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Purpose: Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden.Experimental Design: IL8 levels were monitored by sandwich ELISAs in cultured tumor cells supernatants, tumor-xenografted mice serum, and in samples from 126 patients with cancer. We correlated IL8 serum levels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis.Results: IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n = 16), renal cell carcinoma (RCC; n = 23), non–small cell lung cancer (NSCLC; n = 21), or hepatocellular carcinoma (HCC; n = 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n = 16; RCC, n = 23; HCC, n = 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n = 16) and immunomodulatory monoclonal antibodies (melanoma, n = 8). IL8 concentrations in urine (n = 18) were mainly elevated in tumors with direct contact with the urinary tract.Conclusions: IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance. Clin Cancer Res; 20(22); 5697–707. ©2014 AACR.

Supplementary Figure 4. Comparison of IL-8 serum concentrations with the serum concentration of IL-6 and c-reactive protein (CRP) in available samples from 14 melanoma and 19 RCC patients from Figure 2A. (**, p

Supplementary Figure 1B. Time course of the serum concentrations of IL-8 (lower panels) and tumor volume (upper panels) in Rag2-/-IL2Rγc-/- mice xenografted with the indicated cell lines. Individual mice are represented and at the time point indicated by the arrow the tumor was surgically removed. Serum IL-8 concentrations are depicted at 2h and 24h after surgery.

Supplementary Figure 2. Serum IL-8 levels before (day -1) and after (day 5-7) disease-reduction surgery of 7 patients: 1 hepatocellular carcinoma (HCC); 2 colorectal carcinoma (CRC); 1 pancreatic cancer (PC); 3 renal cell carcinoma (RCC).

Supplementary Figure 3. Quantitative RT-PCR analyses of the mRNA encoding IL-8 in malignant cells from the biopsy of three melanoma patients. The serum IL-8 levels at the time of the biopsy from each patient is provided under the graph.

Supplementary Table 2. Surgical patient description 2

Supplemental Legend

Supplementary Table 1. Patient description 1

Legends to supplementary figures

Timing of peripheral tissue infiltration by transferred human T-lymphocytes into Rag2-/-IL2Rgcnull mice.

Urelumab and Nivolumab bind to hCD137 and hPD-1 expressed on human T-lymphocytes engrafted in Rag2-/-IL2Rgcnull mice.

Anti-hCD137 (Urelumab) and anti-hPD-1 (Nivolumab) treatment as single agents or in combination show antitumor effects against a xenografted human gastric cancer transferred with autologous lymphocytes drawn from the same patient.

LDH (upper panels) and NSE (lower panels) individual log-transformed concentration-time profiles from training dataset (left panels) and external dataset (right panels). Thick lines are loess smooth of the data and dashed gray lines represent the threshold normal values of each biomarker.

Legends for supplementary Figures S1, S2 and S3

hPD-1 expression on TILs and PD-L1/B7-H1 expression in tumor compartment.

Supplementary methods Appendix

Anti-mCD137 and anti-mPD-1 combined antitumor effects are solely CD8 T-cells dependent in a murine colon cancer model.

xGVHD and human IFN-γ elevation in plasma are dependent on human CD4 T cells.

PD-L1/B7-H1 expression on tumor cells is preferentially observed in tumors of the Combo group mice.

hCD137 and hPD1 expression in human T-lymphocytes infiltrating spleen and liver.

A current pressing need in cancer immunology is the development of preclinical model systems that are immunocompetent for the study of human tumors. Here, we report the development of a humanized murine model that can be used to analyze the pharmacodynamics and antitumor properties of immunostimulatory monoclonal antibodies (mAb) in settings where the receptors targeted by the mAbs are expressed. Human lymphocytes transferred into immunodeficient mice underwent activation and redistribution to murine organs, where they exhibited cell-surface expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations resulted in a lethal CD4+ T cell–mediated disease (xenograft-versus-host disease), which was aggravated when murine subjects were administered clinical-grade anti-hCD137 (urelumab) and anti-hPD-1 (nivolumab). In mice engrafted with human colorectal HT-29 carcinoma cells and allogeneic human peripheral blood mononuclear cells (PBMC), or with a patient-derived gastric carcinoma and PBMCs from the same patient, we found that coadministration of urelumab and nivolumab was sufficient to significantly slow tumor growth. Correlated with this result were increased numbers of activated human T lymphocytes producing IFNγ and decreased numbers of human regulatory T lymphocytes in the tumor xenografts, possibly explaining the efficacy of the therapeutic regimen. Our results offer a proof of concept for the use of humanized mouse models for surrogate efficacy and histology investigations of immune checkpoint drugs and their combinations. Cancer Res; 75(17); 3466–78. ©2015 AACR.

PURPOSEEffective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product.METHODSWe conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1.RESULTSSixty-six patients received a mean of 3.3 prior therapies (anti–programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti–PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2.CONCLUSIONLifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti–PD-1 or PD-L1 therapy subset.

PURPOSE This study aimed to assess the efficacy of the combination of nivolumab (nivo) plus ipilimumab (ipi) as a first-line therapy with respect to the 12-month overall survival (OS) in patients with metastatic uveal melanoma (MUM) who are not eligible for liver resection. METHODS This was a single-arm, phase II trial led by the Spanish Multidisciplinary Melanoma Group (GEM) on nivo plus ipi for systemic treatment-naïve patients of age > 18 years, with histologically confirmed MUM, Eastern Cooperative Oncology Group-PS 0/1, and confirmed progressive metastatic disease (M1). Nivo (1 mg/kg once every 3 weeks) and ipi (3 mg/kg once every 3 weeks) were administered during four inductions, followed by nivo (3 mg/kg once every 2 weeks) until progressive disease, toxicity, or withdrawal. The primary end point was 12-month OS. OS, progression-free survival (PFS), and overall response rate were evaluated every 6 weeks using RECIST (v1.1). Safety was also evaluated. Logistic regression and Cox proportional hazard models comprising relevant clinical factors were used to evaluate the potential association with response to treatment and survival. Cytokines were quantified in serum samples for their putative role in immune modulation/angiogenesis and/or earlier evidence of involvement in immunotherapy. RESULTS A total of 52 patients with a median age of 59 years (range, 26-84 years) were enrolled. Overall, 78.8%, 56%, and 32% of patients had liver M1, extra-liver M1, and elevated lactate dehydrogenase. Stable disease was the most common outcome (51.9%). The primary end point was 12-month OS, which was 51.9% (95% CI, 38.3 to 65.5). The median OS and PFS were 12.7 months and 3.0 months, respectively. PFS was influenced by higher LDH values. CONCLUSIONS Nivo plus ipi in the first-line setting for MUM showed a modest improvement in OS over historical benchmarks of chemotherapy, with a manageable toxicity profile.

Considerables avances se han vivido en los últimos años, tanto en el conocimiento de la biología del melanoma como en el desarrollo de nuevas terapias médicas que han acreditado ser muy activas, capaces no sólo de inducir respuestas clínicas y radiológicas, sino también de controlar la enfermedad a largo plazo. Más aún, los resultados actualizados de los ensayos fase 3 randomizado en pacientes con enfermedad avanzada o de alto riesgo, han hecho a muchos investigadores especular sobre la posibilidad de que se haya conseguido incluso curar a algunos pacientes. No se puede obviar que los resultados actuales se han precedido de numerosos años de fracasos en la investigación médica con quimioterapia y bioquimioterapia, de varias décadas de investigación y refinamiento en las técnicas quirúrgicas que demostraron ser curativas para la enfermedad localizada y, literalmente, de centurias de perplejidad, ante una enfermedad desconcertante por su comportamiento y agresividad clínica. Presentamos una breve revisión histórica del conocimiento del melanoma, desde una perspectiva médico quirúrgica, con el objetivo que despertar en el lector el interés por avanzar en el conocimiento del pasado y sobre todo del futuro de una patología tumoral, que hasta hace muy poco no tenía opciones terapéuticas, pero que ha abierto las puertas para la innovación terapéutica en oncología.

Advanced melanoma remains a disease with poor prognosis. Several serologic markers have been investigated to help monitoring and prognostication, but to date only lactate dehydrogenase (LDH) has been validated as a standard prognostic factor biomarker for this disease by the American Joint Committee on Cancer. In this work, we built a semi-mechanistic model to explore the relationship between the time course of several circulating biomarkers and overall or progression free survival in advanced melanoma patients treated with adjuvant high-dose interferon-$${\boldsymbol{\alpha }}{\bf{2}}{\bf{b}}$$α2b. Additionally, due to the adverse interferon tolerability, a semi-mechanistic model describing the side effects of the treatment in the absolute neutrophil counts is proposed in order to simultaneously analyze the benefits and toxic effects of this treatment. The results of our analysis suggest that the relative change from baseline of LDH was the most significant predictor of the overall survival of the patients. Unfortunately, there was no significant difference in the proportion of patients with elevated serum biomarkers between the patients who recurred and those who remained free of disease. Still, we believe that the modelling framework presented in this work of circulating biomarkers and adverse effects could constitute an additional strategy for disease monitoring in advance melanoma patients.

Given the approval of dabrafenib in patients with BRAF-mutant metastatic melanoma, a better understanding of treatment patterns and clinical outcomes with dabrafenib in a clinical setting is warranted. We performed a retrospective chart review of patients who received dabrafenib in a compassionate use setting through the Named Patient Program (DESCRIBE I study) during December 2010-August 2013 in Europe, New Zealand and Australia. Of the 331 Named Patient Program patients included, the majority (95.8%) had stage IV disease at dabrafenib initiation and 39.9% had brain metastases (BMs). Dabrafenib was used first line in 67.7% of patients, and median treatment duration was 6.4 months. Dabrafenib was well tolerated. Common grade 2/3 adverse events were hyperkeratosis (7.6%), pyrexia/fever (6.6%), fatigue (5.1%), hand-foot syndrome (5.4%) and nausea (3.6%). Overall response rate was 45.9%, median progression-free survival was 5.2 months (95% confidence interval, 4.2-6.1 months), and median overall survival was 12.4 months (95% confidence interval, 10.2-15.0 months). In patients with known brain metastases (n = 132) versus patients without (n = 199), overall response rate was 42.4% versus 48.2%, progression-free survival was 3.9 months (95% confidence interval, 3.8-5.5 months) versus 5.9 months (95% confidence interval, 4.8-7.8 months) and overall survival was 9.5 months (95% confidence interval, 6.7-12.4 months) versus 15 months (95% confidence interval, 11.1-20.5 months), respectively. Safety and effectiveness of dabrafenib in patients with unresectable advanced BRAF V600-mutant melanoma treated in an Named Patient Program was similar to the clinical trial experience, demonstrating effectiveness of dabrafenib in a nontrial setting.

Colony-stimulating factor 1 receptor (CSF1R) inhibitors represent a new class of immune-modulatory drugs, mostly investigated in clinical trials in different malignant neoplasms. Four patients, diagnosed with recurrent or advanced malignant neoplasm and treated with a combination of anti-programmed death ligand 1 and anti-CSF1R monoclonal antibodies, developed an asymptomatic cutaneous eruption characterized by an ill-defined pseudoedematous to waxy diffuse infiltration with a reticular cobblestone-like pattern. Histopathological examination revealed diffuse mucin deposition involving the superficial and mid-dermis with fragmented and scattered elastic fibers. The exact pathogenic mechanisms implicated in the development of mucin deposits in patients treated with CSF1R inhibitors remain to be elucidated. A reduced degradation and clearance of components of the extracellular matrix by macrophages secondary to CSF1 pathway inhibition may be hypothesized. Shredding and fragmentation of elastic fibers may be a result of the increased accumulation of mucopolysaccharides. This observation illustrates the new spectrum of skin-related toxicities secondary to new targeting therapies. This may contribute to a better understanding of the underlying pathogenic mechanisms in skin diseases characterized by a persistent dermal glycosaminoglycan deposition.

Background Previous findings from the MASTERKEY-265 phase 1b study showed that the combination of T-VEC and pembrolizumab was well tolerated and produced a high complete response (CR) rate of 43% in patients with advanced melanoma.1 The 3-year progression-free survival (PFS) and overall survival (OS) rates at that time were 53.6% and 71%, respectively. Here, we report the results of the long-term follow-up efficacy analyses. Methods The MASTERKEY-265 phase 1b trial (NCT02263508) was an open-label, single-arm study that enrolled patients who had unresectable, stage IIIB-IVM1c melanoma with injectable, measurable lesions and no prior systemic treatment. T-VEC was administered intralesionally at the approved dosing starting day 1 of week 1. Pembrolizumab (200 mg) was administered intravenously Q2W beginning on day 1 of week 6. The maximum treatment period was 2 years. The primary endpoint was dose-limiting toxicities; key secondary endpoints included objective response rate and PFS per modified irRC, OS, and safety. Results As of the data cutoff (Mar 2, 2020), all 21 patients enrolled were off treatment; 6 died and 15 are in long-term follow-up. The median follow-up time was 58.6 months (range: 1.4–61.6). The CR rate remained 43% (9/21 patients). Twelve of the 13 responders (92.3%) are still in response, including all 9 patients with a CR. Median duration of response was not reached (range: 2.8+–54.3+ months). Median PFS and OS were not reached at the data cutoff. KM estimates of 4-year PFS and OS rates were 55.9% and 71.4%, respectively, which have held stable since the 3-year analysis. Patients who achieved a CR or partial response had better OS (p=0.0056) compared to those who did not respond. Median OS for non-responders was 24.4 months and was not reached for responders. No additional safety signals were detected. Conclusions At almost 5 years of follow-up, median PFS and OS were not reached for patients treated with the combination of T-VEC and pembrolizumab in this phase 1b study of unresectable metastatic melanoma. 92% of responders remained in response with improved OS observed in responders compared with non-responders. The corresponding randomized phase 3 trial has completed enrollment and is currently ongoing. Trial Registration NCT02263508 Ethics Approval The study was approved by the Ethics Board of each institution involved in this study and can be produced upon request. Reference Long G, Dummer R, Andtbacka R, et al. Follow-up analysis of MASTERKEY-265 Phase 1b (ph1b) trial of talimogene laherparepvec (T-VEC) in combination (combo) with pembrolizumab (pembro) in patients (pts) with unresectable stage IIIB–IVM1c melanoma (MEL). Pigment Cell Melanoma Res 2019;32:133–134.

Intratumoral therapies, especially Toll-like receptor agonists, can trigger both the innate and adaptive immune systems. BO-112 is a nanoplexed form of polyinosinic:polycytidylic acid (poly I:C) that induces local and systemic immunotherapeutic effects in mouse models. In a multicenter phase 1 clinical trial, repeated intratumoral administrations of BO-112 induced an increase in tumor cell necrosis and apoptosis, as well as augmented immune reactivity according to gene expression profiling. The first three cohorts receiving BO-112 as a monotherapy resulted in a recommended dose of 1 mg that could be safely repeated. Two grade 3 to 4 adverse reactions in the form of reversible thrombocytopenia were reported. In a fourth cohort of 28 patients with tumors that had primary resistance to anti-programmed cell death protein-1 (PD-1), the combination of intratumoral BO-112 with nivolumab or pembrolizumab was also well tolerated, and 3 patients (2 with melanoma and 1 with renal cell carcinoma) achieved partial responses, with 10 more patients having stable disease at 8 to 12 weeks. Thus, local BO-112 combined with a systemic anti-PD-1 agent might be a strategy to revert anti-PD-1 resistance.

Background Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days+8 and+10 of each cycle, patients received intratumoral image-guided 0.25mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing. Results Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

To assess the emetogenic potential of different chemotherapy (CT) regimens in daily clinical practice in an outpatient setting. To optimize antiemetic prophylaxis if necessary METHODS: Prospective and retrospective review of the emetogenic potential of CT regimens used in adult patients in an outpatient setting RESULTS: We assess the chemotherapy-induced nausea and vomiting (CINV) of 50 different CT regimens used on 157 different patients in an outpatient setting. We found that the CT usually classified as highly emetogenic, including cisplatin and anthracycline-cyclophosphamide combination, had the higher incidence of CINV (37.5 and 54.4% respectively). The antineoplastic drugs usually considered to be moderately emetogenic had, as expected, lower rates of emesis with the exception of irinotecan, which presented a pattern of nausea and/or vomiting (NV) similar to the highly emetogenic CT with a global incidence of 48.5%. The appearance of emetic symptoms had impact on quality of life in 70% of the patients, with nausea being the main emetic symptom.Antiemetic prophylaxis for highly emetogenic CT could be improve. Irinotecan CT regimens have a high emetogenic potential more than moderate and require more intensive antiemetic prophylaxis too.

Background Beneficial treatment options are limited for advanced melanoma patients who progress after or do not respond to immune checkpoint inhibitors (ICI) and targeted therapies. Lifileucel is an adoptive cell therapy using tumor-infiltrating lymphocytes (TIL), that has shown efficacy in patients with advanced melanoma who have progressed on/after anti-PD-1therapy (Sarnaik et al., ASCO 2020). We present the 28-month (mos) follow-up data here. Methods C-144-01 (NCT02360579) is a global Phase 2 open-label, multicenter study of efficacy and safety of lifileucel in patients with unresectable metastatic melanoma who have progressed on anti-PD-1 therapy and BRAF/MEK inhibitors, if BRAF V600 mutant. We report on Cohort 2 (N = 66) patients who have received lifileucel. Tumors were resected at local institutions, processed in central GMP facilities for TIL production, manufactured, cryopreserved and shipped back to sites in a 22-day process. Therapy consisted of one week of nonmyeloablative lymphodepletion using cyclophosphamide (60 mg/kg on Day -7, -6) and fludarabine (25 mg/m2 on Day -5 through -1), a single infusion of lifileucel, and up to six doses of IL-2 doses (600,000 IU/kg/dose). Objective response rate (ORR) was based on RECIST v1.1 as assessed by investigators. Data cutoff was December 14, 2020. Results Baseline characteristics: 3.3 mean prior therapies (100% anti-PD-1; 80% anti-CTLA-4; 23% BRAF/MEK inhibitor), high baseline tumor burden (106 mm mean target lesion sum of diameters), 42% liver/brain lesions, 40.9% had LDH > ULN. Median time from last therapy to tumor harvest was 2.2 mos and 58% of the tumors resected were extra-nodal or non-skin/subcutaneous. ORR by Investigator was 36.4% (3 CR, 21 PR). One patient converted from a PR to CR at 24 mo after lifileucel therapy. Median time to first response was 1.4 mos (range: 1.3-5.6 mos). Median duration of response (mDOR) was still not reached at median follow-up of 28 mos (DOR range: 2.2-35.2 mos). No new safety risks have been identified for lifileucel during the long-term follow-up. Exploratory analyses of product-specific characteristics, including levels of phenotypic markers of T-cell lineage, memory subset, youth, activation/exhaustion, or trafficking did not demonstrate association with response. Conclusions Lifileucel treatment results in a 36.4% ORR and mDOR was not reached at 28 mo of median study follow up in heavily pretreated advanced melanoma patients with high baseline disease burden who progressed on multiple prior therapies, including anti-PD1 and BRAF/MEK inhibitors, if BRAF V600 mutant. Citation Format: Jason Alan Chesney, James M. Larkin, John M. Kirkwood, Jeffrey S. Weber, Nikhil I. Khushalani, Karl Lewis, Theresa M. Medina, Harriet M. Kluger, Sajeve S. Thomas, Evidio Domingo-Musibay, Judit Oláh, Eric D. Whitman, Salvador Martin-Algarra, Philippa G. Corrie, Jose Lutzky, Omid Hamid, Wen Shi, Xiao Wu, Madan Jagasia, Friedrich Graf Finckenstein, Maria Fardis, Amod A. Sarnaik. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT008.

To describe patient characteristics by disease stage, resectability status and current treatment management after first diagnosis of IIIB to IV1c advanced (AM)/metastatic melanoma (MM). Multicentre, retrospective study based on data from medical charts of patients > 18 years at MM first diagnosis, visited by oncologists at 4 reference centres in Spain: Hospital Universitario Gregorio Maranon (Madrid), Hospital General de Valencia (Valencia), Clinica Universidad de Navarra (Pamplona), and Hospital Clinic (Barcelona). Metastatic non-visceral melanoma (IIIB, IIIC, IV M1a) was reported in 139 (48.6%) patients and 40.9% (n = 117) were diagnosed with IV-M1c disease. 160 (55.9%) metastases were resectable. Available therapies under clinical practice were used in 210 patients; 74 were treated under clinical trials (CT). Intention-to-cure surgery (47.6%) was the most common treatment at time of MM diagnosis. Systemic (45.1% overall) therapy included chemo-, targeted- and immunotherapy (19.6%, 14.3%, 8.4%, respectively). At time of data collection, 26 patients were still alive and 120 had progressed to IV-M1c. Median overall survival (OS) was significantly larger in IIIB patients, 28.9 m (25.2–32.7); the shortest for IV-M1c patients, 11.0 m (8.7–13.3). Novel treatments are undoubtedly a major step forward in AM/MM, however these are often only available in the CT setting because early stages of development or country-specific regulations. Further prospective studies and multifactorial analysis should be performed to clearly identify possible clinical associations for outcome in Spanish patients with AM/MM.

Merkel cell carcinoma (MCC) is a rare, aggressive, primary cutaneous neuroendocrine tumor that typically presents as an indurated nodule on sun‐exposed areas of the head and neck in the white population. Major risk factors include immunosuppression, UV light exposure, and advanced age. Up to 80% of MCC are associated with Merkel cell polyomavirus. About 50% of patients present with localized disease, and surgical resection with or without adjuvant radiotherapy is generally indicated in this context. However, recurrence rates are high and overall prognosis rather poor, with mortality rates of 33%–46%. MCC is a chemosensitive disease, but responses in the advanced setting are seldom durable and not clearly associated with improved survival. Several recent trials with checkpoint inhibitors (pembrolizumab, avelumab, nivolumab) have shown very promising results with a favorable safety profile, in both chemonaïve and pretreated patients. In 2017, avelumab was approved by several regulatory agencies for the treatment of metastatic MCC, the first drug to be approved for this orphan disease. More recently, pembrolizumab has also been approved by the U.S. Food and Drug Administration in this setting. Immunotherapy has therefore become the new standard of care in advanced MCC. This article reviews current evidence and recommendations for the diagnosis and treatment of MCC and discusses recent therapeutic advances and their implications for care in patients with advanced disease. This consensus statement is the result of a collaboration between the Spanish Cooperative Group for Neuroendocrine Tumors, the Spanish Group of Treatment on Head and Neck Tumors, and the Spanish Melanoma Group., Merck KGaA and Pfizer financially supported medical writer assistance and should also be acknowledged.

585 Background: Breast cancer (BC) in early stages exhibit a naïve and competent immune system that translates into a more prominent TIL infiltration and higher PD-L1 expression as compared to the advanced BC scenario were immunoescape and exhaustion are more prevalent. Expression of PD-L1 has been related to a better pCR when immune checkpoint inhibitors (IPI) have been added to neaodjuvant chemotherapy (NACT) in triple negative BC (TNBC). Our prior results shown dendritic cells vaccines (DCV) increased pCR in both TNBC and luminal B subtypes, with an absolute gain of 20% (p = 0.03) and a safe tolerance. Methods: Eighty-three HER2 negative BC patients with untreated stage II-III were included: 39 patients from the NCT01431196 trial that combine NACT with autologous DCV and 44 patients from a historic control group treated with the same NACT alone. NACT consists of dose dense Epirubicin plus Cyclophosphamide for 4 cycles sequenced to Docetaxel for 4 cycles. PD-L1 expression was measured in the membrane of tumoral cells with monoclonal rabbit anti PD-L1 28.8 pharmaDX (DAKO, Agilent Technologies) in FFPE samples at diagnosis. Primary endpoint was pathologic complete response (pCR) stratified by PD-L1 expression (positive or negative), while secondary endpoints were event-free survival (EFS) and overall survival (OS), also stratified by PD-L1 expression. Results: Both cohorts were well balanced in most of the features. Thirty-three percent of the tumors in the experimental group were PD-L1 positive, whereas 50% of them in the CG expressed PD-L1 (p = 0.06). Pathological CR was observed in 50% of the PD-L1 positive population, in contrast to a 2.8% in the PD-L1 negative in the NACT cohort (p < 0.01) as compared to the patients assigned to the DCV group (33.4% in PD-L1 positive vs 23.1% in PD-L1 negative population; p = 0.16). Among PD-L1 positive population, more pCR were seen in the CG than in the DCV group (50% vs 33.4%; p = 0.06). Within the PD-L1 negative population, more pCR were observed in the DCV group than in the CG (23.1% vs 2.8%; p < 0.05). With a median follow-up of 7 years, no significant differences were observed between the different subgroups neither in EFS (HR = 1.7; 0.42-6.8; p = 0.19) nor in OS (HR = 2.5; 0.56-11, p = 0.43). At 7 years, 20% and 14.4% of the patients relapsed according to the PD-L1 positive versus negative status respectively, and 10.78% versus 13.33% were dead. Conclusions: The benefit of DCV seems to be outstanding in the PD-L1 negative tumors that have a basal immune appropriate milieu. PD-L1 expression implies a more suppressed niche in which DCV are not able to stimulate antigen presentation and cell cytotoxic activity. PD-L1 positive population reach higher responses with both NACT±DCV than PD-L1 negative group, although the benefit seem to be higher in the NACT alone cohort. Further studies combining DVC+IPI together with NACT are needed. Clinical trial information: NCT01431196.

9505 Background: Immune checkpoint inhibitors (ICI) have become standard of care for treatment of metastatic melanoma. Most patients with advanced melanoma progress on ICI and treatment options are limited for these patients. Progression may be through primary resistance (lack of response) or secondary resistance (initial response then progression). Lifileucel is an adoptive cell therapy using TIL, that has shown efficacy in patients with advanced melanoma who progress on/after an anti-PD-1 (Sarnaik, 2020). We present the 28-month (mos) follow-up data and highlight the impact of prior anti-PD-1 response and duration of exposure on outcome with lifileucel. Methods: C-144-01 is a Phase 2, open-label, multicenter study of efficacy and safety of lifileucel in patients with advanced melanoma who have progressed on anti-PD-1 therapy and BRAFi ± MEKi, if BRAF V600+. We report long-term follow up on Cohort 2 (N = 66). Tumors were resected at local sites, processed in central GMP facilities for TIL production in a 22-day manufacturing process. Therapy consisted of nonmyeloablative lymphodepletion using 2 days of cyclophosphamide and 5 days of fludarabine, a single infusion of lifileucel, and up to six doses of IL-2. Objective response rate (ORR) was assessed by RECIST 1.1. Data cutoff was Dec. 14, 2020. Results: Baseline characteristics: 3.3 mean prior therapies (100% anti-PD-1; 80% anti-CTLA-4; 23% BRAFi/MEKi), high baseline tumor burden (106 mm mean target lesion SOD), 42% liver/brain lesions, 40.9% LDH > ULN. ORR by investigator was 36.4% (3 CR, one new CR developed at 24 mos; 21 PR). Median duration of response (mDOR) was not reached at median follow-up of 28 mos (DOR range: 2.2- 35.2 mos). In responders, the median cumulative duration and median prior lines of anti-PD-1 therapy was 4.4 mos (range: 1.4-22.5 mos), and 1.5 (range: 1-4). Data in Table demonstrates a meaningful increase in DOR to TIL with primary anti-PD-1 resistance and lower duration of time on prior anti-PD-1 therapy. No new safety risks have been identified for lifileucel during long-term follow-up. Conclusions: One-time lifileucel treatment results in a 36.4% ORR, and mDOR was not reached at 28 mos of median study follow up. One PR converted to a new CR at 24 months as responses continue to deepen. DOR is positively associated with primary resistance to prior anti-PD-1 therapy and with shorter cumulative prior duration of anti-PD-1 therapy. Lifileucel may offer a better clinical outcome when used earlier upon detection of progression on prior anti-PD-1 rather than retreatment with anti-PD-1 based regimens. Clinical trial information: NCT02360579. [Table: see text]

e22022 Background: In the past decade, melanoma treatment has improved due to the advances in targeted therapy and immunotherapy. There are few data, however, about the treatment elections and the outcomes of the patients in the real world setting, specifically in a prospective manner. Methods: GEM1801 is a prospective cohort study that analyses the clinical and pathological disease presentation patterns, the different lines of treatment choices and the health outcomes derived from these treatments in 400 patients (pts) diagnosed with resected stage III (N = 47) and irresectable III/IV melanoma (N = 353). Here we focus on the pts diagnosed with advanced melanoma and the first line (1L) treatments. Results: Pts diagnosed after Jan 2018 were included from 35 hospitals in 15 different Spanish regions (recruitment Aug 2018 to Aug 2019). A survival cutoff was made by January 2020. 55.2% pts were male; median age was 65.1 (23.3- 95.2). 66% were cutaneous, 5.4% acral, 2.8% uveal, 17.3% non-disclosed and 4.2% were classified as “other” subtypes. According to AJCC 8th edition, 9.3% were unresectable IIIB/C/D and 90.7% IV (27.5% A, 16.6% B, 37.5% C and 18.4% D). ECOG was 0-1 in 85%; LDH levels were available in 282 pts (79.9%), being normal in 61.7%, > 1x to 2x ULN in 29.8% and > 2x ULN in 8.5%. BRAF was evaluated in 344 pts (97.5%), being 52.9% mutated. Median survival follow up was 9.7 months (0.2-24) with 73.9% patients alive at time of analysis (over 345 pts with data available). Median overall survival was not reached, with a median follow up of 9.7 months (0.2-24.0). 72.2% of pts were alive at the time of analysis. Table summarize the 1L options according to BRAF status in the 326 pts with data available (17 received no systemic treatment and in 10 was unknown). Conclusions: this study reflects real world data in a representative cohort of pts with melanoma in Spain. Survival results, pending on more follow up, could be considered consistent with the results of modern clinical trials. TT is the most frequent 1L choice for patients with BRAF+ melanoma (almost 2/3 of cases). In terms of IT, monotherapy based in anti PD-1 is the most frequent 1L choice, with a rank between 75-90% of cases. [Table: see text]

10006 Background: Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) leverages and enhances the body’s natural defense against cancer and has shown durable responses in heavily pretreated melanoma patients. Methods: C-144-01 is a global Phase 2 open-label, multicenter study of efficacy & safety of lifileucel in patients with unresectable metastatic melanoma who have progressed on checkpoint inhibitors and BRAF/MEK inhibitors, if BRAFv600 mutant. We report on Cohort 2 (N = 66) patients who have received TIL. Tumors were resected at local institutions, processed in central GMP facilities for TIL production, manufactured, cryopreserved & shipped back to sites in a 22-day process. Therapy consisted of one week of lymphodepletion, a single lifileucel infusion, and up to 6 IL-2 doses. ORR was based on RECIST v1.1 by investigator assessment. Data cutoff was Feb 2, 2020. Results: Baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), high baseline tumor burden (106 mm mean target lesion sum of diameters), 44% liver/brain lesions, 40.9% LDH > ULN. ORR by investigator was 36.4% (2 CR, 22 PR) and DCR was 80.3%. Mean time to response was 1.9 months (range: 1.3-5.6). After a median study follow-up of 17.0 months, median DOR (mDOR) was still not reached. Six responders have progressed, 2 have died and 2 started other anti-cancer therapy without progression. The adverse event profile was consistent with the underlying advanced disease and the lymphodepletion and IL-2 regimens. Additional follow-up data will be available for presentation. Conclusions: Lifileucel treatment results in a 36.4% ORR and mDOR was not reached at 17.0 months of median study follow up in a heavily pretreated metastatic melanoma patients with high baseline disease burden who progressed on multiple prior therapies, including anti-PD1 and BRAF/MEK inhibitors, if BRAFv600 mutant. Clinical trial information: NCT02360579.

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%–84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r ¼ 0.91) with the ORR following antiPD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low ¼ 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

UNLABELLED Despite much investment and progress, oncology is still an area with significant unmet medical needs, with new therapies and more effective use of current therapies needed. The emergent field of pharmacometrics combines principles from pharmacology (pharmacokinetics [PK] and pharmacodynamics [PD]), statistics, and computational modeling to support drug development and optimize the use of already marketed drugs. Although it has gained a role within drug development, its use in clinical practice remains scarce. The aim of the present study was to review the principal pharmacometric concepts and provide some examples of its use in oncology. Integrated population PK/PD/disease progression models as part of the pharmacometrics platform provide a powerful tool to predict outcomes so that the right dose can be given to the right patient to maximize drug efficacy and reduce drug toxicity. Population models often can be developed with routinely collected medical record data; therefore, we encourage the application of such models in the clinical setting by generating close collaborations between physicians and pharmacometricians. IMPLICATIONS FOR PRACTICE The present review details how the emerging field of pharmacometrics can integrate medical record data with predictive pharmacological and statistical models of drug response to optimize and individualize therapies. In order to make this routine practice in the clinic, greater awareness of the potential benefits of the field is required among clinicians, together with closer collaboration between pharmacometricians and clinicians to ensure the requisite data are collected in a suitable format for pharmacometrics analysis.

Advanced melanoma is a relatively uncommon condition whose therapeutic management has undergone major changes over the past four years. The present article aims to establish recommendations for the management of these patients based on the best available evidence reached by consensus of a group of professionals familiar in the treatment of these patients. These professionals, belonging to Spanish Multidisciplinary Melanoma Group, reviewed the diagnostic process and the incorporation of new techniques of molecular diagnosis of advanced disease; treatment and monitoring of stage III both as adjuvant locoregional treatments have been addressed, as well as new therapies for stage IV. We have reviewed the palliative treatment alternatives for disseminated disease, such as surgery, radiotherapy or non-cytotoxic systemic treatments. Finally, we have also reviewed the most relevant toxicities of new drugs and their management in clinical practice.

A current pressing need in cancer immunology is the development of preclinical model systems that are immunocompetent for the study of human tumors. Here, we report the development of a humanized murine model that can be used to analyze the pharmacodynamics and antitumor properties of immunostimulatory monoclonal antibodies (mAb) in settings where the receptors targeted by the mAbs are expressed. Human lymphocytes transferred into immunodeficient mice underwent activation and redistribution to murine organs, where they exhibited cell-surface expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations resulted in a lethal CD4+ T cell–mediated disease (xenograft-versus-host disease), which was aggravated when murine subjects were administered clinical-grade anti-hCD137 (urelumab) and anti-hPD-1 (nivolumab). In mice engrafted with human colorectal HT-29 carcinoma cells and allogeneic human peripheral blood mononuclear cells (PBMC), or with a patient-derived gastric carcinoma and PBMCs from the same patient, we found that coadministration of urelumab and nivolumab was sufficient to significantly slow tumor growth. Correlated with this result were increased numbers of activated human T lymphocytes producing IFNγ and decreased numbers of human regulatory T lymphocytes in the tumor xenografts, possibly explaining the efficacy of the therapeutic regimen. Our results offer a proof of concept for the use of humanized mouse models for surrogate efficacy and histology investigations of immune checkpoint drugs and their combinations. Cancer Res; 75(17); 3466–78. ©2015 AACR.

Predictive biomarkers can play a key role in individualized disease monitoring. Unfortunately, the use of biomarkers in clinical settings has thus far been limited. We have previously shown that mechanism-based pharmacokinetic/pharmacodynamic modeling enables integration of nonvalidated biomarker data to provide predictive model-based biomarkers for response classification. The biomarker model we developed incorporates an underlying latent variable (disease) representing (unobserved) tumor size dynamics, which is assumed to drive biomarker production and to be influenced by exposure to treatment. Here, we show that by integrating CT scan data, the population model can be expanded to include patient outcome. Moreover, we show that in conjunction with routine medical monitoring data, the population model can support accurate individual predictions of outcome. Our combined model predicts that a change in disease of 29.2% (relative standard error 20%) between two consecutive CT scans (i.e., 6–8 weeks) gives a probability of disease progression of 50%. We apply this framework to an external dataset containing biomarker data from 22 small cell lung cancer patients (four patients progressing during follow-up). Using only data up until the end of treatment (a total of 137 lactate dehydrogenase and 77 neuron-specific enolase observations), the statistical framework prospectively identified 75% of the individuals as having a predictable outcome in follow-up visits. This included two of the four patients who eventually progressed. In all identified individuals, the model-predicted outcomes matched the observed outcomes. This framework allows at risk patients to be identified early and therapeutic intervention/monitoring to be adjusted individually, which may improve overall patient survival. Cancer Res; 75(12); 2416–25. ©2015 AACR.

Immunotherapy has become a key element in the treatment of several tumors, such as lung carcinoma and melanoma. Immunotherapy, unlike classical chemotherapy and targeted drugs, may yield long-term survival, even in patients who stop treatment due to toxicity. This fact has generated considerable excitement and a real shift in the paradigm of cancer treatment. However, only a small subset of patients benefit from immunotherapy. Survival curves show that most patients have progression of the disease in the first months after starting immunotherapy, followed by a slower decrease over the first 3 years, until curves reach a plateau. This early progression suggests the presence of mechanisms for primary resistance. In addition, some patients have tumor relapse after years of response, suggesting that there is also acquired resistance in a small subset of patients. Resistance mechanisms are now being elucidated. PD-L1 expression in tumor and immune cells correlates with higher chances of response, but melanoma patients with PD-L1 negative tumors can also respond. Several studies have demonstrated an increased probability of clinical benefit when tumors are infiltrated by CD8 T cells, have a high mutation burden or have an interferon gamma signature. But none of these factors has been implemented in the clinical practice, since more studies confirming their value are needed, as well as the development of standardized techniques.

Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients.Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves.Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P 0.001), and significantly increased upon progression (P = 0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P = 0.013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P 0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P = 0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P 0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P = 0.001) and NSCLC (P = 0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression.Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.

In the last years there has been great progress in the treatment of advanced melanoma patients. This explosion of melanoma research has not declined, but rather has continued exponentially growing. In this review, the Spanish Group of Melanoma (GEM) compiles the highlights of melanoma treatment communicated or published between ASCO 2016 and AACR 2017. In this period, definitive data have been published about the possibility of achieving a long term survival with the use of single anti-PD-1 antibodies, as well as data on the description of clinical subgroups of patients that can also obtain a long term survival with the use of targeted drugs combining the oral BRAF and MEK inhibitors. The first immunotherapy combination including nivolumab, an anti-PD-1 antibody, plus ipilimumab, an anti-CTLA-4 antibody, has been approved, based on its demonstrated benefit in terms of overall survival versus ipilimumab alone.

Purpose: Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden. Experimental Design: IL8 levelsweremonitored by sandwich ELISAs incultured tumor cells supernatants, tumor-xenograftedmice serum, and in samples from126 patients with cancer. Wecorrelated IL8 serumlevels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis. Results: IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n = 16), renal cell carcinoma (RCC; n = 23), non-small cell lung cancer (NSCLC; n = 21), or hepatocellular carcinoma (HCC; n = 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n = 16; RCC, n = 23; HCC, n = 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n = 16) and immunomodulatory monoclonal antibodies (melanoma, n = 8). IL8 concentrations in urine (n = 18) were mainly elevated in tumors with direct contact with the urinary tract. Conclusions: IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance. Fil: Sanmamed, Miguel F.. Universidad de Navarra; España Fil: Carranza Rua, Omar. Universidad de Navarra; España Fil: Alfaro, Carlos. Universidad de Navarra; España Fil: Oñate, Carmen. Universidad de Navarra; España Fil: Martín Algarra, Salvador. Universidad de Navarra; España Fil: Perez, Guiomar. Universidad de Navarra; España Fil: Landazuri, Sara F.. Universidad de Navarra; España Fil: Gonzalez, Alvaro. Universidad de Navarra; España Fil: Gross, Stefanie. University Hospital Erlangen; Alemania Fil: Rodriguez, Inmaculada. Universidad de Navarra; España Fil: Muñoz Calleja, Cecilia. Universidad Autonoma de Madrid. Hospital Universitario de la Princesa; España Fil: Rodríguez Ruiz, María. Universidad de Navarra; España Fil: Sangro, Bruno. Universidad de Navarra; España Fil: López Picazo, José M.. Universidad de Navarra; España Fil: Rizzo, Manglio Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pascual, Juan I.. Universidad de Navarra; España Fil: Andueza, Maria Pilar. Universidad de Navarra; España Fil: Perez Gracia, Jose Luis. Universidad de Navarra; España Fil: Melero, Ignacio. Universidad de Navarra; España

Background: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18–0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. Methods: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. Results: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. Conclusions: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. Clinical Trials.gov identifier NCT01227889.