganglioside vaccine (GMK, E1694). A meta-analysis of 13 randomized trials evaluating adjuvant IFN therapy has now also demonstrated significant benefits for IFN in terms of RFS and OS. Research of IFN-alpha in melanoma is now focused on identifying prognostic markers of outcome and predictors of therapeutic response.

BACKGROUND: Phase 1 studies demonstrated evidence of recombinant human IL-18 (rhIL-18)-mediated immunomodulatory and clinical activity, and defined a biologically active dose range. METHODS: A phase 2 study of rhIL-18 was conducted in untreated AJCC stage IV melanoma. Patients were randomized to 1 of 3 dose groups (0.01, 0.1, and 1.0 mg/kg/d) of rhIL-18 administered as 5 daily intravenous infusions repeated every 28 days. A 2-stage design with a stopping rule was used. RESULTS: A total of 64 patients (median age, 57.5 years) with metastatic melanoma (M1a/b (30), M1c (34)) were accrued to stage I, and randomized to 3 groups (21 [0.01 mg/kg/d], 21 [0.1 mg/kg/d], 22 [1.0 mg/kg/d]). Five patients experienced 10 grade 3 drug-related adverse events (AEs): polyarthritis (1 subject: 0.01 mg/kg); deep vein thrombosis, pulmonary embolism (1:0.01 mg/kg); cognitive disorder (1:0.1 mg/kg); fatigue, dyspnea, pleural effusion, lymphopenia (1:1.0 mg/kg); fatigue, lymphopenia (1:1.0 mg/kg). One patient experienced a grade 4 AE of increased lipase (0.1 mg/kg) that led to permanent discontinuation from the study. Among 63 subjects evaluable for response, 1 (M1c; 0.01 mg/kg) achieved a partial response after 4 cycles. Four subjects (3 at 0.01 mg/kg and 1 at 1.0 mg/kg) had stable disease maintained for 6 months or longer. Due to the low apparent level of clinical efficacy using RECIST criteria, the study was terminated at the end of stage 1. The median progression free survival for the 3 groups was 7.5 (0.01), 7.4 (0.1), and 7.3 (1.0) weeks. CONCLUSIONS: rIL-18 as tested in this trial was well tolerated, but had limited activity as a single agent in patients with metastatic melanoma. Cancer 2009. © 2009 American Cancer Society.

Patients with clinically palpable regional lymph node metastases (AJCC stage IIIB-C) carry a risk of relapse and death that approaches 70% at 5 years. Surgical excision with complete regional lymph node dissection is the cornerstone of management, followed by adjuvant therapy with high-dose interferon-α2b (HDI). Neoadjuvant therapy has been demonstrated to improve outcome in the management of patients of multiple different solid tumors. In patients with melanoma, the quality of the host immune response differs between those with earlier and those with more advanced disease settings. Host immune tolerance is now understood to impede the results of therapy for advanced disease, but may be less an issue for patients with microscopic high-risk operable disease, where the host may be more susceptible to immunologic interventions. Phase II studies have shown that neoadjuvant biochemotherapy has limited activity in melanoma patients with local-regional metastases, where chemotherapy may potentially antagonize or alter the effects of immunotherapeutic agents. Studies of neoadjuvant HDI therapy for high-risk melanoma patients with bulky regional stage IIIB-C lymphadenopathy are ongoing and preliminary results have shown unexpectedly high clinical and pathologic response rates, without increased morbidity. Through the design of neoadjuvant trials in which it is possible to obtain biopsy samples before and after therapy, a greater understanding of the dynamic interaction between tumors and the immune system is possible. This should lead to the identification of new targets for the treatment of melanoma and aid the development of new immunotherapies that may have greater specificity and less toxicity. This will simplify the evaluation of promising new combinations of agents with HDI to build on the clinical, immunologic, and molecular effect of this therapy for patients with melanoma.

Purpose We evaluated adjuvant trial E1694 to more precisely define the prognostic significance of serum S100B in patients with high-risk resected melanoma. Patients and Methods Sera from 670 E1694 patients banked at baseline and three additional time points were tested for S100B protein using chemiluminescence. Results S100B testing results showed that the higher the S100B level is, the higher the risk of relapse and death, regardless of the cutoff value. Univariate analysis showed that baseline S100B ≥ 0.15 μg/L is significantly correlated with overall survival (OS; P = .01). Multivariate analysis was performed adjusting for significant prognostic factors (ulceration and lymph node status) and treatment. Baseline S100B was a significant prognostic factor for survival (hazard ratio = 1.39; 95% CI, 1.01 to 1.92; P = .043). S100B values measured at later time points over 1 year were also demonstrated to be significant prognostic factors for relapse-free survival (RFS) and OS. Lower S100B values at baseline and during follow-up were associated with longer survival. A changing S100B from low at baseline to high on follow-up seemed to be associated with the worst RFS and OS. Conclusion For patients with high-risk surgically resected melanoma, a high baseline or increasing serum S100B is an independent prognostic marker of risk for mortality that may allow us to refine the application of adjuvant therapy in the future.

Purpose Chemoimmunotherapy combining fludarabine, cyclophosphamide, and rituximab (FCR) is an active regimen for untreated patients with chronic lymphocytic leukemia (CLL) with 70% complete responses (CRs) and 95% overall responses (ORs). However, grade 3/4 neutropenia was reported in 52% of cycles of treatment. The purpose of this trial was to maintain the high responses but reduce the toxicity of FCR by decreasing the fludarabine and cyclophosphamide (FCR-Lite). Patients and Methods We conducted a single arm study of FCR-Lite which includes maintenance rituximab in 50 untreated CLL patients. Patients were evaluated for response using both the 1996 National Cancer Institute Working Group (NCIWG) guidelines and the 2008 guidelines. Two thirds of patients were treated by community physicians. Results The median age was 58 years (range, 36 to 85 years); 20 patients had Rai stage 1, 22 had Rai stage 2, and eight had Rai stage 3 and 4. The OR and CR rates were 100% and 79%, respectively, using the 1996 NCIWG guidelines and 100% and 77% using the 2008 guidelines. Median duration of complete response was 22.3 months (range, 5.2 to 42.5 months) and none of the complete responders have relapsed. Grade 3/4 neutropenia was noted in 13% of the cycles of therapy. Conclusion FCR-Lite is highly effective in previously untreated CLL patients. Grade 3/4 neutropenia was dramatically reduced compared to standard FCR and our data demonstrated FCR-Lite can be safely administered in the community setting.

PurposeImmunotherapy has a long history with striking but limited success in patients with melanoma. To date, interleukin-2 and interferon-alfa2b are the only approved immunotherapeutic agents for melanoma in the United States.DesignTumor evasion of host immune responses, and strategies for overcoming tumor-induced immunosuppression are reviewed. Several novel immunotherapies currently in worldwide phase III clinical testing for melanoma are discussed.ResultsThe limitations of immunotherapy for melanoma stem from tumor-induced mechanisms of immune evasion that render the host tolerant of tumor antigens. For example, melanoma inhibits the maturation of antigen-presenting cells, preventing full T-cell activation and downregulating the effector antitumor immune response. New immunotherapies targeting critical regulatory elements of the immune system may overcome tolerance and promote a more effective antitumor immune response. These include monoclonal antibodies that block the cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and toll-like receptor 9 (TLR9) agonists. Blockade of CTLA4 prevents inhibitory signals that downregulate T-cell activation. TLR9 agonists stimulate dendritic cell maturation and ultimately induce a more effective immune response. These approaches have been shown to stimulate acute immune activation with concomitant appearance of transient adverse events mediated by the immune system. The pattern and duration of immune responses associated with these new modalities differ from those associated with cytokines and cytotoxic agents. In addition, vaccines are being developed that may ultimately target melanoma either alone or in combination with these immunomodulatory therapies.ConclusionThe successes of cytokine and interferon therapy of melanoma, coupled with an array of new approaches, are generating new enthusiasm for the immunotherapy of melanoma.

Pfizer Inc is developing tremelimumab, a fully human monoclonal IgG2 antibody against cytotoxic T-lymphocyte-associated antigen, for the potential intravenous treatment of cancer. Phase III clinical trials to confirm the role of tremelimumab in the treatment of metastatic melanoma are ongoing, as are phase II trials in patients with NSCLC and colorectal cancer.

The immunosuppressive impact of melanoma upon the human body is now beginning to be understood and interferon α2b at high dosage is critical to the reversal of signaling defects in the T cells of melanoma patients. The authors of this Viewpoint discuss the use of high dose interferon α2b in patients with high risk melanoma.

Oblimersen (Genasense®) is a Bcl-2 antisense compound that selectively targets Bcl-2 RNA for degradation by RNase H and thereby decreases Bcl-2 protein production. Bcl-2 protein plays a major role in preventing apoptosis and has been linked to chemotherapy resistance in melanoma. Preclinical studies with oblimersen in melanoma cell lines and xenograft models of melanoma have demonstrated downregulation of Bcl-2 protein, induction of apoptosis and enhanced tumor response when combined with chemotherapy. Results of a Phase I/II study have shown that reducing Bcl-2 with oblimersen coincident with the administration of dacarbazine may amplify apoptosis and improve therapeutic outcome. A subsequent Phase III trial showed that the addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes relative to dacarbazine alone based on an intent-to-treat analysis of progression-free survival and response rate (overall, complete and durable), as well as overall survival in patients with normal lactate dehydrogenase. This article reviews the biochemistry, pharmacodynamics and pharmacokinetics, safety and efficacy data related to oblimersen in melanoma.

Background: Anti-PD1/PDL1 immunotherapy has demonstrated unprecedented clinical antitumor activity in patients with metastatic melanoma supporting planned testing as adjuvant therapy in patients with operable disease at high risk of recurrence and death. Characterization of PDL1 expression within clinically/radiologically negative but microscopically tumor positive sentinel lymph nodes is critical to our understanding of the relevance of this immune checkpoint pathway for adjuvant therapy. Methods: Cut sections (5 µm) of sentinel lymph node from 25 patients reported positive for melanoma micrometastasis were included. H&E staining was performed, followed by PD-L1 immunohistochemical (IHC) staining using a preliminary IHC assay with anti-PD-L1 antibody clone 22C3. Slides from 2 patients were also stained using an anti-HMB45/MelA protocol to better ascertain the presence and/or localization of melanoma lesions in the tissue in order to facilitate interpretation of the PD-L1 staining in those samples. The slides were separately evaluated by 2 pathologists. Samples containing metastatic melanoma lesions were scored separately for PD-L1 expression in intratumoral (including along tumor periphery but with clear tumor cell labeling) and peritumoral (expression external to tumor nodule in immediately surrounding tissue) locations. For intratumoral signal, attempts were made to classify the expression as tumor cell associated (T), non-tumor cell associated (NT), or both (T/NT). Scores were assigned using a 0-5 semiquantitative scale assessing prevalence of positive cells where 0 = negative, 1 = minimal or rare, 2 = low, 3 = moderate, 4 = high, and 5 = very high. Samples where melanin content was too high to confidently assign a PD-L1 score were specifically noted. Results: Twenty patients where metastatic melanoma presence in regional sentinel nodes was confirmed by H&E review of the cut sections were included in the final analysis of PDL1 expression in the target population. Table 1 summarizes the study results. Except for samples where melanin content was too high to confidently assign a PD-L1 score, all SLNs examined demonstrated evidence of intratumoral and/or peritumoral PD-L1 expression. Conclusions: PD-L1 expression is readily detectable intratumorally and/or peritumorally within melanoma micrometastases in the SLN. These results support the testing of a therapeutic role for PD1/PDL1 inhibition in the adjuvant therapy setting, targeting melanoma micrometastases. Patient with SLN+ Tumor Associated Expression PD-L1 Score / Tumor ---- PD-L1 Score / Peritumoral 1. 1 T, very weak ---- 1 2. 4, predominantly T, peripheral ---- 1 3. melanin confounds ---- 2 4. 0 ---- 2 (adjacent subcapsular sinus) 5. 4 T/NT---- 2 6. 2, predominantly NT ---- 3 7. 0 ---- 3 (adjacent subcapsular sinus) 8. 2.5, predominantly NT ---- 3 9. 4.5, predominantly T, weak ---- 2 (adjacent sinus) 10. melanin confounds ---- 0 11. 1 T ---- 2.5 12. 0* ---- 2 13. 1 T ---- 1 14. 2.5 NT ---- 2 15. 2 predominantly NT ---- 3 16. 1 T ---- 2 17. melanin confounds ---- 0 18. 1 ---- 1 19. 1 NT ---- 2.5 20. 2 T, melanin confounds ---- 2 *Very few tumor cells. In one region where a few tumor cells were present, a dense area of PD-L1 positivity was present directly adjacent but was impossible to say if all were non-tumor; this is interpreted as most likely. Citation Format: Ahmad A. Tarhini, Jennifer A. Yearley, Christopher Gibson, Uma N. M. Rao, Cindy Sander, John M. Kirkwood. Tumor associated PDL1 expression pattern in microsopically tumor positive sentinel lymph nodes (SLN) in patients with melanoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A90.

Background: Patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab in a previously reported study (Tarhini. PLOS One 2014) where significant changes in circulating Treg, MDSC and peptide specific type I CD4+ and CD8+ T cells were observed early on-treatment (6 weeks) that correlated with clinical outcome. Methods: Patients were treated with ipilimumab (10 mg/kg IV every 3 weeks x 2 doses) bracketing surgery. Blood (serum / peripheral blood mononuclear cells) specimens were collected at baseline and during treatment for up to 9 months. We conducted longer term monitoring in patients with available specimens at 3 (n = 28), 6 (n = 22) and 9 (n = 13) months utilizing multicolor flow cytometry. We compared the frequencies of circulating suppressive Treg and MDSC on-study to baseline levels, as well as frequencies of CD4+ and CD8+ T cells specific to shared tumor-associated antigens (Gp-100, MART-1, NY-ESO-1) utilizing overlapping peptide libraries (15-mer peptides overlapping by 4). The prognostic value of cell frequencies in relation to the probability of the event of progression at 9 months was tested. Results: Baseline levels of Treg (CD4+/CD25hi+/CD39+) were significantly associated with 9 months progression free survival (PFS) (p = 0.04). A significant increase in Treg (CD4+CD25hi+Foxp3+ and CD4+/CD25hi+/CD39+) frequencies reported previously at 6 weeks after initiation of ipilimumab appears to have reversed starting 3 months as no significant changes were seen at this or any of the later time points compared to baseline. However, in monitoring the time dependent change over time in circulating Treg there was a trend towards an association with PFS (p = 0.09). Unlike what we had observed and reported at 6 weeks, no significant decrease in MDSC levels was seen at 3 months or later time points compared to baseline. We detected evidence of spontaneous in vivo cross presentation resulting in type I (interferon-γ producing), fully activated (CD69+) CD4+ and CD8+ antigen-specific T-cell immunity against cancer-testis (NY-ESO-1) as well as melanocytic lineage (MART-1, gp100) antigens in the absence of therapeutic vaccination. These responses were significantly potentiated at 6 weeks and persisted at 3, 6 and 9 months following the initiation of ipilimumab. Conclusions: Neoadjuvant ipilimumab significantly modulates the levels of cellular mediators of immune suppression (Treg and MDSC) early on-treatment with less significant changes seen on long term follow up. Significant potentiation of the type I effector T cell response is seen early and persists on long term monitoring. These biomarkers warrant further investigation in relation to the mechanism of action of ipilimumab and for their potential prognostic and therapeutic predictive value. (Supported by NIH award P50CA121973 and BMS) Citation Format: Janet Retseck, Amanda Gillespie-Twardy, Alexis Nasr, Hui-Min Lin, Yan Lin, John Kirkwood, Lisa H. Butterfield, Haris Zahoor, Cindy Sander, Ahmad A. Tarhini. Long term monitoring of circulating regulatory T cells (Treg), myeloid derived suppressor cella (MDSC) and type I effector T cells in melanoma patients treated with neoadjuvant ipilimumab. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4302. doi:10.1158/1538-7445.AM2015-4302

TPS9088 Background: Significant advances in the management of melanoma have improved the prognosis and overall survival of patients (pts) with metastatic disease. However, pts with active melanoma ...

TPS9085 Background: Current adjuvant treatment for patients with a surgically resected stage III-IV melanoma is limited to high dose Interferon (HDI) and pegylated interferon (pegIFN), which have s...

8092 Background: MET is frequently overexpressed in NSCLC. Amplification of MET and its ligand (HGF), are mechanisms of resistance to EGFR inhibitors. R is an IgG2 human mAb that targets HGF. This ...

e20106 Background: A recent pooled analysis of overall survival (OS) data across multiple studies has shown that IPI confirms long-term survival benefit up to 10 years in patients (pts) with advanc...

e20018 Background: The anti-PD-1 antibody pembrolizumab provides durable clinical benefits to 30-40% of patents with advanced melanoma.A number of murine and human studies suggest that pre-existing...

Current therapeutic options for the treatment of advanced melanoma are inadequate. Chemotherapy with dacarbazine remains a 'gold standard' despite no evidence of improved survival or durable remissions. Interleukin (IL)-2 is an immunotherapeutic agent that, when administered in a high-dose bolus schedule, produces a small number of durable remissions in patients with metastatic melanoma, and on this basis it was approved for use in the US in 1998. In randomized clinical trials, IL-2, administered as a continuous infusion either alone or in combination with chemotherapy (biochemotherapy), has not improved response rates over chemotherapy alone. Low-dose IL-2, while less toxic and more convenient, produces low response rates and appears to be ineffective in metastatic melanoma. Newer, innovative approaches such as IL-2 gene therapy and strategies to ameliorate the toxicity of this agent are now being explored in clinical trials.

In 2005, melanoma is estimated to affect 55,000 Americans. Of these, 7700 are estimated to die from the disease. Immunological approaches have yielded the only newly FDA-approved agents for melanoma in 30 years, which includes high-dose bolus IL-2, based on durable responses in some patients with metastatic melanoma. A survival advantage was shown in two of three randomised clinical trials with high-dose IFN-alpha2b in the high-risk adjuvant setting. However, both agents are associated with high cost and toxicity rates. A number of novel therapeutic agents are undergoing active clinical investigation. The more promising of these will be discussed in this review, including bcl-2 antisense therapy, v-raf murine sarcoma viral oncogene homologue B1 inhibition, heat-shock proteins, anti-alphavbeta3 integrin monoclonal antibody, thalidomide and newer immunomodulatory drugs, and anti-cytotoxic T lymphocyte-associated protein-4 monoclonal antibody.

Does childhood vaccination and exposure to infection improve long-term survival in patients with malignant melanoma?

The incidence of melanoma continues to rise at a rate greater than all other cancers. Survival in melanoma varies widely by stage, and is affected by a number of prognostic factors including tumour thickness, ulceration and lymph node involvement. New AJCC staging criteria adopted in the 6(th) edition reflect the prognostic value of tumour ulceration, the number of positive lymph nodes as a better prognostic indicator than the size of nodal metastasis, and the similar prognostic value provided by nodal, in-transit and local recurrences. It also recognises the pathologic information about staging provided by lymphatic mapping and sentinel lymphadenectomy. High-risk resected melanoma is defined as disease that after surgery is at higher than 40 to 50% risk of recurrence and death. The urgency to the effort to develop effective therapy for melanoma has led to a wide variety of approaches that have been tested over the years in the high-risk adjuvant setting. Among the many therapeutic modalities tested, the only agent that has shown a significant and reproducible benefit in terms of survival and relapse-free interval has been high-dose interferon-alpha2b. We here review the evidence that has led to the regulatory approval of this regimen, as well as ongoing studies using high-dose interferon-alpha in the high-risk adjuvant setting. We also present selected ongoing trials testing potential future therapies that may prove effective for patients with high-risk resected melanoma.

PURPOSE: The toxicity associated with adjuvant high-dose interferon-alfa-2b therapy (HDI) for high-risk melanoma can lead to premature discontinuation. It is important to understand the expected adverse events and their underlying mechanisms and to anticipate and aggressively manage toxicity during treatment in order to ensure that patients receive the maximum therapeutic benefit. METHODS: The toxicity profile of HDI was reviewed by examining data from the United States cooperative group trials. Available published data related to the potential mechanisms responsible for the observed adverse events are discussed, and comprehensive recommendations for managing side effects are presented. RESULTS: The HDI regimen is associated with acute constitutional symptoms, chronic fatigue, myelosuppression, elevated liver enzyme levels, and neurologic symptoms. The majority of patients tolerate 1 year of therapy with an understanding of the anticipated toxicities in conjunction with appropriate dose modifications and supportive care. Ongoing monitoring for liver dysfunction and hematologic toxicity is critical to ensure safety. Many of the toxicities associated with interferon-alfa (IFN-α) seem to be the result of endogenous cytokines and their effects on the neuroendocrine system. Recent data have also demonstrated that IFN-α suppresses the activity of specific CYP450 isoenzymes and that this correlates with discrete toxicities. Pharmacologic interventions are under study for fatigue and depression. An increased understanding of the mechanisms of IFN-α–associated toxicity will lead to more rational and effective supportive care and improved quality of life. CONCLUSION: Continued research in this area should lead to improvements in the safety and tolerability of adjuvant therapy for melanoma.

Background Patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab in a previously reported study (ASCO 2012). Gene expression profiles of tumors of treated patients were investigated for their therapeutic predictive value. Methods Patients were treated with ipilimumab (10mg/kg IV every 3weeks x2 doses) bracketing surgery. Tumor specimens were obtained at baseline and at definitive surgery (week 6-8). Gene expression profiling was performed on the tumor biopsies of 32 patients using U133A 2.0 Affymetrix gene chips. Significance Analysis of Microarrays (SAMR) was performed to test the association of each gene with outcome. Pathway analysis was performed using Ingenuity Pathway Analysis software. The Benjamini and Hochberg method was used to adjust for multiple testing in the pathway analysis. Results Pathway analysis identified biologically relevant pathways enriched with genes that are significantly associated with clinical outcome at baseline in relation to progression free survival (PFS) and disease non-progression (NP) as well as early on-treatment outcomes (PFS and overall survival, OS). These pathways and the top associated molecules were notably immune related and highly statistically significant. Pathways associated with clinical outcome overlapped between baseline and on-treatment specimens as well as across clinical endpoints tested. Table1 summarizes the top canonical pathways identified at baseline (PRE) and on-treatment (POST) and their association with PFS, NP and OS. Conclusions Gene expression profiling identified pathways and genes related to inflammation and autoimmunity that significantly predict clinical benefit from neoadjuvant ipilimumab at baseline and early on-treatment. These findings warrant further investigation in relation to ipilimumab and other immunotherapeutics. (Supported by NIH award P50CA121973 and BMS) Table 1.Pathways identified at baseline and on-treatment and their association with PFS, NP and OSPathwaysPRE/PFS (Adjusted P)PRE/NP (Adj. p)POST/PFS (Adj. p)POST/OS (Adj. p)Antigen Presentation0.00024.2x10-050.0043.1x10-05Cytotoxic T Lymphocyte-mediated Apoptosis of Target Cells0.00043.9x10-070.0040.0009T Helper Cell Differentiation0.0010.00050.050.023B Cell Development7.0x10-121.1x10-132.3x10-064.3x10-07iCOS-iCOSL Signaling in T Helper Cells0.0064.2x10-070.110.11OX40 Signaling0.0071.3x10-050.0050.0002CD28 Signaling in T Helper Cells0.048.3x10-050.040.15IL-4 Signaling0.020.00080.060.002PKCθ Signaling in T Lymphocytes0.048.0x10-050.140.04Nur77 Signaling in T Lymphocytes0.030.00010.030.008SLE Signaling1.5x10-054.3x10-06Allograft Rejection Signaling0.00034.3x10-060.0040.0006Autoimmune Thyroid Signaling0.0044.5x10-050.0210.003 Citation Format: Ahmad A. Tarhini, Yan Lin, Hui-Min Lin, Cindy Sander, William A. La Framboise, John M. Kirkwood. Immune related melanoma gene expression profile predicts neoadjuvant ipilimumab clinical benefit. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2911. doi:10.1158/1538-7445.AM2014-2911

Aim: A recent large pooled survival analysis has shown that ipilimumab (ipi) conveys long-term survival benefit in a significant proportion of patients (pts) with advanced melanoma (mel). We conducted a retrospective study of clinical outcomes and adverse events (AEs) among pts receiving ipi in a real world setting which may define whether longer survival is associated with increased HCRU. The present analysis describes HCRU by length of survival and baseline ECOG status. Methods: This medical chart review comprised adult pts in the US with unresectable stage III/IV mel treated in a community setting with ≥1 dose of ipi 3 mg/kg as first-line monotherapy between 04/2011 and 09/2012. Demographic/clinical characteristics, details of ipi dosing and subsequent therapies, AEs, and HCRU (hospitalizations, emergency department (ED) visits, nursing home stays) were collected. Pts were categorized according to survival ( Results: Data were abstracted from 273 pt charts at 34 sites. As of 12/20/2013, 231 pts had been followed ≥1 year or until death, and 200 had ECOG status recorded. The 4 groups were similar in age (median 64 years), sex (66% male), and race (95% white). More hospitalizations per pt occurred among pts surviving Conclusions: In this population, the rate of resource use was lower among those surviving ≥1 year than among those surviving Healthcare Resource Utilization during Follow-Up, Mean (SD) Survived ≥1 year ECOG 0 N = 55 Survived ≥1 year ECOG ≥1 N = 51 Survived ECOG 0 N = 26 Survived ECOG ≥1 N = 68 Hospitalizations Number per pt per 100 days* Total days per pt per 100 days * 0.08 (0.16) 0.49 (1.17) 0.09 (0.19) 0.35 (0.79) 0.50 (0.70) 2.22 (3.45) 1.13 (1.77) 5.12 (8.93) Emergency department visits, number per pt per 100 days 0.01 (0.05) 0.02 (0.11) 0 (0) 0.02 (0.07) Nursing home stays Pts (%) Total days per pt per 100 days 1.8% 0.04 (0.30) 5.9% 0.46 (2.01) 7.7% 1.63 (7.20) 7.4% 1.89 (9.00) * p Disclosure: A. Tarhini: Advisory boards: Bristol-Myers Squibb, Merck, and Genentech; Corporate-sponsored research: Bristol-Myers Squibb, Merck, Novartis, Amgen, and Prometheus. A.S. Rao: Employee of Bristol-Myers Squibb. S. Corman: Employee of Pharmerit International; consulting fee or honorarium paid by Bristol-Myers Squibb to Pharmerit International. M. Botteman: employee of Pharmerit International; consulting fee from Bristol-Myers Squibb during the conduct of the study. S. Mehta: employee of Pharmerit International; consulting fee or honorarium paid by Bristol-Myers Squibb to Pharmerit International. X. Ji: employee of Pharmerit International; consulting fee or honorarium paid by Bristol-Myers Squibb to Pharmerit International. M. Katyal: Employee of Medical Data Analytics; corporate-sponsored research: Medical Data Analytics is consultant vendor to Bristol-Myers Squibb, Inc., the financial sponsor of this research study. K. Margolin: Corporate-sponsored research: GlaxoSmithKline, Bristol-Myers Squibb, Genentech, Pfizer, Altor, and Prometheus.

e19065 Background: MET is frequently overexpressed in NSCLC and amplification of MET and its ligand, hepatic growth factor (HGF), are mechanisms of resistance to epidermal growth factor receptor (E...

TPS9110 Background: New immunotherapies and BRAF inhibitors (BRAFi) have improved the prognosis of advanced melanoma. Although BRAFi induce regression in ~50% of patients (pts), responses are incom...

9087 Background: Molecular characterization through gene expression (exp) profiling of node positive and node negative sentinel lymph nodes (SLNs) in patients with clinical stage I-II melanoma may ...