bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Phase 2 study of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with metastatic cutaneous squamous cell carcinoma (mCSCC; Group 1): 12-month follow-up.
Authors: Guminski Alexander David , Lim Annette May Ling , Khushalani Nikhil I. , Schmults Chrysalyne D. , Hernandez-Aya Leonel Fernando , Modi Badri , Dunn Lara , Hughes Brett Gordon Maxwell , Chang Anne Lynn S. , Hauschild Axel , Migden Michael Robert , Gutzmer Ralf , Alam Murad , Jankovic Vladimir , Stankevich Elizabeth , Booth Jocelyn , Li Siyu , Lowy Israel , Fury Matthew G. , Rischin Danny
Published: May 2019

9526

Background: Primary analysis (Oct 2017) of cemiplimab (REGN2810) in pts with mCSCC in a Phase 2 study demonstrated substantial antitumor activity, durable responses, and acceptable safety profile. We now report 12-month follow-up data from these pts (NCT02760498; data cutoff date: Sep 20, 2018). Methods: Pts with mCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 59 pts (median age: 71 years) were enrolled. Median duration of follow-up was 16.5 months (range: 1.1–26.6). ORR by central review was 49.2% (95% CI: 35.9–62.5; 10 CRs and 19 PRs [4 CRs and 25 PRs by investigator-assessment (INV)]). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 21.6 months and was still ongoing. Observed DOR exceeded 12 months in 22/29 pts (75.9%) with response. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.7% (95% CI: 49.1–75.0). Median observed time to response was 1.9 months (range: 1.7–9.1). Median progression-free survival was 18.4 months (95% CI: 7.3–not evaluable); median overall survival has not been reached. The most common treatment-emergent adverse events (all grades, Grade ≥3) were diarrhea (28.8%, 1.7%), fatigue (25.4%, 1.7%), and nausea (23.7%, 0%). By INV, grade ≥3 immune-related adverse events occurred in 13.6% of pts. Conclusions: This analysis demonstrates substantial antitumor activity and increasing DOR with cemiplimab 3 mg/kg Q2W in pts with mCSCC. There were no new safety signals. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.
High incidence of brain metastases (BrM) in patients with metastatic cutaneous melanoma (MCM) and mutations in the APC/β-catenin (CTNNB1).
Authors: Karachaliou Georgia Sofia , Carroll Sarah Bass , Patel Nirali M. , Zhao Xiaobei , Pegna Guillaume Joe , Collichio Frances A. , Lee Carrie B. , Ollila David W. , Moschos Stergios J.
Published: May 2019

9527

Background: Activation of the WNT/β-catenin pathway is associated with low/absent tumor-infiltrating lymphocytes (TILs) and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. We aimed to investigate if APC/CTNNB1 mutations in melanoma pts are associated with TIL status, prediction of response to immunotherapy (IT), and overall survival (OS). Methods: Pts with CM and APC or CTNNB1 mutations identified in melanoma tumors using the TruSight Tumor 26 Illumina assay were enrolled. Demographics, clinical (stage, treatment response, follow-up), pathologic (TIL status), and molecular (BRAF/NRAS, C→T (i.e. UV signature) nucleotide transition, functional significance by IMPACT, mutant allele frequency (MAF) corrected from the % tumor) characteristics were investigated. Results: We identified a total of 25 pts (13 males; age at original diagnosis (median 61 yrs, range 22-78 yrs). CTNNB1 and APC mutations were mutually exclusive. 48% (12/25) had APC mutations and 52% (13/25) had CTNNB1 mutations; of which (i.e. CTNNB1 mutations) 69% (9/13) had absent TILs. 88% (22/25) of APC/CTNNB1 mutations had moderate functional significance, 64% (16/25) of the mutations had a C→T nucleotide change, 36% (9/25) had BRAFV600, and 20% (5/25) NRASQ61 mutations. 64% (14/22) of pts with stage II-III progressed to stage IV; of these 14 pts, 8 (57%) developed parenchymal BrM. 13 of the stage II-III 22 pts who progressed to stage IV received IT; of these 13 pts, 7 (53%) had absent TILs. APC/CTNNB1 mutations did not influence response to IT, irrespective of the MAF of the mutations. Of the 12 pts with MCM and measurable disease who received IT 9/12 had absent TILs and 7/12 responded. The median OS from the time of diagnosis of distant MCM (N = 17; 14 pts who progressed from initial stage II-III and 3 pts who were originally diagnosed with stage IV) was 18.8 months (range, 2.4-48.0 months). Conclusions: APC & CTNNB1 mutations are mutually exclusive. CTNNB1 mutations are more frequently associated with absent TILs. Pts with MCM had relatively shorter OS (18.8 months) in part due to development of BrM. In this small cohort APC/CTNNB1 mutations did not seem to impair response to immunotherapy.
IL-12p40 and MIP3a to predict clinical responses to anti-PD-1 therapy in patients with metastatic melanoma.
Authors: Vera Aguilera Jesus , Erskine Courtney L. , Suman Vera J. , Paludo Jonas , McWilliams Robert R. , Kottschade Lisa A. , Yan Yiyi , Dronca Roxana Stefania , Dong Haidong , Markovic Svetomir , Block Matthew Stephen
Published: May 2019

9535

Background: A broad understanding of baseline immunity is needed in order to predict responses to PD-1 blockade. We previously reported in a preclinical model that elevated Th1 signature cytokines are present after successful therapy with PD-1 blockade. In this study we evaluated serum cytokines as biomarkers of response in a cohort of patients with metastatic melanoma undergoing anti-PD1 therapy. Methods: 27 pts diagnosed with metastatic melanoma (MM) received anti-PD-1 therapy and had peripheral blood collected prior to anti-PD-1 therapy start and 12 weeks after; 55 proinflammatory-related serum cytokines were analyzed at both times using the Meso Scale Discovery (MSD) assay. At week 12, we identified 15 pts who had radiographic complete or partial response (TR) and 12 had progressive disease (PD) using RECIST criteria. Spearman rank correlation coefficients (rho) were used to assess association between pre-treatment serum cytokine levels. For each cytokine, differences in pretreatment serum levels and the ratio of the 12 week to pre-treatment serum levels between TR and PD groups were assessed using Wilcoxon rank sum tests. Results: Pretreatment serum IL-12p40 and MIP3a (CCL20) were moderately correlated (rho=0.3944). Pretreatment IL-12p40 and was found to be significantly higher (p=0.0025) in the TR group (median=48.5; 25th to 75th percentile [IQR]:25.3-63.8) relative to the PD group (median=17.3; IQR: 8.6-30.3). Pretreatment MIP3a was also found to be significantly higher (p=0.0359) in the TR group (median=1.72; IQR: 1.41-2.65) relative to the PD group (median=1.33; IQR: 1.09-1.98). The 12th week pretreatment IL-12p40 ratio (median=1.98; IQR: 1.4-11.3) in the TR group was greater than that (median=0.64; IQR: 0.23-1.61) in the PD group (p=0.0029); we identified that baseline serum levels >15pg/ml of IL12p40 prior to immunotherapy were associated with significantly prolonged event free survival (p=0.001). Conclusions: Measurements of IL-12p40 and MIP-3a levels before immunotherapy may help to select patients who are likely to benefit from anti-PD1 therapy. Additionally, exploration of combination therapies that increase IL-12P40 and MIP3 prior or during immunotherapy should be undertaken.
Immune profile of metastatic uveal melanoma during treatment with pembrolizumab.
Authors: Rossi Ernesto , Zizzari Ilaria , Schinzari Giovanni , Di Filippo Alessandra , Maiorano Brigida Anna , Dosa Tommaso , Pagliara Monica Maria , Bria Emilio , Blasi Maria Antonietta , Tortora Giampaolo , Nuti Marianna
Published: May 2019

9536

Background: Metastatic uveal melanoma (mUM) is a rare and aggressive disease. No standard therapy has been established. All the available treatments derive from trials in cutaneous melanoma. A minority of patients with mUM can benefit from immunotherapy. Immunological features of a group of patients with metastatic UM treated with Pembrolizumab were analyzed in order to explore the immune-response in this disease and the potential factors able to select the patients who can benefit from immunotherapy. Methods: Blood samples from 12 UM patients before (T0) and during treatment with Pembrolizumab (T1: after 1 cycle of Pembrolizumab; T2: after 3 cycle of Pembrolizumab) were collected. Peripheral blood mononucleated cells (PBMCs) were isolated and characterized for markers expression. Sera were analyzed for a panel of soluble (s) immune checkpoints and cytokines. The correlation between immunological parameters with PFS and OS was explored. Blood samples from 6 metastatic cutaneous melanoma (CM) patients with a confirmed response to anti PD-1 agents were also collected during the treatment and analyzed for PBMCs and sera. Results: Soluble CTLA4, sPD-L1, sCD137, sTIM3 were significantly higher in UM than in CM. CD137 was significantly higher in UM patients progressed with Pembrolizumab than in the 2 responsive patients (512 pg/ml vs < 12.9 pg/ml, respectively, p = 0.04) who are still alive and on treatment after a median follow-up of 24 months. Low sGITR, sCD137, sHVEM, and sTIM3 are associated with longer PFS. IL-8 was lower in CM than UM (2.5 pg/ml vs 40.7 pg/ml) and in the responsive versus progressed UM patients (3,7 pg/ml vs 118 pg/ml, p = 0,042). Low levels of IL-8 and IL-1-alpha are significantly associated with longer PFS (p = 0.011 and 0.010 respectively). In responsive patients CD137 expression on CD3+, CD4+ and CD8+ T cells was higher than in progressed patients, while sCD137 was absent. Conclusions: A group of s-immune checkpoints and cytokines correlate with Pembrolizumab effectiveness in mUM. High expression of CD137 on T cells associated with the absence of its soluble form in responders could suggest the correlation between the retention of this co-stimulatory molecule and efficacy of anti-PD1.
A phase II open labeled, randomized study of poly-ICLC matured dendritic cells for NY-ESO-1 and Mean-A peptide vaccination compared to Montanide, in melanoma patients in complete clinical remission.
Authors: Pavlick Anna C. , Blazquez Ana , Meseck Marcia , Donovan Michael J. , Castillo-Martin Mireia , Htwe Thin Tin , Sabado Rachel , Mandeli John P. , Gnjatic Sacha , Friedlander Philip Adam , Bhardwaj Nina
Published: May 2019

9538

Background: Dendritic cells (DC) play a critical role in tumor immune-surveillance. Combination therapies by utilizing check point inhibitors may revert tumor-induced-T cell exhaustion; however, DCs are necessary to prime/activate T cells to target tumor cells. Montanide is a mineral oil-based adjuvant that enhances the immune response to vaccination. In this study, we compared the immunogenicity of Montanide and poly-ICLC-matured DCs. Methods: This is a Phase II open label, randomized two arm study to compare Poly-ICLC matured DC with systemic administration of Poly-ICLC on days 1 and 2 (ARM A) to Montanide ISA-51 and Poly-ICLC as adjuvants for NY-ESO-1 and Melan-A/MART-1 peptide vaccination with systemic administration of Poly-ICLC on day 2 (ARM B) in study subjects with melanoma in complete clinical remission but at high risk of disease recurrence (NCT02334735). Evaluation of primary tumor expression of NY-ESO-1 and Melan-A tumor was determined by immunohistochemistry (IHC). Humoral responses were assessed by Seromics (ELISA) and T-cell responses were performed ex-vivo by interferon (IFN)-g enzyme-linked immunospot assay (ELISPOT) and after expansion by intracellular cytokine staining (ICS). Results: Twenty-nine patients have been enrolled in this study. IHC studies demonstrated tumor expression of NY-ESO-1 and Melan-A in 78% and 81% of the patients, respectively. 100% of patients within arm B became seropositive for NY-ESO-1 peptide by cycle 2 day 8 (C2D8). 80% of patients within arm A also seroconverted to this antigen but titers were significantly lower. Melan-A-specific antibody responses were also found in arm B patients, but to a lesser degree. However, arm A patients failed to develop seroreactivity to Melan-A. Cellular responses are under analysis. Preliminary data show that subjects in both arms develop T cell responses to both antigens. Conclusions: This vaccine trial reached the primary endpoint of safety and tolerability. Patients vaccinated with either DC or Montanide had demonstrable antibody titers to immunizing antigens, although the latter reproducibly induced higher titers. Evaluation of cellular responses is ongoing. Clinical trial information: NCT02334735.
Therapeutic implications of a novel driver classification system for cutaneous and unknown primary melanomas.
Authors: Shoushtari Alexander Noor , Sanchez-Vega Francisco , Kantheti Havish , Callahan Margaret K. , Postow Michael A. , Barker Christopher Andrew , Chatila Walid K. , Jonsson Philip , Ariyan Charlotte Eielson , Brady Mary Susan , Coit Daniel G. , Nair Suresh , Chapman Paul B. , Busam Klaus J. , Solit David B. , Wolchok Jedd D. , Schultz Nikolaus
Published: May 2019

9539

Background: Cutaneous and “unknown primary” melanomas frequently harbor alterations that activate the Mitogen Activated Protein Kinase (MAPK) pathway, and are often classified as BRAF, NRAS, NF1 mutant, or “triple wild type.” Multigene sequencing may identify additional oncogenic drivers, but the clinical impact of this information is unknown. Methods: Patients with BRAF inhibitor naïve melanoma underwent prospective tumor molecular profiling using a targeted capture-based assay (MSK-IMPACT), and demographic and treatment data were collected. Time to treatment failure was assessed for patients who received frontline PD-1 monotherapy or nivolumab plus ipilimumab. Results: 576 patients were successfully sequenced. 533 samples (96%) harbored a known or presumed oncogenic mutation in 1 of 28 genes in the RTK-RAS-MAPK pathway. 187 tumors (32%) had two or more drivers in this pathway, and the rates of driver co-alterations varied widely by specific driver. A hierarchical classification of 9 driver groups (BRAF V600E; V600K/R/M; BRAF non-V600; NRAS Q61; Other RAS; NF1; KIT; Other driver; Unknown driver) was significantly associated with tumor mutational burden, primary melanoma site, and patient age. Time to treatment failure varied by driver class and site of primary melanoma for PD-1 monotherapy but not nivolumab plus ipilimumab. 150 patients with BRAF V600 wild-type melanoma required systemic therapy after progression on checkpoint blockade. 21 were given genomically matched therapy, and 5/21 had clinical benefit for ≥6 months. Complete and durable responses were observed with TRK and ROS1 inhibitors in patients with NTRK1/2/3 and ROS1 fusion positive tumors. Conclusions: Oncogenic alterations in the RTK-RAS-MAPK pathway can be detected using targeted capture NGS in the vast majority of cutaneous and unknown primary melanomas. A hierarchical classification of 9 driver groups revealed clinically relevant melanoma subsets with varying clinical outcomes to PD-1 monotherapy. Select patients with oncogenic kinase fusions can achieve durable therapeutic benefit with targeted inhibitors of these rare drivers.
Clinical and FDG-PET markers of immune checkpoint inhibitor (ICI) response in patients with metastatic Merkel cell carcinoma (mMCC).
Authors: Weppler Alison , Bhave Prachi , De Ieso Paolo , Raleigh Jeanette , Hatzimihalis Athena , Gill Anthony J. , Balachander Shiva , Callahan Jason , Pattison Andrew , Chua Margaret , Au-Yeung George , McArthur Grant A. , Hicks Rodney J. , Tothill Richard , Sandhu Shahneen Kaur
Published: May 2019

9540

Background: mMCC is a rare, highly aggressive neuroendocrine cancer with a poor prognosis. ICIs have favourable efficacy and safety in clinical trials. We outline single centre experience utilising ICIs in mMCC. Methods: Medical records of patients (pts) with mMCC treated with ICIs from Aug 2015 to Dec 2018 at Peter MacCallum Cancer Centre in Australia were retrospectively analysed. RNA sequencing and immunohistochemistry for PD-L1, CD3 and Merkel cell polyomavirus (MCPyV) on tumor samples were performed. Baseline tumor volumes and responses were assessed with FDG-PET scans using the Hicks criteria. Results: 23 pts with mMCC were treated with ICIs. Pt characteristics are summarised in Table. A median of 8 cycles (range 1 to 47) were administered, with treatment ongoing in 7 pts. Objective responses (OR) were observed in 14 pts (61%); 10 (44%) complete metabolic responses (CMR) and 4 (17%) partial metabolic responses (PMR). Median time to response was 9 weeks (range 4 to 11) and 12-month progression-free survival (PFS) rate was 32%. Increased OR were seen in pts aged less than 75 (OR 8/10, 80% vs 46%), no prior history of chemotherapy (OR 10/14, 71% vs 44%), pts with an immune-related adverse event (irAE) (OR 6/6, 100% vs 47%) and in MCPyV negative pts (OR 9/11, 82% vs 50%). Pts with a CMR had lower mean-tumor volume on baseline FDG-PET scan (CMR: 35.7mL, no CMR: 187.8mL, p value 0.05). 10 pts received radiation (RT) during ICI: 4 pts started RT concurrently (OR 75%, CMR 50%), 3 pts had isolated ICI-resistant lesions successfully treated with RT and 3 pts with multisite progression continued to progress despite RT. 6 pts (26%) had a Grade 1-2 irAE. Conclusions: ICIs showed efficacy and safety consistent with trial data. Younger age, negative MCPyV status, no prior chemotherapy, lower baseline FDG-PET tumor volume and irAEs are potentially associated with better responses. [Table: see text]
Lymphodepletion (LD), tumor-infiltrating lymphocytes (TIL) and high (HD-IL2) versus low-dose (LD-IL2) IL-2 followed by pembrolizumab (pembro) in patients (pts) with metastatic melanoma (MM).
Authors: Amaria Rodabe Navroze , Haymaker Cara L. , Forget Marie-Andree , Bassett Roland , Cormier Janice N. , Davies Michael A. , Diab Adi , Gershenwald Jeffrey E. , Glitza Isabella Claudia , Lee Jeffrey Edwin , Lucci Anthony , McQuade Jennifer Leigh , Patel Sapna Pradyuman , Royal Richard Eldon , Ross Merrick I. , Tawbi Hussein Abdul-Hassan , Wargo Jennifer Ann , Wong Michael K.K. , Bernatchez Chantale , Hwu Patrick
Published: May 2019

9543

Background: TIL adoptive cell transfer (ACT) therapy can produce durable responses for MM pts although efficacy appears lower in the era of checkpoint inhibitors. Toxicities from HD-IL2, including sepsis physiology, limits widespread use of this regimen. Suppression of transferred TIL by either tumor cells or the tumor microenvironment could limit TIL responses. Pembro is known to promote T cell activation, thus, we evaluated the efficacy and safety of TIL with pembro with HD-IL2 versus LD-IL2. Methods: Pts with MM who had tumor harvested and cryopreserved TIL at MD Anderson with PS 0-1 and normal organ function were eligible. All pts received a standard LD regimen consisting of cyclophosphamide and fludarabine, followed by infusion of pooled ex-vivo expanded TIL and either HD-IL2 (Arm 1: 720,000 IU/kg IV q 8 hrs up to 15 doses) or LD-IL2 (Arm 2: 2 million IU SC for 14 d). Pts received pembro 200mg IV starting 21 d post T cell infusion every 3 wks for up to 2 yrs. Pts were randomized 1:1 based on stage and LDH. Paired blood and tumor biopsies were obtained prior to LD, prior to first and second dose of pembro and at time of progression. Results: A total of 36 pts were planned to enroll (18 in each arm); however, the protocol met pre-specified futility boundaries in Arm 1 which prompted early closure after treatment of 14 pts (7 in each Arm). Median age was 50 yrs, 6 were female, 8 had cutaneous melanoma, 2 mucosal, 2 uveal and 2 unknown primary. 86% were stage M1c, 14% M1D, 50% had LDH elevation. Median lines of prior therapy were 3 (range 1-6), including prior anti PD-1 in 13 pts. Best overall response was 1 PR (for 10 mos), 2 SD, 3 PD, 1 NE in Arm 1; 1 PR (ongoing over 36 mos), 1 SD, 5 PD in Arm 2. With median follow up of 9.2 mos, PFS was 3.9 mos for Arm 1 and 2.1 mos for Arm 2 (p = 0.99). Median OS was 9.7 mos for Arm 1 and 8.8 mos for Arm 2 (p = 0.71). Toxicity was similar in both Arms but with lower rates of grade 3 febrile neutropenia (57% vs. 71%) and shorter hospital stay (median 16 vs. 18 d) in Arm 2 vs. Arm 1. Conclusions: In a heavily treated pt population, TIL with pembro achieved low response rates. Use of LD-IL2 did not diminish efficacy and may be better tolerated than HD-IL2 for TIL ACT. Correlative studies are ongoing to determine mechanisms of treatment response and failure. Clinical trial information: NCT02500576.
Pembrolizumab as first-line therapy in patients with unresectable cutaneous squamous cell carcinoma (cSCC): Phase 2 results from CARSKIN.
Authors: Maubec Eve , Boubaya Marouane , Petrow Peter , Basset-Seguin Nicole , Grob Jean Jacques , Dréno Brigitte , Beylot-Barry Marie , Scheer-Senyarich Isabelle , Helfen Sabine , Leccia Marie Thérèse , Stefan Andreea Raluca , Saiag Philippe , De Quatrebarbes Julie , Meyer Nicolas , Deschamps Lydia , Alloux Céline , Lopez Isabelle , Cherbal Soufian , Tibi Annick , Lévy Vincent ,   Groupe de Cancérologie Cutanée
Published: May 2019

9547

Background: Cemiplimab, a PD-1-axis blocking agent, has recently been approved for unresectable cSCCs. We report results of the CARSKIN study evaluating pembrolizumab in the first-line setting. Methods: Chemotherapy naive patients (pts) with unresectable cSCCs, either locally or regionally advanced or metastatic, and ECOG PS ≤1 were accrued to this multi-institutional phase II trial to assess tumor response rate (RR) and safety of pembrolizumab administered IV (200 mg Q3W) for a period up to 24 months (mo). Baseline PD-L1 expression was centrally assessed on tumor. The primary endpoint was the RR at 15 weeks (wks) per RECIST v1.1 (independent review). A Simon two-stage design was used. Results: From 03/2017 to 01/2018, 39 pts (79% males, median age 79 years) were enrolled. Disease was local (18%), regional (62%) or metastatic (21%); 38% of pts were PS 0. The median number of infusions was 8. The median follow-up was 10.2 mo; 15 pts are still on pembrolizumab. Thirty-four pts were evaluable for tumor response, and 39 for toxicity. The RR at 15 wks was 38.5 % (95% CI: 24–55%) in the ITT population corresponding to 2 CR and 13 PR. The best responses were 3 CR and 12 PR. The DCR was 51% (20/39 including 5 SD) at 15 wks. The median PFS was 8.4 mo and the median OS was not reached. No responder has progressed to date including 2 pts who discontinued pembrolizumab for 6 to 12 mo. Treatment-related AEs (TRAEs) occurred in 67% of pts, including 8% with severe TRAEs (1 gr 3 cholestasis, 1 gr 3 colitis and 1 death due to recurrence of a non-related head and neck cancer) and 10% who discontinued because of a TRAE. Centrally assessed baseline PD-L1 expression was positive in 77% of patients (1% tumor staining threshold), but it failed to predict response at 15 wks with a median PD-L1 expression of 10% in responders and non-responders at 15 wks (P = .55). Conclusions: In this series of 39 elderly pts with unresectable cSCCs, the safety profile was consistent with previous pembrolizumab studies. First-line pembrolizumab provided robust antitumor activity regardless of PD-L1 expression levels. Clinical trial information: NCT02883556.
Sensitivity of treatment-free survival (TFS), a novel outcome, to subgroup analyses of patients (pts) with advanced melanoma (MEL) treated with immune checkpoint inhibitors (ICI).
Authors: Mantia Charlene , Werner Lillian , Rao Sumati , Ritchings Corey , Tarhini Ahmad A. , Atkins Michael B. , McDermott David F. , Regan Meredith M.
Published: May 2019

9550

Background: Many pts treated with ICIs can discontinue treatment and experience ongoing disease control and toxicity. We previously proposed a novel outcome, TFS, as the time between ICI therapy cessation and subsequent therapy initiation or death, with integrated graphical analysis to better characterize the unique effects of ICIs (ASCO 2018 #9531). In the CheckMate 067 and 069 trials of ipilimumab (IPI) and nivolumab (NIVO) alone or in combination (NIVO+IPI) in pts with MEL, the 36-month restricted mean TFS was 8.7, 4.6 and 11.1 mo, respectively. We explored the sensitivity of TFS to be informative of overall survival (OS) differences through subgroup analysis. Methods: Data from MEL pts in the CheckMate 067 and 069 trials were pooled and analyzed. TFS was defined as the area between the Kaplan-Meier curves for two endpoints, from randomization: (A) time to ICI therapy cessation; and (B) time to subsequent therapy initiation or death. TFS was estimated by restricted mean survival time until 36 mo since randomization. Differences in restricted mean TFS between subgroups of pts (such as PD-L1 status, lactate dehydrogenase [LDH], performance status [PS], gender) were calculated with bootstrapped 95% CIs. OS from randomization was also estimated. Results: Among 407 pts treated with NIVO+IPI, restricted mean TFS ranged from 8-13 mo across subgroups (Table). Subgroup differences in mean TFS were larger for prognostic factors LDH and PS and smaller in non-prognostic PD-L1 status and gender subgroups. Conclusions: Clinically meaningful TFS was seen across all subgroups. TFS was sensitive to prognostic subgroup differences. These results provide further support for TFS as a relevant clinical endpoint. Additional subgroups and comparisons with single agent NIVO and IPI arms will be presented at the meeting. [Table: see text]
Organ site-specific radiological responses in anti-PD-1 monotherapy treated advanced melanoma patients.
Authors: Bai Xue , Kim Michelle S. , Kasumova Gyulnara , Cohen Justine Vanessa , Lawrence Donald P. , Freedman Christine , Fadden Riley , Rubin Krista M. , Sharova Tatyana , Frederick Dennie T. , Flaherty Keith , Sullivan Ryan J. , Boland Genevieve Marie
Published: May 2019

9552

Background: Melanoma is notorious for its high degree of heterogeneity with the implication that metastases in different sites react differently to immunotherapy. We aimed to explore the site-specific response pattern in anti-PD-1 monotherapy treated advanced melanoma patients. Methods: Clinical data was collected retrospectively from advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital (MGH) from Sept 2009 to Dec 2017. Radiological evaluations were carried out by radiologists from the MGH Tumor Imaging Metrics Core using irRECIST 1.1. Statistical analysis was carried out using ANOVA test. Results: Among 61 evaluated patients, 56 (91.8%) had at least one measurable target lesion(s) at baseline, including 35 (57.4%) patients with measurable lymph nodes (LN)/subcutaneous lesion(s), 25 (50.0%) with lung lesion(s), and 21 (34.4%) with liver lesion(s). At week-12 radiological evaluation after anti-PD-1 monotherapy initiation, lesions at different sites responded differently at marginal statistical significance (P = 0.071), namely mean percent changes compared with baseline were 3.75%, 5.12%, and -30.95% for LN/subcutaneous, liver, and lung lesions, respectively. Among patients who had disease under control (CR/PR/SD) (n = 37, 60.7%) by week-12 evaluation, the mean tumor percentage change at week-24 compared with week-12 were -8.94%, -12.18%, and -5.91% for LN/subcutaneous, liver, and lung lesions, respectively (P = 0.479). Conclusions: Although our small sample size limits definitive discrimination in organ site-specific response differences, it appears that lung lesions respond more quickly and to a greater extent compared with LN/subcutaneous and liver lesions in advanced melanoma patients treated with anti-PD-1 monotherapy. We will explore this in a larger, multicenter cohort.
Phase I study of vemurafenib (VEM) and cobimetinib (COB) with heat shock protein 90 (HSP90) inhibitor XL888 in advanced BRAFV600 mutant melanoma.
Authors: Eroglu Zeynep , Chen Ann , Li Jiannong , Markowitz Joseph , Brohl Andrew Scott , Tetteh Leticia , Karpisek Adam , Taylor Hayley , Messina Jane , Sondak Vernon K. , Khushalani Nikhil I. , Smalley Keiran
Published: May 2019

9553

Background: Resistance to BRAF+MEK inhibitors(i) in BRAF-mutant melanoma is common. Multiple resistance mechanisms involve HSP90 clients, and a phase 1 study of VEM with XL888 showed PFS rates similar to the combination of BRAF+MEKi (Eroglu, CCR, 2018). Methods: Combination of VEM (960 mg PO BID) and COB (60 mg QD for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60 or 90 mg PO twice weekly) was investigated in a phase 1 study of advanced melanoma, with a modified Ji dose escalation design. Dose-limiting toxicity (DLT) was defined as related grade ≥3 adverse event or inability to deliver 75% of XL888 in first 4 weeks. Results: 25 pts (9 female, median age 62, 15 with M1C disease, 6 with prior anti-PD-1 therapy) were enrolled. After 2 DLTs (rash and acute kidney injury) in first cohort, a lower dose of VEM 720 mg BID and COB 40 mg, with the same XL888 cohorts was investigated. 3 DLTs (rash) in 12 pts were observed in the XL888 60 mg cohort, which was determined as the maximum tolerated dose. Most common grade 3 toxicities included diarrhea (8), hypertension (6), rash (5), alkaline phosphate/GGT elevation (4). 11 patients required dose reductions of VEM and/or COB. Objective responses (PR/CR) were observed in 18 of 25 pts (72%; 95% CI: 51-88%). Median PFS was 8.1 months (4.7 – NA); median overall survival was not reached, with 1-year OS of 71% (45-86%). Single cell RNA-Seq (10X genomics) was performed on baseline and on-treatment tumor biopsies; 8 days of treatment was associated with an increase in immune cell influx (CD4+ and CD8+) and a decrease in number of melanoma cells. At day 8, one patient (now without progression for nearly 2 years) had no tumor cells remaining with only immune cells and stromal fibroblasts left. Further analyses will be presented. Serial plasma BRAF circulating tumor (ct)DNA levels were obtained, with decrease in ctDNA levels corresponding with response and 83% of patients with disease progression showing an elevation in ctDNA from baseline. Conclusions: VEM/COB plus XL888 had significant toxicity, requiring dose-reductions that may have contributed to the low PFS rate despite high response rate. Caution must be used in combination of BRAF+MEKi with other agents. Clinical trial information: NCT02721459.
Phase II trial of nab-paclitaxel (ABI) and ipilimumab (ipi) in patients with treatment naïve metastatic melanoma.
Authors: Ludford Kaysia , Johnson Daniel H. , Hennegan Tarin , Gruschkus Stephen K. , Haymaker Cara L. , Bernatchez Chantale , Jackson Natalie , Hwu Patrick , Diab Adi
Published: May 2019

9554

Background: Conventional chemotherapies possess intrinsic immune-regulatory properties. Some taxanes for instance, stimulate antigen presentation and impair regulatory T-cells while leaving effector T cells intact. Combining chemotherapies with immune checkpoint inhibitor at carefully designed dosing regimens may increase tumor cell susceptibility to immune-mediated death and thus enhance therapeutic efficacy. We describe the safety and updated efficacy of ABI and ipi in patients with metastatic melanoma. Methods: In this open-label, single center, phase II trial, ABI was administered to treatment naïve metastatic patients at 150mg/m2 on days 1,8 and 15 every 4 weeks and ipi at 3mg/kg on day 1 every 3 weeks limited to 4 cycles until disease progression or unacceptable toxicity. Endpoints included ORR, OS and safety. Results: 18 of 21 enrollees between 6/2013 and 6/2015 with Stage IV melanoma (M1c: 56%, M1b: 33%, M1a: 11%) were included in the analysis. The median age was 57 years old (33-69) and 67% were men. 44% harbored BRAF mutations. Median duration of treatment was 9 weeks (5 to 17). Median follow-up time for OS analysis was 22.5 months (2 to 52 months). 12 and 24 month OS were 77.8% and 60.6% respectively with median not yet reached. The ORR by by irRECIST was 27.8%. Grade 3 adverse events were reported in 50% of patients, the most common being neutropenia. 17% of patients had grade 3 immune-related adverse events, the most common being hypophysitis and colitis. Immune analysis showed absolute lymphocyte count was significantly elevated post treatment compared with pre-treatment (p = 0.024). In addition, deep immune analysis of peripheral blood samples and tumor tissue including nanostring, gene expression and TCR sequencing will be assessed and reported. Conclusions: The combination of ipi and ABI in this small study demonstrates acceptable safety, tolerability and clinical activity. ABI may contribute to tumor cytoreduction and enhance antitumor clinical response of ipi without impactful immunosuppression. This data together with further immune analysis may provide rationale to design prospective chemo-immunotherapy regimens and treatments for metastatic melanoma and other solid tumors. Clinical trial information: NCT01827111.
Characterization of the genetics of mucosal melanoma in patients treated with immunotherapy.
Authors: Buchbinder Elizabeth Iannotti , Weirather Jason L. , Manos Michael P. , Brennick Ryan C. , Ott Patrick Alexander , Haq Rizwan , Izar Benjamin , Hodi F. Stephen
Published: May 2019

9556

Background: Mucosal melanomas can be effectively treated with checkpoint inhibitors, although the response rates are lower than those observed for melanomas arising in cutaneous sites. The mechanistic basis for the lower efficacy of immunotherapies in mucosal melanoma has been suggested to be related to their lower mutational burden. However, there has been limited characterization of the genetics in this melanoma subtype. Methods: Tumor genotyping was performed on all mucosal melanoma patients seen within the Dana Farber Cancer Institute from 2011 until the present by Oncopanel analysis. Results: We identified a total of 57 mucosal melanoma patients whose tumors had been genotyped. Of these 42 received immunotherapy and had response data available. Within the cohort of mucosal melanoma patients, 37.3% had durable clinical benefit (DCB) to their first line of IO therapy. These patients had an average mutational burden/megabase of 6.41 (95% CI 3.53-11.01) but tumor mutational burden did not correlate with response in this cohort. The pattern of mutations in mucosal melanomas was distinct from cutaneous melanomas, as the most frequent mutations were in SF3B1, ATRX, KIT and NF1 genes. Patients with KIT aberrations had a higher DCB rate compared patients with wildtype KIT (73 vs. 33%). In addition, there were several genetic differences observed based upon the site of origin of the mucosal melanoma. A higher rate of SF3B1 mutations was observed in patients with melanoma of anal/rectal origin while patients with vulvar/vaginal melanoma had higher rates of ATRX mutations, which frequently correlated with p53 ( TP53) mutations. Conclusions: This analysis is one of the first to look at genetic patterns in a large cohort of a relatively rare type of melanoma and correlate with response. Our findings confirm the low mutational burden observed in mucosal melanoma despite the high response rate observed in these patients. In addition, this study uncovered a higher rate of response to immunotherapy in mucosal melanoma patients with a KIT mutation.
Stereotactic radiotherapy combined with immunotherapy is safe and effective: Results from a phase I clinical trial.
Authors: Ratnayake Gishan , Reinwald Simone , Shackleton Mark J. , Moore Maggie A. , Voskoboynik Mark , Ruben Jeremy , Van Zelm Menno , Yu Di , Ward Rachel , Smith Robin , Haydon Andrew Mark , Senthi Sashendra
Published: May 2019

9557

Background: There is growing evidence to suggest synergism between stereotactic ablative radiotherapy (SABR) and immunotherapy (IO) against metastatic melanoma. The optimal timing and dosing of SABR for this purpose has not been established. Here, we report results from a Phase I trial, finding the best outcomes with low dose SABR delivered late. Methods: Metastatic melanoma pts with at least two metastases received SABR to a single metastatic site. All pts had standard dose IO with anti-PD1 and/or anti-CTLA4. Following a standard 3+3 design, pts were escalated through three SABR doses (10Gy, 15Gy and 20Gy) delivered at three different time points (Cycle 1, 2, or 3 of IO). Dose limiting toxicity (DLT) were defined as Grade 3 or higher toxicity within 3 months of first treatment and assessed by an independent data safety monitoring committee (IDSMC). Logistic or cox regressions were used to assess the impact of SABR dose, timing and use of combination IO on toxicity, progression-free (PFS) and overall survival (OS) while controlling age, gender and baseline performance status. Results: Between April 2016 and August 2018, 24 pts were enrolled. The median age was 66 years and most were ECOG 0-1 (92%). The median follow-up was 10 months. Three pts (12.5%) developed DLTs (enterocolitis, hepatitis and liver function derangement). None occurred at SABR treated sites and all were in pts receiving 15Gy. DLTs were not associated with SABR timing (p = 0.44) or use of combination IO (p = 0.72). On this basis the IDSMC recommended stopping the trial and maximum tolerated SABR dose was defined at 10 Gy. The median PFS and OS were respectively 5.4m (95% CI 2.1m-NR) and 16.9m (95% CI 7.1m-NR). The median PFS for those receiving 10Gy was numerically higher than those receiving 15Gy (11.8m vs 2.6 m, p = 0.42). The only treatment related factor associated with improved PFS (HR = 0.14, p = 0.02) and OS (HR = 0.09, p = 0.04) was receiving SABR with Cycle 3. SABR dose (PFS p = 0.75, OS p = 0.67) and IO type (PFS p = 0.13, OS p = 0.06) were not significant. Conclusions: SABR combined with IO is generally safe overall. We found the optimal therapeutic index may be achieved with 10Gy delivered with the third cycle of IO; a strategy that warrants further testing. Clinical trial information: ACTRN12616001064493.
Mutation landscape of Chinese melanoma patients.
Authors: Huang Fuxue , Li Dandan , Wen Xizhi , Wang Fang , Zhang Xiaoshi , Lin Xuan , Chen Shuyin , Liu Hao , Han-Zhang Han , Liu Jing
Published: May 2019

9563

Background: Treatment options for melanoma, which has the highest mutation burden among common cancers, has proliferated in the past decade. Genomic profiling has becoming essential to clinical decision making. However, limited studies have interrogated the genomic landscape of Chinese melanoma patients. We also investigated the correlation between tumor mutation burden (TMB) and clinical outcomes of immunotherapy (IO). Methods: In this study, we retrospectively surveyed the genomic profiling of primary tumors of 81 (40 males, 41 females) metastatic Chinese melanoma patients with a median age of 52, using a panel consisting of 295 cancer-related genes, spanning 2.02MB of human genome. Patients used IO as first line treatment (n = 25) were enrolled for survival analyses. Results: In this cohort, 15, 24 and 42 were acral, mucosal and cutaneous melanoma, respectively. Collectively, we identified 1,114 mutations, spanning 248 genes, with BRAF, MYC and NBN being the most frequently mutated genes, occurring in 40%, 27% and 21% of patients, respectively. Mutation spectrum varied significantly by subtypes. BRAF (57%) and LRP1B (26%) were the most frequently mutated genes in cutaneous melanoma (CM). KIT and NRAS, reported to be frequently mutated in CM, each occurred in only 12% patients in this cohort. MYC amplification was the most commonly seen mutation in acral and mucosal melanoma (MM). Other frequent mutations in MM included: NBN (38%) RUNX1T1(29%) and TP53 (29%). In acral melanoma (AM), CCND1, FGF3/19, NF1and NBN were frequently mutated. It is interesting to note that no TP53 mutation was observed in AM. AM and MM had significantly more CNVs than CM. Of the 25 patients underwent IO, our data revealed a positive correlation between TMB and PFS (p = 0.007). Such correlation also exited in each subtype. Furthermore, we derived a cutoff of 15, which can effectively distinguish clinical response. Patients with TMB > 15 mut/Mb had a significantly longer PFS than patients harboring TMB < 15 mut/Mb (P = 0.02). Patients with CM had a longer PFS than patients with AM or MM (p = 0.018). No correlation between PDL1 expression and PFS was observed. Conclusions: Our study revealed a distinctive mutation landscape for each subtype. Furthermore, we also revealed a positive correlation between TMB and PFS as well as a lack of correlation between PDL1 expression and PFS.
Anal melanoma: A comparative comprehensive genomic profiling study.
Authors: Ross Jeffrey S. , Madison Russell , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Lin Douglas I. , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Edgerly Claire I. , Duncan Daniel , Ali Siraj Mahamed , Schrock Alexa Betzig , Chung Jon , Reddy Prasanth , McGregor Kimberly , Alexander Brian , Jurdi Adham Adel , Miller Vincent A.
Published: May 2019

9566

Background: We performed a comprehensive genomic profiling (CGP) study of AM and CM to learn of potential genomic alterations (GA) linked to targeted and immune checkpoint inhibitor (ICPI) therapies. Methods: 90 AM and 1804 CM FFPE tissues from late stage underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC. Results: AM and CM had a similar age, but AM females and CM males were significantly more common (P < 0.0001). GA/tumor was significantly higher in CM (UV light exposure) as were the median TMB and frequency of TMB ≥ 10 and 20 mutations/Mb (P < 0.0001 for all comparisons). PD-L1 expression was higher in AM than CM (P = 0.0023). AM and CM were all MS-stable. The contrast in S FB1 mutations in AM and TERT GA in CM were significant (P < 0.0001). Of potentially targetable GA, AM featured significantly more KIT GA than CM (P < 0.0001), whereas CM featured significantly more BRAF GA (P < 0.0001). Only 11% of AM BRAF GA were V600E whereas 74% of CM BRAF GA were V600E (P < 0.0001). MTOR pathway GA were common in both tumor types. Additional potentially targetable alterations in PDGFRA and ERBB2 kinases were seen in AM but not in CM. Conclusions: CM is distinct from AM featuring higher GA/tumor, higher TMB and frequent BRAF V600E GA that predict benefit from ICPI and anti-BRAF therapies. Although both AM and CM feature MTOR pathway targets, AM does have higher PD-L1 expression than CM and is characterized by an array of potentially targetable kinase genes including KIT, PDGFRA, ERBB2 and to a lesser extent than CM, BRAF.[Table: see text]
Efficacy of immune checkpoint inhibitors (ICIs) for in-transit melanoma.
Authors: Nan Tie Emilia , Lai-Kwon Julia Elizabeth , Na Lumine , Rtshiladze Michael Alexander , Bozzi James , Read Tavis , Atkinson Victoria , Au-Yeung George , Long Georgina V. , McArthur Grant A. , Sandhu Shahneen Kaur , Saw Robyn , Walpole Euan Thomas , Menzies Alexander M. , Smithers B. Mark , Gyorki David E.
Published: May 2019

9583

Background: The efficacy of ICIs in metastatic melanoma is well-established. However, there is limited data regarding their efficacy in in-transit melanoma metastases (ITM). This study assessed the efficacy of ICI in patients with ITM. Methods: A multisite, retrospective review of patients with ITM treated with ICI from 2004-2018. Demographic and clinicopathological factors (age, sex, primary site, AJCC version 8 stage, BRAF status, prior locoregional therapies) were collected. Objective response rate (ORR) based on a clinician-assessed best overall response, progression free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. Results: Fifty-four patients were included: 27 (50%) female; median age 69 (range 19-89); 12 (22%) stage IIIB, 40 (74%) stage IIIC and 2 (4%) stage IIID; 10(19%) BRAF mutant. Forty (74%) received single agent PD-1 inhibitor (pembrolizumab or nivolumab), 8 (15%) single agent anti-CTLA-4 (ipilimumab), 5 (9%) combination anti-PD-1/anti-CTLA-4 (ipilimumab and nivolumab or pembrolizumab) and 1 (2%) combination anti-PDL-1/MEK inhibitor (atezolizumab and cobimetinib). ORR to ICI was 54%: 14 (26%) complete responses; 15 (28%) partial responses; 9 (17%) stable disease; 16 (30%) progressive disease. Thirteen (46%) responders had only one ITM lesion. ORR was 58% for single agent anti PD-1, 38% for single agent anti-CTLA4, and 40% for anti-PD-1/anti-CTLA-4 (Table). The median follow-up was 15 months (2-46). The median PFS was 11.7 months (6.6-N/A). PFS at 1 and 2 years were 48% and 39%. Fourteen (56%) progressed locoregionally and 11 (44%) progressed distantly. OS at 1 and 2 years were 85% and 63%; the median OS was not reached. No clinicopathological features were associated with ORR. Conclusions: ICI produces objective responses in ITM and should be considered in patients with unresectable ITM or disease recurrence despite locoregional therapies. [Table: see text]