bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of prior immune checkpoint blockade (ICB) with longer progression-free survival (PFS) in patients treated with intermittent versus continuous dabrafenib and trametinib: A post-hoc analysis of S1320.
Authors: Algazi Alain Patrick , Othus Megan , Daud Adil , Mehnert Janice M. , Truong Thach-Giao , Conry Robert Martin , Kendra Kari Lynn , Doolittle Gary C. , Clark Joseph I , Messino Michael J. , Moore Dennis Frederic , Lao Christopher D. , Faller Bryan A. , Govindarajan Rangaswamy , Harker-Murray Amy K. , Dreisbach Luke P. , Moon James , Grossmann Kenneth F. , Lo Roger , Ribas Antoni 
Published: May 2020

10039 Background: S1320 is a phase 2 randomized clinical trial presented at the 2020 AACR Annual Meeting in April demonstrating that continuous dosing of dabrafenib and trametinib yields longer PFS than intermittent dosing of these agents in patients with BRAFV600E/K melanoma. Here we look at the association between prior exposure to ICB and PFS in patients randomized to either intermittent or continuous dosing on S1320. Methods: Patients without disease progression after 8 weeks of dabrafenib and trametinib were randomized 1:1 to proceed with intermittent therapy (3-week-off, 5-week-on) or to stay on the continuous daily dosing schedule. The design called for 206 randomized patients with the primary outcome of PFS. Response assessments were made using RECIST v1.1 at 8-week intervals. A post-hoc analysis assessed differences in PFS in the pool of all randomized patients based on prior exposure to anti-PD1 antibodies, a randomization stratification factor. Kaplan-Meier estimates and multivariable Cox regression models (controlling for pre-randomization age, Zubrod performance status, LDH, unknown primary, M-Stage) were used to evaluate the association between this stratification factor and PFS. Results: Of 242 patients treated on study, 105 were randomized to continuous dosing, 101 to intermittent dosing, and 36 were not randomized due to disease progression at 8 weeks or other factors. 37% of the 242 enrolled and 37% of the 206 randomized patients had previously been treated with ICB. Among all randomized patients, there were no differences in baseline characteristics comparing patients with and without prior immune checkpoint inhibitor exposure: age median 62 vs 59, LDH elevation 37% vs 39%,, stage IVB/C 73% vs 64%, Zubrod performance status 0, 57% vs 58%. PFS was longer in patients with prior ICB exposure (hazard ratio = 0.60, 95% confidence interval 0.41,-0.98, median = 6 vs 9 months from randomization, 8 vs 11 months from starting treatment). There was no difference in the association between prior ICB exposure and PFS between arms (interaction p-value = 0.62). Conclusions: In patients without early progression on dabrafenib and trametinib, PFS was longer with prior to exposure to ICB . Although the groups had similar baseline characteristics and rates of randomization, these results could still be influenced by non-controlled factors influencing clinicians’ decisions to start a patient on immune versus targeted therapy. Clinical trial information: NCT02196181.
Real-world outcomes of advanced melanoma patients not represented in phase III trials.
Authors: Ismail Rawa , van Zeijl Michiel , De Wreede Liesbeth , van den Eertwegh Alfonsus Johannes Maria , De Boer Anthonius , van Dartel Maaike , Hilarius Doranne , Aarts Maureen J.B. , Van Den Berkmortel Franchette , Boers-Sonderen Marye , de Groot Jan Willem , Hospers Geke , Kapiteijn Ellen , Piersma Djura , Van Rijn Rozemarijn , Suijkerbuijk Karijn , ten Tije Albert J. , Van Der Veldt Astrid Aplonia Maria , Haanen John B. A. G. , Wouters Michel W.J.M. 
Published: May 2020

10042 Background: A large proportion of patients with advanced melanoma is not represented in phase III clinical trials, due to ineligibility. Real-world efficacy evidence of immune- and targeted therapies in these patients is lacking. We aimed to provide insight in survival outcomes of systemically treated patients who were not represented in the phase III trials in order to support clinical decision-making. Methods: Systemically treated ineligible patients with advanced melanoma diagnosed between 2014-2017 were analyzed. Prognostic importance of factors associated with overall survival (OS) was assessed by Kaplan Meier method, Cox regression models, predicted OS probabilities of prognostic subgroups and a conditional inference survival (decision) tree. Results: Of 2,536 systemically treated patients with advanced melanoma, 1,004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria most strongly correlated with survival in ineligible systemically treated patients with ECOG Performance Score (PS) ≥2 vs PS 0-1 (HR 1.95 (95%CI: 1.52-2.5)), symptomatic brain metastases (BM) vs absent BM (HR 1.71 (95%CI: 1.34-2.18)) and LDH > 500 U/l vs normal (HR 1.89 (95%CI: 1.49-2.41)). All other factors for ineligibility were not associated with OS. By combining ECOG PS, BM and LDH, 18 subgroups were created. The 3-year survival probability of patients with ECOG PS ≤1, asymptomatic BM and normal LDH was 35.1%. Patients with ECOG PS of ≥2 with or without symptomatic BM had a mOS of 6.5 and 11.3 months and a 3-year survival probability of 9.3% and 23.6% respectively. In the decision tree, the covariate with the strongest predictive distinctive character for survival was LDH, followed by ECOG PS. Prognosis of LDH of > 500 U/L is infaust, although still long-term survival is possible (3-year survival probability of 15.3%). The decision tree showed the prognosis of patients with symptomatic BM can be good if ECOG PS is 0 and patients are aged ≤55 years (mOS of 22.3 months). Conclusions: Patients with advanced melanoma not represented in phase III trials treated with systemic therapy can achieve long term survival. LDH was the strongest predictive factor associated with survival, followed by ECOG PS and symptomatic BM. Other factors for ineligibility were not associated with OS. These results, together with the decision tree, can be used to provide insight in outcomes to facilitate the shared decision-making process when comparative studies are not available.
Association of pathogenic germline variant KDR Q472H with angiogenesis and resistance to treatment in melanoma.
Authors: Chou Margaret , Giles Keith M. , Illa-Bochaca Irineu , Mastroianni Justin , Vega-Saenz de Miera Eleazar , Krogsgaard Michelle , Osman Iman 
Published: May 2020

10060 Background: Preclinical data suggest that melanoma angiogenesis promotes resistance to MAPK-pathway (MAPKi) and immune checkpoint inhibitors (ICIs). However, phase II clinical trials of anti-angiogenic therapy in melanoma were disappointing. We previously identified a pathogenic germline variant Q472H in the kinase insert domain receptor [KDR Q472H; vascular endothelial growth factor receptor-2 (VEGFR-2)] in 35% of primary melanoma patients. We hypothesize that KDR Q472H promotes resistance to MAPKi or ICIs, and that combined MAPKi or ICI and VEGF pathway inhibition may improve outcomes in patients harboring the variant. Methods: Metastatic melanoma (MM) patient clinical data and biospecimens enrolled in the NYU Langone Medical Center Melanoma program were studied. KDR status was determined by TaqMan assays. Tumor microvessel density (MVD) was assessed by CD34 immunohistochemistry. The impact of KDR Q472H on the tumor microenvironment was determined by RNA-seq and Nanostring. Synergy between BRAF (dabrafenib) and VEGFR-2 (lenvatinib) inhibitors in KDR-genotyped MM cell lines was assessed using cell proliferation assays and the Chou-Talalay method. Synergy between ICIs and anti-VEGFR-2 was evaluated in vivo using a B16 melanoma model. Results: We studied 221 MM patients (38% KDR Q472H variants). KDR Q472H variant was significantly associated with higher tumor MVD (P = 0.002). Among the MAPKi-treated patients, KDR Q472H homozygotes had shorter median progression-free survival (PFS, 3.3 vs 9.7 months, P = 0.009) than KDR wild type (WT). In patients treated with anti-PD-1-based therapies, response rates were lower in KDR Q472H variant patients compared to WT (P = 0.012), with shorter median PFS (8.4 months vs not reached, P = 0.0443). Transcriptomic analyses identified an immunosuppressive phenotype in KDR Q472H tumors, with reduced expression of genes associated with chemotaxis, inflammation, T cell activity, and antigen presentation. Consistent with this finding, VEGFR-2 blockade in a KDR Q472H B16 mouse melanoma model augmented the anti-melanoma immune response. KDR Q472H cell lines displayed synergistic cytotoxicity with dabrafenib and lenvatinib, compared to KDR WT cells. Conclusions: Our data demonstrate that melanoma patients with pathogenic germline variant KDR Q472H may be more resistant to both ICIs and MAPKi. Anti-angiogenic therapy should be reconsidered within this specific subset of patients in prospective clinical trials.
Incidence and trends of skin cancer in the United States, 1999-2016.
Authors: Le Hoa Van , LE CHI HUU HONG , LE Phuong HUU UYEN , Truong CHI THI LE 
Published: May 2020

10077 Background: Cutaneous skin cancer is among the most common malignancies in US. While Surveillance, Epidemiology and End Results (SEER) data are vital to estimate its incidence, delays and under-reporting remained major limitations. Surveillance is hindered due to exclusion from states’ reportable diseases and possible outpatient diagnoses’ omission from registries. Thus, exact incidence has not been known. This study determined skin cancer incidence and trends from 1999 to 2016 in a nationally representative sample. Methods: New melanoma, non-melanoma and other skin cancer cases among adults aged ≥20 years were identified in the National Health and Nutrition Examination Survey (NHANES), 1999-2016. Crude and age-adjusted incidences and 95% CIs were estimated by survey year cohorts (1999-2008 and 2009-2016) based on the 2000 US standard population. Sex and age-stratified longitudinal trends were examined in age and sex-adjusted regression models. Statistical analyses accounted for complex survey design with examination sample weight and adjusted for nonresponse. Sensitivity analyses included unadjusted, sex- and age- adjusted modeling. Statistical significance was determined by 2-sided p-value of .05. Results: Among 47,172 adults and 21,192 non-Hispanic whites from 1999-2016, the overall age-standardized incidences of skin cancer per 100000 persons were 390.9 (95% CI: 312-469.7) and 519 (95% CI: 413.8-624.3), respectively. The median age at first diagnosis was 72.2 (mean = 69.8, IQR = 57.5-79.5 years). The incidence was higher in men than women (474.7 vs 313.8 per 100000 persons, p< .001) and increased with older age ( p< .001). Between 1999-2008 and 2009-2016, the incidence was significantly higher in those older than 70, 75 and 80 ( p ≤.01). Rising incidence was also observed in overall population, women, and by approximately 90% among those older than 70. Sensitivity analyses showed similar trends. Conclusions: Our incidence rates for skin cancer were high, particularly in the elderly. From 1999 to 2016, the incidence increased in women and those 70 and older, a concerning observation given the aging population. As understanding susceptible groups has public health implications, our study provided an updated depiction of skin cancer incidence and trends in US. [Table: see text]
A phase Ib study to evaluate the oral selective estrogen receptor degrader GDC-9545 alone or combined with palbociclib in metastatic ER-positive HER2-negative breast cancer.
Authors: Lim Elgene , Jhaveri Komal L. , Perez-Fidalgo Jose Alejandro , Bellet Meritxell , Boni Valentina , Perez Garcia Jose Manuel , Estevez Laura , Bardia Aditya , Turner Nicholas C. , Villanueva Rafael , Lopez-Tarruella Cobo Sara , Im Seock-Ah , Kim Sung-Bae , Gates Mary R. , Monemi Sharareh , Chen Ya-Chi , Moore Heather , Loi Sherene , Sohn Joohyuk 
Published: May 2020

1023 Background: GDC-9545 is a potent, orally available, selective estrogen receptor degrader developed for the treatment of ER-positive (ER+) breast cancer alone or combined with CDK4/6 inhibitors. A first-in-human study evaluated 10-250 mg GDC-9545; tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical results support expansion cohorts at ≥30 mg (Jhaveri et al., 2019). Methods: This study evaluated PK, PD, and efficacy of GDC-9545 alone and combined with palbociclib, ± LHRH agonist. Eligible patients (pts) had ER+ (HER2-) metastatic breast cancer (MBC) with ≤ 2 prior therapies in the advanced or metastatic setting. No prior treatment with CDK4/6 inhibitor was allowed in pts receiving palbociclib. Results: Eight-five pts were enrolled in 2 cohorts: GDC-9545 100 mg given once daily ± LHRH agonist (Cohort A), and GDC-9545 100 mg +125 mg palbociclib on a 21 day on/7 day off schedule ± LHRH agonist (Cohort B). Of the 39 pts in Cohort A, adverse events (AE) occurring in ≥10% of pts were fatigue, cough, back pain, pain in extremity, and arthralgia. Related AEs were generally Grade (G) 1-2; there were 3 related G3 AEs of fatigue, transaminase increased, and diarrhea. Two pts had GDC-9545 reduced, one due to G3 diarrhea and another due to G3 transaminitis. Of the 46 pts in Cohort B, AEs in ≥10% of pts were neutropenia, fatigue, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, pruritus, and visual impairment. Twenty-six (57%) pts had G≥3 AEs. G≥3 neutropenia was reported in 23 (50%) pts. One pt had palbociclib reduced due to G3 febrile neutropenia. Eleven (13%) of 85 pts had G1 asymptomatic bradycardia considered related to GDC-9545. No pts in either cohort discontinued study treatment due to AEs. PK analysis and clinical data demonstrate no clinically relevant drug-drug interactions between GDC-9545 and palbociclib. Reduced ER, PR, and Ki67 levels, and an ER activity signature, were observed in paired pre- and on-treatment biopsies (n = 12). Eighteen of 33 pts in Cohort A had either confirmed partial responses or were on study 24 weeks (clinical benefit rate 55%). Clinical benefit was observed in pts with prior fulvestrant treatment and with detectable ESR1 mutations at enrollment. Clinical benefit data for both cohorts are anticipated to be mature in April 2020. Conclusions: GDC-9545 was well-tolerated as a single agent and in combination with palbociclib with encouraging PK, PD, and anti-tumor activity in ER+ MBC to support Phase III development. Clinical trial information: NCT03332797 .
A phase I dose escalation and expansion study of the next generation oral SERD AZD9833 in women with ER-positive, HER2-negative advanced breast cancer.
Authors: Hamilton Erika Paige , Oliveira Mafalda , Banerji Udai , Hernando Cristina , Garcia-Corbacho Javier , Armstrong Anne , Ciruelos Eva , Patel Manish R. , Incorvati Jason , Twelves Chris , Brier Tim , Carroll Danielle , Fox Steven , Klinowska Teresa , Lindemann Justin P O , Mather Richard , Maudsley Rhiannon , McGuinness Sam , Sykes Andy , Baird Richard 
Published: May 2020

1024 Background: AZD9833 is an oral selective estrogen receptor (ER) antagonist and degrader (SERD) that has shown antitumor efficacy in a range of preclinical models of breast cancer. Methods: SERENA-1 (NCT03616587) is an ongoing Phase 1, open-label study in pre- and post-menopausal women, after ≥1 endocrine therapy and ≤2 prior chemotherapies for ER+ HER2- advanced breast cancer (ABC). The primary objective is to determine the safety and tolerability of AZD9833 once daily (QD), with dose-limiting toxicities (DLTs) in 28d defining the maximum tolerated dose. Secondary objectives include pharmacokinetics and anti-tumor response. Pharmacodynamic (PD) analysis includes ER modulation in paired tumor biopsies and ctDNA dynamic changes. Results: At 20 January 2020: 60 patients were treated (median prior therapies 5 (1–9); prior fulvestrant (Fv) 82%; prior CDK4/6i 68%) across five doses; 25 mg QD n=12, 75 mg QD n=12, 150 mg QD n=13, 300 mg QD n=13, 450 mg QD n=10. AZD9833 exposure was dose proportional after multiple doses, with a median terminal t1/2 of 12h. Treatment-related AEs experienced by ≥10% of patients were visual disturbances (53%; 91% G1, 6% G2, 3% G3), bradycardia/sinus bradycardia (45%; 93% G1, 7% G2), nausea (18%; 46% G1, 55% G2), fatigue (13%; 38% G1, 63% G2), dizziness (10%; 83% G1, 17% G3) vomiting (10%; 50% G1, 33% G2, 17% G3), and asthenia (10%; 67% G1, 33% G2). Three patients experienced DLTs: G3 QTcF prolongation (300 mg); G3 vomiting (450 mg); and a combination of G2 visual disturbance, G2 headache and G2 gait disturbance (450 mg). DLTs resolved with dose reduction. No G4 or 5 AEs were reported. Efficacy data are presented in the table below; objective response rate (ORR) and clinical benefit rate (CBR) at 24 weeks. Clinical trial information: NCT03616587 . ER signalling pathway modulation was observed in all dose cohorts. In patients where clinical responses occurred and paired biopsies obtained, 98% reduction in Ki67 was measured. Updated data will be presented. Conclusions: AZD9833 has an encouraging efficacy and dose-dependent safety profile. Evidence of clinical benefit and target engagement was observed at all dose levels in women with ER+ ABC, including patients pre-treated with CDK4/6i and Fv, and those with ESR1 mutations. A Phase 2 study comparing efficacy and safety of three doses AZD9833 vs Fv is planned (NCT04214288). [Table: see text]
Genomic mapping to identify mutations in RYR2 and AHNAK in basal-like breast tumors expressing PD-L1.
Authors: Cimas Francisco J , Manzano Aránzazu , Baliu Piqué Mariona , Perez Pedro , Nagy Ádám , Pandiella Atanasio , Gyorffy Balazs , Ocana Alberto 
Published: May 2020

1027 Background: Basal-like breast cancer is a specific subtype of breast tumors with limited therapeutic options. Although treatment with the anti-PD-L1 antibody atezolizumab has recently shown clinical activity in this setting, not all patients do respond even expressing high levels of PD-L1. In the present article we explored the presence of mutations in breast cancer tumors with high expression of PD1 and PD-L1 with the aim to identify molecular correlates associated with outcome. Methods: We used RNA-seq and mutational data from 971 breast cancer patients using the TCGA dataset, to identify mutations in patients with high levels of PD1 and PD-L1. Data analysis was performed using DESeq R and MAFTools Bioconductor packages. Transcriptomic signatures from the identified mutations were associated with outcome using the Kapplan-Meyer Plotter tool. We correlated the identified transcripts with immune populations using TIMER online tool and correlation between genes with Cancertool online platform. Results: We identified co-occurrent mutations in RYR2 and AHNAK in 8% and 5% of basal like tumors, respectively, in patients with high levels of PD1 and PD-1. The transcriptomic signature of these mutations conferred good prognosis for relapse free survival (RFS) and overall survival (OS). CXCL9 for RYR2 and GBP5, C1QA, IL2RG, CSF2RB and IDO1 for AHNAK were the most relevant genes identified in these signatures. Expression of CXCL9, GBP5, IL2RG and IDO1 correlated with the presence of immune cell populations mainly dendritic cells. This signature, including CXCL9, GBP5, C1QA, IL2RG, CSF2RB and IDO1 classified patients with favorable RFS (HR 0.27 CI 0.2-0.30; p = 1.1e-16) and OS (HR 0.18 CI 0.09-0.34; p = 6.8e-9). This signature showed a stronger prediction capacity compared with already described immunologic signatures. Finally we identify that LAG3 was the only gene commonly present in both signatures and correlated positively with the expression of PD1 and PD-L1. Conclusions: We describe two novel mutations which transcriptomic signatures associated with favorable outcome in basal-like tumors that express elevated levels of PD1 and PD-L1. Future studies should be performed to confirm the role of these mutations and signatures in relation with clinical activity of PD1/PD-L1 inhibitors.
Organ specificity dictates tumor immune infiltration and composition in metastatic breast cancer; lessons from a rapid autopsy tissue collection study.
Authors: Egelston Colt , Guo Weihua , Bacon Eliza , Ihle Kena , Simons Diana L , Avalos Christian , Tan Jiayi , Ye Jian , Wang Lei , Lim Min Hui , Han Zhen , Zhang Robert , Solomon Shawn T , Nwangwu Mary , Schmolze Dan , Lee Peter P. , Waisman James Ross 
Published: May 2020

1032 Background: Immune composition in the tumor microenvironment (TME) of patient tumors has proven to play a central role in the propensity of tumors to metastasize and respond to therapy. Evidence has suggested that the metastatic TME is immune aberrant, however limited sample size and numbers has made assessment of the immune TME in the development of multi-organ metastases difficult. Here we utilize a rapid autopsy tissue collection protocol to assess the infiltration and composition of the immune TME in numerous metastatic tissue sites, paired disease-free tissue sites, and the associated tissue draining lymph nodes. Methods: Post-mortem tissues were collected from six metastatic breast cancer patients shortly after death through City of Hope’s “Legacy Project for Rapid Tissue Donation” Program. The average post mortem interval (PMI) for tissue collection was 6 hours. Collected specimens include metastatic lesions and paired non-cancer samples from every cancer-involved organ, disease-free specimens from non-involved major organs, distant and tumor-draining lymph nodes (both cancer-infiltrated and disease free), as well as blood. Immediately following collection, specimens were processed into single cell suspension for flow cytometry. Over 80 immune cell phenotypes were assessed, including CD8+ and CD4+ T cell subsets, B cell subsets, natural killer (NK) cells, tumor associated macrophages (TAMs), dendritic cell subsets, and other cells. Results: Tumor infiltrated tissues were found to have comparable immune cell densities and composition compared to paired disease-free tissues of the same organ type. However, immune cell densities in metastatic tissues and disease-free tissues were significantly different between organ types, with lung immune infiltration consistently being greater than liver tissues. Differences in immune composition between tissue sites were also observed. Notably, liver tissues favored the presence of central memory CD8+ T cells, while lung tissues favored the presence of CD8+ tissue resident memory T cells. Relative to disease-free lung tissues, tumor infiltrated lungs contained diminished frequencies of CD8+ tissue resident memory T cells and altered B cell phenotypes. Conclusions: These data suggest that immune monitoring and trafficking of metastatic tissues site is dictated by organ type, which can be altered in composition by tumor infiltration. Further studies such as these may reveal organ-specific mechanisms of response to therapeutic interventions.