bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of antidisialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma (AOST1421): A report from the Children’s Oncology Group.
Authors: Hingorani Pooja , Krailo Mark D. , Buxton Allen , Hutson Paul R. , Davis Justin , Janeway Katherine A. , Gorlick Richard Greg , Isakoff Michael
Published: May 2020

10508

Background: Treatment of patients with recurrent osteosarcoma (OS) is challenging and novel effective therapies are urgently needed. This study evaluated disease control rate (DCR) in patients with recurrent pulmonary OS, when treated with dinutuximab plus cytokine therapy as compared to a historical benchmark. The rationale for dinutuximab was the ubiquitous ( > 95%) GD2 positivity in OS tumors and cell lines. Methods: AOST1421 was a single-arm phase 2 study. Patients with recurrent pulmonary OS in complete surgical remission were eligible. Patients received five cycles of dinutuximab 70mg/m2/cycle with GM-CSF. Two different dinutuximab infusion schedules were used - 35mg/m2/day over 20 hours (2-day) and 17.5mg/m2/day over 10 hours (4-day) schedule. Primary end point was DCR, defined as proportion of patients event-free at 12 months from enrollment. Events were progressive disease or death within 12 months attributed to treatment or progression. The historical benchmark was AOST0221 with a 12-month DCR of 20% (95% CI 10-34%). Success was defined as ≥16/ 39 patients ( > 40%) event-free at 12 months from enrollment. Secondary objectives included toxicity evaluation and dinutuximab pharmacokinetics (PK). Results: Forty-one patients were enrolled from Nov 2015 - Jan 2018. Thirty nine were eligible and evaluable (age 7-26 yr; median 15 yr). Data current to December 31, 2019 was used for analysis. Accrual rate was higher than expected (22.1 vs. 19.2 patients/ yr.) despite a concurrently open competing study. One of 136 administered therapy cycles met criteria for unacceptable toxicity when one patient receiving the 2-day schedule died after cycle 2 due to an unknown cause, attributed as probably related to protocol therapy. The protocol was revised to allow only the 4-day schedule. Other ≥ Grade 3 toxicities occurring in > 10 % participants were expected dinutuximab toxicities such as pain, diarrhea, hypoxia and hypotension. Dinutuximab did not demonstrate sufficient evidence of efficacy as 27/ 39 patients experienced an event for a DCR of 30.7% (95% CI 17- 47%). PK studies are pending and will be reported. Conclusions: Dinutuximab toxicity in adolescent and young adult OS patients was similar to younger patients. While GD2 remains a relevant target in OS, combination of dinutuximab with GM-CSF did not meet the targeted successful DCR in patients with completely resected tumor. Other strategies for targeting GD2 or dinituximab combination therapy may still be warranted. Clinical trial information: NCT02484443.
A phase Ib study of abemaciclib in combination with pembrolizumab for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer (MBC) (NCT02779751): Interim results.
Authors: Rugo Hope S. , Kabos Peter , Beck Joseph Thaddeus , Chisamore Michael Jon , Hossain Anwar , Chen Yanyun , Tolaney Sara M.
Published: May 2020

1051

Background: Abemaciclib is an orally administered, selective small molecule cyclin-dependent kinase (CDK)4 and 6 inhibitor, approved to treat HR+, HER2- MBC patients (pts) on a continuous twice daily dosing schedule as monotherapy or in combination with an aromatase inhibitor as initial endocrine based therapy or in combination with fulvestrant. Abemaciclib monotherapy increased tumor immunogenicity and synergized with anti-PD-1 to boost antitumor efficacy in murine models. Here we report safety and antitumor activity of abemaciclib plus pembrolizumab in HR+, HER2- MBC pts. Methods: This multicenter, nonrandomized, open-label, multi-cohort phase Ib study of abemaciclib plus pembrolizumab enrolled a cohort of endocrine resistant HR+, HER2- MBC pts who had received 1 or 2 prior chemotherapy regimens for MBC. No prior CDK4/6 inhibitor was allowed. Patients received 150mg abemaciclib orally every 12 hours plus pembrolizumab 200mg IV on day 1 every 21 days. Primary objective was to characterize safety of the abemaciclib plus pembrolizumab combination. Secondary objectives included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Of 28 pts enrolled, 15 (54%) received 1 line and 10 (36%) 2 lines of prior systemic chemotherapy in the locally advanced/metastatic setting. Safety of the combination was generally consistent with known side effects of abemaciclib and pembrolizumab and was generally manageable. Grade 3/4 adverse events in >2 pts included neutropenia (8 pts/29%), AST increase (5 pts/18%), diarrhea, and ALT increase (3 pts/11% each). Eight pts had confirmed partial response (29% ORR), and disease control rate (complete response [CR]+partial response [PR]+stable disease [SD]) was 82%. Clinical benefit rate (CR+PR+SD persisting for ≥6 months) was 46%. Median PFS and OS were 8.9 months (95% CI 3.9, 11.1) and 26.3 months (95% CI 20.0, 31.0), respectively. Conclusions: Combination of abemaciclib plus pembrolizumab demonstrated a generally tolerable safety profile with numerically higher rate of transaminase elevations than reported for the individual treatments. Compared to historical data for abemaciclib monotherapy in a similar pt population, a numerically higher but not obviously different ORR, PFS, and OS was observed. Clinical trial information: NCT02779751 .
Underdiagnosis and undertreament of modifiable cardiovascular risk factors: A Childhood Cancer Survivor Study (CCSS) report.
Authors: Chow Eric Jessen , Chen Yan , Armstrong Gregory T. , Baldwin Laura-Mae , Gibson Todd M. , Hudson Melissa M. , McDonald Aaron , Nathan Paul C. , Syrjala Karen L , Tonorezos Emily S. , Oeffinger Kevin C. , Yasui Yutaka
Published: May 2020

10515

Background: Survivors of childhood cancer exposed to cardiotoxic therapies are at increased risk of heart disease. Hypertension, dyslipidemia, and diabetes are modifiable cardiovascular risk factors (CVRFs) that synergistically increase this risk. Therefore, we aimed to determine the prevalence of and predictors associated with CVRF underdiagnosis and undertreatment in this population. Methods: CCSS participants at increased risk of heart disease due to prior cancer therapy were enrolled in an ongoing randomized intervention trial (NCT03104543) to improve CVRF identification and treatment. Participants completed a baseline survey (CVRF status, lifestyle habits, attitudes towards healthcare), anthropometry, and blood draw. Blood pressure, low density lipoprotein, triglyceride, glucose and Hgb A1c were measured and classified as normal/abnormal per standard clinical criteria. Multivariable logistic regression estimated odds ratios (OR [95% confidence intervals]) associated with predictors and risk of CVRF underdiagnosis and undertreatment. Results: As of January 2020, 522 participants (43% male) were available for analysis (47% response), with a median age 38y (range 20-65) and 28y (18-49) from original cancer treatment (75% anthracycline, 47% chest radiation). With mean measured BMI 27.3±6.5 kg/m2, self-reported prevalence rates were hypertension 27%, dyslipidemia 33%, and diabetes 9%. While 90% of participants had a routine check-up ≤2y ago, 58% had a measured CVRF in the abnormal range. Specifically, among previously undiagnosed participants, we observed rates of abnormal blood pressure (26%), lipids (17%), and glucose tolerance (27%). Among those with pre-existing hypertension, dyslipidemia, and diabetes, 11%, 49%, and 54%, respectively, had measurements outside of the usual therapeutic target range. In multivariable analysis, BMI ≥25 kg/m2 (vs < 25) was associated with risk of underdiagnosis (OR 1.8 [1.2-2.8]). For undertreatment, significant adverse factors included older age ( > 35 vs ≤35y: OR 2.5 [1.2-5.1]), BMI ≥30 kg/m2 (vs < 25: OR 3.3 [1.7-6.4]), and greater perceived reliance on others for healthcare decisions (OR 1.7 [1.2-2.4]). Those with greater health-related self-efficacy were less likely to be undertreated (OR 0.5 [0.3-0.96]). Conclusions: CVRF underdiagnosis and undertreatment among childhood cancer survivors at increased risk of heart disease was common. Greater awareness among survivors and primary care providers and more aggressive control of CVRFs may mitigate this risk.
Evaluation of CD22 modulation as a mechanism of resistance to inotuzumab ozogamicin (InO): Results from central CD22 testing on the Children’s Oncology Group (COG) phase II trial of INO in children and young adults with CD22+ B-acute lymphoblastic leukemia (B-ALL).
Authors: Shah Nirali N. , O'Brien Maureen Megan , Yuan Constance , Ji Lingyun , Xu Xinxin , Rheingold Susan R. , Bhojwani Deepa , Yi Joanna , Harris Andrew , Brown Patrick A. , Borowitz Michael J. , Devidas Meenakshi , Raetz Elizabeth A. , Gore Lia , Loh Mignon L.
Published: May 2020

10519

Background: The COG AALL1621 phase 2 trial evaluated the efficacy of InO in children and young adults with relapsed/refractory CD22+ B-cell ALL. We report results of central surface CD22 expression on ALL and impact on response. Methods: Optional central CD22 testing was performed on bone marrow and/or peripheral blood at the NCI flow cytometry (FC) laboratory pre/post cycle 1. Percentage of blasts with CD22+ expression (CD22%) was measured by multiparameter FC and the BD Biosciences QuantiBRITE system quantified the CD22 site density by measuring CD22 antibody bound per cell (ABC). Comparison of ABC and CD22% between subgroups was based on Wilcoxon rank sum test or signed rank test as appropriate. Post-treatment CD22 assessments could only be performed on those with residual ALL. Results: Amongst 48 patients, 28 (58.3%) achieved a complete response (CR) or CR with incomplete count recovery. The median CD22 ABC, pre and post-cycle 1, was 2688 (range, 290-10715, n = 33) and 1098 (184-6822, n = 15) respectively. Amongst 27 subjects with paired pre/post samples, median pre-treatment CD22 ABC was lower in those with residual ALL (n = 13) than in those without residual ALL (ABC 1005 (290-8848) vs ABC 4123 (762-10715), p = 0.003). Baseline CD22% ranged more widely in those with residual ALL, median 99% (40-100%) vs. 99% (92.9-100%, no residual ALL) p = 0.025; and significant decreases in CD22% were seen compared to baseline in those with residual ALL, with median post-treatment CD22% 82% (1.4%-100%), p = 0.007. Amongst 3 subjects with baseline partial CD22% (40%, 79% and 83% partial CD22+ populations), post-cycle 1 evaluations revealed emergence of predominantly CD22 negative populations (6.5%, 34% and 48% CD22+, respectively), precluding eradication of minimal residual disease. Amongst those with KMT2A rearrangement, 2 of 4 had partial CD22 expression and 4 of 4 had low ABC ( < 1500). Conclusions: Baseline CD22 expression, specifically low CD22 ABC and partial CD22% were significantly associated with response to treatment, emerging as potential biomarkers for poor InO response. This is particularly relevant to patients with KMT2Arearrangement who may be predisposed to CD22 partial positivity and low ABC. Evolution of CD22 negative/dim disease post-therapy suggests CD22 modulation is a mechanism of resistance to InO. Response to InO monotherapy may be limited in those with baseline CD22 negative/dim populations. Clinical trial information: NCT02981628.
Comparison of chemotherapy dose intensity for AYAs on COG AALL1131 versus CALGB 10403.
Authors: McNeer Jennifer Lynn , Ji Lingyun , Xu Xinxin , Burke Michael , Salzer Wanda , Devidas Meenakshi , Laumann Kristina M , Wood Charlotte , Advani Anjali S. , Larson Richard A. , Luger Selina M. , Stock Wendy , Loh Mignon L. , Hunger Stephen , Raetz Elizabeth A.
Published: May 2020

10520

Background: Outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are superior with pediatric-inspired therapy. CALGB 10403, the first US adult cooperative group prospective trial using a pediatric-inspired augmented BFM (ABFM)-based regimen, demonstrated feasibility and improved survival. We examined differences in drug delivery and targeted toxicities in AYAs who received the same therapy on C10403 vs the Children’s Oncology Group (COG) study AALL1131. Methods: The proportion of AYAs receiving full dose (within 10% of protocol- specified) vincristine (VCR) and pegaspargase (PEG) during induction (IND), consolidation (CON), and delayed intensification (DI); the likelihood of selected grade ≥3 adverse events (AEs); and the impact of patient characteristics were compared in AYAs 16-30 years. Targeted AEs with analogous reporting requirements in both studies included hyperbilirubinemia, pancreatitis, sensory neuropathy, and GI/intracranial hemorrhage. Thrombosis, transaminitis and hyperglycemia were not comparably captured. Fisher’s Exact test and logistic regression models were used for analyses. Results: After excluding AYAs removed from study after induction, 87 AALL1131 AYAs (accrued 2012-2016) and 188 C10403 AYAs (accrued 2007-2012) were analyzed with median ages of 17 (16-26) vs 22 (17-30) years, p < 0.001. There was no difference in the intensity of VCR delivery during IND, but in CON and DI, AALL1131 AYAs were more likely to receive all specified VCR (93.1% vs 81.9%, p = 0.02; 92.7% vs 72.1%, p = 0.01). Women were less likely to receive all specified VCR (OR 0.57, 95% CI 0.34-0.94, p = 0.03), and overweight/obese AYAs were somewhat less likely to receive all VCR compared to those considered normal weight (OR 0.88 and 0.59, p = 0.09). More C10403 AYAs were obese/overweight compared to AALL1131 AYAs (p = 0.04). There were no significant differences in dosing of PEG during IND/CON, but in DI AALL1131 AYAs were more likely to receive both doses (75.6% vs 57.1%, p = 0.03). No patient variables impacted delivery of PEG. There was no significant difference in grade ≥3 toxicities captured similarly on both studies. Conclusions: AYAs enrolled on AALL1131 were more likely to receive all protocol-specified VCR and PEG compared to those on C10403. Selected AE rates were comparable, suggesting that older AYAs do not tolerate doses of VCR and PEG for reasons other than toxicity, with body habitus as one potential variable. Further analyses to compare dose density, toxicities, and outcomes experienced by younger AYAs versus older are ongoing.
OSTPDL1: A phase II study of avelumab, a monoclonal antibody targeting programmed death-ligand 1 (PD-L1) in adolescent and young adult patients with recurrent or progressive osteosarcoma.
Authors: Bishop Michael William , Kaste Sue C. , Sykes April , Pan Haitao , Dela Cruz Filemon S. , Whittle Sarah , Mascarenhas Leo , Thomas Paul G , Youngblood Ben , Harman Jennifer L , Wang Lisa L. , Meyers Paul A. , Pappo Alberto S.
Published: May 2020

10521

Background: Outcomes for recurrent osteosarcoma are poor and novel therapies are needed. Osteosarcoma has a high mutational burden with overexpression of PD-L1 in metastatic lesions, providing a rationale for testing immune checkpoint inhibitors in this population. We therefore evaluated the activity of the PD-L1 inhibitor avelumab in patients with recurrent or progressive osteosarcoma. Methods: We conducted a single-arm, open-label phase 2 trial at 4 collaborating institutions. Eligible subjects were ages 12 to ≤50 years with recurrent or progressive osteosarcoma and radiographic evidence of measurable disease. Subjects received avelumab 10 mg/kg intravenously every 2 weeks of 28-day cycles until disease progression or unacceptable toxicity. Primary endpoints were objective response rate (CR + PR according to RECIST v.1.1), and progression-free survival (PFS) at 16 weeks. Kaplan-Meier methods were used to estimate PFS. Secondary endpoints included toxicity. Correlative objectives included measurement of subsets of peripheral blood mononuclear cells and serum markers of immune activation, and measures of cell proliferation, co-inhibitory receptor expression on CD8 T cells, T cell repertoire, and epigenetic programming of T cells. Results: Between February 2017 and October 2019, 18 eligible subjects [67% male, median age 16.8 years (12.8-22.9)] were enrolled. Subjects had received median 3 prior systemic therapies (range 1-5). Sites of disease included lung/pleura (94%), bone (56%), and soft tissue (28%). Subjects received a median of 2 cycles (range 1-4) of avelumab. Median PFS was 8 weeks (95% CI 6.7-9.1). No objective responses occurred (17 with progressive disease), and the 16-week PFS was 0%. The most common adverse events (AEs) were alanine aminotransferase (ALT) elevation (17%), aspartate aminotransferase (AST) elevation, dyspnea, hyponatremia, and pain (each 11%). Treatment-related serious AEs (≥Grade 3) included dyspnea (n = 2), ALT/ALT elevation, hyponatremia, pericardial effusion and anemia (n = 1). Immune-related AEs included pneumonitis, Hashimoto thyroiditis, and pericardial effusion (all n = 1). One patient discontinued therapy after 1 dose due to grade 4 ischemic stroke, unrelated to avelumab. One death occurred on study due to rapid disease progression. Conclusions: Avelumab did not demonstrate activity in recurrent osteosarcoma. Correlative biology studies are ongoing to elucidate mechanisms of resistance to this therapy. Clinical trial information: NCT03006848.
Phase I trial of pazopanib in combination with irinotecan and temozolomide (PAZIT) for children and young adults with advanced sarcoma.
Authors: Vo Kieuhoa T. , Michlitsch Jennifer G. , Shah Avanthi T. , Reid Joel M. , Burhow Sarah A. , Graham Eloise M. , Hollinger Fabienne , Zapala Matthew A. , Long-Boyle Janel , Kim Mi-Ok , Matthay Katherine K. , DuBois Steven G.
Published: May 2020

10526

Background: Pro-angiogenic factors may represent therapeutic targets in sarcoma. Preclinical studies have demonstrated a potential additive or synergistic interaction between anti-angiogenic agents and chemotherapy. The purpose of this study was to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetic (PK) and pharmacodynamics (PD) effects of PAZIT in patients with advanced sarcoma. Methods: Patients 6-30 years of age with relapsed/refractory sarcomas were eligible. In the initial dose escalation plan (A), patients received pazopanib PO (225-450 mg/m2/dose) on Days 1-21 of 21-day cycles. Pazopanib was combined with fixed doses of irinotecan (IV 50 or PO 90 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Due to DLTs, an amendment was made to the dose escalation plan (B) and patients received fixed doses of pazopanib PO (225 mg/m2/dose) on Days 1-21 of 21-day cycles and reduced irinotecan doses (IV 25-37.5 or PO 45-67.5 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Oral cephalosporin diarrhea prophylaxis was required. Dose escalation followed a 3+3 design. Correlative studies included PK (pazopanib, irinotecan) and PD (angiogenic factors, ctDNA) effects. Results: Sixteen patients were treated (median age 16 years, range 7-21). The dose levels in the table were evaluated. First cycle DLTs occurred at all dose levels (Table) and included diarrhea, pancreatitis, colitis, neutropenia, hypertension, deep vein thrombosis, and ALT increase. Due to excessive toxicity, an MTD could not be established. One patient with osteosarcoma had a partial response. Four patients had prolonged stable disease > 4 cycles, including 2 patients with Ewing sarcoma (5 and 6 cycles), rhabdomyosarcoma (9 cycles), and desmoplastic small round cell tumor (6 cycles). Mean±SD plasma exposures to pazopanib, irinotecan, and SN-38 in patients treated on dose level 1B (n = 4) on Day 4 were 601±83, 1.4±0.2 and 0.1±0.04 ug/mL*hr, respectively. Analyses of correlative studies are ongoing. Conclusions: Combination PAZIT therapy is not tolerable as evaluated at these doses/schedules. This study provides important toxicity data to inform future clinical trials using combination anti-angiogenic strategies in sarcoma. Clinical trial information: NCT03139331. [Table: see text]
Tag-n-trak study: Preliminary analysis of an unselected biobank tumors with NTRK fusion transcript, the French SFCE society contribution.
Authors: Lemelle Lauriane , Guillemot Delphine , Brisse Hervé , Gauthier Arnaud , Carton Matthieu , Hermann Anne-Laure , Corradini Nadege , Rome Angélique , Boutroux Hélène , Jourdain Anne , Marie Cardine Aude , Jannier Sarah , Castex Marie Pierre , Defachelles Anne Sophie , Aerts Isabelle , Karanian Marie , Doz Francois P. , Delattre Olivier , Pierron Gaëlle , Orbach Daniel
Published: May 2020

10540

Background: NTRK ( Neurotrophic receptor tyrosine kinase) fusion transcript was initially described in infantile fibrosarcoma (IFS) and is now known to be present in many other rare types of tumor with a lower incidence. The main objective of the study is to describe the presentation and outcome of unselected tumors with NTRK fusion transcript (NTRK-FTT) to better consider the role of TRK inhibitors (TRKi) in such entities. Methods: We selected patients (pts) from the Institut Curie biobank (adults and children) with NTRK-FTT and which were assessed by RT-qPCR then RNA sequencing in a prospective or retrospective process, between 2001 and 2019. Results: We identified 62 NTRK-FTT among 2119 screened tumors (2.2 cases/year with RT-qPCR and 6.9 cases/year with RNA seq after 2016), NTRK3 (44 cases) (including 41 NTRK3-ETV6), NTRK2 (9) or NTRK1 (9). Most of pts had under 2 years (y) (74%) and only 7 pts were adults. We report preliminary analysis of clinical observation for the first 27 pts. Median age was 0.4 y [0-60.2]. Pathologic diagnosis was IFS (12 cases), various CNS tumors (4), atypical teratoid rhabdoid tumor (1), myofibroblastic inflammatory tumor (2), benign tumors (3), cellular congenital mesoblastic nephroma (2), lipofibromatosis like neural tumor, myxoïd liposarcoma, unclassifiable sarcoma (1 each). Two pts had metastatic tumors. Among all, 22 had surgery (1 mutilating), 15 chemotherapy, 4 radiotherapy, and 5 received TRKi, as second line treatment (2 pts) or ≥ third line (3 pts). After a median follow-up of 50 months [range, 1-155], 20/27 pts remained in complete remission, 3 had stable residue, and 4 had progressive disease (associated to 1 disease-related and 1 toxic deaths). Five-year OS is 88% [95%CI, 73.5-100] and 5y-EFS 59.5% [95%CI, 41.7-84.9]. Conclusions: This descriptive study showed that NTRK-FTT is rare (2.9%), encompasses a variety of different histotypes (n = 14). Systematic RNA sequencing allowed to depict 3.5 times more NTRK-FTT than targeted RT-qPCR. Overall outcome is favorable despite frequent tumor events. According to tumor type and the uncertainties regarding the long-term side effects of TRKi, the benefit/risk ratio must be carefully evaluated before using these drugs in first line.
Naxitamab, a new generation anti-GD2 monoclonal antibody (mAb) for treatment of relapsed/refractory high-risk neuroblastoma (HR-NB).
Authors: Mora Jaume , Chan Godfrey Chi-Fung , Morgenstern Daniel A. , Nysom Karsten , Bear Melissa K , Dalby Lene Worsaae , Lisby Steen , Kushner Brian H.
Published: May 2020

10543

Background: NB is a rare cancer but represents the most common extracranial solid tumor of childhood. Most HR-NB patients present with or develop metastatic disease typically in bone or bone marrow (BM). Despite advances in frontline multimodal therapy ~50% of patients relapse. Refractory or relapsed disease represents an unmet medical need. GD2 is an adhesion molecule abundantly expressed in NB. Naxitamab is a humanized anti-GD2 mAb with high receptor affinity. Methods: We evaluated naxitamab in HR-NB patients with disease in bone and/or BM, who were refractory to initial treatment(s) or who had insufficient response to therapy for progressive/relapsed disease. Patients were treated in an outpatient setting with naxitamab as a planned 30-minute i.v. infusion and s.c. granulocyte-macrophage colony-stimulating factor (GM-CSF). Patients received 3 infusions of naxitamab 3 mg/kg/dose during the first week of a treatment cycle repeated initially every 4 weeks. Patients were evaluated for safety (CTCAE V4.0) and efficacy (INRC, Park et al. 2017). Results: We report on 24 patients recruited from April 2018 with a data cut off in June 2019. At diagnosis, 21 patients were stage 4, 1 was stage 3, 2 were unknown. At study entry, 11 patients had metastases in bone, 1 in BM and 12 in both bone and BM. Overall objective response was 75% (18/24), with complete response (CR) in 67% (16/24) and partial response in 8% (2/24). Of the 13 patients with BM involvement at enrollment, 12 achieved CR in BM during trial therapy. 6 treatment-related SAEs were reported in 5 patients (anaphylactic reaction, pyrexia, and respiratory depression). Conclusions: Naxitamab is an anti-GD2 mAb under development for HR-NB. In addition to a high CR rate of 67% and an overall objective response rate of 75% in a high-risk patient population, naxitamab offers an unique option for treatment of patients in the outpatient setting. These data and convenience to patients are strongly supportive of further drug development. Clinical trial information: NCT03363373.
Frailty and neurocognitive decline in young adult survivors of childhood cancer: A longitudinal analysis from the St. Jude lifetime cohort.
Authors: Williams AnnaLynn , Krull Kevin R. , Howell Carrie R , Banerjee Pia , Brinkman Tara M. , Kaste Sue C. , Partin, MS Robyn , Srivastava Deokumar , Armstrong Gregory T. , Robison Leslie L. , Hudson Melissa M. , Ness Kirsten K.
Published: May 2020

10555

Background: Among young adult childhood cancer survivors, 8% meet the criteria for frailty, an aging phenotype associated with poor health. Frailty is associated with neurocognitive decline in the elderly general population, but this association has not been examined in young adult survivors of childhood cancer. Methods: Childhood cancer survivors (N = 845, mean [SD] age 30 [7] years, 22 [7] years post diagnosis, 52% male) were clinically evaluated for prefrailty/frailty (defined as ≥2/≥3 of muscle wasting, muscle weakness, low energy expenditure, slow walking speed, exhaustion) and completed neuropsychological assessments at baseline and five years later. Linear regression models estimated mean differences in neurocognitive decline in prefrail/frail survivors vs. non-frail survivors adjusting for age, sex, race, CNS therapy (cranial radiation, intrathecal chemotherapy, neurosurgery), and baseline neurocognitive performance. P-values were adjusted for multiple comparisons using false discovery rate (FDR). Results: 18% and 6% of survivors were prefrail and frail at baseline. Baseline frailty was associated with declines in visual-motor processing speed, short-term memory, and sustained attention (Table). Prefrailty and frailty were associated with declines in focused attention and executive function (Table). No significant associations were observed between prefrailty or frailty and decline in global cognition, academics, motor processing speed, long-term memory, verbal learning, or verbal fluency despite significant baseline cross-sectional associations. Conclusions: Young adult prefrail and frail survivors had greater declines in attention and executive function compared to non-frail survivors, domains commonly associated with aging. These findings suggest that interventions designed to mitigate components of frailty may also mitigate or prevent neurocognitive decline. [Table: see text]
Prevalence and predictors of high-intensity end-of-life care among adolescents and young adults with cancer in Ontario: a population-based study using the IMPACT cohort.
Authors: Coltin Hallie , Rapoport Adam , Nagamuthu Chenthila , Baxter Nancy N. , Nathan Paul C. , Pole Jason D. , Momoli Franco , Gupta Sumit
Published: May 2020

10559

Background: End-of-life (EOL) care in adolescents and young adults (AYA) with cancer is poorly characterized, though this group may be at risk of elevated rates of high-intensity (HI) care and consequently, increased EOL suffering. Few population-based studies exist, and are limited by incomplete clinical information. AYA care patterns can vary by locus of care (LOC – pediatric v. adult), but LOC disparities in AYA EOL care are unstudied. Methods: We conducted a retrospective decedent population-based cohort study of all Ontario AYA diagnosed between 15-21 years of age with 6 prevalent primary cancers between 1992-2012, who died ≤5 years from diagnosis. Chart-abstracted clinical data were linked to health services data. The primary composite outcome (HI-EOL care) included any of: intravenous chemotherapy ≤14 days from death; > 1 emergency department visit ≤30 days from death; or > 1 hospitalization or intensive care unit (ICU) admission ≤30 days from death. Secondary outcomes included measures of the most invasive (MI) EOL care: mechanical ventilation ≤14 days from death, and death in the ICU. Factors associated with HI-EOL were examined. Results: Of 483 patients, 292 (60.5%) experienced HI-EOL care, 98 (20.3%) were mechanically ventilated ≤14 days from death, and 110 (22.8%) died in the ICU. Patients with hematological malignancies (v. solid tumors) were at greatest risk of HI-EOL care (OR, 2.3; 95CI, 1.5-3.5, p < 0.01), mechanical ventilation (OR, 5.4; 95CI, 3.0-9.7, p < 0.01), and death in an ICU (OR, 4.9; 95CI, 2.8-8.5, p < 0.01). AYA who died in a pediatric center were substantially more likely to experience MI-EOL measures compared to those dying in adult centers (mechanical ventilation, OR 3.2, 95CI 1.3-7.6, p = 0.01). Assessment of interactions showed LOC-based disparities widening over the study period (ICU death in pediatric v. adult centres: early period OR 0.9, 95CI 0.3-2.9, p = 0.91; late period OR 3.3, 95CI 1.2-9.2, p = 0.02; interaction term p = 0.04). AYA living in rural areas were also at higher risk of experiencing mechanical ventilation (OR, 2.0; 95CI, 1.0-3.8, p = 0.04) and death in ICU (OR, 2.1; 95CI, 1.1-4.0, p = 0.02). Conclusions: AYA with cancer experience high rates of HI-EOL care, with patients in pediatric centers and those living in rural areas at highest risk of MI-EOL care. Our study is the first to identify LOC-based disparities in AYA EOL care. Future studies should explore mechanisms underlying these disparities, including potential differences in palliative care services.
Serum biomarkers of inflammation (ferritin, IL-8, TNFR1) and outcomes in BOLERO-2, a phase III trial of HR+/HER2- metastatic breast cancer treated with everolimus (mTOR inhibitor).
Authors: Ali Suhail M. , Reising Albert , Leitzel Kim , Drabick Joseph J. , Truica Cristina I. , Vasekar Monali K. , Menon Harry , Nagabhairu Vinod , Polimera Hyma Vani , Pancholy Neha , Moku Prashanth Reddy , Maddukuri Ashok , Schmid Herbert , He Wei , Millholland John , Lavin Meredith , Hofsess Scott J. , Sweetman Robert William , Hortobagyi Gabriel N. , Lipton Allan
Published: May 2020

1067

Background: Everolimus (EVE) plus exemestane (EXE) doubled PFS while maintaining quality of life versus EXE alone in postmenopausal hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (MBC) (BOLERO-2 phase 3; NCT00863655). Here we investigated several serum biomarkers of inflammation: ferritin, interleukin-8 (IL-8), and tumor necrosis factor receptor 1 (TNFR1). Both higher IL-8 (ASCO 2018, #3025) and TNF (Nature 569:428-32, 2019) have been reported to be associated with worsened outcome to immune checkpoint inhibitors (ICI), and IL-8- and TNF-targeted therapies combined with ICIs are in phase I trials. We evaluated the prognostic/predictive ability of serum ferritin, IL-8, and TNFR1 to everolimus in BOLERO-2. Methods: Serum biomarkers were determined on pretreatment serum samples using the ELLA immunoassay platform (ProteinSimple, San Jose, CA). Cox-proportional hazards model was used to assess the efficacy of EVE, and the prognostic and predictive effect on PFS and OS. Results: Pretreatment serum biomarker levels were determined in 510 patients (70 %) of 725 BOLERO-2 patients randomized 2:1 to EVE+EXE or EXE). Serum levels (25%, 50%, 75%) were: ferritin (68.9, 125.5, 253.1 ng/ml); IL-8 (14.5, 19.4, 27.7 pg/ml); and TNFR1 (1205, 1470, 1868 pg/ml). Ferritin correlated significantly with TNFR1 (r=0.45, p<0.0001), while IL-8 correlated weakly with TNFR1 (r=0.10, p=0.023). Higher levels of all 3 biomarkers were prognostic for significantly shorter PFS and OS (table). But no biomarkers were predictive: everolimus was efficacious regardless of the 3 biomarker levels (p>0.05). Conclusions: High levels of serum ferritin, IL-8, and TNFR1 were significantly associated with shorter PFS and OS in HR+/HER2- MBC patients. Everolimus had superior outcomes compared to placebo, regardless of serum biomarker level. These 3 significant prognostic biomarkers are all associated with increased inflammatory processes through different pathways. Anti-inflammatory therapy targeted against these biomarkers should be evaluated based on serum level as potential combination therapy with everolimus or CDK 4/6 inhibitors in HR+ MBC. [Table: see text]
Disparities in the receipt of National Comprehensive Cancer Network (NCCN) guideline adherent care in triple-negative breast cancer (TNBC) by race/ethnicity, socioeconomic status, and insurance type.
Authors: Ubbaonu Chimezie , Chang Jenny , Ziogas Argyrios , Clair Kiran , Tanjasiri Sora Park , Bristow Robert E. , Patel Neha , Mehta Rita S. , Kansal Kari Joanne , Zell Jason A.
Published: May 2020

1080

Background: Breast cancer is the most commonly diagnosed cancer in women in the United States and the second leading cause of cancer mortality in women.TNBC is more likely to present at an earlier age with more advanced and aggressive disease. The overarching goal of treatment recommendations listed in the National Comprehensive Cancer Network (NCCN) guidelines are to improve patient outcomes. Here we examine factors which may contribute to NCCN guideline adherence. Methods: This was a retrospective cohort study of women with triple negative breast cancer using data from the California Cancer Registry (CCR) between 2004-2016 (with follow-up through 11/2018). Indicators for concordance with NCCN guidelines for TNBC was used as the dependent variable in the analysis. A multivariable logistic regression was used to determine the effects of independent variables on adherence to NCCN guidelines. Odds ratios and 95% Confidence Intervals (CI) were calculated. Non-Hispanic Whites, having medical insurance and highest socioeconomic status (SES) were set as references values in the regression models. Disease specific survival was calculated using the Cox regression analysis. Results: A total of 16,858 women were included in this study, 32.5% (n = 5,472) received NCCN adherent care (p < 0.0001). Non-Hispanic Blacks (NHB) and Hispanic patients were less likely to receive guideline adherent care (respectively, OR 0.87, 95%CI 0.79-0.95 and OR 0.87, 95%CI 0.79-0.95). Patients of lowest and lower-middle socioeconomic status (SES) were less likely to receive NCCN guideline adherent care (respectively, OR 0.77, 95%CI 0.68-0.87 and OR 0.88, 95%CI 0.79-0.98). Overall, non-adherent care was associated with an increased disease-specific mortality (HR 1.21, 95%CI 1.11-1.31, p < 0.0001). Hazard ratios were calculated after adjusting for adherent care and NHB patients had an increased disease-specific mortality (HR 1.28, 95%CI 1.16-1.42, p < 0.0001) in addition to patients with Medicare or Medicaid payer status (respectively, HR 1.20, 95%CI 1.08-1.34, p < 0.001 and HR 1.29, 95%CI 1.15-1.43, p < 0.0001). Conclusions: A significant portion of TNBC patients in California continue to receive non-guideline adherent care. Non-Hispanic black patients and lower SES quintile groups were less likely to receive guideline adherent care. Patients with non-adherent care had worse disease specific survival compared to recipients of NCCN-adherent care.
Diagnostic yield and clinical utility of germline genetic testing following somatic testing in breast cancer patients.
Authors: Lincoln Stephen E , Das Kingshuk , Ngo Nhu , Nielsen Sarah M. , Michalski Scott T. , Yang Shan , Pineda Alvarez Daniel Esteban , Nussbaum Robert Luke , Esplin Edward D.
Published: May 2020

1092

Background: Germline genetic testing is recommended for breast cancer patients with specific presentations or family histories. Separately, tumor DNA sequencing is increasingly used to inform therapy, most often in patients with advanced disease. Recent NCCN and ESMO guidelines recommend germline testing following somatic testing, under specific circumstances and for specific genes. We examined the utility of germline findings in patients referred for both test modalities. Methods: We reviewed somatic and germline mutations in a consecutive series of patients who: (a) had a current or previous breast cancer diagnosis, (b) were referred for germline testing, and (c) previously received tumor sequencing. Diverse reasons for germline testing included: a tumor finding of potential germline origin, treatment or surgical planning, personal or family history, and patient concern. Results: 227 patients met study criteria of whom 88 (39%) harbored a pathogenic germline variant (PGV) in a high or moderate risk cancer predisposition gene. Mutations in certain genes were most likely to be of germline origin, and most PGVs were potentially actionable (Table). 13% of PGVs were not reported by tumor tests as either germline or somatic findings, usually a result of tumor test limitations. Of note, 27 of the patients with PGVs (31%) had these variants uncovered only after presenting with a second, possibly preventable, malignancy. Conclusions: Germline testing following tumor sequencing often yielded findings that may impact care. Indeed, the 39% PGV rate we observed suggests that such testing may be underutilized. We observed actionable PGVs missed by somatic tests, PGVs uncovered in patients’ second malignancies, and PGVs not within germline reflex testing criteria. These results reinforce the utility of germline testing separate from somatic testing in appropriate patients. [Table: see text]
Veliparib (V) monotherapy after progression on placebo (PL) + carboplatin/paclitaxel (CP) in patients with advanced HER2-negative gBRCA-associated breast cancer: Crossover outcomes and exploratory biomarker analyses in BROCADE3.
Authors: Puhalla Shannon L , Dieras Veronique , Arun Banu , Kaufman Bella , Wildiers Hans , Han Hyo S. , Ayoub Jean-Pierre M. , Stearns Vered , Yuan Yuan , Helsten Teresa L. , Riley-Gillis Bridget , Murphy Erin , Kundu Madan Gopal , Wu Meijing , Maag David , Ratajczak Christine , Ramathal Cyril , Friedlander Michael
Published: May 2020

1097

Background: In BROCADE3 (NCT02163694), addition of the PARP inhibitor (PARPi) V to CP improved PFS in patients (pts) with g BRCA-associated advanced breast cancer (hazard ratio 0.71 [95% CI 0.57–0.88], p = 0.002). Reversion mutations may account for resistance to platinum-based CT and PARPi. Efficacy, safety, and exploratory biomarker analyses for pts randomized to PL + CP who received crossover (Cx) V monotherapy after progression are reported. Methods: 513 total pts were randomized 2:1 to V + CP or PL + CP. V/PL, C, and P could be discontinued independently prior to progression, leading to varying platinum-free intervals at the time of progression. After progression, pts in the PL + CP arm could receive open-label Cx V monotherapy (300–400 mg BID continuous), beginning within 60 d of progression and continuing to second progression. Adverse events (AEs) and activity during Cx V were assessed. Exploratory analysis of BRCA reversion mutations restoring BRCA1/2 protein function that emerged during PL + CP treatment was performed on plasma circulating tumor DNA using targeted-amplicon next generation sequencing. Results: At data cutoff, 75 pts initially randomized to PL + CP had ≥1 dose of Cx V. Mean (range) duration of Cx V was 154 d (2–966). Activity during Cx V is in the Table. Mean (range) platinum-free interval at time of first dose of Cx V was 3.1 mos (0.4–10.9) vs 8.1 mos (1.0–34.9) in pts who had progressed vs had not progressed by 24 wks after first dose of Cx V. BRCA reversion analysis was completed for 18 Cx pts. Reversion mutations were identified in 1/18 pts (5.6%). This patient had Cx V duration of 19 d and had progressed by 24 wks. BRCA reversion analysis on additional Cx pts will be presented. Most common AEs during Cx V were nausea (61%), vomiting (29%), fatigue (24%), and diarrhea (21%). Any grade anemia, neutropenia, and thrombocytopenia occurred in 7%, 15%, and 7% of pts. Three pts (4%) experienced a convulsion event. Conclusions: Platinum-free interval may influence efficacy of subsequent PARPi. Impact of BRCA reversion mutations warrants further evaluation. Cross-resistance may limit PARPi efficacy after platinum failure. Clinical trial information: NCT02163694 . [Table: see text]
A comprehensive analysis of the demographics and citation-based productivity of radiation oncologists practicing at comprehensive cancer centers.
Authors: McClelland Shearwood , Huang Christina C , Holliday Emma Brey , Jagsi Reshma , Zellars Richard C.
Published: May 2020

11001

Background: Academic radiation oncology represents a constantly changing landscape. We sought to determine the demographic makeup of the current academic radiation oncology workforce. Methods: Internet searches of the 51 National Cancer Institute-designated Comprehensive Cancer Centers were conducted in September 2019. The Scopus database was subsequently searched in December 2019 to ascertain the h-index for each radiation oncologist. H-indices were analyzed by faculty rank (junior faculty versus associate professor versus full professor) and gender. Variables were coalesced for statistical analysis using Fisher’s exact test and two-tailed t-tests. Results: Analysis of 993 radiation oncologists revealed that 53.6% are junior faculty, 24.8% are associate professors, and 21.7% are full professors. The average radiation oncologist has been an MD for 19.6 years; 32.5% (232/993) are women, and less than 5% (47/993) are underrepresented minorities (URM). Of the 51 department chairs, 11.8% are women and 5.6% are underrepresented minorities. Women are significantly underrepresented among full professors (odds ratio = 1.78; p = 0.010) and departmental chairs (odds ratio = 3.80; p = 0.0007); there was no significant difference for assistant professorship (p = 0.067) nor associate professorship (p = 0.348). The overall mean h-index for all faculty was 17.64. Mean h-index was 8.21 for junior faculty, 18.46 for associate professors, and 40.05 for full professors; these differences were statistically significant (p < 0.0001). The overall mean h-index was 19.35 for men (n = 668) and 14.11 for women (n = 323); this difference was statistically significant (p < 0.0001). Conclusions: The majority of academic radiation oncologists are assistant professors; fewer than 5% are underrepresented minorities. Men comprise more than two-thirds of the workforce, and are significantly overrepresented at the full professor (by 78%) and departmental chair (by 280%) levels in academic radiation oncology. The average radiation oncologist at a comprehensive cancer center has published more than 17 manuscripts cited at least 17 times. Contrary to previous findings comparing male and female residents, the difference in academic productivity by gender among faculty was statistically significant. These findings provide objective data to assess the radiation oncology academic workforce and provide a useful benchmark to measure change going forward.
Student loan debt and visa status influence on career choices for hematology and medical oncology fellows in the United States.
Authors: Al-Issa Karam , Rangaraju Sravanti , Al-Hader Ahmad Abdelfattah
Published: May 2020

11024

Background: There are multiple factors influencing future career plans for US hematology/oncology fellows. The objective of this study is to evaluate the effects of student loan debt and visa status as potential factors affecting their career choices. Methods: A total of 159 US hematology/oncology fellowship programs were contacted, program directors forwarded the survey to current hematology/oncology fellows and recent graduates (classes of 2019, 2018 and 2017). The survey consisted of 13 questions regarding their student loan debt and visa status, research experience, initial career plan, current career for graduates, the influence of student loan debt and visa status on their career decisions (academic, private practice, industry), and whether or not their training programs had resources or mentorship to help them deal with those factors. We used a scale of 1-5 to determine how much each factor affected career choice (1 = extremely unaffected, 5 = extremely affected). Results: A total of 220 physicians have participated, 177 (80.5%) fellows and 43 (19.5%) graduates. For graduates, 35% had student loans during fellowship, 40% of them thought that their loans affected their career choice with a score of 4-5. 93% of graduates with student loans answered that they weren't aware of resources/mentorship to address their loans effect on their career. 44% of graduates were on J1/H1 visa during training, 74% of them thought that their visa status affected their career choice with score of 4-5. 63% of graduates who were on visa answered that they weren't aware of resources/mentorship to address visa status as a factor influencing their career options. For current fellows, 51% have student loans, one third of them thought that their loans affected their career choice with score 4-5. 77% of fellows with student loans answered that they weren't aware of resources/mentorship to address their loans effect on their career. 16% of current fellows are on J1/H1 visa, 66% of them thought that their visa status is affecting their career choice with score 4-5. 62% of fellows who are on visa answered that they weren't aware of resources/mentorship to address visa status as a factor influencing their career options. Conclusions: Hematology/oncology fellows report that student loan debt and visa status are important factors affecting their career decisions. The majority of hematology/oncology fellows in this survey weren’t aware of resources or mentorship to help deal with these factors. Mentors need to be aware of these factors to help fellows achieve their career goals.