bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors for survival after relapsed acute lymphoblastic leukemia (ALL): A Children’s Oncology Group (COG) study.
Authors: Rheingold Susan R. , Ji Lingyun , Xu Xinxin , Devidas Meenakshi , Brown Patrick A. , Gore Lia , Winick Naomi J. , Carroll William L. , Hunger Stephen , Raetz Elizabeth A. , Loh Mignon L. , Bhojwani Deepa
Published: May 2019

10008

Background: Survival of pediatric ALL patients (pts) now approaches 90%, but is historically poor for those who relapse. Methods: In the largest cohort assembled to date we analyzed overall survival (OS) rate post relapse, defined as duration between date of relapse and death, among pts diagnosed from 1996-2014 treated on 10 contemporary COG frontline trials. Comparisons of post-relapse OS were based on logrank tests, with two-sided p values reported. Results: Of 15,874 pts enrolled on frontline trials, 1,967(12%) relapsed. Relapse rates ranged from 35% in infant ALL to 9.7% in pts with NCI standard risk B-ALL. Rates were similar for T and B-ALL, 11% vs. 12%. Relapse patterns differed by phenotype: almost half of non-infant B-ALL relapses occurred late (≥36 mos), and at all time periods bone marrow (BM) relapse predominated. Conversely 65% of T-ALL relapses were early ( < 18 mos) with similar number of isolated CNS (iCNS) and isolated BM (iBM) relapses. Median time to relapse was shorter for infant ALL and T-ALL (both 13.8 mos) compared to B-ALL (34.4 mos). The 5yr OS rates (±SE) after relapse for B, T, and infant ALL were 52±1%, 33±3% and 19±4%, respectively, with greater variability in OS by site in T vs. B-ALL. 5yr OS rates for pts with early BM relapse was similar for both B and T-ALL (28%), but pts with B-ALL who relapsed between 18-36 mos fared better than pts with T-ALL (OS 50±2% vs 34±8%, p = 0.014). The 5yr OS rates for pts with late relapses were 65±2% for B-ALL and 50±12% for T-ALL. In multivariable analysis, time to relapse, site of relapse, age < 1 or > 10 yrs at diagnosis, initial WBC > 100K, and T-cell phenotype were associated with worse outcomes post relapse (all p < 0.01). Sex, CNS status at diagnosis, or prior therapy on POG versus CCG/COG backbone did not influence OS. Compared to pts treated from 1988-2002 (Nguyen et al. Leukemia 2008), 5yr OS rate post relapse has improved over time for B-ALL from 37±2% to 52±1% (p < 0.001) and T-ALL from 23±4% to 33±3% (p < 0.05). 5-yr OS rates improved significantly for pts with iBM from 24±2% to 45±2% (p < 0.001) and marginally for pts with iCNS from 59±3% to 65±3% (p = 0.15). Conclusions: In the modern era there are fewer relapses for B and T-ALL, however sites of recurrence and outcomes differ by phenotype. Infants continue to do poorly. Compared to prior analyses, survival after relapse is significantly improved.
Pyrotinib combined with capecitabine in women with HER2+ metastatic breast cancer previously treated with trastuzumab and taxanes: A randomized phase III study.
Authors: Jiang Zefei , Yan Min , Hu Xichun , Zhang Qingyuan , Ouyang Quchang , Feng Jifeng , Yin Yongmei , Sun Tao , Tong Zhongsheng , Wang Xiaojia , Yao Herui , Zou Jianjun , Zhu Xiaoyu ,   for the PHENIX Study Group
Published: May 2019

1001

Background: Pyrotinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising anti-tumour activity and acceptable tolerability in patients with HER2+ metastatic breast cancer (MBC) in phase 1/2 trials. Methods: This double-blinded, multicentre, randomised phase 3 trial was conducted in Chinese patients with HER2+ MBC previously treated with taxanes and trastuzumab. Patients were randomly assigned (2:1) to receive 400 mg pyrotinib or placebo orally once daily for 21-day cycles in combination with capecitabine (1000 mg/m2 orally twice daily on days 1–14). The primary endpoint (IRC-assessed progression free survival [PFS]) was assessed in patients who received ≥1 dose of study treatment. Patients whose disease progressed on placebo plus capecitabine received subsequent single agent pyrotinib. Results: Between July, 2016 and November, 2017, 279 patients were randomised to pyrotinib plus capecitabine (n = 185) or placebo plus capecitabine (n = 94) arms. The median PFS was 11.1 months (95% CI 9.66, 16.53) in the pyrotinib plus capecitabine arm and 4.1 months (95% CI 2.79, 4.17) in the placebo plus capecitabine arm. seventy-one patients in placebo plus capecitabine arm received subsequent pyrotinib, showing single-agent response rate of 38.0% (95%CI 26.7%, 49.3%) and median PFS of 5.5 months (95% CI 4.07, 6.90). The most frequent (≥5%) treatment-related ≥ grade 3 adverse events were diarrhoea (30.8% vs 12.8% ) and hand-foot syndrome (15.7% vs 5.3%). Conclusions: In women with HER2+ MBC previously treated with taxanes and trastuzumab, pyrotinib plus capecitabine yield statistically significant better PFS. Pyrotinib monotherapy showed anti-tumour activity. Clinical trial information: NCT02973737. [Table: see text]
Upfront azacitidine (AZA) in juvenile myelomonocytic leukemia (JMML): Interim analysis of the prospective AZA-JMML-001 study.
Authors: Niemeyer Charlotte M. , Flotho Christian , Lipka Daniel B. , Starý Jan , Rössig Claudia , Baruchel Andre , Klingebiel Thomas , Micalizzi Concetta , Michel Gérard , Nysom Karsten , Rives Susana , Schmugge Liner Markus , Zecca Marco , Baumann Irith , Benettaib Bouchra , Poon Jennifer , Simcock Mathew , Patturajan Meera , Van Den Heuvel-Eibrink Marry M. , Locatelli Franco
Published: May 2019

10031

Background: Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for JMML patients (pts). Novel therapies controlling the disorder prior to HSCT are urgently needed. A phase 2, multicenter, open-label study was conducted to evaluate safety and anti-leukemia activity of AZA monotherapy prior to HSCT in pts with newly diagnosed (ND) JMML. Methods: AZA (75 mg/m2 IV) was administered once daily on days 1–7 of each 28-day cycle (C). Primary endpoint was number of pts with clinical complete remission or clinical partial remission (cPR) at C3 day (D) 28 (C3D28). Results: 18 JMML pts (13 PTPN11-, 3 NRAS-, 1 KRAS-, 1 NF1-mutated) were enrolled from 09/2015 to 11/2017. Median (range) white blood cell and platelet (Plt) counts were 19.7 (4.3–59.0) × 109/L and 28 (7–85) × 109/L, respectively. DNA methylation class (MC) was high, intermediate (int), or low in 11, 5, and 2 pts, respectively. 16 pts completed C3 and 5 pts C6. 2 pts discontinued treatment (Tx) pre-C3D28 due to disease progression (PD). 6 pts (33%) had ≥ 1 grade (Gr) 3–4 manageable adverse event (AE) related to AZA. Most common Gr 3–4 AEs related to AZA were neutropenia (2) and anemia (2). 11 pts (61%) were in cPR at C3D28; 7 had PD at C3D28 or prior. All 7 pts of the int/low MC and 4/11 in high MC achieved cPR. 17 pts received HSCT at median of 58 days (37–518) from last AZA dose; 14 were leukemia-free at a median follow-up of 15.7 months (0.1–31.7) after HSCT. 2 pts (high MC) given HSCT relapsed after allograft. 16/18 pts were alive at a median follow-up of 19.8 months (2.6–37.3) from diagnosis. 1 pt discontinuing Tx prior to C3 died from PD; 1 non-responder died from transplant-related causes. Plt response in pts with cPR prompted retrospective comparison of Plt counts at time of HSCT with a historical registry control cohort. Pts with NF1-mutated JMML with higher Plt counts versus other genetic subtypes were excluded. While 7/16 (44%) study pts had Plt counts ≥ 100 × 109/L at HSCT, only 10/58 (17%) historical cohort pts reached this cutoff ( P < 0.01). Conclusions: This study shows that AZA monotherapy was well tolerated in pts with ND JMML. Although the long-term advantage of AZA Tx remains to be fully assessed, responses show it was effective in JMML and provided clinical benefit to pts in this study. Clinical trial information: NCT02447666.
A phase II clinical study of pomalidomide (CC-4047) monotherapy for children and young adults with recurrent or progressive primary brain tumors.
Authors: Fangusaro Jason R. , Locatelli Franco , Garré Maria Luisa , Marshall Lynley V. , Massimino Maura , Benettaib Bouchra , Biserna Noha , Poon Jennifer , Quan Jackie , Conlin Erin , Lewandowski John , Simcock Mathew , Jeste Neelum , Hargrave Darren R , Doz Francois P. , Warren Katherine E.
Published: May 2019

10035

Background: Central nervous system (CNS) tumors are the most common cause of pediatric cancer mortality and novel therapies are needed for refractory disease. Pomalidomide (pom) is an oral immunomodulatory agent with CNS penetration, anti-angiogenic, anti-inflammatory and cytotoxic activity. Methods: This Phase 2 study evaluated both safety and efficacy of pom in pediatric patients with recurrent/progressive CNS tumors. Using a Simon’s two-stage design, patients were stratified to high-grade glioma [HGG], ependymoma, medulloblastoma or diffuse intrinsic pontine glioma [DIPG] cohorts. Patients received pom 2.6 mg/m2 for 21 days of a 28-day cycle. The primary endpoint was objective response rate (complete response [CR], partial response [PR]) or prolonged stable disease [SD] (defined as ≥ 6 cycles, or ≥ 3 for DIPG). Stage 1 required ≥ 2/9 subjects, within each cohort, to have a response or prolonged SD to move into Stage 2, and ≥ 5/20 responders or patients with prolonged SD at the end of Stage 2 for pom to be deemed effective. Results: Of 52 treated patients (median age 11.5 y/o; range 4-18), 47 were evaluable for primary endpoint. Median treatment duration was 2 cycles (range 1-16). Only the HGG cohort met protocol-defined criteria to advance to Stage 2, with one PR and one prolonged SD in Stage 1. Forty-six of 47 evaluable patients discontinued pom, due to adverse event (n = 1; pneumonia), withdrawal by parent/guardian (n = 2), death (n = 4; 3 progressive disease, 1 sepsis), or progressive disease (n = 39). Nineteen of 52 treated patients experienced ≥ 1 grade 3–4 treatment-emergent adverse event (TEAE) related to pom, neutropenia (n = 15) being the most commonly reported. Twenty-six patients died on study. All deaths were attributed to either disease progression or complications from disease. Conclusions: Single agent pomalidomide failed to meet a clinically meaningful level of efficacy in children with recurrent/progressive HGG, DIPG, medulloblastoma or ependymoma. However, it should be noted that a sustained response was observed in a child with HGG, replicating the outcome observed in one child with HGG in the Phase 1 (PBTC-043) trial. Clinical trial information: NCT03257631.
Alfa-feto protein (AFP) as a predictor of outcome for children with germ cell tumors: A report from the malignant germ cell international consortium.
Authors: O'Neill Allison Frances , Xia Caihong , Krailo Mark D. , Shaikh Furqan , Pashankar Farzana D. , Billmire Deborah F , Olson Thomas Arthur , Amatruda James F. , Villaluna Doojduen , Malogolowkin Marcio H. , Rodriguez-Galindo Carlos , Frazier A. Lindsay
Published: May 2019

10036

Background: There are several studies describing the correlation between unsatisfactory tumor marker decline and poor prognosis in adult patients treated for germ cell tumors. In pediatric patients the data is limited. We therefore retrospectively analyzed data collected from pediatric patients treated on the Children’s Oncology Group (COG) Protocol AGCT0132 to determine whether a relationship exists between AFP decline and outcome. Methods: One hundred and thirty-one patients with germ cell tumors enrolled on Children’s Oncology Group Protocol AGCT0132 were eligible for analysis of AFP decline. Serum AFP half-life was calculated from levels collected post-operatively and after the start of chemotherapy, excluding values in the first 7 days of chemotherapy to accommodate unpredictable increases in the initial days of treatment. AFP decline was defined as automatically satisfactory (AFP normalized within the first two AFP measures following the start of chemotherapy), calculated satisfactory (AFP half-life ≤7 days following the start of chemotherapy), and unsatisfactory. Results: The 3-year event-free survival (EFS) was 87 % (95% confidence interval-CI: 79-92 %) for patients with a satisfactory decline and 62 % (95% CI: 31-82 %) for patients with an unsatisfactory decline (p = 0.006). In stratified analyses, this effect was limited to patients ≥11 years of age and with standard risk (SR2) disease ((p = 0.002 and p = 0.004, respectively). Three-year overall survival for patients with satisfactory versus unsatisfactory decline was not statistically significant. Conclusions: This study is the first to show an association between AFP decline and EFS in pediatric patients. Although there is no statistically significant association between tumor marker decline and overall survival, recognition of patients at high-risk of relapse may allow for early intensification of therapy and impact the rationale for future clinical trial design.
Randomized phase II study of eribulin mesylate (E) with or without pembrolizumab (P) for hormone receptor-positive (HR+) metastatic breast cancer (MBC).
Authors: Tolaney Sara M. , Barroso-Sousa Romualdo , Keenan Tanya , Trippa Lorenzo , Hu Jiani , Luis Ines Maria Vaz Duarte , Wulf Gerburg M. , Spring Laura , Sinclair Natalie Faye , Andrews Chelsea , Pittenger Jessica Demeo , Richardson Edward T. , Dillon Deborah , Lin Nancy U. , Overmoyer Beth , Partridge Ann H. , VanAllen Eliezer , Mittendorf Elizabeth A. , Winer Eric P. , Krop Ian E.
Published: May 2019

1004

Background: Studies of checkpoint inhibitor monotherapy show only modest activity in HR+ MBC. We report data from the first randomized study comparing E plus P versus E alone in HR+/HER2- MBC. Methods: Eligible patients (pts) had HR+/HER2- MBC, ≥2 lines of hormonal therapies and 0-2 lines of chemotherapy for MBC. Pts were randomized 1:1 to E 1.4mg/m2 intravenously (IV) on d1 and d8 with P 200 mg/m2 IV on d1 of a 21-day cycle (Arm A) or E alone (Arm B). At time of progression, pts in arm B could crossover and receive P alone. Primary endpoint was progression-free survival (PFS). Key secondary endpoints were: objective response rate (ORR) and overall survival (OS). Exploratory analyses assessed the association between PFS and PD-L1 status, tumor-infiltrating lymphocytes (TILs), neutrophil-lymphocyte ratio (NLR), tumor mutation burden (TMB), and genomic alterations by next generation sequencing on archival tissue. Results: 88 pts initiated protocol therapy; the median age was 58, median prior lines of chemotherapy 1, prior lines of hormonal therapy 2. Median follow-up was 6.3 months. Median PFS and ORR were not different between Arms A and B (PFS 4.1 vs 4.2 months p = 0.38; ORR 25% and 34% respectively (p = 0.49). 14 patients initiated crossover treatment with pembrolizumab; 1 patient experienced a PR (ORR 7%). All-cause AEs occurred in 100% of pts (G3-4, 54.6%) including 2 treatment related deaths on Arm A, both from known AEs attributed to both drugs. PD-L1 assay was performed in 65 pts: 24 (36.9%) had PD-L1 positive ( > 1% with 22C3, centrally tested) tumors. PD-L1 status, TILs, NLR, TMB, and genomic alterations were not associated with PFS (Table). Updated data, including OS and genomic results, will be presented. Conclusions: Among pts with HR+/HER2- MBC, the combination of E and P was not associated with longer PFS than E alone in the ITT or PD-L1+ population, though the PD-L1+ subgroup had very limited power to assess P benefit. Clinical trial information: NCT03051659. [Table: see text]
Sponsorship of pediatric oncology interventional trials.
Authors: Neel Dylan , Shulman David Stephen , DuBois Steven G.
Published: May 2019

10044

Background: The sponsor of a clinical trial is the single entity responsible for the overall conduct and oversight of the trial. Sponsors may be pharmaceutical/biotech companies (“industry”), government agencies (e.g. NIH), or other entities such as academic institutions. Trial sponsorship may have important regulatory and financial implications for the trial intervention under investigation. We sought to compare oncology trial sponsorship based upon age of eligibility. Methods: We used the clinicaltrials.gov database to evaluate all interventional trials from September 1, 2009 to December 1, 2018. We included all trials regardless of indication and then separately analyzed only oncology trials. We analyzed sponsor status as “industry”, “government”, or “other”. Results: Sponsorship data were available for 59,582 interventional trials across all disciplines (n = 15,564 oncology trials). Across all disciplines and ages of eligibility, lead trial sponsorship was 34% industry, 5% government, and 61% other. Across all oncology trials, sponsorship mix was similar: 31% industry; 6% government, and 62% other. Among adult oncology trials (age of eligibility starting at age 18 years), trial sponsorship was 33% industry, 6% government, and 61% other. Among pediatric-only oncology trials (age of eligibility capped < 18 years), trial sponsorship was 25% industry, 1% government, and 74% other. 5% of industry sponsored trials across all indications were pediatric-only compared to 0.63% of industry-sponsored trials in oncology. 95% of industry sponsored pediatric-only oncology trials were phase 1 or 2 trials, compared to 90% in adults. Conclusions: Pediatric-only interventional oncology trials are less likely to be industry sponsored compared to adult oncology trials or trials across all disciplines. Less than 1% of industry sponsored interventional trials in oncology focus on children < 18 years of age.
Male fertility preservation (FP) at pediatric cancer centers: A report from the Children’s Oncology Group (COG).
Authors: Levine Jennifer , Brackett Julienne , Cherven Brooke , Frederick Natasha , Klosky James L. , Ahmed-Winston Sameeya , Bryson Elyse , Kelvin Joanne Frankel , Quinn Gwendolyn P. , Meacham Lillian R. , Freyer David Robert , Dvorak Christopher C. , Chow Eric Jessen
Published: May 2019

10050

Background: Preserved fertility after cancer is a priority for male survivors and their families. Sperm banking (SB) before initiation of treatment is standard of care for post-pubertal males. Experimental testicular tissue cryopreservation (TTC) is the only current option for pre-pubertal boys. ASCO recommends TTC be carried out under an experimental protocol. We surveyed COG sites about their FP infrastructure and practices. Methods: A REDcap survey was emailed to one individual previously identified as knowledgeable about FP or the Principal Investigator at each COG site. Site specific factors associated with outcomes were determined using logistic regression. All study procedures were IRB-approved. Results: Responses were received from 144 of 220 institutions (65%). Discussions about fertility were reported as routinely held with all post-pubertal males, all males “at risk” of infertility, and all males at 108 (75%), 100 (69%), and 55 (38%) institutions, respectively. SB was available at 135 (94%) sites; 105 (73%) offer SB inpatient and outpatient, 88 (64%) offer SB to all post-pubertal males, and 39 (28%) offer SB after chemotherapy has started. TTC was accessible at 37 (27%) sites and was independently associated with large (>120 new patients/year) size (odds ratio [OR] 3.3 95% confidence interval [CI] 1.2-9.3), and the presence of a FP navigator/team [OR 3.3 CI 1.4-7.8). Seventeen sites (12%) offered TTC by referring elsewhere, 14 (10%) under an IRB protocol and 6 (4%) as a clinical service. Conclusions: SB is widely available across participating COG sites, however only 2/3 of sites offer banking to all post-pubertal males. The availability of TTC at treating institutions is quite limited. This access may be modifiable given the association of an established FP navigator/team with the ability to offer and/or refer patients to outside institutions for TTC. There are practices, such as SB after the start of treatment and offering TTC as a clinical service, that do not align with guideline recommendations. These survey results suggest FP services remain inadequate in this patient population and highlight opportunities for research leading to interventions.
Morbidity and mortality in a national cohort of pediatric patients with hemophagocytic lymphohistiocytosis.
Authors: Allen Steven William , McCormick Meghan , Kalpatthi Ram , Rapkin Louis
Published: May 2019

10062

Background: Despite significant advances in diagnosing and treating hemophagocytic lymphohistiocytosis (HLH) in the pediatric population, survival remains low and the extent of disease morbidity and health care utilization is poorly characterized. Thus, we sought to investigate morbidity, mortality, and the health care burden of HLH in a pediatric population. Methods: We queried the Pediatric Health Information System (PHIS) for children admitted with HLH and treated with etoposide and dexamethasone between 1/1/2004 – 9/30/2018. Collected data included demographics and clinical variables associated with morbidity and mortality. Results: A total of 493 patients (10.5 per 100,000 patients admitted) met inclusion criteria during the study period. The majority of patients (n = 284, 58%) were less than 5 years of age. A total of 331 patients were readmitted after the initial hospitalization, with 29% of readmissions complicated by infections. Median cost for initial hospitalization was $101,906 (IQR: $47,552 – $271,822). A significant number of patients required ICU care during both the initial admission (60%) and readmission (57%). Hematopoietic stem cell transplant (HSCT) was performed in 136 patients (28%) with a median time to HSCT of 126 days (IQR: 75-193 days). Overall mortality was 32% (n = 158), half occurring during the initial admission. There was a trend towards increased mortality in younger age groups. Median time to death during and after the initial admission was 45 days (IQR: 20-84 days) and 198 days (IQR: 108-368 days), respectively. Post-HSCT mortality rate was 35%. Conclusions: This represents the largest cohort of pediatric patients treated for HLH. Overall and post-HSCT mortality was consistent with prior publications. We observed significant morbidity and increased health care resource utilization in our cohort. These findings emphasize the need for novel therapeutic approaches to improve not only patient survival but also long-term quality of life. Planned future analysis of the PHIS data will be aimed at assessing treatment variability, morbidity and mortality depending on treatment, and risk factors associated with mortality in pediatric patients with HLH.
A randomized phase II study of palbociclib plus exemestane with GNRH agonist versus capecitabine in premenopausal women with hormone receptor-positive metastatic breast cancer (KCSG-BR 15-10, NCT02592746).
Authors: Park Yeon Hee , Kim Tae Yong , Kim Gun Min , Jung Kyung Hae , Kang Seok Yun , Park In Hae , Kim Jee Hyun , Lee Kyoung Eun , Ahn Hee Kyung , Lee Moon Hee , Kim Hee Jun , Kim Han Jo , Lee Jong In , Koh Su-Jin , Kim Ji-Yeon , Lee Kyung-Hun , Sohn Joohyuk , Kim Sung-Bae , Im Young-Hyuck , Im Seock-Ah
Published: May 2019

1007

Background: Endocrine treatment is preferred recommendation by clinical guidelines in premenopausal as well as postmenopausal women with hormone receptor(HR)-positive, HER2-negative metastatic breast cancer(MBC). In real-world clinical practice, however, substantial numbers of patients are treated with chemotherapy in earlier lines based on endocrine resistance and/or on physician’s concern of worse prognosis associated with aggressive tumor behavior and younger age. In terms of the chemotherapy regimens, capecitabine seems one of the most popular options. The purpose of this phase II study is to assess the safety and the clinical anti-tumor activity of exemestane plus GNRH agonist in combination with palbociclib versus capecitabine in premenopausal HR-positive MBC patients. Methods: This is a prospective, two-arm, randomized, multi-center open-label phase II study of the Korean Cancer Study Group. Patients were allowed with previous 1 line of chemotherapy for MBC. De Novo metastatic patients should have been treated with tamoxifen before enrollment. Patients were randomized to chemotherapy (capecitabine 1250 ㎎/㎡twice a day from day 1 to 14 every 3 weeks) or endocrine therapy combination (exemestane 25 mg for 28 days and palbociclib 125 mg for 21 days every 4 weeks with GNRH agoinst). Primary endpoint was Progression-Free Survival (PFS). Results: Among 189 patients enrolled between 2016 and 2018 from 14 centers, 184 patients were randomly assigned to chemotherapy (n = 92) or endocrine therapy with palbociclib (n = 92). Median age was 44 (range 28-58). De Novo MBC was found equally in both arm (30%). During median 14 months of follow-up, median PFS was superior in endocrine with palbociclib than in capecitabine arm [19.0 vs. 11.3 months, p = 0.0493 by log-rank test; Hazard Ratio (HR) 0.643 (0.415-0.999), p = 0.0493]. Approximately half of the patients (51%) were treatment naïve in the advanced setting (49% for palbociclib vs. 51% for capecitabine). Grade III or more hematologic toxicities were more common in palbociclib than in capecitabine with statistical significance (60.9% vs. 19.2%, p < 0.0001). Diarrhea (11% vs. 38%) and Hand-Foot syndromes (1% vs. 76%) were more common in capecitabine arm. Conclusions: Exemestane plus palbociclib with ovarian suppression showed clinical benefit in terms of PFS compared with capecitabine in patients with premenopausal ER-positive MBC. Clinical trial information: NCT02592746.
Real-world treatment patterns and outcomes in ER+/PR+/HER2+ metastatic breast cancer (MBC) patients: A National Cancer Database analysis.
Authors: Statler Abby , Nahleh Zeina A. , Hobbs Brian , Wei Wei (Auston) , Gupta Annie , Blake Cassann N.
Published: May 2019

1033

Background: Treatment patterns and clinical outcomes are unclear for MBC patients diagnosed with estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+) human epidermal growth factor 2 positive (HER2+) disease (i.e. triple positive). This study aimed to: 1) examine the utilization of first-line therapy among ER+/PR+/HER2+ MBC patients and 2) compare overall survival (OS) between the identified regimens. Methods: We analyzed triple positive MBC patients included in the National Cancer Database who were treated with endocrine therapy (ET) or chemotherapy (chemo) between 2010 and 2015. Kaplan-Meier method was used to estimate distributions of OS, which were compared among patient cohorts using the log-rank test. Results: A total of 6,234 patients were included in the analysis; of these, 3770 (60%) received ET and 2464 (40%) received chemo. Of those with complete survival data, there was no difference in median OS between patients treated with chemo vs. ET; however, those who received anti-HER2 therapy had significantly better OS than those who did not (median OS 49.4 vs. 41.0 months, p < 0.0001). Median OS stratified by ET or chemo with and without anti-HER2 further supported these findings, revealing the addition of anit-HER2 therapy to chemotherapy and ET resulted in superior median OS (Table). Conclusions: This is the first study to evaluate treatment utilization and OS among real-world triple positive MBC patients treated with ET or chemo. Our results suggest the majority of patients in the United States are treated with first-line ET; furthermore, the reported OS outcomes support the consideration of ET plus anti-HER2 therapy as a first-line treatment option for ER+/PR+/HER2+ MBC. Prospective trials evaluating de-escalation of systemic therapy in this subgroup of patients and future research to identify biomarkers to determine which patients can avoid chemotherapy are warranted. [Table: see text]
Interim results from the full population of the phase 3b CompLEEment-1 study of ribociclib (RIBO) plus letrozole (LET) in the treatment of HR+/HER2– advanced breast cancer (ABC).
Authors: DeLaurentiis Michelino , Borstnar Simona , Campone Mario , Warner Ellen , Bofill Salvador , Jacot William , Dent Susan Faye , Martin Miguel , Ring Alistair E. , Cottu Paul H. , Lu Janice M. , Ciruelos Eva , Azim Hamdy A. , Chatterjee Sanjoy , Zhou Katie , Wu Jiwen , Ankrah Nii , Zamagni Claudio
Published: May 2019

1041

Background: RIBO, an oral, selective inhibitor of CDK4/6 (CDK4/6i), is approved for use in combination with endocrine therapy (ET) in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC in multiple countries worldwide. Here we report interim safety and efficacy results from CompLEEment-1, a phase 3b trial evaluating RIBO+LET in an expanded patient (pt) population and the largest CDK4/6i trial in ABC to date. Methods: Pts with HR+, HER2– ABC, ≤1 line of prior chemotherapy (CT), and no prior ET for ABC received RIBO+LET. Treatment regimens and study endpoints have been reported previously (De Laurentiis, et al. ASCO 2018. Poster 1056). Results: Overall, 3,246 pts, who received ≥1 dose of study treatment, were evaluated (cut-off date, August 8, 2018). Median duration of RIBO exposure was 8.1 months (min, 0.0; max, 22.4). Demographic and baseline characteristics indicated a diverse population including men (1.2%), premenopausal women (22.2%), and patients aged ≥70 years (19.5%). Pts were well represented in terms of age, race, and disease history; 5.9% of pts received prior CT for ABC. The only non-hematologic any-cause grade ≥3 AEs ≥5% were increased alanine (7.3%) and aspartate (5.3%) aminotransferase. Treatment-related AEs (any grade) led to discontinuation in 11.4% of pts. Of the 51 (1.6%) on-treatment deaths, 26 were due to study indication and 25 to other reasons. The median time to progression was not estimable (NE) (95% confidence interval [CI], 17.1-NE). Overall response rate was 20.5% (95% CI, 19.1%-21.9%) and clinical benefit rate was 66.1% (95% CI, 64.4%-67.7%). Consistent mean change from baseline in Functional Assessment of Cancer Therapy – Breast Cancer questionnaire scores indicated that pts maintained their quality of life throughout treatment. Conclusions: This interim analysis demonstrates the safety, tolerability, and efficacy of RIBO+LET in a large, diverse cohort of pts with HR+, HER2– ABC who had not previously received ET for ABC. Safety results were consistent with those observed in RIBO pivotal studies and no new safety signals were observed. Clinical trial information: NCT02941926.
A GINECO randomized phase II assessing addition of an aromatase inhibitor to oral vinorelbine in pretreated metastatic breast cancer patients.
Authors: Heudel Pierre , Arnaud Antoine , Frenel Jean-Sebastien , Chabaud Sylvie , You Benoit , Stefani Laetitia , Garnier-Tixidre Claire , Simon Helene , Beal-Ardisson Dominique , Jacquin Jean-Philippe , Del Piano Francesco , Lortholary Alain , Cornea Claudiu , Lharidon Tifenn , Largillier Remy , Brocard Fabien , Legouffe Eric , Atlassi Mustapha , Hardy-Bessard Anne-Claire , Bachelot Thomas Denis
Published: May 2019

1043

Background: For ER+/HER2- metastatic breast cancer (mBC), efficacy of endocrine therapy + chemotherapy combination remain an open question. We hypothesized that continuing ER targeted therapy after progression in combination with chemotherapy may improve disease control. The objective of the CHEOPS trial was to assess the benefit of adding aromatase inhibitor (AI) to metronomic chemotherapy,oral vinorelbine, 50mg/3 time a week (OV) for AI pre-treated, ER+/HER2- mBC patients. Methods: Eligible patients had to have progressed on endocrine therapy and one or two lines of chemotherapy. They were randomized between vinorelbine (OV) and vinorelbine + AI (OV+AI). Primary end point was progression-free survival (PFS). To show an increase of median PFS (from 3.5 to 5.5 month, HR 0.636), with alpha = 5% and power = 80%, 130 evaluable patients were needed. Results: 121 patients were Included (OV = 61; OV+AI = 60). Median age was 68 (range: 49-87), Median time from metastatic diagnosis was 3.2 years (range 0 - 16.9). 109 patients (90%) had visceral metastases. They all had previously received an AI and had been treated with one line (N = 66, 54.5%), or 2 lines (N = 55, 45.5%) of chemotherapy. Median PFS was increased from 2.3 months with OV to 3.7 months with OV+AI, but this difference was not significant (HR 0.73 [95 % CI 0.50-1.06], log-rank test: P = 0.09) 81 patients (67%) had at least one adverse event (AE) of grade ≥ 3 (40 (66%) for OV vs 41 (68%) for OV+AI). The most common grade ≥ 3 AE were: GT gammas (23%), neutropenia (18%), arterial hypertension and lymphopenia (17%). The occurrence of 3 toxic deaths (OV = 1; OV+AI = 2) secondary to febrile aplasia motivated the early cessation of this clinical trial. 9 patients (5 OV (10%) and 4 OV+AI (8%) presented an objective complete or partial response. Conclusions: The addition of AI to OV over OV alone in AI resistant mBC was associated with a non-significant improvement of PFS, but both PFS are lower than expected. Metronomic OV schedule, at 50 mg three times a week, requires close biological monitoring. The question of hormonal treatment and chemotherapy combination remains open. Clinical trial information: EudraCT Number: 2015-000401-39.
A phase Ib/II trial of lenvatinib (len) and letrozole (let) incorporating pharmacodynamics studies in postmenopausal women with hormone receptor positive (HR+) locally advanced/metastatic breast cancer (LABC/MBC).
Authors: Lim Joline Si Jing , Wong Andrea Li Ann , Ow Samuel Guan Wei , Eng Lim Siew , Sundar Raghav , Chan Gloria HJ , Yadav Kritika , Heong Valerie , Tan David Shao Peng , Soo Ross A. , Chee Cheng Ean , Yong Wei-Peng , Goh Boon C. , Lee Soo-Chin
Published: May 2019

1045

Background: Endocrine blockade (EB) is standard of care for patients (pts) with HR+ LABC/MBC. RET over-expression (RET+) occurs in up to 75% of HR+ breast cancers and is a postulated mechanism of endocrine resistance. Preclinical studies show cross talk between RET and estrogen receptor, and at least additive treatment (Tx) effect of Len+EB. Methods: We performed a phase Ib trial (3+3 dose escalation) to study safety, tolerability, pharmacodynamics and efficacy of Len+Let. Both drugs were given as continuous daily dosing with 2 weeks (wks) of Len alone, followed by Len+Let for 12 wks then surgery (LABC), or till disease progression (PD) (MBC). Serial tumor biopsies (n = 15) were done at baseline, after Len alone, 4 wks post Len+Let, and at surgery [LABC] / upon PD [MBC]. Results: 16 pts were treated (4 LABC, 12 MBC); Among MBC pts, median lines of prior Tx was 3 (range 0-10); 84.6%, 66.7%, and 58.3% had prior EB, EB+CDK4/6 inhibitor (i), and chemotherapy (CT) respectively. At dose level (DL) 1, 2/4 pts had dose-limiting toxicities (DLT). There was no DLT at DL-1, but 6/6 pts needed dose reductions (DR), with 4/6 DR within 6 wks of Len+Let (3 G3 hypertension [HTN], 1 G3 wound pain), deeming DL-1 intolerable. At DL-2, 0/6 pts had DLT; this was declared recommended phase 2 dose (RP2D). Most frequent G3 toxicities (tox) were HTN (6/16), proteinuria (2/16) and palmar-plantar erythrodysesthesia (PPE) (2/16), with no G4/5 tox. Len+Let was active with 93.8% overall disease control rate (DCR) (50.0% partial response [PR], 43.8% stable disease [SD]). Among MBCts (8/12 had prior EB+CDK4/6i), DCR ≥12 wks was 91.7%; 1 pt had sustained PR for 48 wks and 1 ongoing PR at 40 wks. 9/16 pts had RET+ tumors on immunohistochemistry at baseline, and 66.7% showed down-regulation with Tx (RECIST: 4 PR, 2 SD). Conclusions: Len+Let showed significant anti-tumor activity, even in pts who failed prior CT or EB+CDK4/6i. RP2D of 14mg Len and 2.5mg Let is tolerated with efficacy; dose expansion is currently underway. Clinical trial information: NCT02562118. [Table: see text]
Real-world evidence of male breast cancer (BC) patients treated with palbociclib (PAL) in combination with endocrine therapy (ET).
Authors: Bartlett Cynthia Huang , Mardekian Jack , Yu-Kite Michelle , Cotter Matthew James , Kim Sindy , Decembrino Jaclyn , Snow Tamara , Carson Kenneth R. , Motyl Rockland Jillian , Kraus Albert L. , Wilner Keith D. , Oharu Norihiko , Schnell Patrick , Lu Dongrui (Ray) , Tursi Jennifer
Published: May 2019

1055

Background: The rarity of BC in men limits the feasibility of randomized clinical studies in this population. Treatment guidelines recommend that men with BC be treated similarly to postmenopausal women. PAL, a cyclin-dependent kinase 4/6 inhibitor, is used in men with metastatic BC (mBC) in real-world clinical practice, presenting an opportunity to utilize real-world evidence to enable healthcare providers to assess novel agents in this space. Methods: Two parallel approaches were taken. In the first approach, pharmacy and medical claims data from IQVIA Inc were retrospectively analyzed to describe the treatment patterns and duration of PAL + ET (aromatase inhibitor or fulvestrant) compared to ET in men with mBC. The second approach was a retrospective analysis of data derived from electronic health records in the Flatiron Health database to understand real-world clinical response to PAL + ET vs ET alone. Median duration of treatment (mDOT) was estimated by the Kaplan-Meier method. Results: Between Feb 2015 and Apr 2017, 12.9% (147/1139 [IQVIA dataset]) of men receiving treatment for mBC were prescribed PAL + ET for any line of therapy. The mDOT in the first-line setting was numerically longer in the PAL cohort (n=37) compared with the non-PAL cohort (n=214; 8.5 vs 4.3 mo, respectively). In particular, mDOT in the first-line setting was longer with PAL + letrozole (LET; n=26) than with LET alone (n=63; 9.4 vs 3.0 mo, respectively). In the Flatiron Health dataset between Feb 2015 and July 2017, the real-world maximum response rate in the PAL + ET cohort across all lines of therapy in the mBC setting (n=12) was 33.3% (2 complete responses [CR], 2 partial responses [PR]) vs 12.5% (0 CR, 1 PR) for the ET alone cohort (n=8). Conclusions: The real-world data sources used in this study support that men with mBC derive clinical benefit from the addition of PAL to ET. Given the challenges of conducting randomized clinical trials in men with mBC, noninterventional, real-world evidence data appear to be useful to delineate the benefit of such therapies in this setting. Funding: Pfizer.
The clinical utility of strict laboratory monitoring of CDK 4/6 inhibitors in metastatic breast cancer patients.
Authors: Patel Urvi , Meisel Jane Lowe , Barbee Meagan Spencer , Frinzi Kristina , Sakach Elizabeth , Chen Zhengjia
Published: May 2019

1062

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) are widely used in the treatment of hormone receptor positive, metastatic breast cancer (MBC). CDK 4/6is are well-tolerated and highly effective, but can cause neutropenia. Therefore, the FDA mandates assessment of the absolute neutrophil count (ANC) every 2 weeks for the first 2 cycles of therapy and monthly thereafter. Strict ANC monitoring is optimal in theory, but presents a challenge in the real world, impacting quality of life for patients (pts) and adding financial burden to the healthcare system. This study aims to evaluate whether strict monitoring of ANC significantly impacts treatment decisions, pt safety, and disease outcomes. Methods: A retrospective chart review of 160 pts with MBC was conducted at the Winship Cancer Institute in pts prescribed CDK 4/6is from Feb 2015 to Jan 2019. The pt’s ANC at C1D1, C1D14, C2D1, C2D14 were recorded along with various pt outcomes. Pts were divided into strict monitoring (SM) or relaxed monitoring (RM) groups. SM is defined as pts who received ANC testing within 72h of C1D14, C2D1, and C2D14. RM was defined as not meeting those criteria. Results: Palbociclib was used in 152 pts; abemaciclib was used in 8. Average age was 58. Study population was 55% Caucasian; 38% African American; 6% Asian. Pts had an average of 3 lines of prior therapy and average of 9 cycles on a CDK 4/6i. 71% of pts suffered neutropenia (40% grade 3, 4% grade 4, 2.5% febrile neutropenia). PFS and OS did not statistically differ between groups (Table), but OS data is immature. Conclusions: This study analyzed a more diverse and heavily pre-treated MBC population than previous CDK 4/6 studies. The prevalence of neutropenia (grade 3/4) aligns with results described in the PALOMA trial. PFS was higher in the RM group than in the SM group, suggesting strict monitoring for neutropenia does not improve PFS. If ANC monitoring parameters could be safely relaxed for CDK 4/6i, it could improve quality of life and decrease financial toxicity across the system. This is a topic worthy of further study. [Table: see text]
AL101 mediated tumor inhibition in notch-altered TNBC PDX models.
Authors: Broner Esther Channah , Alpert Genia , Gluschnaider Udi , Mondshine Adi , Solomon Oz , Sloma Ido , Rauch Rami , Izumchenko Evgeny , Aster Jon Christopher , Davis Matti
Published: May 2019

1064

Background: The Notch pathway is activated during mammary gland development and has been implicated as a key driver in breast cancer. There is an urgent need to identify new therapeutic strategies for triple-negative breast cancer (TNBC), a sub-type associated with poor prognosis and no available targeted therapies. Notch gain of function (GOF) genetic alterations are potential tumor drivers found in ~10% of TNBC. This motivated the development of Notch inhibitors, including AL101 a pan-Notch, gamma secretase inhibitor (J Clin Oncol 36, 2018 abstract 2515). AL101 is currently being evaluated in Adenoid Cystic Carcinoma patients with activating Notch mutations (NCT03691207, ACCURACY trial). Here, we aim to test the activity of AL101 in TNBC patient derived xenograft (PDX) models with Notch activating genetic alterations. Methods: Gene expression cluster analysis was performed for 38 TNBC PDX tumors using a list of 21 Notch target genes. Seven tumors, bearing a “Notch-on” signature, were enriched with mutated/fusion (M/F) Notch genes and clustered separately from all other tumors. Of 9 models selected for study, 4 had a Notch-on signature and were expected to respond to AL101. Tumors were implanted into female athymic nude mice. Once tumors reached an average size of 150-300 mm3, mice (n = 5/group) were randomized to Vehicle or AL101 treatment arms (3 mg/kg, PO, 4on/3off) until tumors reached 1500 mm3 or day 60. Results: As measured by tumor growth inhibition (TGI), AL101 was more potent in tumors with a putative Notch-on signature. Within these 4 models, M/F genes were present in Notch1-NRR GOF (103% TGI p = 0.0004); Notch2-fusion (62%TGI p = 0.036); Notch3-fusion (75% TGI p = 0.032); or Notch4-fusion (147% TGI p < 0.00001). Tumors lacking the Notch signature did not respond significantly to AL101: WT Notch (43% TGI p = 0.0104; 64% TGI p = 0.13); Notch1 with a predicted loss of function mutation (12% TGI p = 0.53), Notch1 Variant of Unknown Significance (VUS) (30% TGI p = 0.44), Notch2 VUS (41% TGI p = 0.44). Conclusions: We demonstrate that in TNBC PDX models, the presence of a Notch-on signature and Notch GOF mutations/fusions correlates with potent response to AL101. These data support the clinical development of AL101 as a targeted therapy for TNBC with Notch GOF alterations.
Randomized, optimal dose-finding, phase II study of tri-weekly nab-paclitaxel in patients with metastatic breast cancer (ABROAD).
Authors: Hara Fumikata , Kitada Masahiro , Takahashi Masato , Kikawa Yuichiro , Kato Hiroaki , Sakata Eiko , Naito Yoichi , Hasegawa Yoshie , Saito Tsuyoshi , Iwasa Tsutomu , Tsurutani Junji , Taira Naruto , Takashima Tsutomu , Kashiwabara Kosuke , Aihara Tomohiko , Mukai Hirofumi
Published: May 2019

1070

Background: Although nab-paclitaxel (nab-PTX) has shown superior efficacy compared to conventional paclitaxel in metastatic breast cancer (MBC), chemotherapy induced peripheral neuropathy (CIPN) was more frequently observed in nab-PTX. In a single arm Phase 2 trail (CA002-0LD), low dose nab-PTX (175mg/m2) every 3 weeks (q3w) demonstrated a good objective response rate (39.5%) without grade 3 or higher CIPN. Herein, we conducted multicenter randomized controlled study to evaluate optimal dose of nab-PTX comparing lower dose (LD or MD) to standard dose (SD). Methods: This study compared three different doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2) in patients with HER2 negative metastatic breast cancer. Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses are estimated by the logistic regression. Optimal dose was selected by 2 step selection. At first, if hazard ratio (HR) for PFS was less than 0.75 or more than 1.33, the inferior dose was dropped. Then, if estimated incidence rate of grade 3/4 neurotoxicity exceed10%, that dose was also dropped. This trial is registered with the University Hospital Medical Information Network (UMIN), Japan (protocol ID C000012429). Results: In this study, 141 patients were randomly assigned to SD (n = 47), MD (n = 46) or LD (n = 48). Median PFS was 6.66 vs 7.34 vs 6.82 months, respectively. HR was 0.73 (95% confidence interval (CI): 0.42-1.28) in MD vs SD. SD was dropped due to inferiority to MD. HR was 0.77 (95%CI 0.47-1.28) in LD vs SD, and 0.96 (95%CI 0.56-1.66) in LD vs MD. LD and MD were carried over to next step due to equivalence. Overall survival was not different among all dose arms. Rate of dose reduction by treatment course was significantly higher in SD arm. Estimated incidence of grade 3/4 neurotoxicity rate was 29.5% in SD, 14.0% in MD and 5.9% in LD. Final selected dose was LD 180mg/m2. HR-QOL results will be presented. Conclusions: Low dose nab-PTX at 180 mg/m2/3 weeks could be an optimal dose with good clinical efficacy and tolerability for patients with MBC. Clinical trial information: C000012429.
Reversion and non-reversion mechanisms of resistance (MoR) to PARP inhibitor (PARPi) or platinum chemotherapy (chemotx) in patients (pts) with BRCA1/2-mutant metastatic breast cancer (MBC).
Authors: Waks Adrienne Gropper , Cohen Ofir , Kochupurakkal Bose , Kim Dewey , Wander Seth Andrew , Buendia-Buendia Jorge , Helvie Karla , Matulonis Ursula A. , Krop Ian E. , Tolaney Sara M. , Winer Eric P. , D'Andrea Alan D. , Shapiro Geoffrey , Lin Nancy U. , Wagle Nikhil
Published: May 2019

1085

Background: Little is known about MoR to PARPi and platinum chemotx in MBC pts with BRCA1/2 mutations. Biomarkers predictive of response/resistance have not been identified, but could have clinical utility. Methods: We obtained 8 BRCA-mutant metastatic tumor biopsies from MBC pts with acquired resistance to DNA-damaging tx (PARPi/platinum) on a prospective tissue collection protocol. In 7/8 patients, we also obtained pre-tx biopsies. Whole exome sequencing (WES) was performed on each tumor and on germline DNA from blood. We performed immunohistochemical (IHC) staining for RAD51 foci for functional assessment of intact homologous recombination (HR). Results: 4/7 pts with complete WES analysis acquired a somatic reversion mutation likely to result in functional BRCA1/2 protein in the post-tx tumor specimen after platinum (2 pts) or PARPi (2 pts; Table). 4/7 pts had plausible non-reversion MoR identified by WES, including alterations in genes involved in replication fork protection and DNA end resection. As expected, in all pts with genomic reversion, RAD51 foci were acquired in the post-resistance tumor, consistent with reconstitution of HR. In 2 pts without reversion, presence of RAD51 foci post-resistance was mixed. Reversion mutations occurred both with and without other alterations that could possibly lead to fork protection, suggesting > 1 MoR could occur in the same tumor. 3 pts whose tumors demonstrated RAD51 foci post-resistance were later re-exposed to DNA-damaging tx, to which all had intrinsic resistance. Conclusions: BRCA1/2 reversion was identified as a MoR in the majority of pts. WES identified potential novel MoR in fork protection and end resection genes. The presence of RAD51 foci by IHC was consistent with BRCA protein functional status from genomic data and predicted response to later DNA-damaging tx, suggesting RAD51 IHC may be a clinically useful biomarker. [Table: see text]