stage-IV Melanoma Research Articles

Early versus late response to PD-1-based immunotherapy in metastatic melanoma

BackgroundImmune checkpoint inhibition (ICI) currently is the most effective treatment to induce durable responses in metastatic melanoma. The aims of this study are the characterization of patients with early, late and non-response to ICI and analysis of survival outcomes in a real-world patient cohort. MethodsPatients who received PD-1-based immunotherapy for non-resectable stage-IV melanoma in any therapy line were selected from the prospective multicenter real-world DeCOG study ADOREG-TRIM (NCT05750511). Patients showing complete (CR) or partial (PR) response already during the first 3 months of treatment (Early Responders, EarlyR) were compared to patients showing CR/PR at a later time (Late Responders, LateR), a stable disease (SD) and to patients showing progressive disease (Non-Responders, NonR). ResultsOf 522 patients, 8.2 % were EarlyR (n = 43), 19.0 % were LateR (n = 99), 37.0 % had a SD (n = 193) and 35.8 % were NonR (n = 187). EarlyR, LateR and SD patients had comparable baseline characteristics. Multivariate logbinomial regression analyses adjusted for age and sex revealed positive tumor PD-L1 (RR=1.99, 95 %-CI=1.14–3.46, p = 0.015), and normal serum CRP (RR=1.59, 95 %-CI=0.93–2.70, p = 0.036) as independently associated with the achievement of an early response compared to NonR. The median progression-free and overall survival was 46.0 months (95 % CI 19.1; NR) and 47.8 months (95 %-CI 36.9; NR) for EarlyR, NR (95 %-CI NR; NR) for LateR, 8.1 months (7.0; 10.4) and 35.4 months (29.2; NR) for SD, and 2.0 months (95 %-CI 1.9; 2.1) and 6.1 months (95 %-CI 4.6; 8.8) for NonR patients. ConclusionLess than 10 % of metastatic melanoma patients achieved an early response during the first 3 months of PD-1-based immunotherapy. Early responders were not superior to late responders in terms of response durability and survival.

Combination of Whole-Body Baseline CT Radiomics and Clinical Parameters to Predict Response and Survival in a Stage-IV Melanoma Cohort Undergoing Immunotherapy.

Simple SummaryThe use of immunotherapeutic agents significantly improved stage-IV melanoma patients’ overall progression-free survival. To identify patients who do not benefit from immunotherapy, both clinical parameters and experimental biomarkers such as radiomics are currently being evaluated. However, no radiomic biomarker is widely accepted for routine clinical use. In a large cohort of 262 stage-IV melanoma patients given first-line immunotherapy treatment, we investigated whether radiomics—based on the segmentation of all baseline metastases in the whole body—in combination with clinical parameters offered added value compared to the usage of clinical parameters alone in a machine-learning prediction model. The primary endpoints were response at three months, and survival rates at six and twelve months. The study indicated a potential, but non-significant, added value of radiomics for six-month and twelve-month survival prediction, thus underlining the relevance of clinical parameters.Background: This study investigated whether a machine-learning-based combination of radiomics and clinical parameters was superior to the use of clinical parameters alone in predicting therapy response after three months, and overall survival after six and twelve months, in stage-IV malignant melanoma patients undergoing immunotherapy with PD-1 checkpoint inhibitors and CTLA-4 checkpoint inhibitors. Methods: A random forest model using clinical parameters (demographic variables and tumor markers = baseline model) was compared to a random forest model using clinical parameters and radiomics (extended model) via repeated 5-fold cross-validation. For this purpose, the baseline computed tomographies of 262 stage-IV malignant melanoma patients treated at a tertiary referral center were identified in the Central Malignant Melanoma Registry, and all visible metastases were three-dimensionally segmented (n = 6404). Results: The extended model was not significantly superior compared to the baseline model for survival prediction after six and twelve months (AUC (95% CI): 0.664 (0.598, 0.729) vs. 0.620 (0.545, 0.692) and AUC (95% CI): 0.600 (0.526, 0.667) vs. 0.588 (0.481, 0.629), respectively). The extended model was not significantly superior compared to the baseline model for response prediction after three months (AUC (95% CI): 0.641 (0.581, 0.700) vs. 0.656 (0.587, 0.719)). Conclusions: The study indicated a potential, but non-significant, added value of radiomics for six-month and twelve-month survival prediction of stage-IV melanoma patients undergoing immunotherapy.

Abstract 594: FcγRIIB expressed on activated CD8+ T cells restrains T cell responsiveness to αPD-1 immune checkpoint blockade in melanoma patients

Abstract In this study, we show that FcγRIIB on the surface of CD8+ T cells reduces responsiveness to αPD-1 antibody in melanoma patients, and we suggest therapeutic strategies to improve CD8+ T cell response to PD-1 blockade. Immune checkpoint blockade (ICB) such as PD-1 blockade has drastically improved melanoma patient survival, but not all patients respond to ICB. Elevated expression of inhibitory molecules on CD8+ T cells dampens the antitumor T cell response and limits patient response to ICB. We recently showed that the inhibitory receptor FcγRIIB is expressed on effector-like memory CD8+ T cells and functions in a cell-intrinsic manner to temper activated CD8+ T cells in vivo. We found that FcγRIIB+ CD8+ T cells were more proliferative and secreted more pro-inflammatory cytokines than their FcγRIIB- counterparts. FcγRIIB+ CD8+ T cells also expressed elevated levels of exhaustion/activation markers (PD-1, CTLA-4, etc.). As these markers are also the targets of immune checkpoint blockade, we investigated the response of these cells to checkpoint therapy. Interestingly, FcγRIIB+ cells exhibited significantly reduced proliferation to αPD-1 and αCTLA-4 in vitro compared to FcγRIIB- cells (p<0.05). In stage-IV melanoma patients, we observed a decrease in FcγRIIB+ CD8+ T cells (p<0.05) following administration of nivolumab (αPD-1), a finding replicated in mouse models in vivo. Because ICB utilizes IgG antibody, a canonical ligand for FcγRs, we hypothesized that ICB antibodies could bind FcγRIIB on CD8+ T cells and elicit counterproductive negative signaling. In a B16-melanoma mouse model, genetic deletion of FcγRIIB on CD8+ T cells increased CD8+ T-cell infiltration and IFNγ production at the tumor in αPD-1 treated mice (p<0.05). Further, blocking inhibitory signaling through FcγRIIB in αPD-1-treated animals increased the number of Ki67+, TNF+, and IFNγ+ CD8+ T cells at the tumor and delayed tumor growth compared to αPD-1 treatment alone (p<0.05). Thus, we show that FcγRIIB is a novel inhibitory molecule on CD8+ T cells that limits T-cell responsiveness to αPD-1 immunotherapy and that T cell-expressed FcγRIIB should be a consideration in the development of therapeutic antibodies. We also demonstrate the efficacy of blocking FcγRIIB to enhance the CD8+ T-cell response to αPD-1 in mice, illuminating a potential new therapeutic target to improve melanoma patient response to ICB. Citation Format: Kelsey B. Bennion, Marvi Tariq, Kirsten M. Baecher, Chrystal M. Paulos, Ragini Kudchadkar, Michael C. Lowe, Mandy L. Ford. FcγRIIB expressed on activated CD8+ T cells restrains T cell responsiveness to αPD-1 immune checkpoint blockade in melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 594.

Exploratory study on the effectiveness of integrative neurocognitive remediation therapy (iNCRT) for cancer survivors

IntroductionCancer survivors frequently report suffering from neurocognitive impairment, that persists after physical recovery from their disease. Cognitive impairment is associated with important emotional disturbances, socio-professional consequences and diminished quality of life.ObjectivesThis observational study aims to assess the effectives of an integrative neurocognitive remediation therapy (iNRCT), offered as a 12-week program (1day/week), organized within our Cognitive Remediation Clinic. The iNCRT combines personalized computerized cognitive training and neurocognitive strategy training, with group sessions of physical exercise, mindfulness, and cognitive behavior therapy (CBT).MethodsThe assessment before and after NCRT includes neuropsychological testing (10 subtests), assessment of daily functioning and subjective neurocognitive function (NCF).ResultsOut of 16 eligible cancer survivors, 12 patients were recruited and 11 completed the iNCRT; median age 53 years [range, 41-71]; 3 patients had a prior history of a central nervous system tumor, 5 patients of breast cancer, 2 patients of stage-IV melanoma, and 1 patient of gastric cancer. After iNCRT subjective NCF did not improve significantly (p=0.13) according to the Cognitive Failure Questionnaire. However neuropsychological assessment revealed an improvement on ≥ 1 impaired subtest in all patients; 6 patients improved on ≥ 4 impaired subtests. Improvement was most prominent in long-term verbal and visual memory, working memory and executive function. All patients reported a clinical benefit in their daily function after completion of iNCRT.ConclusionsOur iNRCT, which combines personalized neurocognitive training with physical exercise, mindfulness and CBT can be an effective therapeutic model for treating neurocognitive impairment in cancer survivors, with a clinically relevant impact on their daily function.DisclosureNo significant relationships.

RNA Drugs

RNA Drugs

561 Metastasectomy for Stage IV Melanoma in the Effective Systemic Treatment Era

Abstract Aim Historically, a diagnosis of Stage IV melanoma was a dire one, with low survival rates and ineffective treatment. The only beneficial treatment option was metastasectomy in very selected cases. The recent introduction of the effective systemic therapy agents (EST) (immunotherapy and BRAF inhibitors) dramatically changed this. This research’s aim is to determine if EST + Metastectomy significantly improves OS. And if so, should be considered as the main therapeutic approach to stage IV melanoma patients. Method Single-centre retrospective cohort study from the Melanoma Unit at Calvary Mater Hospital in Australia was conducted, approved by the ethics committee. Inclusion criteria was Stage IV Melanoma patients who received EST from 2009-2019. OS of those who received EST alone are compared to EST + Metastasectomy. The 2 groups were compared retrospectively based on their disease characteristics, using probability score weighting analysis and survival curve. Results This is a preliminary analysis for the first 200 patients, data collection is ongoing. Mean OS is 2 years. Several combinations of immunotherapy treatments were identified. Of the 200 patients, 35% underwent metastasectomy. Mean survival for those who had surgery is 3 years, as oppose to 2 years for those who had EST alone. OS in the Metastasectomy group was higher than those who had EST alone, of 47.1% and 42.3% respectively. The Kaplan Meier curve also shows increase survival in the metastasectomy group, up to year 6 post diagnosis. Conclusions Metastasectomy for stage iv melanoma in the EST era appears to offer a survival benefit in selected patients

Patients with BRAF-Mutant Advanced/Metastatic Melanoma: Original Research on the Treatment Reality in Germany and Austria in the Era of Choice.

Cutaneous melanoma isone of the most aggressive forms of skin neoplasms and represents a major cause of neoplastic or cancer death in Europe. Without adequate therapy, the 5-year survival rate is 15% when the disease metastasizes to distant organs. The objective of our study was to evaluate the status quo of the current treatment standards in stageIV melanoma and rationale for therapy decisions in Germany and Austria between January 2016 and September 2018. In this retrospective, anonymized registry, data of male and female patients with unresectable advanced/metastatic BRAF-positive cutaneous melanoma treated in the first, second, and third line with registered substances were analyzed using descriptive statistics. Ninety-nine patients (50.5% male) received a total of 172 treatment lines. The first (99 patients), second (56 patients), and third (17 patients) treatment lines were documented. Within the 80.8% of patients with stageIV melanoma, targeted therapy (TT) was more frequently administered as a first-line treatment than immunotherapy (IO) with checkpoint inhibitors (59.6% TT vs. 40.4% IO). Across all lines, patients received TT in 54.7% and IO in 43.0% of the cases. As targeted agents, dabrafenib plus trametinib was predominantly prescribed (72.3%), whereas the monotherapy with anti-programmed cell death protein1 and anti-cytotoxic Tlymphocyte-associated protein4 antibodies or their combination was prescribed similarly often (50.0% vs. 47.3%). Most commonly, the treatment type was switched from TT to IO or vice versa upon disease progression. The most frequent rationales for prescribing either TT or IO were remission pressure (72.9%) or physician's preference (45.0%), respectively. Disease progression was a more frequent cause of treatment discontinuation than undesired events. Patients in Germany and Austria with unresectable advanced or metastatic BRAF-mutant melanoma predominantly receive guideline-recommended treatments. TT was more frequently administered than IO while the rationale for prescribing a specific treatment type differed between the two.

Immunity to X-linked inhibitor of apoptosis protein (XIAP) in malignant melanoma and check-point blockade.

Expression of inhibitors of apoptosis protein (IAP) family members is associated with poor prognosis in cancer patients. Immunity to ML-IAP (livin) and survivin has been well studied in patients with a variety of tumors. XIAP, the most potent inhibitor of apoptosis, is widely expressed in melanoma. To better define its potential role as an immunogenic target, cellular and humoral responses to XIAP were investigated in patients with advanced melanoma. An overlapping peptide library covering the full length of the XIAP protein was used to screen T cell responses of peripheral blood mononuclear cells (PBMC) from stage-IV melanoma patients treated with or without anti-CTLA4 (ipilimumab). The screen identified an array of peptides that predominantly induced CD4+ T cell responses. XIAP epitope-specific CD4+ T cells revealed proliferative responses to melanoma cells that express XIAP. Humoral responses to XIAP were also explored. Cellular and humoral responses to XIAP were associated with beneficial clinical outcomes after ipilimumab-based treatment, supporting XIAP as a potential therapeutic target.

Use of immunotherapy for stage-III and IV melanoma and likelihood of regional and distant lymph node resection and surgical resection for distant metastasis.

9558 Background: Immunotherapy (IMT) for stages-III and IV melanoma has dramatically changed overall prognosis and treatment strategies. The aim of this study was to evaluate if use of IMT significantly changed the likelihood of regional/distant lymph node (LN) resection and surgical resection for distant metastases (DM) among patients with stages-III and IV melanoma, respectively, in the pre- and post-2011 era. Methods: The National Cancer Database (2004-2015) was used to evaluate the likelihood of regional/distant LN resection and surgical resection for DM among patients with stages-III and IV melanoma, respectively, with use of IMT. Multivariable stepwise with forward selection Poisson regression with robust standard errors was used to adjust for potential confounders (age, gender, race, year of diagnosis, Charlson-Deyo Score, facility type, facility location, insurance status, 2012 median income quartile, and 2013 urban/rural status). A stratified analysis was performed to evaluate differences among facility type. Results: There were 28,847 patients (median age 62 (IQR 53-73); 36.3% female) with stage-III melanoma and 14,443 patients (median age 66 (IQR 56-76); 31.7% female) with stage-IV melanoma. Overall, 24.3% (n = 7,018) and 17.0% (n = 2,459) with stage-III and IV melanoma, respectively, received IMT. The adjusted relative risk (aRR) of regional/distant LN resection among patients with stage-III melanoma was significantly higher with use of IMT (aRR 1.16, 95% CI 1.05–1.28, P = 0.004), while the aRR of surgical resection for DM was significantly lower with use of IMT for stage-IV melanoma (aRR 0.85, 95% CI 0.78–0.92, P < 0.001). Stratified analysis demonstrated that the findings were principally reflective of academic/research hospitals. Conclusions: The higher likelihood of regional/distant LN resection in stage-III melanoma may be due to the curative role of surgery and preceded the post-MSLT-II era. Conversely, in stage-IV melanoma, surgery may be limited to resectable oligometastatic disease given the durable and systemic benefit of first-line IMT.

Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma

IntroductionTreatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. Methods & resultsOur preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor–pretreated compared with MAPK-inhibitor–naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. ConclusionThe level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

Incidental pulmonary emboli in stage IV melanoma patients: Prevalence in CT staging examinations and improved detection with vessel reconstructions based on dual energy CT.

ObjectivesMalignancy is the strongest predictor for venous thromboembolism. Dual energy CT (DECT) can support assessment of pulmonary emboli (PE) by providing vessel reconstructions (DECT-VR) and highlighting thrombi. Purpose was to determine prevalence and risk factors of PE in staging examinations of stage IV-melanoma patients and to evaluate the potential of DECT-VR to improve PE diagnosis.Material and methodsThis retrospective study was approved by IRB. Contrast-enhanced, conventional grey scale CT (cCT) and DECT-VR of 200 stage IV-melanoma patients were reviewed by three radiologists in consensus. Overall prevalence was determined. One-sided Wilcoxon-test was performed to compare the number of detected emboli between cCT and cCT with supplementary DECT-VR. Frequencies of risk factors were compared with χ2 test.ResultsOn cCT, 9 PE were detected (6 patients, correlating to 3% of the study population with 0.05 emboli per patient). With the supplementary DECT-VR, number of diagnosed emboli increased from 9 to 17 (p < 0.05) (in total 9 patients, correlating to 0.09 emboli per patient). Emboli on DECT-VR were mainly subsegmentally (7 of 8). There was no significant difference in the frequency of risk factors.ConclusionsThe prevalence of pulmonary emboli in our cohort of 200 stage IV melanoma patients was 5%. DECT-VR improved significantly diagnosis of PE, especially when located subsegmentally.

Characterising the phenotypic evolution of circulating tumour cells during treatment

Real-time monitoring of cancer cells’ phenotypic evolution during therapy can provide vital tumour biology information for treatment management. Circulating tumour cell (CTC) analysis has emerged as a useful monitoring tool, but its routine usage is restricted by either limited multiplexing capability or sensitivity. Here, we demonstrate the use of antibody-conjugated and Raman reporter-coated gold nanoparticles for simultaneous labelling and monitoring of multiple CTC surface markers (named as “cell signature”), without the need for isolating individual CTCs. We observe cell heterogeneity and phenotypic changes of melanoma cell lines during molecular targeted treatment. Furthermore, we follow the CTC signature changes of 10 stage-IV melanoma patients receiving immunological or molecular targeted therapies. Our technique maps the phenotypic evolution of patient CTCs sensitively and rapidly, and shows drug-resistant clones having different CTC signatures of potential clinical value. We believe our proposed method is of general interest in the CTC relevant research and translation fields.

The value of metastasectomy in stageIV cutaneous melanoma.

Cutaneous melanoma is an aggressive neoplasia of melanocytes. Prognosis is dependent on tumor stage. StageIV melanoma is characterized by the occurrence of distant metastases. Response of metastases to classical chemotherapy is limited and toxicity of treatment is high. In recent years, new developments in immunotherapy and targeted therapies improved prognosis of stageIV melanoma patients with better tolerability of treatment. There is no dispute about surgical treatment of primary melanoma. But what is the value of metastasectomy in the era of new systemic treatments? This review aims to discuss available data for surgical removal of distant metastases for several organs and tissues. The available evidence suggests that for selected patients with possible complete resection of all tumor metastases, metastasectomy remains an effective treatment option with abenefit in overall survival.

5-羟甲基胞嘧啶表达与黑素瘤侵袭、转移、预后的相关性分析

Objective To detect the level of 5-hydroxymethyl-cytosine (5-hmc) in melanoma tissues, and to analyze the correlation between 5-hmc and the invasion, metastasis and prognosis of melanoma. Methods A streptavidin-peroxidase immunohistochemical method was used to detect the level of 5-hmc in 67 melanoma tissues and 20 pigmented nevi tissues. Univariate and multivariate analyses were performed with the Cox′s proportional hazards regression model to analyze the correlation between the expression of 5-hmc and the prognosis of melanoma. Results The expression rate of 5-hmc was significantly lower in melanoma tissues than in pigmented nevus tissues (40.30%[27/67] vs. 75%[15/20], χ2 = 7.428, P = 0.006) . According to American Joint Committee on Cancer (AJCC) TNM staging system, the expression level of 5-hmc was significantly lower in the stage Ⅳmelanoma tissues than in the stage Ⅱ and stage Ⅲ melanoma tissues (χ2 = 4.416, P = 0.036) . Patients with lymph node metastasis showed significantly lower expression of 5-hmc compared with those without lymph node metastasis (χ2 = 5.902, P = 0.015) , and the level of 5-hmc expression significantly decreased along with the increase of Clark grade (χ2 = 4.828, P = 0.028) . There were no significant differences in the level of 5-hmc expression between patients of different ages, genders or nationalities (P > 0.05) . Multivariate Cox regression analysis showed that distant lymph node metastasis (HR: 2.67, 95% CI: 1.22-5.84) , not receiving surgical resection (HR: 0.41, 95% CI: 0.18-0.95) , and low expression of 5-hmc (HR: 3.54, 95% CI: 1.09-11.43) were independent risk factors for poor prognosis of melanoma. Conclusion 5-Hmc may participate in the invasion and metastasis of melanoma, and be associated with the prognosis of melanoma. Key words: 5-Methylcytosine; Nevi and melanomas; Biological marker; Prognosis; Neoplasm metastasis

Cutaneous Angiosarcoma: The Possibility of New Treatment Options Especially for Patients with Large Primary Tumor.

The most widely accepted treatment for cutaneous angiosarcoma (CAS) is wide local excision and postoperative radiation to decrease the risk of recurrence. Positive surgical margins and large tumors (T2, >5 cm) are known to be associated with poor prognosis. Moreover, T2 tumors are known to be associated with positive surgical margins. According to previous reports, the majority of CAS patients in Japan had T2 tumors, whereas less than half of the patients in the studies from western countries did so. Consequently, the reported 5-year overall survival of Japanese CAS patients without distant metastasis was only 9%, lower than that for stage-IV melanoma. For patients with T2 tumors, management of subclinical metastasis should be considered when planning the initial treatment. Several attempts to control subclinical metastasis have been reported, such as using adjuvant/neoadjuvant chemotherapy in addition to conventional surgery plus radiation. Unfortunately, those attempts did not show any clinical benefit. Besides surgery, new chemotherapeutic approaches for advanced CAS have been introduced in the past couple of decades, such as paclitaxel and docetaxel. We proposed the use of chemoradiotherapy (CRT) using taxanes instead of surgery plus radiation for patients with T2 tumors without distant metastasis and showed a high response ratio with prolonged survival. However, this prolonged survival was seen only in patients who received maintenance chemotherapy after CRT, indicating that continuous chemotherapy is mandatory to control subclinical residual tumors. With the recent development of targeted drugs for cancer, many potential drugs for CAS are now available. Given that CAS expresses a high level of vascular endothelial growth factor (VEGF) receptor, drugs that target VEGF signaling pathways such as anti-VEGF monoclonal antibody and tyrosine kinase inhibitors are also promising, and several successful treatments have been reported. Besides targeted drugs, several new cytotoxic anticancer drugs such as eribulin or trabectedin have also been shown to be effective for advanced sarcoma. However, most of the clinical trials did not include a sufficient number of CAS patients. Therefore, clinical trials focusing only on CAS should be performed to evaluate the effectiveness of these new drugs.

PS1 - 140 The Effect of Timing of Stereotactic Radiosurgery Treatment of Melanoma Brain Metastases Treated with Ipilimumab

Melanoma represents the third most common cause of CNS metastases. Immunotherapy has evolved as a treatment option for patients with stage-IV melanoma. Stereotactic radiosurgery (SRS) also elicits an immune response within the brain and may interact with immunotherapy. We report a cohort of patients treated for brain metastasis with immunotherapy and evaluate the effect of SRS timing on the intracranial response. Methods: All consecutively treated melanoma patients receiving Ipilimumab and SRS for their brain metastasis were included in the retrospective analysis. 46 patients harboring 232 brain metastases were reviewed. The median clinical follow-up was 7.9 months (3-42.6). Median age was 63 years (24.3-83.6). 32 patients received SRS before or during ipilimumab cycles (Group-A) whereas 14 patients received SRS after the ipilimumab treatment (Group-B). Radiographic and clinical responses were assessed at approximately 3 months intervals after SRS. Results: The two cohorts were comparable in pertinent pre-treatment aspects with the exception of SRS timing relative to ipilimumab. Local recurrence free duration (LRFD) was significantly longer in Group-A patients (19.6 months, range 1.1-34.7 months) as compared to group-B patients (3 months, range 0.4-20.4 months), respectively (p=0.002). Post-SRS perilesional edema was more significant in Group-A. Conclusions: The effect of SRS and ipilimumab in attaining LRFD seems greater when SRS is performed before or during ipilimumab treatments. The timing of immunotherapy and SRS may effect LRFD and post-radiosurgical edema. The interactions between immunotherapy and SRS warrant further investigation so as to optimize the therapeutic benefits and mitigate the risks associated with multimodality, targeted therapy.

SU-F-T-568: QA of a Multi-Target Multi-Dose VMAT SRS

Purpose: To, experimentally, corroborated the prescribed doses utilizing dosimeters (e.g. films and TLDs) that can provide high spatial resolution, allow dose measurement of multiple targets at once, and provide accurate dosimetric results. Methods: A single-isocenter 6FFF SRS VMAT plan consisting of one 358° arc at 0° couch angle and four 179° arcs at 30°, 60°, 330° and 300° couch angles respectively, was generated in ECLIPSE v.11 using a Rando-Alderson anthropomorphic head phantom CT study. This plan was a reproduction of a clinical plan generated for a stage-IV melanoma patient diagnosed with 19 intracranial lesions. The phantom was loaded with axially mounted (between phantom slabs) Gafchromic EBT3 film and TLDs strategically positioned within various target volumes. Film and TLDS were calibrated according to established protocols. Target prescription doses were 16 Gy (3cc≤, 3 lesions), 18 Gy (∼1–3cc, 10 lesions) and 20 Gy (≤1cc, 6 lesions). Phantom setup was verified through CBCT imaging prior to irradiation. Gafchromic films were scanned in transmission mode and TLDs were read, respectively, ∼24 hrs after irradiation. Results: Dose calibrated Gafchromic film data were compared to the ECLIPSE calculated data using a 3% / 3mm gamma function analysis. Results for the gamma values were 96–99% in agreement with the calculated data and with 84–90% of the film pixels within the 3% dose difference. TLD data showed a dose difference of 0.4–8% while the film data for those same locations yielded a difference of 0.4–4%. It was observed that the highest dose discrepancies correlated with the location of the small volume targets. Conclusion: Overall this study corroborated that a VMAT SRS treatment, employing various treatment table rotations and arcs, to multiple intracranial lesions with multiple dose prescriptions can be delivered accurately with the existing radiotherapy technology.

The Comparative Efficacy of First-Line (1L) Treatments for Stage Iiic and Stage Iv Melanoma: Results of a Systematic Review and Network Meta-Analysis

ABSTRACT Aim: Network meta-analysis (NMA) is used to compare treatment effects, taking all available evidence into account. This study describes a NMA of 1L treatments for stages IIIC and IV melanoma using the accelerated failure time (AFT) scale. The comparators were selected based on European clinical practice and included: dacarbazine (DTIC), DTIC + tamoxifen (TMX), temozolomide (TMZ), interferon (IFN), ipilimumab (IPI), vemurafenib (VM), dabrafenib (DB) and trametinib (TR). Reported outcomes were overall survival (OS) and progression-free survival (PFS). Methods: Studies in the systematic literature were identified through the Embase, Medline, and Cochrane databases. Kaplan-Meier curves were scanned, and individual patient level data were recreated using a published algorithm. Treatment effect estimates for each study were obtained using Cox proportional hazards (PH) and the AFT models. For the AFT, a generalized gamma distribution was assumed. Bayesian fixed-effects NMAs were conducted and assumed that treatment effects were comparable across trials. Results: Fourteen studies were identified and included in the analysis. Diagnostic tests results indicated that treatment effects were not constant over time in the PH model, and the AFT model better fit the trial data and, therefore, was used in the analysis. Studies using lower dose intensities of DTIC (800 mg/m2/d) were excluded due to heterogeneity. The inverse acceleration factors for OS and PFS for each treatment, compared with DTIC, are shown in the table (values lower than 1 indicate increased survival). Conclusions: VM is the only treatment that shows a statistically significant increase in both OS and PFS, compared with DTIC, when published RCT data are compared. Disclosure: C. Bexelius: I am an employee of F.Hoffmann-La Roche; J.M. Quigley: Consultant for Roche with compensation for conducting systematic review; P. Thuresson: I am an employee of F. Hoffmann-La Roche; N. Hawkins: I am employed by ICON PLC, a consultant to F. Hoffmann-La Roche. Table: 1095P . Inverse Acceleration Factor Compared With DTIC. Median (95% confidence interval) DB DB + TR 1mg DB + TR 2 mg DTIC + IFN DTIC + IFN + TMX DTIC + TMX IPI IPI + DTIC TMZ VM OS 0.86 (0.62,1.2) 0.87 (0.53,1.43) 0.7 (0.43,1.16) 1.13 (0.95,1.33) 3.35 (2.23,5.02) 3.53 (2.36,5.3) 1.05 (0.65,1.69) 0.77 (0.63,0.96) 0.97 (0.86,1.1) 0.74 (0.61,0.89) PFS 0.37 (0.29,0.46) 0.27 (0.19,0.38) 0.21 (0.15,0.29) 1.11 (0.89,1.38) 1.22 (0.85,1.75) 1.15 (0.8,1.65) 0.84 (0.7,1.02) - 0.91 (0.8,1.03) 0.32 (0.28,0.37)

Low-dose inhalation of interleukin-2 bio-chemotherapy for the treatment of pulmonary metastases in melanoma patients

Background:Interleukin-2 (IL-2) treatment for patients with metastatic melanoma has shown remarkable durable responses. Systemic administration of IL-2 may cause severe side effects, whereas local administration is considered to be a safe alternative. The lungs are common sites of metastases in melanoma patients causing considerable respiratory problems. We sought to evaluate the potential antitumoral effect of a low-dose inhalative IL-2 (lh-IL-2) regimen for patients with melanoma lung metastases. In addition, we explored the prophylactic potential of Ih-IL-2 after surgical removal of lung metastases in a study carried out in an outpatient setting.Methods:Twenty patients with American Joint Committee on Cancer stage-IV (M1b and M1c) melanoma were enrolled in this study and treated with 3 × 3 million IU inhalative IL-2 q.d. together with monthly dacarbazine bolus injections. Five patients received lh-IL-2 after surgical resection of lung metastases to prevent recurrence of the disease (prophylaxis group, N=5). All other patients were enrolled in the treatment group (N=15). Clinical evaluations were carried out monthly and radiological follow-up was performed every third month.Results:Nine patients in the treatment group had a clinical benefit with partial regression (27%) or stable disease (33%). Four patients had progression of lung metastases (26.7%) and two patients were not evaluable (13.3%). In the prophylaxis group, none of the patients developed new lung metastases during lh-IL-2 therapy. The median follow-up period was 7.8 months in the treatment group and 25.7 months in the prophylaxis group. In the majority of patients, treatment was well tolerated.Conclusions:Low-dose IL-2 inhalation might offer an effective and safe treatment option for lung metastases in melanoma patients. In addition, lh-IL-2 may have a prophylactic potential to prevent recurrence in the lungs after pulmonary melanoma metastasectomy. Administration can easily be performed in an outpatient setting, thus offering an attractive treatment option.

Toll-like receptor 4 gene polymorphism influences dendritic cell in vitro function and clinical outcomes in vaccinated melanoma patients.

Toll-like receptor 4 (TLR4) is expressed on dendritic cells (DCs), sensing environmental danger molecules that induce their activation and maturation. Recently, we reported a method for the production of therapeutic DCs against melanoma, called tumor antigen-presenting cells (TAPCells), using a heat-shocked allogeneic melanoma cell lysate (TRIMEL) as an activation factor and antigen provider. Since TRIMEL contains endogenous TLR4 ligands, we evaluated the role of TLR4 in TAPCells differentiation by antibody neutralization and the association of a Tlr4 polymorphism (896A/G) (Asp299Gly), determined by PCR-RFLP, with the in vitro activation capacity and the clinical outcome of TAPCells-vaccinated patients. Antibody blocking of monocyte TLR4 inhibited surface expression, determined by flow cytometry, of the major histocompatibility complex class I, CCR7, CD80, CD83 and CD86 on TAPCells, reduced interleukin (IL)-6 and tumor necrosis factor -α gene expression evaluated by qRT-PCR, and also inhibited the TAPCells-mediated interferon-γ (IFN-γ) secretion of melanoma-specific CD8(+) T cells determined by ELISpot (p < 0.01). Moreover, CD8(+) T-cell activation capacity was significantly reduced in TAPCells bearing the TLR4 Asp299Gly receptor (p < 0.05). Finally, TAPCells-vaccinated stage-IV melanoma patients bearing the Tlr4 896G allele showed a shortened post-therapy median survival rate compared with those carrying the Tlr4 896A allele (p < 0.05; log-rank test). Our results indicate that TLR4 is a key receptor for the tumor lysate-mediated in vitro generation of clinically efficient antigen-presenting cells. Further analysis of patients included in different vaccine protocols is necessary for definitively establishing a role for TLR4 polymorphism in clinical responses.