bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I trial of lorlatinib in patients with ALK-driven refractory or relapsed neuroblastoma: A New Approaches to Neuroblastoma Consortium study.
Authors: Goldsmith Kelly C. , Kayser Kimberly , Groshen Susan G. , Chioda Marc , Thurm Holger C. , Chen Joseph , Peltz Gerson , Granger Meaghan , Maris John , Matthay Katherine K. , Ghazarian Suzy , Park Julie R. , Berko Esther , Marachelian Araz , Mosse Yael P.
Published: May 2020

10504

Background: Lorlatinib, a potent ALK inhibitor, exerts unprecedented activity against neuroblastoma (NB) derived xenografts harboring common crizotinib-resistant ALK mutations, leading to a first in child phase I study. Methods: R/R NB patients (pts) > 12 months, with ALK mutations/amplification and prior ALK inhibitor (ALKi) treatment were eligible. Lorlatinib was administered in 28-day courses (C). For pts < 18 years, 5 dose levels (DL) (45, 60, 75, 95, 115 mg/m2/day) were assessed. DL5 (115 mg/m2/day) expansion is enrolling (cohort A1). For patients > 18 years, two DL (DL3a the adult RP2D of 100 mg/day and DL4a at 150mg/day) were assessed (cohort A2). Primary endpoint was dose-limiting toxicity (DLT) during C1 and neurocognitive toxicity through C2. Blood samples for circulating tumor DNA (ctDNA) were matched to radiologic restaging. Results: From 9/2017 to 1/2019, 33 eligible patients enrolled (13 with prior ALKi therapy), with median age (range) 5.5 years (2-17) on A1, 21.5 years (15-50) on A2. In A1, 3 pts each enrolled onto DL1-3, with no DLT’s. 5/10 pts enrolled on DL4, with no DLT’s. 1/3 on DL5 had a DLT of grade 3 diarrhea, with expansion ongoing. In cohort A2, 5 patients enrolled at 100 mg/day with no DLT’s; 6 enrolled at 150 mg/day, with one DLT (grade 4 reversible psychosis). Most common treatment-related adverse events were weight gain (90%, grade 1-3), hyperlipidemia (90%, grade 1-3), concentration/memory impairment (23%, grade 1-2), peripheral neuropathy (13%; grade 1-2, A2 only), and peripheral edema (10%; grade 1, A2 only). Lorlatinib steady state exposure at DL3 and DL4 was in the range of exposures seen in adult lung cancer patients at the 100 mg and 200 mg DLs. In A1, 1/18 had partial response (PR), 3/18 had minor responses (MR), and 4/18 had stable disease (SD). Of pts with MR, 2/3 had PR of soft tissue and 1/3 had complete response (CR) by MIBG. In A2 pts, 1/10 had CR, 3/10 PR, and 3/10 MR; Notably, 2/3 with PR had CR by MIBG. Of the pts with MR, one had PR and one CR by MIBG. Responses occurred across dose levels, ALK mutations, and in ALKi pre-treated pts with median courses of 2 (1-24) on A1 and 10.5 (2-28) on A2. Serial ctDNA results showed mutant ALK variant allele frequency trajectories that correlated with clinical response and emergence of novel ALK mutations in cis that corresponded with disease progression. Conclusions: Inhibition of ALK-driven NB with lorlatinib occurs with manageable toxicity and objective anti-tumor activity. Prospective ctDNA allows for monitoring of disease and evolution of resistance. Clinical trial information: NCT03107988.
Cardiomyopathy risk among childhood cancer survivors of African ancestry and its molecular mechanisms.
Authors: Sapkota Yadav , Qin Na , Ehrhardt Matthew J. , Wang Zhaoming , Wilson Carmen Louise , Estepp Jeremie , Rai Parul , Hankins Jane E , Burridge Paul , Jefferies John L. , Zhang Jinghui , Hudson Melissa M. , Robison Leslie L. , Armstrong Gregory T. , Mulrooney Daniel A. , Yasui Yutaka
Published: May 2020

10514

Background: Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial/ethnic disparities. Utilizing whole-genome sequencing data in the St. Jude Lifetime Cohort (SJLIFE), we previously identified two risk loci on chromosomes 1 (rs6689879) and 15 (rs9788776) for ejection fraction (EF) and cardiomyopathy in survivors of African ancestry. The rs6689879*C was associated with 4.2% reduction in EF and 21.6-fold risk of cardiomyopathy and the rs9788776*G was associated with 5.6% reduction in EF and 46.8-fold risk of cardiomyopathy. However, molecular mechanisms behind these genetic associations are unknown. Methods: We assessed the risk of clinically-assessed/graded (per the National Cancer Institute Common Terminology Criteria for Adverse Events) cardiomyopathy in childhood cancer survivors of African ancestry (n = 301) by comparing them with those of European ancestry (n = 1870), adjusting for known cardiovascular risk factors including hypertension, abnormal glucose metabolism, hypercholesteremia, hypertriglyceridemia, sedentary behavior, risky alcohol drinking and smoking. Molecular mechanisms underlying the chromosome 1 locus was investigated using DNA methylation data in 265 SJLIFE survivors of African ancestry and gene expression profiles in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of breast cancer patients. Results: Multivariable analysis showed survivors of African ancestry had 1.46-fold ( P= 0.067) and 2.43-fold ( P= 0.0039) higher risks of grade 2-4 and grade 3-4 cardiomyopathy. Results from DNA methylation data showed rs6689879*C was correlated with hypomethylation of a probe (cg16996019) located within the promoter region of PHTF1 (β = -0.10; P= 0.0014). Notably, the cg16996019 was also hypomethylated in survivors with cardiomyopathy (β = -0.15; P= 0.0028). These observations were further supported by upregulation (β = 0.45; P= 0.028) of PHTF1 in hiPSC-CMs samples derived from doxorubicin-exposed breast cancer patients with and without experiencing cardiotoxicity (n = 3 each). Conclusions: Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry. Dysregulation of PHTF1 may represent the molecular mechanism underlying the rs6689879-cardiomyopathy association. These findings have potential implications for long-term cardiac surveillance as well as up front cancer care for patients of African descent.
Phase I study of tazemetostat, an enhancer of zeste homolog-2 inhibitor, in pediatric pts with relapsed/refractory integrase interactor 1-negative tumors.
Authors: Chi Susan N. , Bourdeaut Franck , Laetsch Theodore Willis , Fouladi Maryam , Macy Margaret E , Makin Guy WJ , Shukla Neerav Narendra , Wetmore Cynthia , Margol Ashley S. , Casanova Michela , Kilburn Lindsay Baker , Yi Joanna , Hargrave Darren R. , McCowage Geoffrey Brian , Pinto Navin R. , Ebb David , Robinson Giles W. , Sierra Laura , Merchant Melinda , Nysom Karsten
Published: May 2020

10525

Background: Absence of integrase interactor 1 (INI1) expression is a defining molecular feature of rhabdoid tumors (RT), epithelioid sarcoma (ES), and chordomas, inducing dependence on enhancer of zeste homolog-2 (EZH2). Tazemetostat (TAZ) is a selective EZH2 inhibitor approved by the FDA for treatment of patients (pts) ≥16 yrs with metastatic or locally advanced ES ineligible for complete resection. Data from a Phase 1 (Ph1) pediatric dose-escalation study (Ph1a) of TAZ were previously reported; herein we report interim efficacy and safety from the Ph1 pediatric dose-expansion study (Ph1b). Methods: NCT02601937 is a Ph1, multicenter study in pts 6 months – 18 yrs evaluating TAZ administered BID at 1200 mg/m2 in Ph1b, per Ph1a recommendation. Ph1b cohorts enrolled pts based on tumor type: Atypical teratoid RT (ATRT), RT, and other INI1-negative tumors (including ES and chordoma). The Ph1b primary endpoint was overall response rate (ORR). Secondary endpoints included safety/tolerability, duration of response (DOR), and survival. Results: Ph1b has enrolled 47 pts who received TAZ oral suspension. Across all tumor types, ORR was 17% (Table). Responses were observed in ATRT (4/21), chordoma (2/4), and ES (2/7); 1 pt dosed at 520mg/m2 and 7pts at 1200mg/m2. In the ATRT cohort, 19% of pts responded to TAZ with a median DOR of 6.5 months. The median DOR has not yet been reached in the other cohorts, with ongoing responses in 3 pts. TAZ was generally well tolerated with no drug-related deaths. Most common adverse events (AE) include vomiting, nausea, and cough. During Ph1b enrollment, 1 pt with chordoma (dosed at TAZ 900 mg/m2 for 15 months in Ph1a) developed a secondary malignancy (T-cell lymphoblastic lymphoma). In response, the pediatric recommended Ph2 dose was revised to limit exposure in pts without CNS involvement to 520 mg/m2 TAZ (maximum dosing of 1 yr after response, pts to go off-treatment until disease progression). Conclusions: Interim results indicate TAZ is generally well tolerated in children with an AE profile similar to adults. Pt enrollment in the non-ATRT, INI1-negative cohorts is ongoing. TAZ shows promising anti-tumor activity in a subset of pediatric tumors, including ATRT, chordoma, and ES. Clinical trial information: NCT02601937. [Table: see text]
Assisted reproductive technology outcomes in childhood cancer survivors: A report from the Childhood Cancer Survivor Study.
Authors: Keefe Kimberly W. , Lanes Andrea , Stratton Kayla , Green Daniel M. , Chow Eric Jessen , Oeffinger Kevin C. , Barton Sara , Diller Lisa , Yasui Yutaka , Leisenring Wendy M. , Armstrong Gregory T. , Ginsburg Elizabeth S.
Published: May 2020

10528

Background: Some treatment exposures for childhood cancer reduce ovarian reserve. Registry-based evaluation has not been conducted for assisted reproductive technology (ART) outcomes of female survivors. Methods: The Childhood Cancer Survivor Study, a retrospective cohort of five-year survivors and siblings, was linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS), which captures nationwide, CDC-required reporting of ART outcomes. We assessed live birth rate and relative risk (RR, 95% CI) as a function of treatment exposure, using generalized estimating equation to account for multiple ovarian stimulations per subject. Results: Among 9885 female survivors, 137 (1.4%; median age at diagnosis 10 years, range 0-20; 11 years of follow-up, 2-11) underwent 243 ART cycles (mean 1.8 cycles) and among 2419 siblings, 33 (1.4%) underwent 60 ART cycles (mean 1.8). Median age at autologous egg retrieval was 30 years (19-44) for survivors and 34 (24-43) for siblings. In the subset using autologous eggs (Table), 99 survivors underwent 155 ovarian stimulation cycles that resulted in 113 embryo transfers and 49 live births for a live birth rate of 32% per ovarian stimulation and 43% per transfer. Sibling live birth rate was 38% (p = 0.39 compared to survivors) per autologous ovarian stimulation and 53% (p = 0.33) per transfer. 38 survivors and 1 sibling underwent egg donor ovarian stimulation cycles. Two survivors used autologous eggs with gestational carriers and one cycle resulted in live birth. Cranial radiation therapy (RT) [RR 0.48 (0.27-0.87) p = 0.02] and pelvic RT [0.30 (0.14-0.66) p = 0.002], compared with no RT, resulted in lower RR of live birth in survivors. The likelihood of live birth after ART in survivors was not impacted by alkylator exposure [CED < 8000 mg/m2 vs. none: 1.14 (0.65-2.02); CED >8000 mg/m2 vs none: 1.07 (0.06-1.91)]. Conclusions: While live birth rates among survivors were lower compared with siblings, differences were not statistically significant. Pelvic and cranial RT were associated with a decreased likelihood of live birth, with no association with alkylator exposure identified. [Table: see text]
Overall survival (OS) in patients (pts) with advanced breast cancer (ABC) with visceral metastases (mets), including those with liver mets, treated with ribociclib (RIB) plus endocrine therapy (ET) in the MONALEESA (ML) -3 and -7 trials.
Authors: Yardley Denise A. , Nusch Arnd , Yap Yoon Sim , Sonke Gabe S. , Bachelot Thomas , Chan Arlene , Neven Patrick , Slamon Dennis J. , Wheatley-Price Paul , Lteif Agnes , Sondhi Manu , Rodriguez-Lorenc Karen , Gaur Anil , Chia Stephen K. L.
Published: May 2020

1054

Background: In the Phase III ML-3 (NCT02422615) and ML-7 (NCT02278120) trials, RIB + ET demonstrated a significant OS benefit (ML-3: HR, 0.72, P = 0.00455; ML-7: HR, 0.71, P = 0.00973) over placebo (PBO) + ET in pts with HR+/HER2- ABC (Im et al. N Engl J Med. 2019; Slamon et al. N Engl J Med. 2019). The presence of visceral mets generally portends a poor prognosis, which is especially poor in pts with liver mets (He et al. Ann Oncol. 2019). Here we report OS in pts with visceral mets with a focus on those with liver mets in ML-3 and ML-7. Methods: In ML-3, postmenopausal pts were randomized 2:1 to receive RIB + fulvestrant (FUL) or PBO + FUL as first- (1L) or second-line (2L) treatment. In ML-7, premenopausal pts were randomized 1:1 to receive RIB + ET or PBO + ET (this analysis included only pts who received an NSAI as ET partner to match approved indication). Results: Visceral mets were identified in 293 pts (60.5%) in the RIB arm and 147 (60.7%) in the PBO arm in ML-3 and 150 (44.8%) and 142 pts (42.1%), respectively, in ML-7. In ML-3, the median age of pts with visceral mets was 63 and 65 years in the RIB and PBO arms, and in ML-7 it was 42.5 and 45.0 years, respectively. In ML-3, 214 pts with visceral mets received 1L therapy (RIB, n = 137; PBO, n = 77), while 219 pts received 2L therapy or had early relapse (RIB, n = 151; PBO, n = 68). Lung and liver were the most common sites of visceral mets for pts in ML-3 (49.8% and 44.8%, respectively) and ML-7 (51.4% and 58.2%, respectively). OS HRs in pts with visceral mets were consistent with the benefit in the overall pt populations and suggested a particularly substantial OS benefit in pts with liver mets (HR for liver mets group in ML-3, 0.629 [95% CI, 0.421-0.942]; HR in ML-7, 0.531 [95% CI, 0.321-0.877]; Table). No new safety signals were observed. Conclusions: Approximately half of the pts in ML-3 and ML-7 had visceral mets. The OS data in these pts are consistent with the benefit observed with RIB in the overall populations of each trial. In pts with liver mets, a group with an especially poor prognosis, RIB + ET demonstrated a substantial OS benefit compared with PBO + ET. Clinical trial information: NCT02422615; NCT02278120 . [Table: see text]
Phase II study of alisertib as a single agent in recurrent or progressive atypical teratoid rhabdoid tumors.
Authors: Upadhyaya Santhosh , Campagne Olivia , Robinson Giles W. , Onar-Thomas Arzu , Orr Brent , Billups Catherine A , Tatevossian Ruth G , Broniscer Alberto , Kilburn Lindsay Baker , Baxter Patricia Ann , Smith Amy A. , Crawford John , Partap Sonia , Ellison David W. , Stewart Clinton F. , Patay Zoltan , Gajjar Amar J.
Published: May 2020

10542

Background: We conducted a Phase II study of alisertib, small-molecule inhibitor of Aurora A kinase, as single-agent treatment in patients < 22 y with recurrent or progressive atypical teratoid rhabdoid tumors (ATRT) (NCT02114229). Methods: Patients received alisertib once daily [80 mg/m2 (enteric-coated tablets) or 60 mg/m2 (liquid)] on Days 1–7 of a 21-day cycle for 2 y or until progressive disease (PD). Therapy was considered promising if ≥10 patients were without PD by MR imaging at 12 wk. Molecular groups were determined using Infinium Methylation EPIC BeadChips and the Heidelberg classifier. Alisertib plasma concentrations were measured in cycle 1, on Days 1 (single dose) and 7 (steady state) and analyzed using population-based modeling. Results: Data from 30 patients representing all 3 molecular groups [SHH (10/26), MYC (10/26), TYR (6/26), unknown (4/26)] was analyzed. One patient remains on therapy. The study did not meet the efficacy end point as only 8/29 patients were without PD after 12 wk, including 1 with partial response. Progression-free survival (PFS) was 31%±8.2% at 6 months and 15.8%±6.5% at 1 y. One- year overall survival (OS) was 42.1%±9.2%. One patient remained on treatment for > 12 months, and another for > 18 months. The median treatment duration was 44 days (range, 2–653 days). There was no difference in OS (p = 0.096) or PFS (p = 0.98) by molecular groups. Neutropenia was the most common adverse effect (77%). After single-dose alisertib, we observed higher mean maximum concentration (Cmax) 10.1±3.0 µM and faster time to Cmax (Tmax = 1.2±0.7 h) in the 22 patients who received liquid formulation than those who received tablets (Cmax = 5.7±2.4 µM, Tmax = 3.4±1.4 h). Drug exposure did not differ between the formulations (AUC0-∞ = 58.6±25 h·µM). Average apparent oral clearance was 2.32 L/h per m2, which was about half that reported in adults. Serial CSF samples were collected in 2 patients; the CSF/plasma AUC ratios were 1.2%-2.7%. Conclusions: Although the study did not meet the efficacy end point, alisertib was well tolerated as a single agent in children with recurrent ATRT. A third of the patients demonstrated disease stabilization for > 6 months. Treatment response beyond 1 y was seen in 2 patients Clinical trial information: NCT02114229.
Prediabetes and progression to diabetes among adult survivors of childhood cancer in the St. Jude Lifetime Cohort.
Authors: Dixon Stephanie , Lu Lu , Wilson Carmen Louise , Jefferies John L. , Merchant Thomas E. , Howell Rebecca M. , Ness Kirsten K. , Srivastava Deo Kumar , Hudson Melissa M. , Robison Leslie L. , Chemaitilly Wassim , Armstrong Gregory T.
Published: May 2020

10548

Background: Cardiac death among survivors of childhood cancer occurs at > 10 times the rate expected in the general population. Modifiable cardiovascular risk factors, including diabetes, increase risk for major cardiac events in a near multiplicative fashion. Thus, prevention of progression from prediabetes to diabetes could improve long-term cardiac morbidity and mortality. However, little is known about prediabetes in survivors. Methods: Prevalence of prediabetes (fasting glucose 100-125 mg/dL or HbA1c 5.7-6.4%) and diabetes were assessed in 3529 5+ year survivors ≥18 years of age and compared to 450 community controls stratified by age and matched for race/ethnicity, sex, and BMI using Chi-squared statistics. Logistic regression estimated risk factors for prediabetes and cox proportional hazards regression for progression from prediabetes to diabetes among survivors with multiple visits, reported as odds (OR) and hazard ratio (HR), respectively, with 95% confidence intervals (CI). Results: Among 3529 survivors (median age 30 years, range 18-65), the prevalence of prediabetes overall was 29.2% (95% CI 27.7-30.7) and diabetes was 6.5% (5.7-7.3). In each age strata, survivors had significantly higher prevalence of prediabetes and diabetes than controls with over 50% of middle-aged survivors (35-44 years) having prediabetes or diabetes (Table). In a multivariable model, therapy-related risk factors for prediabetes included high pancreatic tail dose (≥20 Gy: 2.9 [1.8-4.8]) and moderate prescribed cranial radiation dose (OR [95% CI] > 0- < 20 Gy: 1.4 [1.1-1.8], 20- < 30 Gy: 1.4 [1.0-1.9]) independent of age, sex, race/ethnicity and BMI. Among 695 survivors with prediabetes and longitudinal follow-up, median 5.1 years, 68 (10%) progressed to diabetes. After adjustment for age, sex, race/ethnicity and BMI, risk of progression from prediabetes to diabetes was increased by the presence of insulin resistance (HR 4.9 [95% CI 2.3-10.6]) or prior treatment with hematopoietic cell transplant (HR 2.9 [1.1-7.7]) or total body irradiation (HR 4.6 [1.6-13.5]). Conclusions: Survivors of childhood cancer have a high prevalence of prediabetes and high rates of progression to diabetes. Strategies that prevent progression to diabetes should be considered to decrease diabetes risk and subsequent cardiac morbidity and mortality in this high-risk population. [Table: see text]
Cell-free DNA comparative analysis of hormone receptor-positive, first-line metastatic breast cancer genomic landscape in the United States and China.
Authors: Li Huiping , Davis Andrew A. , Liu Xiao-ran , Xie Feng , Gui Xin-Yu , Chen Yi-Fei , Zhang Qiang , Gerratana Lorenzo , Zhang Youbin , Shah Ami N. , Behdad Amir , Wehbe Firas , Huang Yong , Yu Jian-Jun , Du Peter , Jia Shi-Dong , Cristofanilli Massimo
Published: May 2020

1059

Background: Metastatic breast cancer (MBC) is a heterogeneous disease associated with known somatic mutations of variable biological value in different subtypes. Furthermore, the clinical evolution of the disease demonstrates clonal evolution resulting in disease resistance more accurately detected using blood-based sequencing. Few studies have explored differences in genomic features of tumors across populations. Here, we performed circulating tumor DNA (ctDNA) sequencing to compare the genomic landscape of patients with hormone-receptor positive MBC at time of first recurrence or de-novo metastatic diagnosis in the United States (US) and China. Methods: Twenty-three US patients from Northwestern University and 65 Chinese patients from Peking University had ctDNA sequencing from plasma performed using the harmonized CLIA-certified, 152-gene PredicineCARE assay in laboratories in the US and China, respectively. The data analysis was conducted in China. Institutional Review Boards at each site approved the study. Fisher’s exact test was performed to compare mutational frequencies across populations. Results: Median age of patients at MBC diagnosis was 51 in the US cohort and 55 in the Chinese cohort. 87% of US patients and 82% of Chinese patients had received prior therapy for primary breast cancer, including endocrine therapy. Mutations were detected in 17 of 23 (74%) US patients and 59 of 65 (91%) Chinese patients. CNAs were observed in 57% of US patients and 58% of Chinese patients. The most common mutations detected in US patients were TP53 (26%), PIK3CA (22%), AKT1 (22%), CDH1 (17%), PTEN (13%), and ESR1 (9%) vs. PIK3CA (46%), TP53 (35%), ESR1 (12%), and BRCA2 (11%) in Chinese patients. Frequency of AKT1 and CDH1 mutations were significantly higher in the US population (P < 0.05), while PIK3CA mutations were higher in the Chinese population (P < 0.05). CNA gains in CCND3 and CDK4 were significantly higher in the US cohort, and FGFR1 was significantly more common in the Chinese cohort (all P < 0.05). Conclusions: To our knowledge, this is a first cross-regional comparison study in HR+ MBC patients in the US and China using a harmonized cfDNA NGS platform. At a population level, there were notable differences observed in somatic variants in two cohorts. Future sequencing efforts and clinical trials should include patients of diverse ethnic backgrounds to explore the impact of differences in genomic landscape on probability of benefit from treatments. A larger validation cohort is required to confirm these findings.
Meta-analysis of cyclin-dependent kinase (CDK) 4/6 inhibitors with endocrine therapy versus endocrine therapy alone on progression-free survival (PFS) and overall survival (OS) for metastatic breast cancer (MBC).
Authors: Kunwor Ranju , Baniya Ramkaji , Abu-Khalaf Maysa M.
Published: May 2020

1060

Background: CDK 4/6 inhibitors with Endocrine therapy (ET) are the preferred first line treatment for Hormone Receptor positive and Human Epidermal Growth factor receptor 2 negative (HR+/HER2-) MBC. Over the last few years multiple trials have shown benefit in PFS. Only two studies evaluating Ribociclib and Abemaciclib showed an OS benefit while no statistically significant OS benefit has been reported in any of the studies evaluating Palbociclib raising the possibility that this benefit may be drug specific rather than applicable to all CDK 4/6 Inhibitors. This updated meta-analysis of randomized controlled trials (RCTs) aims to assess the PFS and OS of all three CDK 4/6 inhibitors in HR+/HER2- MBC. Methods: We performed a systematic search for RCTs using Cochrane Library, PubMed, Embase, and Web of Science. Only the phase II and III RCTs comparing CKD 4/6 inhibitors plus ET with ET alone were eligible for this meta-analysis. The pooled analysis of Hazard Ratio (HR) was performed with Review Manager 5.3 using random effect model. Results: A total of 8 RCTs including 4338 patients with HR+/HER2- MBC were included in this meta-analysis (table). The pooled HR for PFS was 0.55 (95% confidence interval (CI), 0.50-0.59; P < .00001) and the pooled HR for OS was 0.75 (95% CI, 0.68-0.84; P < .00001). Conclusions: The result of our meta-analysis confirms the previously reported PFS benefit from CDK 4/6 inhibitors plus ET and shows an OS benefit when including RCTs of all 3 CDK 4/6 inhibitors for the treatment of HR+/HER2- MBC. [Table: see text]
Phase Ib trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy and a CDK4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC).
Authors: Wander Seth Andrew , Juric Dejan , Supko Jeffrey G. , Micalizzi Douglas Scott , Spring Laura , Vidula Neelima , Beeler Maureen , Habin Karleen R. , Viscosi Elene , Fitzgerald Donna Michelle , Scarpetti Lauren , Tripp Elizabeth , Hepp Rachel , Moy Beverly , Isakoff Steven J. , Ellisen Leif W. , Bardia Aditya
Published: May 2020

1066

Background: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), with an anti-estrogen, are the standard of care for HR+/HER2- MBC. Insights from patient biopsies and preclinical analysis suggest that AKT1 activation can provoke CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may provide clinical benefit. Methods: TAKTIC is an open-label phase Ib trial exploring the combination of the AKT1 inhibitor, ipatasertib (ipat), with an aromatase inhibitor (Arm A), fulvestrant (Arm B), or the triplet combination (Arm C) of fulvestrant + ipat + palbociclib (palbo). The primary objective is to evaluate the safety and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an interim analysis from the triplet combination (Arm C). Results: As of 1/31/2020, 25 pts have enrolled, including 12 on Arm C, all of whom received prior CDK4/6i (median no of prior lines = 5.5, range 2-7). Along with fulvestrant, 3 pts received ipat at 200mg + 125mg palbo, 7 pts received 300mg + 125mg palbo, and 2 pts received 400mg + 100mg palbo. To date, 8/12 pts remain on treatment including 2 with partial response, 3 with stable disease, 3 with restaging studies pending and 4 with progressive disease. The triplet combination was well tolerated. Grade 3 toxicities included reduced WBC (8/12), reduced neutrophil count (11/12), reduced lymphocyte count (2/12) and single instances of transaminitis, rash, and reduced platelet count. The only grade 4 toxicity was reduced neutrophil count (4/12). There were no DLTs observed and no discontinuations due to toxicity. Mean steady state pharmacokinetic parameters for ipat were similar to historical data from single agent trials suggesting that combined treatment with palbo + fulvestrant did not affect the pharmacokinetics of ipat. Updated analysis will be presented at the meeting. Conclusions: The triplet combination of endocrine therapy with CDK 4/6i and AKTi appears to be well tolerated in heavily pre-treated pts, with a subset demonstrating signs of clinical benefit. The trial demonstrates how insights into the molecular mechanisms of CDK4/6i resistance could be leveraged into actionable therapeutic regimens for HR+/HER2- MBC. Clinical trial information: NCT03959891 .
A phase Ib trial of the cyclin-dependent kinase inhibitor dinaciclib (dina) in combination with pembrolizumab (P) in patients with advanced triple-negative breast cancer (TNBC) and response correlation with MYC-overexpression.
Authors: Chien Amy Jo , Gliwa Amelia S , Rahmaputri Siti , Dittrich Heidi F , Majure Melanie Catherine , Rugo Hope S. , Melisko Michelle E. , Munster Pamela N. , Park John W. , Moasser Mark M. , Matloubian Mehrdad , Lea Tasha , Rohrberg Julia , Krings Gregor , Goga Andrei
Published: May 2020

1076

Background: Increased expression of the MYC transcriptional oncogene is found in about 70% of TNBC and is associated with poor prognosis. In MYC-overexpressing TN xenografts, CDK1 inhibition with dina results in synthetic lethality, and attenuates distant metastasis. In syngeneic models, the combination of dina with anti-PD1 therapy is synergistic and increases immune cell tumor infiltration and activation. Methods: Patients (pts) with advanced TNBC received dina IV day 1 and 8 in combination with fixed dose P 200 mg once every 21 days. Dina was dose escalated using a toxicity probability interval design targeting a dose limiting toxicity (DLT) rate of 25%. Evaluable disease and pre-treatment metastatic biopsies were required. After 17 pts were enrolled, eligibility was amended to require ≤2 lines of prior chemotherapy, and LDH ≤1.5x normal. MYC IHC was performed on baseline tumor biopsies and correlated with clinical response using Welch’s unequal variances t-test. Results: 32 pts were enrolled (median age 53, median 2 prior lines of therapy, 13 pts (41%) had disease which was previously ER+). 18 pts were enrolled in the dose escalation phase with no observed DLTs; 33 mg/m2 was determined to be the recommended phase 2 dose (RP2D). 14 additional patients were enrolled in dose expansion at 33 mg/m2, completing trial accrual. Grade ≥3 adverse events (AEs) in all pts included neutropenia (ntp) (37.5%), febrile ntp (12.5%), fatigue (12.5%), transaminitis (3.2%), and neuromuscular weakness (3.2%). Most common all grade AEs included fatigue (63%), diarrhea (63%), nausea (63%), and ntp (53%). Possible immune-related AEs included sinusitis (4 pts), hemolytic anemia (1 pt), pneumonitis (1 pt), rash (2 pts), neuromuscular weakness (1 pt), and transaminitis (1 pt). Of the 29 patients evaluable for response, 1 pt (3.4%) had a CR, 4 pts (13.8%) had a PR, and 6 pts (20.6%) had SD. MYC IHC staining on baseline metastatic tumor biopsies in 19 pts correlated significantly with clinical response. Additional biomarker testing will be reported. Conclusions: The RP2D of dina given in combination with standard dose P is 33 mg/m2 on D1, 8 of a 21-day cycle. Toxicities were generally manageable and non-overlapping. In exploratory analysis, greater MYC IHC staining correlated significantly with response to study therapy. Clinical trial information: NCT01676753 .
Real-world clinical effectiveness and safety of olaparib monotherapy in HER2-negative gBRCA-mutated metastatic breast cancer: Phase IIIb LUCY interim analysis.
Authors: Gelmon Karen A. , Fasching Peter A. , Couch Fergus , Balmana Gelpi Judith , Delaloge Suzette , Labidi-Galy Intidhar , Bennett James , McCutcheon Susan , Ano Sabine , O'Shaughnessy Joyce
Published: May 2020

1087

Background: OlympiAD (NCT02000622) demonstrated the benefit of olaparib over standard of care in patients (pts) with HER2-negative (HER2-) metastatic breast cancer (MBC) and germline BRCA mutations (gBRCAm). LUCY (NCT03286842) aimed to provide additional data on the real-world effectiveness and safety of olaparib monotherapy in this setting. Methods: This Phase IIIb, open-label, single-arm study of olaparib 300 mg twice-daily, enrolled pts with HER2- gBRCAm MBC who had received a taxane and/or anthracycline in the (neo)adjuvant/metastatic setting, and ≤2 lines of chemotherapy for MBC. Hormone receptor-positive (HR+) pts had progressed on prior endocrine therapy (ET), and further ET was considered unsuitable. Primary endpoint: investigator-defined progression-free survival (PFS). Secondary endpoints: overall survival, time to first subsequent therapy or death (TFST), and investigator-assessed clinical response rate (CRR). The interim analysis was planned after 160 PFS events. Results: From Oct 2018-Sept 2019, 252 pts were enrolled (160 sites, 15 countries; mean age 46.2 [range 22-75] years; 73.4% ECOG PS 0). Median total treatment duration: 7.9 months (mo; range 0.2-20.0). Median PFS: 8.1 mo (95% confidence interval [CI] 6.9, 8.7; 166 events [65.9%]). Clinical trial information: NCT03286842 . Median TFST: 9.7 mo (95% CI 8.7, 11.1). CRR: 48.6% (95% CI 42.2, 55.0). Adverse events (AEs) in >20% of pts (all grades): nausea, anemia, asthenia, vomiting, and fatigue. 24.6% of pts reported a grade ≥3 AE, including anemia (n=33 [13.1%]). 4.4% of pts had an AE leading to treatment discontinuation. Conclusions: Interim results in this real-world population of pts with HER2- gBRCAm MBC were consistent with the OlympiAD study, and support olaparib as a chemotherapy-free alternative treatment for pts with gBRCAm advanced BC. [Table: see text]
Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion+ solid tumors.
Authors: Subbiah Vivek , Hu Mimi I-Nan , Gainor Justin F. , Mansfield Aaron Scott , Alonso Guzman , Taylor Matthew H. , Zhu Viola Weijia , Garrido Lopez Pilar , Amatu Alessio , Doebele Robert C , Cassier Philippe Alexandre , Keam Bhumsuk , Schuler Martin H. , Zhang Hui , Clifford Corinne , Palmer Michael , Green Jennifer , Turner Christopher D. , Curigliano Giuseppe
Published: May 2020

109

Background: RET gene fusions are targetable oncogenic drivers in multiple tumor types, including up to 20% of papillary thyroid cancers (PTC). Pralsetinib is an investigational, highly potent, selective inhibitor of oncogenic RET alterations. In the registration-enabling Phase 1/2 ARROW study (NCT03037385), pralsetinib demonstrated an overall response rate (ORR; response-evaluable patients [REP], central review) of 73% (19/26) in treatment-naïve patients and 61% (49/80; 2 pending confirmation) in platinum-exposed patients with RET fusion+ non-small cell lung cancer (NSCLC) and was well tolerated (data cut-off November 18, 2019). We provide an update on the clinical activity of pralsetinib in other RET fusion+ solid tumor types. Methods: ARROW consists of a phase 1 dose escalation (30–600 mg once [QD] or twice daily) followed by a phase 2 expansion (400 mg QD) in patients with advanced RET-altered solid tumors. Primary objectives were ORR and safety. Results: As of November 18, 2019, 29 patients with metastatic solid tumor types other than NSCLC (16 PTC, 1 undifferentiated thyroid, 3 pancreatic, 3 colon, 6 other) bearing a RET fusion have received pralsetinib. Efficacy data are presented for REP enrolled by July 11, 2019. In patients with thyroid cancer that is RET fusion+, ORR (investigator assessment) was 75% (9/12; all confirmed). Median (range) duration of response (DOR) was 14.5 (3.7+, 16.8) months (mo), with 67% of responding patients continuing treatment. Two patients with stable disease were continuing treatment at 11.5+ and 19.3+ mo. In other RET fusion+ cancers, ORR was 60% (3/5; all confirmed) with partial responses in 2/2 patients with pancreatic cancer (DOR 5.5, 7.4+ mo) and 1 patient with intrahepatic bile duct carcinoma (DOR 7.5 mo). Two patients with colon cancer had stable disease for 7.3 and 9.3 mo. Responses were observed across multiple fusion genotypes. In the entire safety population (all patients treated with 400 mg QD pralsetinib, regardless of diagnosis; n = 354), most treatment-related adverse events (TRAEs) were grade 1-2, and included increased aspartate aminotransferase (31%), anemia (22%), increased alanine aminotransferase (21%), constipation (21%) and hypertension (20%). Only 4% of patients in the safety population discontinued due to TRAEs. Conclusions: Pralsetinib demonstrated broad and durable antitumor activity across multiple advanced solid tumor types, regardless of RET fusion genotype, and was well tolerated. The study is ongoing and still enrolling patients in this cohort. Clinical trial information: NCT03037385.
Systemic therapy for patients with breast cancer and one to three brain metastases (BM).
Authors: Soomro Zaid A , Alhalabi Omar , Sun Ryan , Albittar Aya , Hsu Limin , Valero Vicente , Ibrahim Nuhad K.
Published: May 2020

1090

Background: Despite advances in systemic therapies and improved overall survival of metastatic breast cancer (MBC) patients, the development of brain metastases (BMs) remains a challenging complication that affects quality of life and increases morbidity and mortality. Current clinical practice guidelines recommend local treatment of BMs without changing systemic therapy (CST) in patients with stable systemic disease. Methods: We retrospectively investigated the impact of CST (when applicable as per treating physician’s discretion) after diagnosis of the initial 1-3 BMs on the patient’s progression-free survival time (PFS), defined as time to death, to a second BMs or to extracranial metastases. All MBC patients with 1 to 3 BMs only (without extracranial disease) treated at our institution between 2002 and 2017 were identified. For each patient, full information on follow-up and administered therapies were mandatory for inclusion. Hazard ratios (HR) were calculated using the Cox proportional hazard model. We also computed the restricted mean survival time (RMST) up to 5 years of follow-up. Results: Among the 2645 patient with BM treated at our institution, 80 were included for analysis. In regards to primary BMs management in patients, 46 of 80 (57%) were treated by radiation therapy, 6 of 80 (7.5%) underwent surgical resection, and 28 of 80 (35%) were managed by a combination of surgery and radiation therapy. All patients had staging imaging documenting lack of extracranial metastases at the time of local therapy of BMs. Following the primary management of BM, we observed that providers changed systemic therapy in 32 of 80 (40%), defined as the CST group. CST included both initiation of therapy in 16 of 80 (20%) and switching of adjuvant therapy in 16 of 80 (20%). Median PFS among CST was 7.7 months vs. 7.2 months among no CST (HR = 0.855, 95% confidence interval (CI) 0.53-1.38, p = 0.52). 5-year RMST for the CST group was 16.6 months vs. 12.8 months in no CST group. The difference of 3.8 months (95% CI 4.3-11.8) was not statistically significant. Conclusions: Patients with 1-3 BMs without extracranial disease had a median PFS close to 7.5 months after local therapy. Consistent with current standard of care of maintaining the same systemic therapy approach upon developing isolated BMs, our findings did not demonstrate a significant difference in PFS between patients who experienced a change in systemic therapy compared to those who did not.
Trends of skeletal related events in patients with breast cancer metastasized to bone.
Authors: Lingamaneni Prasanth , Vohra Ishaan , Moturi Krishna Rekha , Farooq Muhammad Zain , Ba Aqeel Sheeba Habeeb , Gupta Shweta
Published: May 2020

1098

Background: Up to three-quarters of women with advanced breast cancer develop bone metastases, predisposing to Skeletal Related Events (SRE), which are associated with a significant health care burden, poor prognosis, loss of functional independence and a decrease in quality of life. We performed a retrospective analysis on predictors of SRE in this population. We also evaluated temporal trends of outcomes and resource utilization in those with SRE. Methods: Adult breast cancer patients with metastases to bone, admitted from January 2012 to September 2015 were identified from the Nationwide Inpatient Sample database. Based on previous studies, SRE was defined by using ICD-9 codes for pathologic fracture, spinal cord compression, necessity for radiation to bone or surgery to bone. Multivariable analysis of predictors of SRE in patients with breast cancer metastatic to bone, as well as mortality in the SRE group were performed. Temporal trends of resource utilization across the years were evaluated. Results: A total of 143,455 patients with breast cancer with metastases to bone were identified, of which 17.2% had SRE. Patients with SRE had a mean age of 66 years and were predominantly white (70.2%). After adjusting for confounders, African Americans and Hispanics were less likely than Whites to develop SRE. On multivariable analysis, only comorbidity burden (in the form of high Charlson comorbidity index) predicted inpatient mortality. Rates of SRE in breast cancer patients with bone metastases did not change over the years (17.2% to 17.1%). Inpatient mortality of patients with SRE remained stable (3.76% to 3.79%). There was a statistically significant increase in surgical intervention (43.4% to 47.7%, p<0.01) and decrease in radiation to bone (25.7% to 19.7%, p<0.001) over time. Length of hospital stay and total hospital charges, after adjusting for inflation, remained largely unchanged. Conclusions: Incidence of SRE, inpatient outcomes and health care costs remained stagnant in those with metastatic breast cancer between 2012 and 2015, despite the advent of novel bone-targeted agents. There has been an increased trend towards surgical intervention and less utilization of local radiation over time. [Table: see text]
Trainee and workforce diversity in hematology and oncology: Ten years later what has changed?
Authors: Velazquez Manana Ana I. , Leibrandt Ryan , Duma Narjust
Published: May 2020

11000

Background: The diversification of the healthcare workforce has been identified as a strategy to address health disparities and increase patient-physician trust. A prior review of diversity among oncology fellows up to 2010, showed an increase in female representation over 17 years, but no change in underrepresented minorities (URM). We aim to assess the changes in hematology and oncology (HO) fellowship diversity over the last decade and how this compares to our workforce. Methods: Publicly available registries were used to assess differences among female and URM HO fellows, HO fellowship applicants, internal medicine (IM) academic faculty, IM residents, medical school graduates (MSG), and the US population in 2019. These were compared to the 2016 HO practicing physicians. Changes in URM and female HO fellow representation from 2009 to 2019 were assessed. Data was analyzed using binomial tests and simple linear regression models. Results: Female representation among HO fellows (43.8%) was increased when compared with HO practicing physicians (+11.8%, p < 0.0001) and IM faculty (+3.2%, p = 0.0079); no difference from IM residents or HO applicants. Female HO fellows were underrepresented when compared with MSG (-4.0%, p = 0.0014) and US population (P < 0.0001). Hispanic HO fellows (6.1%) had increased representation when compared to IM faculty (+2.7%, p < 0.0001), but were underrepresented when compared to IM residents (-2.2%, p = 0.0012) and US population (p < 0.0001). The proportion of Hispanic HO fellows was no different when compared to HO practicing physicians, HO applicants, and MSG. African American (AA) fellows (3.8%) were underrepresented when compared to IM residents (-2.0%, p = 0.0005), HO applicants (-1.7%, p = 0.0465), MSG (-2.4%, p = 0.0001), and US population (p < 0.0001). AA fellows were increased when compared to HO practicing physicians (+1.5%, p = 0.0002), but no different than IM faculty. Asian HO fellows were increased when compared to IM residents, MSG, and US population. Over the last 10 years there has been no significant change in the proportion of AA or female HO fellow representation, with a decreasing trend in Hispanics (-0.14% per year, p = 0.04).Conclusions: The current state of diversity in HO workforce still requires attention. Despite ongoing efforts, females, AA, and Hispanics continue to be underrepresented. The decreasing trend in Hispanic representation and clear differences in diversity between HO fellowships and IM residencies calls for action among fellowship programs and national societies to increase URM engagement and recruitment.
Feasibility of developing a Twitter journal club for hematology/oncology education.
Authors: Henry Elizabeth , Das Devika Govind , Murphy Martina Cathryn
Published: May 2020

11004

Background: Medical trainees are increasingly utilizing social media platforms for professional development, networking and education. Twitter chats (TC) are a growing tool to engage health professionals in virtual multi-institutional, cross-discipline discussions. A meta-analysis of Twitter as a tool in residency education demonstrated high rates of satisfaction and concept retention. Despite rapid uptake, few studies address needs for social media use and implementation in graduate medical education. Methods: We created a Twitter account (@HOjournalclub) and registered a certified hashtag (#HOJournalClub) with healthcare symplur. For each monthly TC, a specific tumor type and relevant publication was selected. This information was disseminated and amplified to reach trainees on Twitter. A content expert was invited to each TC to provide additional commentary. During TCs, participants answer questions based on domains of critical journal appraisal. Qualitative and quantitative analysis was performed. Basic demographics and tracked hashtag use to measure impressions, participants, and tweets per TC were gathered. Responses were collated and general themes were assessed. Participants were surveyed on ease of participation, article accessibility, and prior use of social media for education. Results: Since inception, @HOJournalClub has grown to >650 followers. Most are US-based (83%) medical trainees or healthcare professionals. Additional followers are in South America, Africa, UK, Europe, Middle East, India, East Asia and Australia. Gender is evenly distributed (51% male, 49% female.) Five #HOJournalClub chats have been held to date. Each attracted a mean of 30 participants, generating a mean of 217 tweets. Chats garnered a mean of 270,000 impressions (221,000-319,000) in the 48h after TC. Most participants accessed the chat in real time, with a small subset responding at alternate times. This asynchronous use has enhanced international participation. In post-TC surveys, majority of respondents report being new (48%) or sporadic (48%) users of TCs. Survey participants reported TC participation increased interaction with others in the field, improved literature appraisal skills and led to changes in clinical practice. Conclusions: Implementation of a Twitter-based journal club is feasible and attracts participation from trainees, promoting engagement and networking. It represents a novel educational tool for engagement in multi-institutional, multi-national and cross-discipline discussion of relevant hematology/oncology literature.