bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.