bluuebunny/crossref_metadata_2025 huggingface dataset:
The nature and management of acquired resistance to PD1-based therapy in melanoma.
Authors: Hepner Adriana , Versluis Judith M. , Gerard Camille Lea , Brown Lauren Julia , Wallace Roslyn , Bhave Prachi , Jansen Yanina , Klein Oliver , Warner Allison Betof , Mangana Joanna , Atkinson Victoria , Lo Serigne , Long Georgina V. , Johnson Douglas Buckner , McQuade Jennifer Leigh , Ascierto Paolo Antonio , Zimmer Lisa , Lebbe Celeste , Blank Christian U. , Menzies Alexander M.
Published: May 2020

10014

Background: Anti-PD1 therapy (PD1), either alone or in combination with anti-CTLA4, has high initial response rates, but 20% of patients (pts) with complete response (CR) and 60% with partial response (PR) experience disease progression by 5 years. The nature and best management of this acquired resistance (AR) remains unknown. Methods: Consecutive pts from 16 centers who achieved CR or PR to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics, nature of progression and subsequent treatments were examined. Results: 300 pts were identified, median age was 64y, 133 (44%) BRAF mutant and 55 (18%) had target therapy (TT) prior to PD1-based therapy. 173 (58%) received PD1 alone, 114 (38%) PD1+CTLA4 and 13 (4%) PD1 + an investigational drug. 89 (30%) pts had CR, 210 (70%) pts had PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2) and 142 (47%) progressed while still on drug. Most pts (N = 194, 65%) progressed in a single organ site, and in a solitary lesion (N = 154, 51%). 38 (25%) progressed in the brain only. AR was in new lesion in 136 (45%), existing lesions in 106 (35%), and both new and existing lesions in 58 (19%). For those with solitary lesion progression, 51 (33%) had local (L) treatment alone, 54 (35%) had local and systemic (L+ST), 46 (30%) had systemic therapy alone (ST) and 3 (2%) had no further treatment (BSC). If progression was non-solitary, 89 (61%) had ST, 33 (23%) L+ST, 17 (12%) L alone and 7 (5%) BSC. For those who received ST after AR, first ST (ST1) was PD1 alone in 130 (51%) [53, 41% continuation, 77, 59% reinduction], PD1+CTLA4 in 31 (12%), CTLA4 alone in 15 (6%), targeted therapy in 49 (19%) and investigational drugs in 29 (11%). Median follow-up from AR was 20 mo (95% CI 18-22). The ORR to ST1 was 46% for PD1 alone (56% continuation, 42% reinduction), 56% for PD1+ CTLA4, 0% for CTLA4 alone, 20% for investigational drugs and 67% for TT. Median OS from AR was 38 mo (95% CI, 34.6-NR). 2y-OS was 69% in those with solitary progression compared to 55% for the pts that had a non-solitary progression (p < 0.001). There was no difference in OS by ST1 class. Detailed analyses including nature and management of AR while on PD1 or after discontinuation will be presented, as will site-specific AR outcomes. Conclusions: Acquired resistance to PD1-based therapy in melanoma is usually oligometastatic, occurring approximately one year after PD1 start. Most pts with isolated progression have local therapy, and the most frequent subsequent systemic therapy is PD1-alone. Patients with AR can have meaningful survival, with median OS over 3 years from AR.
Does body mass index really predict the response to systemic therapies in metastatic melanoma: A multicenter study from the MelBase French National Cohort?
Authors: Di Filippo Yoann , Dalle Stéphane , Mortier Laurent , Dutriaux Caroline , Dalac Sophie , Leccia Marie Thérèse , Legoupil Delphine , Saiag Philippe , Brunet-Possenti Florence , Arnault Jean-Philippe , Maubec Eve , Granel-Brocard Florence , De Quatrebarbes Julie , Aubin Francois , Lesimple Thierry , Stoebner Pierre-Emmanuel , Lefevre Wendy , Dereure Olivier , Lebbe Celeste , Montaudie Henri ,   Team Melbase, Groupe de Canérologie Cutanée
Published: May 2020

10031

Background: Obesity is an established risk factor for several cancers and higher body mass index (BMI) is associated with poor prognosis. These data are still debated in melanoma. Furthermore, recently the concept of “obesity paradox” has emerged. In a large cohort published by McQuade JL et al, higher BMI was associated with better survival in patients with metastatic melanoma (MM) especially for those treated with targeted therapy (TT) and immune checkpoint inhibitors (ICI). We studied the association between BMI and progression-free survival (PFS) and overall survival (OS) in patients with MM treated with systemic therapies. Methods: This study was conducted from the prospective MelBase cohort (NCT02828202). Patients with MM treated with first-line ICI, TT, or CT were included. BMI was categorized by WHO criteria. Underweight patients were excluded. The co-primary outcomes were the associations between BMI and PFS or OS, stratified by treatment, sex and age. Multivariate analyses were performed. Results: A total of 1214 patients were analyzed. The majority of them were treated with ICI, followed by TT. Obese patients represented 22% of cohort (Table). Median follow-up was 13.5 months. The patients who were overweight or obese did not have different PFS (p = 0.88) or OS (p = 0.25) than patients with normal BMI. Stratifying this cohort by treatment received, age, sex and others parameters (such as LDH, number of metastatic site) did not revealed any difference. Multivariate analysis did not change the results. Conclusions: BMI was not associated with clinical outcomes in our cohort, especially in ICI and TT groups. Thus, we did not confirm the results presented by McQuade Jl et al. with a cohort quite similar in term of size. Because BMI is too simplistic and then an imperfect measure of body composition, the published data are not reproducible. We caution the oncologists, about BMI as valuable predictive marker of survival for melanoma patients. [Table: see text]
Health-related quality of life (HRQL) in patients with advanced cutaneous squamous cell carcinoma (CSCC) treated with cemiplimab: Post hoc exploratory analyses of a phase II clinical trial.
Authors: Migden Michael Robert , Rischin Danny , Sasane Medha , Mastey Vera , Pavlick Anna , Schmults Chrysalyne D. , Chen Zhen , Guminski Alexander David , Hauschild Axel , Bury Denise , Chang Anne Lynn S. , Rabinowits Guilherme , Ibrahim Sherrif F. , Lowy Israel , Fury Matthew G. , Li Siyu , Chen Chieh-I
Published: May 2020

10033

Background: Cemiplimab-rwlc (cemiplimab), a PD-1 Inhibitor, showed a robust clinical response in patients (pts) with metastatic (mCSCC) or locally advanced (laCSCC) CSCC not eligible for curative surgery/radiation. This post hoc exploratory analysis examined data from the EORTC cancer specific 30-item HRQL questionnaire (QLQ-C30) for pts participating in a cemiplimab phase 2 clinical trial (clinicaltrials.gov NCT02760498). Methods: Adults (N = 193) with invasive CSCC, ≥1 lesion and ECOG performance status ≤1 received IV cemiplimab 3mg/kg q2w (mCSCC n = 59; laCSCC n = 78) or 350mg q3w (mCSCC n = 56). At baseline (BL) and day 1 of each treatment cycle, pts were administered the QLQ-C30. Mixed effects repeated measures (MMRM) models were used to estimate mean change from BL to cycle 5 (C5) for domains/items of the QLQ-C30. For pts with data from BL to C5, the proportion who reported clinically meaningful improvement or worsening (≥10 points) or maintenance (those who did not have ≥10 point change) on each domain was determined for combined and individual treatment groups. Results: BL scores indicated moderate to high levels of functioning and low symptom burden. From BL to C5, a clinically meaningful improvement in pain score was observed (least squares [LS] mean [standard error] change -12.1 [2.1]; P< .0001); other domains/items remained stable or showed a trend towards improvement (LS mean changes < 10 points). By C5, the majority of pts experienced clinically meaningful improvement or remained stable across key domains (Table). Similar findings were observed on individual symptoms (85%-94% for dyspnea, nausea/vomiting, diarrhea, constipation, appetite loss) and in each treatment group. Conclusions: Cemiplimab-treated patients achieved a clinically meaningful reduction in pain and most pts either improved or maintained their HRQL, function with low symptom burden. Clinical trial information: NCT02760498. [Table: see text]
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.
Predictor of trastuzumab-induced cardiotoxicity in breast cancer (BC) patients: HER2/neu 655 polymorphisms, biochemical and clinical features.
Authors: Blancas Isabel , Gómez Celia , Martín-Pérez Francisco Javier , Garrido Jose Manuel , Rodríguez-Serrano Fernando
Published: May 2020

1033

Background: The introduction of trastuzumab in the treatment scheme of the HER2 BC patients has improved the evolution of the disease. Nevertheless, some of this patients develop cardiotoxicity. We studied some of our population of HER2 positive BC patients treated with trastuzumab trying to find predictors for developing cardiotoxicity, specifically the association of the HER2 Ile655Val A˃G polymorphism with trastuzumab-induced cardiotoxicity and with survival and some biochemical and clinical features. Methods: For the study breast cancer patients were recruited from San Cecilio University Hospital in Granada (Spain) who were treated with trastuzumab. HER2 Ile655Val A˃G polimorphism was performed in 93 patients using Taqman SNP technology. We analyzed the relation of polymorphisms with disease free survival (DFS) and overall survival (OS). We also could asses 66 patients who had biochemical measurement of NTpro BNP during the treatment with trastuzumab and cardiovascular risk factors including diabetes, hypertension, smoking, hypercholesterolemia and body mass index (BMI). Cardiotoxicity was defined as a ≥ 10% decrease of the left ventricular ejection fraction (LVEF) from baseline, a LVEF below 40% or any clinical manifestation of heart insufficiency. NT-proBNP cut-off points were considered to stablish normal or abnormal values adjusted by patient age. Results: Genotype frequencies of HER2/neu 655 met Hardy-Weinberg equilibrium (p = 0.363). Logistic regression analysis adjusted by hormonal status and anthracycline treatment showed higher cardiotoxicity risk for AG vs AA Her2-Ile655 polimorphism (OR = 3.00, CI95% 1.07-8.41, p = 0.037) or for AG vs AA+GG Her2-Ile655 polimorphism (OR = 3.21, CI95% 1.15-8.96, p = 0.026). We did not find association between HER2neu Ile655Val polymorphism and DFS or OS. NT-proBNP baseline higher than the range (OR 5.9, 95% CI 1.2 - 28.5, p = 0.028) and diabetes mellitus (OR 22.0, 95% CI 5.7 - 85.4, p = 0.000) were found to be related with the development of cardiotoxicity. Conclusions: HER2-Ile655 A˃G polymorphism is significantly associated with higher risk of trastuzumab-induced cardiotoxicity but it is not correlated with DFS neither OS. Diabetes or baseline high NT-proBNP levels are predictors for the development of trastuzumab-induced cardiotoxicity. These parameters should be considered for a closer follow up and for preventive actions as accurate glycaemic control for patients who will receive trastuzumab.
Management of adverse events in patients with HER2+ metastatic breast cancer treated with tucatinib, trastuzumab, and capecitabine (HER2CLIMB).
Authors: Okines Alicia Frances Clare , Paplomata Elisavet , Wahl Tanya A. , Wright Gail Lynn Shaw , Sutherland Stephanie , Jakobsen Erik , Valdes Frances , Chan Arlene , Clark Amy Sanders , Conlin Alison Katherine , Lustberg Maryam B. , Specht Jennifer M. , Pluard Timothy J. , Zhu Xiaofu , Krop Ian E. , Gelmon Karen A. , Slamon Dennis J. , Ramos Jorge , An Grace , Hamilton Erika Paige
Published: May 2020

1043

Background: Tucatinib (TUC) is an investigational TKI, highly selective for HER2 without significant inhibition of EGFR. HER2CLIMB is a randomized trial of TUC vs placebo in combination with trastuzumab and capecitabine in patients (pts) with HER2+ breast cancer (NCT02614794, Murthy NEJM 2019). The most common G ≥3 adverse events (AEs) with higher incidence on the TUC arm (diarrhea, palmar-plantar erythrodysesthesia syndrome [PPE], and elevated liver enzymes) are described herein. Methods: Given that pts on the TUC arm had a longer duration of tx than those on the control arm, time-at-risk exposure-adjusted incidence rates of diarrhea, AST, ALT, and PPE were calculated as the number of pts with an event divided by the total exposure time-at-risk of an initial occurrence of the event among pts in the tx group. Time-to-event analyses were conducted for AST/ALT/bilirubin (in aggregate), diarrhea, and PPE. Results: Diarrhea and elevated AST/ALT/bilirubin on both the TUC and control arms were primarily G1/2 and manageable with dose modifications, and in some cases of diarrhea, with antidiarrheal tx. Median time to diarrhea onset was shorter on the TUC arm compared to control. For AST/ALT/bilirubin and PPE, median time to first onset was Cycles 1 and 2. On the TUC arm, antidiarrheals were used in 49.7% of cycles in which diarrhea was reported (39.8% on the control arm), and when used, the median duration of use on each arm was 3 days per cycle. Prophylactic antidiarrheals were not required per protocol. When adjusted for exposure (time-at-risk exposure-adjusted incidence rate per 100 person-years), the difference in G ≥3 events between tx arms becomes similar for diarrhea and PPE (21 vs 17 and 21 vs 19). The difference in G ≥3 events between arms is reduced for AST and ALT (7 vs 1 and 8 vs 1). Conclusions: TUC with trastuzumab and capecitabine was well-tolerated. Rates of G ≥3 diarrhea and PPE were similar between tx arms. Elevated liver enzymes were higher on the TUC arm, but were transient and reversible. Discontinuation of TUC due to AEs was rare. Clinical trial information: NCT02614794 . [Table: see text]
Peripheral endothelial function changes during HER2-directed therapy differ based on whether or not a patient receives anthracycline.
Authors: Hazim Antonious Ziad , Nhola Lara F. , Villarraga Hector R. , Patel Shruti R , Sandhu Nicole , Lerman Amir , Loprinzi Charles L. , Ruddy Kathryn Jean , Herrmann Joerg
Published: May 2020

1044

Background: Trastuzumab is well-demonstrated to be associated with cardiotoxicity (typically reduced ejection fraction), most commonly in patients who also receive anthracycline. The vascular effects of trastuzumab and anthracycline are understudied; we aimed to compare change in endothelial function during and after trastuzumab and to assess how anthracycline receipt affects this. Methods: This is an observational prospective study of women with newly diagnosed HER2-positive breast cancer. All participants underwent baseline evaluation of endothelial function testing by use of the EndoPAT2000 device approximately every three months over the subsequent 18 months after the initiation of HER2-directed therapy +/- anthracycline. The primary endpoint was change in endothelial function over time using the reactive hyperemia index (RHI). Framingham Risk Score (FRS) and lower RHI are both known to be independent predictors of future cardiovascular events in the general population. RHI deterioration was defined as a 20% reduction from baseline RHI to any available follow-up RHI assessment. Univariate analyses assessed if age, FRS, baseline RHI, and RHI deterioration differed between recipients and non-recipients of anthracycline using the Wilcoxon test. A multivariate logistic model evaluated FRS, age, and anthracycline receipt as possible independent predictors of RHI deterioration. Results: Among 38 eligible patients who consented and completed baseline assessments in addition to at least one follow-up assessment, 17 (45%) subsequently received anthracycline. 145 total follow-up RHI assessments were available overall (5 per patient on average). There were no differences between recipients and non-recipients of anthracyclines with regard to age [mean 49 years (SD 12) vs 53 years (SD 11); p=0.25], baseline FRS [mean 1.0 (SD 1.0) vs 1.5 (SD 1.4); p= 0.28] or baseline RHI [mean 2.4 (SD 0.6) vs 2.1 (SD 0.7); p=0.09]. RHI deterioration was more common for anthracycline recipients (mean 43% vs 21%; p=0.004), and in the multivariate model, anthracycline use was the only independent predictor of RHI deterioration (odds ratio: 2.8; 95% confidence interval: 1.35-6.07; p=0.006). Conclusions: This study suggests that endothelial dysfunction is more common after combined anthracycline and HER2-directed therapy than after HER2-directed therapy alone. RHI should be further studied as a possible early biomarker of cardiovascular toxicity in patients receiving treatment for breast cancer.
Patient-matched tissue and liquid biopsies identify shared and acquired genomic alterations in breast cancer.
Authors: Sokol Ethan , Sivakumar Smruthy , Jin Dexter , Danziger Natalie , McGregor Kimberly , Pavlick Dean , Dennis Lucas , Ross Jeffrey S. , Frampton Garrett M. , Venstrom Jeffrey , Hegde Priti , Molinero Luciana , Oesterreich Steffi , Chung Jon
Published: May 2020

1050

Background: Liquid biopsy-based comprehensive genomic profiling (CGP) is a minimally invasive approach to potentially identify truncal driver alterations and mechanisms of acquired resistance. However, there are limited data comparing solid tissue and plasma biopsies from the same patient in breast cancer. Methods: CGP was performed on matched tumor tissue and plasma samples from 444 patients with breast cancer (Foundation Medicine, Inc.) to identify short variant mutations and rearrangements in at least 62 genes. ER/PR/HER2 status was abstracted for a subset of patients (n = 273). Patients were primarily ER+/HER2- (58%) with fewer HER2+ (16%) and TNBC (25%). Results: Samples were temporally heterogeneous with a median time between matched tissue-plasma collection of 276 days (interquartile range 45 - 650). Positive percent agreement (PPA) to tissue biopsy was 81.5% with higher PPA for collection interval ≤1y v > 1y (82.5% v 76.5%). PPA was highest in known truncal driver genes ( AKT1, PTEN, BRCA2, BRCA1, TP53, PIK3CA: 85-89% PPA). PPA of tissue to liquid biopsy was 50.5% with strong time dependence (62.4% ≤1y, 37.9% > 1y), presumably due to intervening therapies. Acquired alterations in liquid biopsy were primarily known resistance mechanisms ( ESR1, NF1, ERBB2, PIK3CA, PTEN, TP53, BRCA1, and BRCA2), were often polyclonal, associated with longer collection intervals, and exhibited higher prevalence in the ER+/HER2- subtype (62% ER+/HER2-, 33% HER2+, 42% TNBC). Acquired alterations significantly enriched in ER+ cases included ESR1, NF1, ERBB2 and TP53. For PIK3CA, a PPA of 84.6% was observed with solid as baseline and 79.1% with liquid as baseline; prevalence was similar (36.5% solid, 35.6% liquid). Alpelisib companion diagnostic alterations (CDx) had a similar PPA (84.0% solid, 83.3% liquid). Overall percent agreement (OPA) for PIK3CA CDx in paired samples was 91.4% (406/444). When acquired PIK3CA alterations are observed they tend to be subclonal, co-occur with shared PIK3CA alterations, and consist of rare alterations (E726K, E453K, M1043I). Conclusions: While high PPA to tissue was observed for alterations in truncal driver genes, acquired alterations observed in plasma were frequently polyclonal, often identify potential mechanisms of therapeutic resistance and are, in part, a function of time and intervening treatments relative to tissue CGP. These results demonstrate high PPA to tissue suggesting that liquid biopsy has clinical validity in identifying truncal alterations and can also identify acquired alterations in breast cancer.
Phase I study of regorafenib in combination with vincristine and irinotecan in pediatric patients with recurrent or refractory solid tumors.
Authors: Casanova Michela , Bautista Francisco , Campbell Hewson Quentin , Makin Guy , Marshall Lynley V. , Verschuur Arnauld , Canete Adela , Corradini Nadège , Ploeger Bart , Mueller Udo , Zebger-Gong Hong , Chung John Woojune , Geoerger Birgit
Published: May 2020

10507

Background: In pediatric patients with solid tumors, regorafenib demonstrated acceptable tolerability and preliminary anti-tumor activity. This phase 1 study evaluated regorafenib in combination with vincristine/irinotecan in pediatric patients with rhabdomyosarcoma (RMS) and other solid tumors. Methods: Patients with relapsed/refractory tumors received intravenous vincristine (1.5 mg/m2, Days 1 and 8) and irinotecan (50 mg/m2/day, Days 1–5) plus once-daily oral regorafenib (patients 6– < 24 months: 60 mg/m2 escalating to 65 mg/m2; patients 2– < 18 years: 72 mg/m2 escalating to 82 mg/m2) on either Days 1–14 (concomitant dosing) or Days 8–21 (sequential dosing) during each 21-day cycle. As per protocol, at least 50% of patients were required to have RMS. Results: At the time of the cut-off, of 21 treated patients (RMS, n = 12; Ewing sarcoma, n = 5; neuroblastoma, n = 3; Wilms tumor, n = 1), two had concomitant (72 mg/m2) and 19 had sequential (72 mg/m2, n = 6; 82 mg/m2, n = 13) dosing. Median age was 10 years (1.5–17.0). Patients received a median of 3 cycles (1–17); dose reductions of irinotecan occurred in 62% of patients. Grade 3 dose-limiting toxicities were reported in both patients receiving concomitant dosing (peripheral neuropathy and liver injury; pain, vomiting, febrile aplasia) and one patient each in the sequential groups (rash and elevated AST; thrombocytopenia). Concomitant dosing was discontinued. The maximum tolerated dose and recommended phase 2 dose (RP2D) of regorafenib in the sequential combination was 82 mg/m2. The most common grade ≥3 treatment-emergent adverse events were neutropenia (71%), thrombocytopenia (33%), leukopenia (29%), anemia (24%), and ALT increased (24%). The response rate was 38%, including 1 complete (RMS) and 7 partial responders (5 RMS, 2 Ewing sarcoma); 3 of whom had prior irinotecan. Six (4 with alveolar subtype) of 12 patients with RMS had a response. Nine patients (43%) had stable disease (maximum duration 17 cycles). After the cut-off, partial response was reported for two additional patients (1 RMS, 1 Ewing sarcoma). Conclusions: Regorafenib can be combined at its single agent RP2D of 82 mg/m2 with standard-dose vincristine/irinotecan (with appropriate dose modifications) in pediatric patients with refractory/relapsed solid tumors in a sequential dosing schedule. Clinical activity was observed in patients with sarcoma. Clinical trial information: NCT02085148.
Maintenance therapy with oral cyclophosphamide plus celecoxib in patients with metastatic Ewing sarcoma: Results of the Italian Sarcoma Group/AIEOP EW-2 study.
Authors: Puma Nadia , Sebastian Asaftei Dorin , Paioli Anna , Bisogno Gianni , Rabusin Marco , Coccoli Luca , Tamburini Angela , Milano Giuseppe Maria , Mascarin Maurizio , Bertulli Rossella , Grignani Giovanni , Manzitti Carla , De Leonardis Francesco , Podda Marta Giorgia , Prete Arcangelo , Picci Piero , Mura Rosamaria , Fagioli Franca , Longhi Alessandra , Luksch Roberto
Published: May 2020

10517

Background: The prognosis of patients with metastatic Ewing sarcoma remains poor. The primary aim of the ISG/AIEOP EW2 Study (EUDRACT# 2009-011197-15) was to evaluate the feasibility and efficacy of maintenance therapy with oral cyclophosphamide plus celecoxib. Methods: From June 1st 2009 to Nov 22nd 2019, 112 patients with metastatic Ewing sarcoma at onset entered the ISG/AIEOP EW2 study, consisting of induction chemotherapy, radiotherapy and/or surgery at the site of the primary tumor, a consolidation phase with high-dose busulphan/melphalan + autologous stem cell rescue, whole-lung irradiation (12-15Gy), and a maintenance phase of 180 days with cyclophosphamide 50 mg daily (35 mg/mq daily if age < 14 years) plus celecoxib 400 mg twice daily (250 mg/mq twice daily if age < 14 years). Exclusion criteria from the maintenance phase were disease progression, cardiac or gastro-intestinal comorbidity. For CTCAE v4.0 grade 3-4 toxicities a temporary interruption was planned. Results: Seventy-one patients were eligible and entered the maintenance phase. Median age was 16 years (range 13-41); sites of metastases were lung or single bone (n = 56) and multicentric metastatic spread (n = 15). Sixty-one patients terminated the maintenance phase, 4 patients are still on treatment, 1 patient interrupted the treatment due to auto-immune thrombocytopenia at 4 months, 5 patients were withdrawn throughout maintenance due to disease progression/relapse. The duration of maintenance therapy was 89% of the scheduled days, with a median suspension length of 12 days (range 1-44 days). Causes of temporary suspension were hematological toxicity (19 episodes), infections (12 episodes), gastrointestinal disorders (9 episodes), fluid retention/distal oedema (3 episodes), renal disorders (3 episodes). Median follow-up was 42 months. The 3-year EFS of patients who entered the maintenance phase was 0.79 ± 0.09 for lung or single bone, and 0.19 ± 0.11 for those with multicentric metastatic spread. Conclusions: This schedule of maintenance phase is feasible, despite previous intensive treatment. A longer follow-up is needed to monitor side effects and to evaluate clinical outcome of patients with lung or single bone metastases, while the outcome remains dismal for multicentric metastatic Ewing sarcoma. Clinical trial information: NCT02727387.