bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surrogate endpoints for overall survival in anti-programmed death-1 and anti-programmed death ligand 1 trials of advanced melanoma.
Authors: Nie Run-Cong , Yuan Shu-Qiang , Li Yuanfang , Chen Yingbo , Zhou Zhiwei 
Published: May 2020

10030 Background: The mechanisms of action of anti-PD-1/PD-L1 agents are markedly distinct from those of cytotoxic agents, thus a critical issue that is under investigation is what is the optimal endpoint and how should tumor response be evaluated in anti-PD-1/PD-L1 trials for metastatic melanoma. Here, we assessed surrogacy of objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) for overall survival (OS) in anti-PD-1/PD-L1 trials of metastatic melanoma through a meta-analysis of randomized controlled trials (RCTs). Methods: PubMed and EMBASE were searched for phase 2/3 RCTs till June 2019 investigating anti-PD-1/PD-L1 agents. Treatment effect (hazard ratio or odds ratio) on potential surrogates (ORR/DCR/PFS) and OS were collected. At trial level, we assessed the correlation between treatment effect on potential surrogates and OS, weighted by sample size, fixed and random effect models, and calculated the surrogate threshold effect (STE). Sensitivity analyses and leave-one-out cross-validation approach were performed to evaluate the robustness of our findings. Results: We included 8 RCTs (4,110 patients; 11 comparisons). We did not identify strong correlations between ORR (coefficient of determination [ R2]: 0.09 to 0.25), DCR (0.41 to 0.57) and OS. However, we noted a strong correlation between PFS and OS, with R2 of 0.82 in sample size, 0.75 in fixed effect, and 0.72 in random effect model weighting, the robustness of which was further verified by leave-one-out cross-validation approach. Sensitivity analyses with restriction to trials with less than 50% crossover ( R2: 0.94-0.94), phase 3 trials ( R2: 0.94-0.95), large trials ( R2: 0.78-0.86) and first-line trials ( R2: 0.83-0.91) strengthened the correlation. The STE for PFS was 0.78. Conclusions: PFS may be the appropriate surrogate for OS in anti-PD-1/PD-L1 trials of metastatic melanoma. A future anti-PD-1/PD-L1 trial would need less than 0.78 for PFS of the upper limit of confidence interval to predict an OS benefit.
A proteomic biomarker discovery platform for predicting clinical benefit of immunotherapy in advanced melanoma.
Authors: Shaked Yuval , Harel Michal , Issler Eran , Fremder Ella , Jacob Eyal , Dahan Nili , Bar Haim , Halaban Ruth , Sznol Mario , Sharon Ofer 
Published: May 2020

10037 Background: Immune checkpoint inhibitor-based immunotherapies that target CTLA-4 and the PD-1/PD-L1 axis have revolutionized the treatment of advanced melanoma due to their remarkable clinical benefit. However, only a limited number of patients respond to treatment. Therefore, biomarkers to identify appropriate candidates who will benefit from such therapy are needed. Our previous studies have identified therapy-induced, host-mediated mechanisms that drive resistance to a variety of cancer treatment modalities. Here, we explored whether assessing the systemic host-mediated response to immunotherapy can serve as a basis for predicting clinical outcome in melanoma patients. Methods: The cohort consisted of 34 advanced melanoma patients receiving anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination therapy. Clinical benefit was assessed. Plasma samples were obtained from patients at baseline and 2-4 weeks after a single treatment. Proteomic profiling of plasma samples was performed using ELISA-based protein arrays. A generalized linear model (GLM) was applied to a subset of the cohort (n = 13) to identify a proteomic signature that can predict clinical response to treatment. The predictive signature was then tested on the entire cohort (n = 33), excluding one patient with stable disease. Results: We identified a 10-protein signature that accurately distinguishes between responders and non-responders with an area under the curve (AUC) of 0.84 (confidence interval: 0.69-0.99, p-value 5.56E-04), and sensitivity and specificity of 0.94 and 0.79, respectively. These results are currently being validated in a larger cohort in an ongoing prospective study (PROPHETIC trial, NCT04056247). To explore the biological basis of resistance to immunotherapy, we performed a pathway enrichment analysis. Multiple mechanisms of resistance were identified in the non-responder group, including signaling pathways associated with immunosuppression and inflammation. Comparison between the two treatment modalities revealed pathways unique to each treatment, implying important differences between the two regimens. Conclusions: Our study provides insights into mechanisms of resistance to immunotherapy and paves the way towards the discovery of novel predictive biomarkers for patient stratification in melanoma.
FDG-PET metabolic tumor volume in advanced melanoma treated with ipilimumab and nivolumab (ipi/nivo).
Authors: Iravani Amir , Wallace Roslyn , Lo Serigne , Galligan Anna , Weppler Alison , Au-Yeung George , Kee Damien , Lau Peter Kar Han , Brady Benjamin M , Lee Belinda , McArthur Grant A. , Sandhu Shahneen Kaur , Hicks Rodney J. 
Published: May 2020

10041 Background: Predictors of outcomes of immune checkpoint inhibitors (ICI) are desirable. We aim to investigate the prognostic value of 18F-fluorodeoxyglucose-PET/CT (FDG-PET) parameters at baseline and response monitoring of patients (pts) with advanced melanoma receiving ipi/nivo. Methods: From 2016-2019, melanoma pts who received ipi/nivo and had PET Response Criteria In Solid Tumors (PERCIST) measurable lesions on baseline FDG-PET were included. Baseline whole-body metabolic tumor volume (wbMTV), tumor stage, mutational status, ECOG performance score, lactate dehydrogenase (LDH) and treatment-line were correlated with overall survival (OS) in univariate and multivariate Cox-regression analysis. Response were assessed for a subset of pts with post-treatment FDG-PET based on PERCIST. Results: Of 162 pts receiving ipi/nivo, 122 pts (median age: 61; male: 73%; ECOG 0: 78%; raised LDH: 52%; M1c: 39%, M1d: 45% and BRAFV600E/Kmutation: 45%) met eligibility criteria. Forty percent received ipi/nivo as first-line treatment, 48% as second-line (25% post BRAF inhibitor(i)/MEKi and 23% post single-agent ICI) and 12% as third-line. At median follow-up of 21 months (mths), median OS was 20 mths (95% CI 11-not reached[NR]). Pts with above the median wbMTV had shorter OS than those with below the median wbMTV (NR vs 10 mths, 95% CI 8-NR; HR 2.0, 95% CI 1.2-3.4, p = 0.009). In multivariate analysis, wbMTV, ECOG and treatment-line were independently associated with OS. In 106 pts with post-treatment FDG-PET, 24 mths OS rate was higher for those with objective response (OR): 91% (95% CI 82-100%) vs stable disease:55% (27-100%) vs progressive disease:17% (8-35%) as best response, p < 0.001. OR was higher in first-line compared to second or third-line treatment, 75% vs 29-33% vs 23%, respectively, p = 0.0012. Conclusions: Increased baseline FDG-PET wbMTV is an independent prognostic biomarker in pts with advanced melanoma receiving ipi/nivo. FDG-PET response accurately predicts outcome. [Table: see text]
Estimating treatment-free survival (TFS) over extended follow-up in patients (pts) with advanced melanoma (MEL) treated with immune-checkpoint inhibitors (ICIs): Five-year follow-up of CheckMate 067.
Authors: Regan Meredith M. , Mantia Charlene , Werner Lillian , Tarhini Ahmad A. , Rao Sumati , Moshyk Andriy , Ritchings Corey , Rizzo Jasmine I. , Atkins Michael B. , McDermott David F. 
Published: May 2020

10043 Background: We previously defined a novel outcome, TFS, to characterize the time between ICI therapy cessation and subsequent therapy initiation/death. TFS is part of an integrated analysis to comprehensively describe how pts spend overall survival (OS) time, on and off treatment, with/without treatment-related toxicity. We reported survival states, including TFS, in ICI-treated pts with MEL in the phase 3 CheckMate 067 trial (NCT01844505) over the 36-mo period since randomization (Regan. J Clin Oncol. 2019); 60-mo results are presented here. Methods: Data were analyzed for 937 pts with MEL who started treatment with nivolumab (NIVO) plus ipilimumab (IPI), NIVO, or IPI in CheckMate 067. TFS was defined as the area between the Kaplan–Meier (KM) curves for 2 conventional time-to-event endpoints defined from randomization: time to protocol therapy cessation and time to subsequent therapy/death. TFS was also divided into TFS with/without grade ≥3 treatment-related adverse events (TRAEs), and OS was estimated. The area under each KM curve was estimated by the 60-mo restricted mean (r-mean) time to event and expressed as a percentage of the 60-mo period. Bootstrapped 95% CIs were calculated for differences. Results: Over the 60-mo period, pts spent an average of 33%, 17%, and 20% of time free of treatment after receiving NIVO+IPI, NIVO, and IPI, respectively (r-mean TFS, 19.7, 9.9, and 11.9 mo; Table). NIVO+IPI-treated pts had r-mean TFS that was 9.8 mo longer than NIVO-treated pts (95% CI, 6.7–12.8) and 7.8 mo longer than IPI-treated pts (95% CI, 4.6–11.0). Mean TFS with grade ≥3 TRAEs remained a small proportion of the 60-mo period at 3%, 2%, and < 1% with NIVO+IPI, NIVO, and IPI, respectively. Conclusions: With extended follow-up, average TFS with/without toxicity represented greater percentages of the 60-mo vs 36-mo period for NIVO+IPI and NIVO, but not for IPI. Pts treated with NIVO+IPI continued to have TFS twice as long as those treated with NIVO alone, due to earlier therapy cessation for toxicity without disease progression and subsequent resolution of many of those toxicities. The majority of TFS time was spent without grade ≥3 TRAEs across all arms. [Table: see text]
Integrated biomarker study of neoadjuvant pepinemab and nivolumab in patients with resectable metastatic melanoma.
Authors: Lowe Michael C. , Olson Brian , Martinez Anthony , Hammons Jacklyn , Delman Keith A. , Yushak Melinda Lynne , Allor Melanie , Reilly Christine A. , Mallow Crystal L. , Evans Elizabeth E. , Fisher Terrence Lee , Lesinski Gregory B. , Kudchadkar Ragini Reiney 
Published: May 2020

10061 Background: SEMA4D has broad immunomodulatory effects in the tumor microenvironment (TME); blocking SEMA4D in combination with checkpoint inhibitors (CI) promotes immune infiltration, reduces recruitment of myeloid cells, enhances T cell activity, and promotes tumor regression. We hypothesized that adding pepinemab (VX15/2503), which targets SEMA4D, to CI would increase immunomodulatory effects and augment response in melanoma (NCT03769155). Methods: Patients with resectable stage IIIB/C/D melanoma were enrolled to control (no neoadjuvant therapy) or treatment cohorts (n = 8 in four cohorts of pepinemab plus nivolumab, ipilimumab, nivolumab/ipilimumab or alone). Here we report results from patients receiving two doses of nivolumab (360mg) and pepinemab (15mg/kg) every three weeks followed by surgery. Primary endpoint was T cell infiltration into the TME; secondary endpoints include pathologic response rates, peripheral immune profile, and safety. Results: Ten patients are reported: two were controls, eight received neoadjuvant therapy. Two patients had pathologic complete response, one had a near-complete pathologic response ( < 1% viable tumor), one had a partial response (41% viable tumor) and four had stable disease (73-90% viable tumor). All neoadjuvant patients underwent surgery without delay; one patient experienced grade 3 post-operative cellulitis. There were two treatment-related grade 3 adverse events (weakness and arthralgia). Pharmacodynamic studies confirmed saturation of PD-1 and SEMA4D in peripheral and tumor-infiltrating T cells. T/B cell (CD8+/CD20+) ratios, a surrogate for T cell infiltration, were higher in post-treatment tumors compared to pre-treatment and were higher in the tumor bed compared to normal adjacent tissue. Flow cytometric evaluation identified an increase in CD26hi CD4+ and CD8+ tumor-infiltrating effectors in treated patients compared to controls and an increase in peripheral frequencies of the PD-1-responsive effector HLA-DR+CD38+Ki67+ CD4+ and CD8+ T cells following treatment. Treatment increased infiltration of myeloid populations into the TME, increased expression of PD-L1 on TME myeloid populations, and increased expression of the SEMA4D receptor Plexin-B2 on the surface of TME CD45− and M2 macrophages and MDSC. Conclusions: Neoadjuvant nivolumab and pepinemab results in increased T cell infiltration with excellent major response rate (38%) and expected safety profile. We continue to enroll patients using other rational combinations of pepinemab and CI. Clinical trial information: NCT03769155.
Survival analysis between narrower surgical margins and guideline-recommended margins for excision of cutaneous squamous cell carcinoma: A multicenter, retrospective study of 1,204 Japanese cases.
Authors: Baba Natsuki , Nakamura Yasuhiro , Kato Hiroshi , Matsushita Shigeto , Fujimoto Noriki , Iino Shiro , Saito Shintaro , Asai Jun , Ishikawa Masashi , Yatsushiro Hiroshi , Kawahara Yu , Matsuya Taisuke , Araki Ryuichiro , Teramoto Yukiko , Sasaki Katsuhito , Asami Yuri , Hasegawa Minoru , Yamamoto Akifumi 
Published: May 2020

10063 Background: Controversy exists regarding the optimal surgical margin for cutaneous squamous cell carcinoma (cSCC). Current NCCN Guidelines recommend excision with a 4–6-mm clinical margin for low-risk cSCC and wider ( > 6-mm) clinical margin for high-risk cSCC tumors. However, adherence to this guideline is often difficult, as high-risk cSCCs frequently occur on the faces of elderly patients. Thus, we aim to investigate the correlation between different surgical margins and prognosis in patients with cSCC. Methods: Patients with cSCC who had undergone surgical excision of the primary site between 2011 and 2019 at 11 Japanese institutions were included in this study. Patients were divided into two groups: the standard margin group (SMG) with excisions adhering to the guideline-recommended margins, and narrower margin group (NMG) with excisions with narrower margins than are guideline-recommended. Local recurrence-free survival (LRFS), relapse-free survival (RFS), and overall survival (OS) were estimated using Kaplan–Meier analysis and compared between the two groups. Results: A total of 1204 patients with cSCC (SMG, 637; NMG, 567) were included in this study. RFS was significantly lower in SMG than in NMG (5-year RFS 72% vs 79%; P = 0.03); however, no statistically significant differences were observed between the two groups in LRFS (5-year LRFS 80% vs 82%; P = 0.41) or OS (5-year OS 84% vs 83%; P = 0.90). Due to striking statistical significance in several characteristics of patients between the two groups, subgroup analyses, focusing on the cohort of head and neck cSCCs, were also performed. The patient characteristics were similar between SMG and NMG in both the T1-sized tumor ( < 2 cm, SMG, 182; NMG, 250) and T2-sized tumor (2 cm ≤ tumor < 4 cm, SMG, 130; NMG, 136) cohorts, based on AJCC-TNM staging (8th edition). There were also no significant differences between the SMG and NMG in LRFS (5-year LRFS, T1: 80% vs 86%; P = 0.59; T2: 85% vs 84%; P = 0.84), RFS (5-year RFS, T1: 80% vs 81%; P = 0.84; T2: 77% vs 76%; P = 0.99), or OS (5-year OS, T1: 82% vs 87%; P = 0.42; T2: 88% vs 85%; P = 0.68). Furthermore, when the NMG was divided into the two margin groups (margins reduced by < 3 mm or ≥3 mm from the standard margin), no significant difference was observed in LRFS, RFS, and OS. Conclusions: This study did not reveal a significant impact of the size of clinical excision margins on survival in patients with cSCCs. Strikingly, the narrower margins may be more appropriate for < 4 cm-sized head and neck cSCCs.
Cemiplimab as first intervention for patients with locally advanced cutaneous squamous cell carcinoma.
Authors: Atlas Jennifer Lynn , Kanos Marina , Symanowski James Thomas , Brickman Daniel , Forster Meghan , Frenkel Catherine , Milas Zvonimir , Sarantou Terry , White Richard L. , Amin Asim 
Published: May 2020

10065 Cemiplimab as First Intervention for Patients with Locally Advanced Cutaneous Squamous Cell Carcinoma (cSCC) Background: Cutaneous squamous cell carcinoma is the second most common non-melanoma skin cancer. Early stage disease is managed with local intervention in the form of surgery or radiation and translates into cure for greater than 95% of the patients. Patients with high risk disease who have large primary lesions, neural, or nodal involvement are usually not amenable to cure with local intervention and may experience significant morbidity, disfigurement, or functional deficits. These patients had no effective systemic treatment options until recent approval of cemiplimab. We report the outcomes for upfront treatment with cemiplimab in locally advanced cSCC. Methods: This is a single institution retrospective study of patients with locally advanced cSCC defined as those requiring more than simple excision and/or complex repair or regional disease with nodal involvement who received at least two doses of cemiplimab between January 1, 2018 through January 17, 2020. Patients with radiologically measurable disease had response evaluated per RECIST criteria. Patients who had no measurable disease had their clinical response (complete resolution or healing of primary lesion) assessed per treating physician and need or lack of local intervention documented. Adverse events were assessed and graded per CTCAE criteria. The primary end point was to ascertain the need for local intervention. Results: Thirty six patients were eligible. Twenty-two (61%) patients treated with upfront cemiplimab were able to avoid local intervention with surgery and/or radiation; four patients progressed or died on treatment. Three (8%) patients received local intervention. Eleven (31%) patients are still receiving cemiplimab and local intervention decision is pending. The overall response rate was 69% and the clinical benefit rate was 92%. The median treatment duration was six months and the median number of doses received was six. Adverse events occurred in 31% of patients; the most common adverse event was dermatitis. Conclusions: Upfront treatment with cemiplimab in patients with locally advanced cSCC obviated need for disfiguring/complex surgery or radiation in majority of patients. Cemiplimab was tolerated well; no new safety signals were observed. Neo-adjuvant phase II study is in development.
Radiomic signatures to predict response to targeted therapy and immune checkpoint blockade in melanoma patients (pts) on neoadjuvant therapy.
Authors: Colen Rivka R. , Ologun Gabriel O. , Zinn Pascal , AK Murat , Arora Reetakshi , Burton Elizabeth M. , Glitza Isabella Claudia , Tawbi Hussein Abdul-Hassan , Patel Sapna Pradyuman , Diab Adi , Wong Michael K. , McQuade Jennifer Leigh , Ross Merrick I. , Ahmed Sara , Elshafeey Nabil , Gershenwald Jeffrey E. , Davies Michael A. , Tetzlaff Michael T. , Amaria Rodabe Navroze , Wargo Jennifer Ann 
Published: May 2020

10067 Background: Metastatic melanoma pt outcomes have been revolutionized by targeted therapy (TT) and immune checkpoint blockade (ICB), which are now being evaluated in the neoadjuvant (neoadj) setting. While tumor-based biomarkers may help predict response, predictors of response obtained by less invasive strategies could greatly benefit pt care and allow real-time treatment response monitoring. Radiomic signatures derived from computerized tomography (CT) images have recently been shown to predict response to ICB in stage IV pts. However, the association of radiomic features with pathological response following neoadj therapy has not been assessed. We sought to determine if radiomic assessment predicts pCR in pts receiving neoadj TT and ICB. Methods: We collected data for a cohort of melanoma pts with locoregional metastases who were treated with neoadj TT (n = 33) or ICB (n = 30). Pts received systemic therapy for 8-10 weeks prior to planned surgical resection. Responses were evaluated radiographically (RECIST 1.1) and via pathological assessment (evaluating for pathologic complete response; (pCR) versus < pCR). Thirty two pts (19 ICB; 13 TT) were included in the radiomics analysis based on the availability of appropriate CT imaging. A total of 310 unique radiomic features (10 histogram-based and 300 second-order texture features) were calculated from each extracted volume of interest (VOI). Feature extraction was performed on baseline and initial on-treatment pre-operative CT scans. Features associated with pCR were assessed using a feature selection approach based on Least Absolute Shrinkage and Selection Operator (LASSO). Selected features were used to build a classification model for prediction of pCR to ICB or TT. Leave-One-Out Cross-Validation was performed to evaluate the robustness of the estimates. Results: Out of 310 radiomic features, three features measured at baseline were able to predict a pCR to neoadj ICB or TT with sensitivity, specificity and accuracy of 100%, though these signatures were non-overlapping. In the on-treatment pre-operative scans, 3 distinct features (also non-overlapping and distinct from the predictive pre-treatment signatures) also predicted pCR to ICB and TT with 100% sensitivity, specificity and accuracy. Conclusions: Radiomic signatures in baseline and on-treatment CT scans accurately predict pCR in melanoma pts with locoregional metastases treated with neoadj TT or ICB. These provocative findings warrant further investigation in larger, independent cohorts.