bluuebunny/crossref_metadata_2025_split huggingface dataset:
United States Intergroup E1609: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon-α2b for resected high-risk melanoma.
Authors: Tarhini Ahmad A. , Lee Sandra J. , Hodi F. Stephen , Rao Uma N. M. , Cohen Gary Irvin , Hamid Omid , Hutchins Laura Fulper , Sosman Jeffrey Alan , Kluger Harriet M. , Sondak Vernon K. , Koon Henry B. , Lawrence Donald P. , Kendra Kari Lynn , Minor David R. , Lee Carrie B. , Albertini Mark R. , Flaherty Lawrence E. , Petrella Teresa M. , Kirkwood John M. 
Published: May 2019

9504 Background: Phase III adjuvant trials reported significant benefits in relapse-free survival (RFS) for 6 FDA-approved regimens and overall survival (OS) for HDI and ipi10 versus observation or placebo. E1609 evaluated the relative safety and efficacy of ipi at 3 and 10 mg/kg compared to HDI, which was the adjuvant standard until recently. Methods: E1609 had 2 co-primary endpoints: OS and RFS; considered positive if either co-primary endpoint comparison was positive. Activated on 5/25/2011 and completed accrual 8/15/2014. A 2-step hierarchical approach evaluated ipi3 vs HDI followed by ipi10 vs HDI. Patients were stratified by AJCC7 stage (IIIB, IIIC, M1a, M1b). Based on protocol criteria, the primary evaluation was conducted using a data cutoff of 2/15/2019. Results: Final adult patient accrual was 1670; 523 randomized to ipi3, 636 to HDI and 511 to ipi10. Treatment related adverse events (AEs) Grade 3 or higher were experienced by 37% pts with ipi3, 79% with HDI and 58% with ipi10, and those of any grade leading to treatment discontinuation were 35% with ipi3, 20% HDI and 54% ipi10. AEs were mostly immune related and consistent with the known toxicity profiles of these agents. Gr5 AEs considered at least possibly related were 3 with ipi3, 2 with HDI and 8 with ipi10. First step comparison of OS and RFS of ipi3 vs. HDI utilized an ITT analysis of concurrently randomized cases (N = 1051) and showed significant OS difference in favor of ipi3; HR 0.78, 95.6% RCI (.61, 1.00); p = 0.044. The prespecified efficacy boundary was crossed. For RFS, HR 0.85, 99.4% CI (.66, 1.09), p = 0.065. In the 2nd step comparison of ipi10 vs. HDI (N = 989), there were trends towards improvement in OS [HR 0.88, 95.6% CI (.69, 1.12)] and RFS [HR 0.84, 99.4% CI (.65, 1.09)] in favor of ipi10 that were not statistically significant. Conclusions: Adjuvant therapy with ipi3 benefits survival of resected high-risk melanoma pts; for the first time in the history of melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in the primary endpoint of OS against an active control regimen previously shown to have OS and RFS benefits, supporting early systemic adjuvant therapy for high-risk melanoma. Clinical trial information: NCT01274338.
Phase 1 study of MK-4166, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as monotherapy or with pembrolizumab (pembro) in patients (pts) with advanced solid tumors.
Authors: Papadopoulos Kyriakos P. , Autio Karen A. , Golan Talia , Dobrenkov Konstantin , Chartash Elliot , Li Xiaoyun Nicole , Wnek Richard , Long Georgina V. 
Published: May 2019

9509 Background: Ligation of GITR on immune cells decreases Treg-mediated suppression and enhances T cell proliferation. MK-4166 is a humanized IgG1 agonist monoclonal antibody targeting GITR. Data from the first-in-human phase 1 study (NCT02132754) of MK-4166 as monotherapy (mono) or in combination with pembro (combo) are presented. Methods: MK-4166 was tested alone (0.0015 mg IV-900 mg Q3W ×4 doses) or with pembro (fixed dose 200 mg IV Q3W up to 35 doses) in the absence of toxicity or progression. Study included a dose escalation/confirmation cohort (metastatic solid tumors) and an expansion cohort (treatment-naive and pretreated melanoma). A T cellinflamed gene expression profile (GEP) was assessed using RNA from baseline tumor samples. End points  primary: safety/tolerability, maximum tolerated dose (MTD) of MK-4166; secondary: pharmacokinetics (PK), pharmacodynamics (PD); exploratory: objective response rate (ORR) per irRECIST1.1. Results: Of 113 pts, 48 received mono and 65 combo; 20 were in the melanoma expansion. Common AEs ( > 20%) were fatigue, infusion-related reaction, nausea, abdominal pain, and pruritus; 43 pts had grade ≥3 AEs (38.1%); 6 (5.3%) were treatment-related. One dose-limiting toxicity (bladder perforation in a urothelial pt with a neobladder) possibly related to study drug was observed with mono. MTD was not reached. No treatment-related deaths were observed. MK-4166 PK/PD showed target-mediated drug disposition concomitant with decreased GITR availability on T cells in blood with increasing doses. Four objective responses (4/45; ORR, 9%) were seen with combo in dose escalation. For ICI-naive melanoma pts (n = 13) in expansion, ORR was 69% (95% CI, 38-91), including 4 CRs and 5 PRs. No response was observed in 7 pts previously treated with ICI. High ORRs were observed in noninflamed and inflamed ICI-naive melanoma pts. Conclusions: MK-4166 at a dose up to 900 mg as monotherapy and in combination with pembro was well tolerated, with dose-related evidence of target engagement. Responses were observed with MK-4166 900 mg plus pembro, particularly in pts with melanoma naive to ICIs. Clinical trial information: NCT02132754.
Circulating tumor DNA (ctDNA) kinetics to predict survival in patients (pts) with unresectable or metastatic melanoma treated with dabrafenib (D) or D + trametinib (T).
Authors: Syeda Mahrukh M , WIGGINS JENNIFER M , Corless Broderick , Long Georgina V. , Flaherty Keith , Schadendorf Dirk , Nathan Paul D. , Robert Caroline , Ribas Antoni , Davies Michael A. , Grob Jean Jacques , Gasal Eduard , Squires Matthew , Marker Mahtab , Brase Jan C. , Polsky David 
Published: May 2019

9510 Background: There are no validated blood-based biomarkers to monitor efficacy in pts with advanced melanoma. Lactate dehydrogenase (LDH) is an established prognostic factor; however, it is not normally used to inform treatment decisions. ctDNA at baseline (BL) is associated with a poor prognosis in pts treated with BRAF inhibitors, but no studies have examined the association between serial changes in ctDNA and survival after BRAF and/or MEK inhibitor therapy. Methods: We measured BRAF V600E/K ctDNA at BL and wk 4 in plasma samples from a pooled population of pts with unresectable or metastatic melanoma treated with D or D+T in the phase 3 COMBI-d trial (NCT01584648). We used mutation-specific droplet digital PCR assays; ctDNA results were categorized as positive/negative (pos/neg) using an analytically validated detection threshold of 0.25 copies/mL. Progression-free (PFS) and overall survival (OS) were analyzed in all pts and by BL LDH level (> or < upper limit of normal). Results: BL ctDNA was detectable in 320/345 pts (92.7%) and was not associated with survival. Nearly all pts had a considerable drop in ctDNA after 4 wks of therapy; 201 pts had paired samples (BL and wk 4) and detectable ctDNA at BL. In 80/201 pts (40%) whose ctDNA changed from pos at BL to neg at wk 4, PFS and OS were prolonged vs in 121/201 (60%) whose ctDNA remained pos (median PFS, 12.9 [95% CI, 9.2-20.2] mo vs 7.1 [5.5-8.9] mo; HR, 0.55 [0.39-0.76]; P = .0003; median OS, 28.2 [20.5-48.8] mo vs 14.6 [11.8-18.7] mo; HR, 0.56 [0.40-0.79]; P = .0007). Undetectable ctDNA at wk 4 was associated with prolonged PFS and OS, especially in pts with high BL LDH (Table). Conclusions: Particularly in pts with high LDH, on-treatment ctDNA monitoring may be helpful for early identification of pts likely to benefit from D or D+T. All ctDNA Samples at Wk 4. Clinical trial information: NCT01584648. [Table: see text]
Responders to anti-PD1 therapy: Long-term outcomes and responses to retreatment in melanoma (mel).
Authors: Betof Warner Allison , Palmer Jessica S. , Shoushtari Alexander Noor , Goldman Debra A , Panageas Katherine , Callahan Margaret K. , Wolchok Jedd D. , Postow Michael A. , Chapman Paul B. 
Published: May 2019

9513 Background: Little is known about patients (pts) who discontinue anti-PD1 therapy after a complete response (CR) outside of clinical trials. There are also limited data about retreatment with a second course of anti-PD1 upon disease progression. Methods: We retrospectively studied pts (n = 398) at MSKCC with unresectable mel (non-uveal) who received ≥1 dose of single-agent anti-PD1 and were followed ≥3 months (mos) after treatment cessation. CR was defined radiographically or by a negative biopsy of residual tissue. Overall survival (OS) and time to treatment failure (TTF, time until next therapy or death) were calculated from time of CR. When to stop therapy and whether to retreat after progressive disease (PD) were at the discretion of the treating oncologist. A subset of pts received a second course of single-agent anti-PD1 ≥3 months after initial discontinuation; retreated pts were evaluable if they had radiographic or clinical evaluation to assess retreatment efficacy. Results: 102 pts (25.6%) achieved CR (n = 89 radiographic, n = 13 pathologic). Median follow-up was 22.6 mos for survivors who had a CR. Estimated 3-year OS from time of CR was 82.5% (95% CI 67.4-91.0). For pts who had a CR, therapy was discontinued due to CR (n = 72), toxicity (n = 24), or other reasons (n = 6). The median duration of treatment for CR pts was 9.4 mos (range 1.6-36.1). 20 CR pts later had progressive disease (PD). Median TTF has not been reached; at 3-years the estimated treatment-free survival for CR pts was 72.3% (95% CI 60.2-81.3). 34 pts received a second course of anti-PD1 for PD after a median of 11.6 mos off treatment (range 3.5-28.6). Best responses to the second course of treatment were: 2 CRs (5.9%), 3 with tumor shrinkage (8.8%), 9 (26.5%) with SD, and 20 with PD (58.8%). Of these pts who had had a CR (n = 8) or some lesser degree of tumor shrinkage (n = 13) to the initial course of anti-PD1 treatment, only 1 and 2 pts responded, respectively, to retreatment. Median duration of retreatment was 10.9 wks. Conclusions: In this largest dataset to knowledge of mel pts treated with a second course of anti-PD1, response rate was low, even in pts who had achieved a response initially. Further study is needed into the necessary duration of initial anti-PD1 treatment and optimal strategies for initial responders who discontinue and later develop PD.
Standard-dose pembrolizumab (pembro) plus alternate-dose ipilimumab (ipi) in advanced melanoma: Initial analysis of KEYNOTE-029 cohort 1C.
Authors: Long Georgina V. , Robert Caroline , Butler Marcus O. , Couture Felix , Carlino Matteo S. , O'Day Steven , Atkinson Victoria , Cebon Jonathan S. , Brown Michael Paul , Dalle Stéphane , Hill Andrew Graham , Gibney Geoffrey Thomas , McCune Steven L. , Menzies Alexander M. , Niu Cuizhen , Ibrahim Nageatte , Homet Moreno Blanca , Diab Adi 
Published: May 2019

9514 Background: KEYNOTE-029 cohort 1B showed substantial efficacy for standard-dose pembro + 4 doses of ipi 1 mg/kg with lower rate of grade 3-5 toxicity than reported for standard-dose nivolumab + ipi in patients (pts) with advanced melanoma. In KEYNOTE-029 cohort 1C, we assessed the toxicity and antitumor activity of standard-dose pembro plus 2 alternate ipi doses (NCT02089685). Methods: Eligible pts with previously untreated stage III/IV melanoma, ECOG PS 0-1, and no active CNS metastases were randomized 1:1 to pembro 200 mg Q3W for 24 mo + 4 doses of ipi 50 mg Q6W (arm A) or pembro 200 mg Q3W for 24 mo + 4 doses of ipi 100 mg Q12W (arm B). Primary endpoints were the grade 3-5 treatment-related AE (TRAE) rate and ORR (RECIST v1.1, central review). With 50 pts per arm and compared with other anti–PD-1 + ipi regimens, a grade 3-5 TRAE rate ≤26% would suggest a meaningful reduction in toxicity and an ORR ≥48% would suggest no decrease in efficacy. Data cutoff date was Jul 17, 2018, and will be updated. Results: 102 pts were randomized: 51 to each arm. Median age was 63.5 y, 70% were male, 15% had ECOG PS 1, 34% had BRAF mutation, and 30% had elevated LDH at baseline. With 9.4 mo median follow-up, 69% of pts in arm A and 71% in arm B remained on treatment. All pts in arm A and 96.1% in arm B had ≥1 TRAE; grade 3-5 TRAE rates were 22% in arm A and 33% in arm B. 1 pt had a grade 5 TRAE (autoimmune myocarditis; arm A). ORR was 49% (95% CI 35-63) in arm A, including 7 CRs and 18 PRs, and 53% (95% CI 39-67) in arm B, including 6 CRs and 21 PRs. An additional 16 pts in each arm had SD or non-CR/non-PD, leading to a DCR of 80% and 84%, respectively. Median response duration was not reached in either arm (range 1.4+ to 9.6+ in arm A, 1.4+ to 9.8+ in arm B). Updated data based on longer follow-up will be presented. Conclusions: Standard-dose pembro + ipi 50 mg Q6W and standard-dose pembro + ipi 100 mg Q12W showed robust antitumor activity in this initial analysis. Both regimens appeared to have a lower rate of grade 3-5 TRAEs than previously observed. Longer follow-up and randomized studies are needed to confirm that these regimens reduce toxicity without compromising efficacy compared with other anti–PD-1 and ipi combinations. Clinical trial information: NCT02089685.
Tumor microenvironment (TME), longitudinal biomarker changes, and clinical outcome in patients (pts) with advanced BRAF V600–mutant melanoma treated with first-line spartalizumab (S) + dabrafenib (D) + trametinib (T).
Authors: Dummer Reinhard , Gusenleitner Daniel , Campbell Catarina D. , Lebbe Celeste , Atkinson Victoria , Mandalà Mario , Nathan Paul D. , Arance Ana , Richtig Erika , Yamazaki Naoya , Robert Caroline , Schadendorf Dirk , Tawbi Hussein Abdul-Hassan , Ascierto Paolo Antonio , Ribas Antoni , Flaherty Keith , Gasal Eduard , Brase Jan C. , Long Georgina V. 
Published: May 2019

9515 Background: Although pts with both low tumor mutation burden (TMB) and T-cell–inflamed gene expression profiles (TI-GEPs) usually have poor outcomes with anti–PD-1 therapy, an analysis in the adjuvant melanoma setting suggested that these pts benefited from adjuvant D+T therapy. Here we analyze TMB/TI-GEPs and other biomarkers in pts receiving a combination of anti–PD-1 and D+T therapy. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating S in combination with D+T in previously untreated pts with BRAF V600–mutant unresectable/metastatic melanoma. In the safety run-in (part [p] 1) and biomarker (p2) cohorts, blood/tissue samples were collected at baseline (BL), after 2-3 and 8-12 wk of treatment, and at disease progression. TMB/circulating tumor DNA (ctDNA) and TI-GEPs were examined by targeted DNA-seq and RNA-seq, respectively. Results: At data cutoff, 6 of 22 pts with DNA- and RNA-seq data available had a PFS event. At BL, these pts had low TMB, low TI-GEPs (4 of 6), or high levels of immunosuppressive TME signatures (eg, fibroblast, M2 macrophages) vs pts without a PFS event. Elevated BL ctDNA was significantly associated with PFS events ( P< .001). Pts with a complete response (CR) on S+D+T had significantly lower levels of BL immunosuppressive TME signatures (eg, M2 macrophages; P< .01) than pts without a CR. We observed a consistent increase in TI-GEPs and decrease in MAPK pathway activity score (MPAS) from BL to biopsy at 2-3 wk in all pts regardless of subsequent progression. Pts with a PFS event and available longitudinal biomarker data were characterized by a subsequent decrease in TI-GEPs and an increase in MPAS per the 8- to 12- wk biopsy sample. Conclusions: These results suggest that S+D+T had an early impact on tumor cells and the TME, potentially promoting antitumor activity. The majority of PFS events occurred in the TMB-low/TI-GEP-low subgroup. An immunosuppressive TME might preclude early CRs. The predictive implications of coupling TMB/GEP subgroups with other TME marker subgroups need further validation. The randomized placebo-controlled p3 of COMBI-i is ongoing. Clinical trial information: NCT02967692.
Circulating PD-L1-exosomes to monitor tumor response in melanoma patients.
Authors: Nardin Charlee , Cordonnier Marine , Chanteloup Gaetan , Derangere Valentin , Algros Marie Paule , Marcion Guillaume , Arnould Laurent , Garrido Carmen , Aubin Francois , Gobbo Jessica 
Published: May 2019

9517 Background: In the era of effective molecular targeted treatments and immunotherapies, there is an urgent need to implement the use of circulating biomarkers in the clinic to facilitate personalized therapy and predict treatment response. We conducted a retrospective study to demonstrate the involvement of circulating PD-L1 exosomes in melanoma patients. Methods: One hundred melanoma patients were included. Exosomes were isolated by ultracentrifugation and evaluated by nanoparticle tracking analysis using a NS300 Instrument (Nanosight, Amesbury, UK). Isolated exosomes were tested for the expression of exosomes markers such as TSG101. PD-L1 expression in plasma and in melanoma plasma-derived exosomes (ExoPD-L1) was measured using an enzyme-linked immunosorbent assay (PD-L1 Human ELISA Kit, Invitrogen). Results: First, ExoPD-L1 was assessed in melanoma cell lines. Exosomes may have a role in cancer immunosuppression mediated by T-cells since they were as efficient as cancer cells to inhibit T-cells activation. In melanoma patients, ExoPD-L1 (median 64,26 pg/mL) was significantly higher than free PD-L1 in the plasma which was barely detectable (0,1 pg/mL). Furthermore, ExoPD-L1 was detected in all patients whereas only 67 % were PD-L1 positive in tumor. Although baseline ExoPD-L1 levels were not associated with clinicopathologic characteristics and tumour burden, ExoPD-L1 variations (ΔExoPD-L1) after treatment correlated with tumor response and survival. A ΔExoPD-L1 cut-off of > 100 was defined, yielding a 83% sensitivity, a 70% specificity, a 91% positive predictive value and a 54% negative predictive values for disease progression. The use of this cut-off allowed stratification in two groups of patients statistically different in terms of overall survival and progression free survival. Conclusions: PD-L1 level in circulating exosomes may be a more reliable marker than PD-L1 expression in the tumor tissue. Monitoring of circulating exosomal PD-L1 may be a promising biomarker to predict tumor response and correlate with survival.
One-year (yr) recurrence-free survival (RFS) from a randomized, open label phase II study of neoadjuvant (neo) talimogene laherparepvec (T-VEC) plus surgery (surgx) versus surgx for resectable stage IIIB-IVM1a melanoma (MEL).
Authors: Dummer Reinhard , Gyorki David E. , Hyngstrom John Robert , Berger Adam C. , Conry Robert Martin , Demidov Lev V. , Sharma Anjali , Treichel Sheryl , Faries Mark B. , Ross Merrick I. 
Published: May 2019

9520 Background: We previously reported that neo T-VEC + surgx resulted in a pathologic CR rate of 21% and an OR rate of 14.7% in a randomized trial of neo T-VEC + surgx vs upfront surgx in pts with resectable stage IIIB/C/IVM1a MEL (Andtbacka et al, ASCO 2018; NCT02211131). Here, we present results from an interim 1-yr analysis of RFS. Methods: Patients (pts) with resectable stage IIIB/C/IVM1a MEL, ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions ≥ 10 mm, and no systemic tx 3 mos prior were randomized 1:1 to 6 doses/12 wks of T-VEC followed by surgx during wks 13-18 (Arm 1) vs upfront surgx during wks 1-6 (Arm 2). T-VEC was given at standard dosing until surgx, no injectable tumors, or intolerance. This analysis conducted on the ITT set estimated a between-group difference in 1-yr RFS per protocol. An RFS event was defined as the first of local, regional or distant recurrence or death due to any cause after surgx. Pts without a R0 surgical outcome or withdrew prior to surgx were considered an event at randomization for RFS. In a sensitivity analysis, RFS was calculated from randomization to the date of the first post-surgx event regardless of surgical outcome. Results: 150 pts were randomized (76 Arm 1, 74 Arm 2). Median (range) follow-up time was 20.6 (0.1, 38.5) mos in Arm 1 and 20.0 (0.1, 35.3) mos in Arm 2. 75% in Arm 1 and 93% in Arm 2 had surgx as planned. R0, R1, and R2 rates, respectively, for Arm 1 were 42.1%, 31.6%, and 1.3% and for Arm 2 were 37.8%, 51.4%, and 4.1%. At 1 yr, 33.5% of pts in Arm 1 and 21.9% of pts in Arm 2 remained recurrence free (HR 0.73, P= 0.048). From the sensitivity analysis, 55.8% of pts in Arm 1 and 39.3 % in Arm 2 remain recurrence free at 1 yr (HR 0.63, P= 0.024). OS rates at 1 yr were 95.9% in Arm 1 and 85.8% in Arm 2 (HR 0.47, P= 0.076). Pts receiving subsequent adjuvant tx was 8 (11%) in Arm 1 and 20 (29%) in Arm 2- most common was immunotherapy 6 (8.2%) and 8 (11.6%), respectively. Conclusions: In the largest randomized neo trial to date in resectable stage IIIB-IVM1a MEL, the following outcomes were improved with neo T-VEC monotherapy vs surgx: R0 surgical resections, 1-yr RFS, and OS. Primary analysis of RFS at 2 yrs is expected. Clinical trial information: NCT02211131.
A randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced mucosal melanoma (NCT02023710).
Authors: Yan Xieqiao , Sheng Xinan , Si Lu , Chi Zhihong , Cui Chuanliang , Li Siming , Mao Lili , Lian Bin , Tang Bixia , Wang Xuan , Kong Yan , Dai Jie , Zhang Xiaoshi , Song Xin , Guo Jun 
Published: May 2019

9521 Background: Mucosal melanoma is rare and associated with extremely poor prognosis. There was no standard treatment for advanced mucosal melanoma patients. BEAM study had demonstrated the effectivity and safety of bevacizumab combined with carboplatin plus paclitaxel in patients with previously untreated metastatic melanoma. This study was to evaluate the activity of bevacizumab combined with carboplatin plus paclitaxel in Patients with Previously Untreated Advanced Mucosal Melanoma. Methods: This study is an open-label, multicenter, randomized phase II trial. Eligible patients had metastatic, recurrent, or unresectable mucosal melanoma and no received any systemic therapy before enrollment. Patients were randomly allocated in a 2:1 ratio to receive bevacizumab (CPB arm, 5mg/kg every two weeks) or placebo (CP arm) with carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m2). Treatment was continued for both groups until disease progression, unacceptable toxicity, death, or withdrawal of consent. The primary study endpoint is progress-free survival (PFS). Overall survival, disease control rate, and safety will also be assessed. Results: The first patient visit was December 1st, 2013, and the final data cutoff was August 30th, 2018. At that time, 114 patients were randomly assigned to receive CP or CPB therapy. Median PFS was 3.2 months for the CP arm and 4.7 months for the CPB arm (HR, 0.50; 95% CI, 0.33-0.72; P = 0.001). Median OS was 9.0 months in the CP arm versus 12.9 months in the CPB arm (HR, 0.61; 95% CI, 0.40-0.92; P = 0.02). The PFS was longer in the CPB arm in the subgroups of patients with neutrophil-to-lymphocyte ratio (NLR) more than 4 and patients with abnormal lactate dehydrogenase concentration (1.2 v 3.0 months, HR, 0.38; 2.0 v 4.7 months, HR, 0.39, respectively). Multivariate analysis using the Cox model showed that combination with bevacizumab was the predictor for better disease control and survival (PFS: HR 0.400, 95% CI 0.251-0.636, P < 0.001; OS: HR 0.505, 95% CI 0.313-0.814, P = 0.005). No new safety signals were observed. Conclusions: To our knowledge this is the largest study about advanced mucosal melanoma. This study demonstrated that bevacizumab in combination with carboplatin plus paclitaxel is active and safe regimen as first line treatment in patients with in advanced mucosal melanoma. A phase III study will be necessary to confirm the benefit, especially in some special setting such as elevated NLR and elevated LDH subgroups. Clinical trial information: NCT02023710.