bluuebunny/crossref_metadata_2025 huggingface dataset:
A revised Children's Oncology Group (COG) neuroblastoma risk classification system: Report from the COG biology study ANBL00B1.
Authors: Irwin Meredith , Naranjo Arlene , Cohn Susan Lerner , London Wendy B , Gastier-Foster Julie M , Maris John M. , Bagatell Rochelle , Park Julie R. , Hogarty Michael D.
Published: May 2019

10012

Background: The COG risk classification system previously used the International Neuroblastoma Staging System (INSS). The pre-treatment INRG staging system (INRGSS) has been adopted internationally, requiring integration of INRGSS with known prognostic biological and clinical characteristics to evaluate outcomes and assess whether this incorporation will require revision to the established COG risk classifier. Methods: 4,037 newly diagnosed neuroblastoma patients were enrolled on COG ANBL00B1 between 2006-2014. Staging per the INSS and INRGSS was determined. Tumor biological and histologic features, including MYCN status [amplified (A) versus not amplified (NA)], ploidy, histology, and segmental chromosome aberrations (SCA) including 1p and 11q LOH, were assessed centrally. Survival analyses were performed to identify independent prognostic factors and to calculate event-free and overall survival (EFS, OS) for combinations of variables used to determine risk group assignments according to COG and INRG classification templates. Results: Using the original COG risk classifier 1,309 low (LR), 992 intermediate (IR) and 1,736 high-risk (HR) patients were identified with 5-year EFS of 91.4±2.1%, 84.3±2.9%, 45.2±3.1%, and OS of 98.1±1.0%, 94.0±1.9%, 54.1±3.0%, respectively. Outcomes based on combinations of clinical and biological prognostic factors were determined and compared for subsets of patients according to the COG (version1) and INRG risk classification systems to develop a revised COG risk classifier that incorporates the INRGSS (version 2, subset shown in table). Conclusions: Use of INRGSS requires a revision to the COG risk classifier. By combining INRGSS and presence of SCA together with age, MYCN status, ploidy, and histology to determine outcome of patients treated with modern era therapies, we developed a revised risk classification system to inform therapy and COG clinical trial eligibility. Clinical trial information: NCT00904241. [Table: see text]
Randomization of dose-reduced subcutaneous interleukin-2 (scIL2) in maintenance immunotherapy (IT) with anti-GD2 antibody dinutuximab beta (DB) long-term infusion (LTI) in front–line high-risk neuroblastoma patients: Early results from the HR-NBL1/SIOPEN trial.
Authors: Ladenstein Ruth Lydia , Poetschger Ulrike , Valteau-Couanet Dominique , Gray Juliet , Luksch Roberto , Balwierz Walentyna , Castel Victoria , Ash Shifra , Beck Popovic Maja , Laureys Genevieve , Chan Godfrey Chi Fung , Ruud Ellen , Vettenranta Kim , Owens Cormac , Schroeder Henrik , Loibner Hans , Ambros Peter F , Sarnacki Sabine , Boterberg Tom , Lode Holger N.
Published: May 2019

10013

Background: We tested dose-reduced scIL2 in combination with DB-LTI and oral isotretinoin and evaluated toxicity and efficacy in high-risk neuroblastoma patients (EudraCT:2006-001489-17). Methods: High-risk patients (stage 4 ≥1y; stage 4 < 1y with MYCN amplification (MNA); stage 2, 3, 0-21y with MNA) received high intensity induction (rapid COJEC or N5-MSKC and TVD for insufficient response), surgery, high dose therapy with busulfan/melphalan and local radiotherapy. Patients ≤9 months between diagnosis and HDT/SCT who achieved at least a partial response prior to HDT/SCT and without progression thereafter were randomized to receive up to 5 cycles of 100mg/m2 DB-LTI (d8-17) ± 3x106 IU/m2 scIL2 (d1-5; d8, d10, d12, d14, d16) and 160mg/m2 oral isotretinoin (d19-32). Results: Between 04/2014 and 06/2018, 408 patients from 18 countries were randomized. Median follow-up is 1.8 years. Stage, age, MNA, induction treatments and remission status were well balanced between randomization arms. The 2yrs-EFS and -OS for DB-LTI (205 pts) vs. DB-LTI&scIL2 (203 pts) was 64%±4%vs63%±5% (p = 0.844) and 83%±3%vs74%±4% (p = 0.337). For patients in CR the 2yrs-EFS was 69%±5% for DB and 66%±6% for DB&scIL2. Patients with evaluable disease prior DB or DB&scIL2, the end of treatment response rate was 57% (26% CR, 31% PR) vs 52% (27% CR, 25% PR) with 2yrs-EFS rates of 58%±7% and 64% ±8%, respectively. Grade 3&4 toxicity was lower in the group with DB vs DB&scIL2 for fever (14%vs31%, p < 0.001) and pain (7%vs18%, p = 0.005), and no significant difference was seen for general condition (17%vs22%,ns), allergy (3%vs3%,ns), capillary leak (4%vs8%,ns), liver enzyme elevation (20%vs27%, ns) and neurological toxicities (2%vs2%,ns). Conclusions: We previously reported grade 3&4 toxicity to DB short-term infusion (STI) ± 10x6x106IU/m2 scIL2 for general condition (16%vs41%, p = 0.000), fever (14%vs40%, p = 0.000), allergic reaction (10%vs20%, p = p = 0.006), capillary leak (4%vs15%, p = 0.004), liver enzyme elevation (17%vs23%, ns), central neurotoxicity (3%vs8%, p = 0.034) and pain (16%vs26%, p = 0.048). Our results indicate that DB-LTI and dose-reduced scIL2 clearly reduced the toxicity profile, but showed absence of benefits of scIL2. DB-LTI achieved 2yrs-EFS in line with DB-STI (Ladenstein, Lancet Oncology 2018; Yu, NEJM, 2010) and a response rate > 50% supporting its use as standard of care IT. Clinical trial information: EudraCT:2006-001489-17.
Chronic health conditions (CHC) and late mortality in survivors of acute lymphoblastic leukemia (ALL) in the Childhood Cancer Survivor Study.
Authors: Dixon Stephanie , Chen Yan , Yasui Yutaka , Pui Ching-Hon , Hunger Stephen , Silverman Lewis B. , Green Daniel M. , Kadan-Lottick Nina S. , Ness Kirsten K. , Leisenring Wendy , Howell Rebecca M. , Oeffinger Kevin C. , Neglia Joseph Philip , Krull Kevin R. , Hudson Melissa M. , Robison Leslie L. , Mertens Ann C. , Armstrong Gregory T. , Nathan Paul C.
Published: May 2019

10016

Background: The impact of evolving risk-stratified therapy on long-term morbidity and mortality in survivors of childhood ALL remains largely unknown. Methods: All-cause and health-related late mortality (HRM; captures death from late-effects occurring > 5 yrs from diagnosis), subsequent (malignant) neoplasm [S(M)N], CTCAE graded CHC and neurocognitive outcomes were assessed in 5-yr survivors of ALL diagnosed < 21 yrs of age from 1970-99. Therapy combinations defined 6 groups: 1970s-like ( 70s), standard and high risk 1980s- and 1990s-like ( 80sSR, 80sHR, 90sSR, 90sHR), relapse/transplant ( R/BMT). Cumulative incidence and standardized mortality ratios (SMR) were calculated. Piecewise exponential and log-binomial models estimated rate ratios (RR) with 95% confidence intervals (CI). Results: Among 6148 survivors (median age 31.5 yrs), 15-yr cumulative incidence of all-cause mortality was 5.8% (CI 5.3-6.2) and HRM was 1.5% (1.2-1.7). Compared to 70s, HRM was lower for 90sSR and 90sHR (RR 0.1, CI 0.0-0.3; 0.2, 0.1-0.7), similar to that in the US population (SMR; CI: 90sSR 1.1; 0.6-1.9, 90sHR 1.9; 0.8-3.7). 20-yr cumulative incidence of SN was 3.5% (CI 3.1-3.9). Compared to 70s, 90sSR had lower risk of benign meningioma (RR 0.1, CI 0.0-0.3) and SMN (0.3, 0.1-0.6) with no absolute excess risk compared to the US population. 90sSR was associated with a lower risk of CHCs (Table). Conclusions: More recent risk-stratified therapy has succeeded in reducing risk of late mortality and CHCs among long-term survivors of ALL. [Table: see text]
Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial.
Authors: Saura Cristina , Oliveira Mafalda , Feng Yin-Hsun , Dai Ming-Shen , Hurvitz Sara A. , Kim Sung-Bae , Moy Beverly , Delaloge Suzette , Gradishar William John , Masuda Norikazu , Palacova Marketa , Trudeau Maureen E. , Mattson Johanna , Yap Yoon Sim , Bryce Richard , Yao Bin , Bebchuk Judith D. , Keyvanjah Kiana , Brufsky Adam ,   NALA Investigators
Published: May 2019

1002

Background: NALA (ClinicalTrials.gov NCT01808573) is a multinational, randomized, open-label, phase III trial of neratinib (an irreversible pan-HER tyrosine kinase inhibitor [TKI]) + capecitabine (N+C) vs lapatinib (a reversible dual TKI) + capecitabine (L+C) in patients with stage IV HER2+ metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens for MBC. Methods: Patients were randomized 1:1 to N (240 mg qd po) + C (750 mg/m2 bid po) or L (1250 mg qd po) + C (1000 mg/m2 bid po). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints were investigator-assessed PFS; objective response rate (ORR); duration of response (DoR); clinical benefit rate (CBR); time to intervention for symptomatic metastatic central nervous system (CNS) disease; safety; and patient-reported health outcomes. Results: 621 patients were randomized (307 to N+C; 314 to L+C). The risk of disease progression or death was reduced by 24% with N+C vs L+C (HR = 0.76; 95% CI 0.63–0.93; p = 0.006); 6- and 12-month PFS rates were 47.2% vs 37.8% and 28.8% vs 14.8% for N+C vs L+C, respectively. OS rates at 6 and 12 months were 90.2% vs 87.5% and 72.5% vs 66.7% for N+C vs L+C, respectively (HR = 0.88; 95% CI 0.72–1.07; p = 0.2086). ORR in patients with measurable disease at screening was improved with N+C vs L+C (32.8% vs 26.7%; p = 0.1201), as was CBR (44.5% vs 35.6%; p = 0.0328) and DoR (HR = 0.50; 95% CI 0.33–0.74; p = 0.0004). Time to intervention for symptomatic CNS disease (overall cumulative incidence 22.8% vs 29.2%; p = 0.043) was delayed with N+C vs L+C. Treatment-emergent adverse events (TEAEs) were similar between arms, but there was a higher rate of grade 3 diarrhea with N+C vs L+C (24.4% vs 12.5%). TEAEs leading to neratinib/lapatinib discontinuation were lower with neratinib (10.9%) than with lapatinib (14.5%). Conclusions: N+C significantly improved PFS with a trend towards improved OS vs L+C. N+C also resulted in a delayed time to intervention for symptomatic CNS disease. Tolerability was similar between the two arms, with no new safety signals observed. Clinical trial information: NCT01808573.
Population-based cancer predisposition testing as a component of newborn screening: A cost-effectiveness analysis.
Authors: Yeh Jennifer , Stout Natasha K. , Chaudhry Aeysha , Gooch Michael , McMahon Pamela , Christensen Kurt D. , Diller Lisa , Wu Ann C.
Published: May 2019

10021

Background: The role of population-based newborn genetic testing to identify infants at high risk of childhood-onset cancers has not been studied, despite the availability of cancer surveillance guidelines for early detection in high-risk infants and children. Methods: We developed the Precision Medicine Prevention and Treatment (PreEMPT) Model to estimate the value of targeted population-based newborn genomic sequencing (tNBS) for a select panel of genes associated with early onset pediatric malignancy. Cohorts of US newborns were simulated under tNBS screening vs. usual care, from birth to death. Six pediatric cancer predisposition syndromes were included in the model with mutations in RET, RB1, TP53, DICER1, SUFU or SMARCB1 assigned at birth, using mutation prevalence and disease risks drawn from the published literature, as well as SEER, ClinVar and gnoMAD databases. Newborns with mutations underwent cancer surveillance based on established guidelines for each gene-related pediatric malignancy. Survival benefit was modeled as a reduction in proportion of advanced disease, cancer deaths, and treatment-related late mortality risks. Costs were based on published literature and national databases. Results: In a typical US birth cohort of 4 million newborns, we estimated 1280 cancer cases in the malignancies associated with this gene panel would be detected before age 20 under usual care, resulting in 451 cancer deaths and 490 living with radiation exposure risks. tNBS would prevent 8 cancers (in RET mutation carriers), avert 34 deaths through surveillance, result in 3190 life-years (LY) gained and a 13% relative reduction in proportion of adult survivors at risk for radiation-associated late mortality. Given a sequencing cost of $30 (e.g., $5/gene), the incremental cost-effectiveness ratio (ICER) for tNBS was $230,500 per LY saved; if no additional cost was incurred beyond standard newborn screening, the ICER decreased to $101,100/LY. Conclusions: Population-based genetic testing of newborns can reduce mortality associated with pediatric cancers and could potentially be cost-effective as sequencing costs decline. Further work will include modeling a broader panel of predisposition genes.
Naxitamab-based chemoimmunotherapy for resistant high-risk neuroblastoma: Preliminary results of HITS pilot/phase II study.
Authors: Mora Jaume , Kushner Brian H. , Flores Miguel Angel , Santa-María Vicente , Garraus Moira , Basu Ellen M. , Roberts Stephen S. , Castañeda Alicia , Gorostegui Maite , Cheung Nai-Kong V. , Modak Shakeel
Published: May 2019

10025

Background: Chemoresistant and relapsed disease are major obstacles to curing high-risk neuroblastoma (HR-NB). Anti-GD2 monoclonal antibody (MoAb) is effective in preventing relapse after remission but responses in relapsed or progressive disease (PD) are rare. We investigated the combination of humanized anti-GD2 MoAb naxitamab, (previously termed Hu3F8), irinotecan, temozolomide and sargramostim (GM-CSF): a pilot HITS protocol against resistant HR-NB now expanded to a phase II study (NCT03189706). Methods: Salient eligibility criteria included evaluable or measurable chemoresistant disease. Prior anti-GD2 MoAb and/or irinotecan/temozolomide (I/T) therapy was permitted. Each cycle comprised of irinotecan 50 mg/m2/day intravenously (IV) plus temozolomide 150 mg/m2/day IV or orally (days 1-5); naxitamab 2.25 mg/kg/day IV over 30 minutes, days 2, 4, 8 and 10 (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously, days 6-10. Toxicity was measured by CTCAE v4.0 and responses by modified International Neuroblastoma Response Criteria. Results: Forty-six (23 enrolled on protocol and 23 on compassionate-use basis) heavily prior-treated patients (median age at enrollment: 6.6 years; median number of prior relapses: 2) have received 175 (median 2; range 1-12) cycles to date. At enrollment, 7 patients had HR-NB refractory to induction chemotherapy while 39 had prior relapse. Toxicities included myelosuppression and diarrhea expected with I/T, and pain and hypertension expected with naxitamab. No other > grade 2 related toxicities occurred; treatment was outpatient. Early responses, assessed after 2 cycles, were documented in 18 (39%) patients and were complete (n = 9), partial (n = 8), and mixed (n = 1); 13 patients had stable disease. Responses were achieved in refractory (3/7;43%) and PD (15/39;38%) subgroups, in patients who had previously received I/T (12/34;35%) and/or anti-GD2 MoAb (14/36;39%), and in soft tissue (6/22; 27%) MIBG-avid skeletal sites (20/36;56%) and on bone marrow histology (9/12; 75%). Conclusions: High-dose naxitamab-based chemoimmunotherapy is safe and effective against chemoresistant HR-NB. This ongoing phase II study may define a broader role for naxitamab which was recently granted breakthrough designation by the FDA. Clinical trial information: NCT03189706.
The promoting resilience in stress management (PRISM) intervention for parents of children with cancer: A randomized controlled trial.
Authors: Taylor Mallory R. , Bradford Miranda C. , Junkins Courtney C. , Kross Erin K. , Curtis J. Randall , Yi-Frazier Joyce P. , Rosenberg Abby R.
Published: May 2019

10029

Background: Parents of children with cancer experience significant levels of distress, which may negatively impact surviving patients and family members. Positive psychology interventions have shown promise, but few address the well-being of parents. The objective of this study was to test the efficacy of a resilience intervention, Promoting Resilience in Stress Management-Parent (PRISM-P), among parents of children with cancer. Methods: This study was a phase 2, 1:1:1 RCT. Eligible participants were English-speaking parents of children 2-24 years-old receiving cancer-directed therapy at Seattle Children’s Hospital. PRISM-P is a skills-based program targeting resilience resources. Parents were randomized to usual care (UC), UC plus individual PRISM-P (1:1), or UC plus group PRISM-P (group). Parents completed surveys at baseline and 3 months measuring resilience (primary outcome, 10-item Connor Davidson Resilience Scale (CDRISC)) and other secondary outcomes including stress, social support, and benefit-finding. We performed an intention-to-treat analysis using unadjusted linear mixed-effects modeling to estimate PRISM effects on score change. With n = 25 per arm, we achieved 80% power to detect an effect size (CDRISC change) of 5.1 (Cohen’s d = 0.8) with a type 1 error rate of 0.05. Results: 107 parents enrolled. Of these, 94 (88%) completed baseline surveys and 77 (72%) completed 3 month surveys. Mean (SD) resilience score change in UC, 1:1 and group arms was -2 (3.5), 1 (5.3) and -1 (5.0), respectively. In mixed models, the estimated 1:1 PRISM benefit for resilience score change vs. UC was +2.8 (95% CI: 0.5,5.2, p = 0.02) while there was no evidence of a group benefit (beta 0.4, 95% CI: -2.1, 2.8, p = 0.76.). Models for secondary outcome score change found a PRISM advantage for benefit finding, where the 1:1 vs. UC difference was +0.5 (95% CI: 0.2, 0.8, p < 0.01) and the group vs. UC difference was +0.4 (0.0, 0.7, p = 0.05). Conclusions: Compared to UC, 1:1 PRISM-P was associated with improved resilience change, and both PRISM-P intervention arms were associated with greater benefit-finding. Future studies will explore larger scale efficacy and alternative delivery design. Clinical trial information: NCT02998086.
Poverty and survival in targeted immunotherapy clinical trials.
Authors: Bona Kira O'Neil , Li Yimei , Winestone Lena , Getz Kelly D. , Huang Yuan-Shung , Fisher Brian , Desai Ami Vijay , Richardson Troy , Hall Matt , Naranjo Arlene , Henderson Tara O. , Aplenc Richard , Bagatell Rochelle
Published: May 2019

10034

Background: Whether precision medicine trials—which tailor medical treatment to a patient’s individual tumor characteristics—should include poverty as an outcome predictor is unknown. In Children’s Oncology Group (COG) trials ANBL0032 and ANBL0931, targeted immunotherapy resulted in the single greatest survival improvement for high-risk neuroblastoma (HR NBL) in decades. We utilized the ANBL0032/ANBL0931 cohort to investigate the hypothesis that poverty independently predicts inferior survival outcomes in targeted immunotherapy trials. Methods: We retrospectively analyzed outcome data for patients uniformly treated with immunotherapy on ANBL0032/ANBL0931 at Pediatric Health Information System-associated hospitals. Poverty exposure was a priori characterized at the neighborhood and household level. Neighborhood poverty was defined as living in a ZIP code with a median household income in the cohort’s lowest quartile ( < $35,916 vs. $46,324-$60,947). Household poverty was defined as Medicaid insurance (vs. private/other). Multivariable Cox regression evaluated associations between poverty exposures and event-free (EFS) and overall (OS) survival adjusting for demographic, clinical and tumor variables (ethnicity, hospital clustering, disease response, disease stage, MYCN status). Post-hoc analyses examined the joint effect of neighborhood and household poverty using a common reference. Results: Among 371 patients, 25% lived in high-poverty ZIP codes; 35% were Medicaid-insured; 14% were exposed to both. Only Medicaid was independently associated with inferior EFS (hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.28-2.84, p = 0.001). OS was inferior in children with Medicaid (HR 2.79, 95%CI 1.63-4.79, p < 0.001) and less than complete disease response (HR 1.89, 95%CI 1.004-3.56, p = 0.049). In post-hoc analysis, joint poverty exposure had a more pronounced impact on EFS (HR 2.21, 95%CI 1.48 to 3.30, p < 0.001) and OS (HR 3.7, 95%CI 2.08-6.59, p < 0.001) than Medicaid alone. No other covariate remained significantly associated with survival. Conclusions: Poverty independently predicted inferior EFS and OS among a cohort of neuroblastoma patients uniformly treated with targeted immunotherapy. For the full potential of precision medicine to be realized, future clinical trials should systematically investigate and intervene upon poverty as a significant predictor of survival.
First experience of LOXO-292 in the management of pediatric patients with RET-altered cancers.
Authors: Gerdemann Ulrike , Lee Young Ah , Henry Dahlia , Smith Steven , Ortiz Michael Vincent , Rothenberg Stephen M. , Govinda Raju Sandya , Cox Michael Craig , Glade Bender Julia Lynne , Pappo Alberto S. , Frazier A. Lindsay , Kang Hyoung Jin
Published: May 2019

10045

Background: Genomic alterations of RET kinase, including chromosomal fusions and activating point mutations, have been identified as oncogenic drivers in pediatric and adult cancers. Multikinase inhibitors have modest activity against RET-altered cancers and are associated with significant toxicity. LOXO-292 is a potent, ATP-competitive, small molecule RET inhibitor with high selectivity for RET, preclinical activity in the brain and excellent pharmacokinetic properties. In an ongoing phase 1/2 study of adult and adolescent patients with advanced RET-altered cancers, LOXO-292 demonstrated marked antitumor activity and was well tolerated. Methods: Pediatric patients with RET-altered cancers who were unable to access LOXO-292 through a phase 1/2 clinical trial were enrolled using FDA-allowed, IRB-approved single patient protocols . Patients received LOXO-292 (capsule/liquid formulation) orally, continuously, at a starting dose of 90 mg/m2 BID. Response was assessed locally by investigators. Results: As of January 31, 2019, 4 female patients aged 13 months–8 years were enrolled from the Republic of Korea (papillary thyroid cancer, n = 1) and the USA (infantile myofibroma/hemangiopericytoma, n = 1; congenital mesoblastic nephroma/infantile fibrosarcoma, n = 1; lipofibromatosis, n = 1). All tumors harbored RET gene fusions (5′ partners: CCDC6, MYH10, SPECC1L, and NCOA4, respectively), detected by next-generation sequencing. Previous therapies included surgery/iodine 131 (n = 1); vandetanib (n = 1); surgery/chemotherapy (n = 1); 1 patient was treatment-naïve. Duration of treatment ranged from 3–120 days and all patients remain on treatment. There were no dose modifications or discontinuations due to adverse events. There were no treatment-related adverse events ≥ grade 3. Two patients who were evaluable for response had partial responses (both ongoing, 1 confirmed, 1 pending confirmation). Conclusions: These preliminary data from a real-world setting suggest that LOXO-292 is effective and safe in pediatric patients whose tumors harbor RET gene fusions.
Capivasertib (AZD5363) plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER-positive breast cancer (FAKTION): A randomized, double-blind, placebo-controlled, phase II trial.
Authors: Jones Robert Hugh , Carucci Margherita , Casbard Angela Claire , Butler Rachel , Alchami Fouad , Bale Catherine Jane , Bezecny Pavel , Joffe Johnathan , Moon Sarah , Twelves Chris , Venkitaraman Ramachandran , Waters Simon , Howell Sacha Jon
Published: May 2019

1005

Background: The PI3K/AKT signalling pathway is frequently activated in patients (pts) with estrogen receptor (ER) positive breast cancer (ER+BC) and has been implicated in endocrine therapy resistance. Capivasertib (AZD5363) is a highly-selective, oral, small molecule AKT inhibitor. The FAKTION trial investigated the addition of capivasertib to fulvestrant for postmenopausal women with ER+ and HER2 negative BC after relapse or disease progression on an aromatase inhibitor (AI). Methods: FAKTION is an investigator-led, double-blind, placebo-controlled, randomised phase II trial. Patients were recruited from 21 UK sites and randomly assigned (1:1) to fulvestrant 500mg (day 1 and 15 of cycle 1 and day 1 only of subsequent 28 day cycles) with either capivasertib 400mg bd or placebo (4 days on/3 days off starting C1D15) until disease progression, unacceptable toxicity or withdrawal of consent. Allocation was balanced by minimisation according to PIK3CA mutation and PTEN expression status, measurable/non-measurable disease, and primary/secondary endocrine resistance. The primary endpoint was progression-free survival (PFS). The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints included overall survival (OS), objective response and clinical benefit rates, safety and the effect of PI3K/Akt pathway activation on PFS. Results: Between Mar 2015 and Mar 2018, 140 pts were randomised to fulvestrant + capivasertib (n = 69) or fulvestrant + placebo (n = 71). In the Intention-to-treat analysis, after 112 events, median PFS was 10.3 months (m) for capivasertib compared to 4.8m for placebo (Hazard Ratio (HR) 0.57; 95% CI: 0.39 to 0.84; one-sided p = 0.0017; two-sided 0.0035). Fifty-two deaths were reported. Median OS was 26.0m for capivasertib compared to 20.0m for placebo, with a survival difference starting to emerge after 12m (HR = 0.59; 95% CI: 0.34 to 1.05; two-sided p = 0.071). Toxicity data and subgroup analyses including relative capivasertib benefit by PI3K/Akt pathway alteration will be presented at the conference. Conclusions: The trial met its primary endpoint. Addition of capivasertib to fulvestrant for patients with endocrine resistant advanced breast cancer resulted in significantly longer PFS and an improvement in OS. The FAKTION results warrant further investigation of capivasertib for the treatment of ER positive breast cancer. Clinical trial information: NCT01992952.
New insights in cisplatin and radiation-induced ototoxicity: A French Childhood Cancer Survivors Study (FCCSS).
Authors: Fresneau Brice , Santos Felicia , Allodji Rodrigue , Fayech Chiraz , Bolle Stephanie , Vu-Bezin Giao , Souchard Vincent , Haddy Nadia , Doz Francois P. , Berchery Delphine , Lemire Pierre , Journy Neige , Veres Cristina , Brugieres Laurence , Valteau-Couanet Dominique , Diallo Ibrahima , Dufour Christelle , De Vathaire Florent
Published: May 2019

10061

Background: Platinum chemotherapy (CT) and cranial radiotherapy (RT) are risk factors of ototoxicity. Effects of RT dose at inner ear and of other CT were investigated. Methods: Of 7670 5-year childhood cancer survivors from the FCCSS treated before 20 years of age in 1942-2000 for solid cancer or lymphoma, 5243 with ototoxicity long-term follow-up data were included. Severe ototoxicity, defined as the need of hearing aids or Brock grade 3-4 hearing loss, was identified from self-administrated questionnaires, clinical visits and cohort linkage with the French Hospital Database and health insurance information system (SNIIRAM). The mean RT dose at inner ear was estimated using home-made software. Multivariable Cox models adjusted for gender, age at diagnosis, time period and social deprivation index was used to identify risk factors for severe ototoxicity. Results: After a mean follow-up of 30 years, 199 cases of severe ototoxicity were identified. Cumulative incidences at 30 and 50 years of age (30,50y-CumInc) were, 2.8% (95%CI = 2.4-3.3) and 5.5% (4.6-6.5), respectively. Mean RT dose at inner ear (Hazard Ratio HR = 1.6 (95%CI = 1.0-2.5), 4.5 (2.7-7.2), 5.7 (3.0-10.8) and 14.0 (9.2-21.2) for 0- < 5, 5- < 30, 30- < 40 and ≥40 Gy), as well as cisplatin (HR = 2.8, 95%CI = 1.9-4.0), melphalan (HR = 3.3, 95%CI = 1.9-5.7) and busulfan exposure (HR = 2.6, 95%CI = 1.6-4.4) were significantly associated with severe ototoxicity. Concerning melphalan (n = 199/5243 exposed), almost all cases were identified in neuroblostma patients (NBL), who also received cisplatin 200mg/m²/cycle (26/92 NBL, 30y-CumInc = 36.4% (95%CI = 25.9-48.4), vs. 3/107 non-NBL, 30y-CumInc = 1.6% (0.4-5.6)). Concerning busulfan (n = 131/5243 exposed), all cases were identified in NBL (n = 16/63, all treated with melphalan and cisplatin) and brain tumors (n = 13/28, all with RT at inner ear ≥5Gy). The 30y-CumInc in patients with RT at inner ear ≥5Gy was 7.4% (95%CI = 5.7-9.6) and 39.8% (22.5-60.0) respectively with and without busulfan. Conclusions: RT at inner ear has significant deleterious impact on audition, with cumulative incidence still worsening > 30years after RT, and with likely potentiation by busulfan. The deleterious effect of melphalan was related to previous treatment with cisplatin, either by interaction between these drugs, or by the high cisplatin dose by cycle used in NBL.
Biomarker analyses from JAVELIN Renal 101: Avelumab + axitinib (A+Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).
Authors: Choueiri Toni K. , Albiges Laurence , Haanen John B. A. G. , Larkin James M.G. , Uemura Motohide , Pal Sumanta K. , Gravis Gwenaelle , Campbell Matthew T , Penkov Konstantin , Lee Jae-Lyun , Ching Keith A. , Mu Xinmeng Jasmine , Wang Xiao , Zhang Weidong , Wang Jing , Chudnovsky Aleksander , di Pietro Alessandra , Robbins Paul B. , Motzer Robert J.
Published: May 2019

101

Background: The phase 3 JAVELIN Renal 101 trial in previously untreated patients (pts) with aRCC demonstrated a progression-free survival (PFS) benefit and higher objective response rate with A+Ax vs S (Motzer, ESMO 2018; LBA6_PR). Here, we report outcomes from biomarker analyses of baseline tumor samples. Methods: We correlated efficacy with the results of molecular analyses of tissue samples from all 886 pts enrolled in JAVELIN Renal 101. Nephrectomy or tumor samples were characterized by immunohistochemistry (CD8 and PD-L1), whole-exome sequencing (WES), and RNAseq. WES and RNAseq were used to examine somatic mutations and analyze relevant gene expression signatures (GES) in relation to clinical outcomes. GES analyses included published and de novo signatures: effector T cell (Teff), angiogenesis (angio),T cell-inflamed (Tinf), and a novel immune-related signature incorporating pathway indicators for T- and NK-cell activation and IFNγ signaling, among others. Results: PD-L1 expression (≥1% immune cells) was associated with the longest PFS in the A+Ax arm and the shortest in the S arm (HR, 0.63; 95% CI, 0.49, 0.81). Significant treatment arm–specific differences in PFS were observed relative to wildtype when mutations in genes such as CD1631L, PTEN, or DNMT1 were present. Tumor mutational burden did not distinguish pts with respect to PFS. High-angio GES was associated with significantly improved PFS in the S arm but did not differentiate PFS in the A+Ax arm. In the low-angio subset, A+Ax improved PFS vs S. Pts with high Teff and Tinf in the A+Ax arm had longer PFS vs the S arm. In the A+Ax arm, PFS was enhanced in patients with immune GES–positive tumors vs those in the negative group (HR, 0.63; 95% CI, 0.46, 0.86; 2-sided p = 0.004), as well as in an independent dataset (JAVELIN Renal 100; Choueiri, Lancet Oncol, 2018) (HR, 0.46; 95% CI, 0.20, 1.05; 2-sided p = 0.064). Updated efficacy, including overall survival, will be presented. Conclusions: These findings define molecular features that differentiate therapy-specific outcomes in first-line aRCC and may inform personalized therapy strategies for pts with aRCC. Funding: Pfizer and Merck KGaA. Clinical trial information: NCT02684006.
Genomic markers of early progression on fulvestrant with or without palbociclib for ER+ advanced breast cancer in the PALOMA-3 trial.
Authors: O'Leary Ben , Cutts Ros , Huang Xin , Hrebien Sarah , Liu Yuan , Garcia-Murillas Isaac , Andre Fabrice , Loi Sherene , Loibl Sibylle , Cristofanilli Massimo , Bartlett Cynthia Huang , Turner Nicholas C.
Published: May 2019

1010

Background: Markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited despite the key role of these combinations in treating of ER+ advanced breast cancer (ABC). We investigated genomic aberrations in patients treated with fulvestrant, with and without palbociclib, with a circulating tumor DNA analysis of baseline plasma in the PALOMA-3 trial. Methods: PALOMA-3 was a phase III trial that randomized 521 patients with ER+/HER2- ABC 2:1 to palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F). Using baseline plasma samples, somatic mutations were assessed with a 17 gene panel. Copy number aberrations (CNA) were characterized with a 14 gene panel including ~800 SNPs in 8 commonly altered regions for estimation of tumor purity, the percentage of plasma DNA that was derived from tumor cells. Results for mutations and CNAs were available in 310 pts (203 P+F, 107 F) and were associated with clinical characteristics and progression free survival (PFS) using univariable and multivariable Cox proportional hazards models, including tumor purity and treatment as variables. Results: In the multivariable analysis of the whole cohort, higher baseline tumor purity in plasma was associated with worse PFS (HR 1.20, 95% CI 1.09 – 1.32, p = 0.0001, HR per 10% increase in purity). Baseline TP53 mutation was also associated with shorter PFS (HR 1.84, 95%CI 1.27 – 2.65, p = 0.0011), as was baseline FGFR1 amplification (HR 2.91, 95%CI 1.61 – 5.25, p = 0.0004). PIK3CA and ESR1 mutations had no significant association with PFS in the multivariable model. Palbociclib treatment effect was comparable with the overall trial result (HR 0.43, 95%CI 0.32 - 0.57, p < 0.0001). TP53 mutations were significantly associated with visceral (q = 0.046) and soft tissue/LN metastases (q = 0.042) and the number of disease sites (q = 0.0086) after correction for multiple testing. Conclusions: TP53 mutation, FGFR1 amplification , and tumor purity in plasma identified patients at risk of early progression In PALOMA-3. If validated these results could inform future clinical trials of CDK4/6 inhibitors combinations.
Pembrolizumab (P) in patients (pts) with metastatic breast cancer (MBC) with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.
Authors: Alva Ajjai Shivaram , Mangat Pam K. , Garrett-Mayer Elizabeth , Halabi Susan , Alvarez Ricardo H. , Calfa Carmen Julia , Khalil Maged F. , Ahn Eugene R , Cannon Timothy Lewis , Crilley Pamela A. , Fisher Julie Gottlieb , Haslem Derrick S. , Shrestha Sagun , Antonelli Kaitlyn R. , Butler Nicole L. , Warren Sasha L. , Rygiel Andrew Lawrence , Ranasinghe Shamika , Bruinooge Suanna S. , Schilsky Richard L.
Published: May 2019

1014

Background: TAPUR is a phase II basket study evaluating the anti-tumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. P is an immune checkpoint inhibitor and HTMB is an emerging predictive biomarker for checkpoint inhibitor therapy. Results in a cohort of MBC pts with HTMB treated with P are reported. Methods: Eligible pts had advanced cancer, no standard treatment options, ECOG PS 0-1, measurable disease and acceptable organ function. Genomic testing was performed using commercially available tests selected by sites. Pts matched to P had HTMB defined as ≥9 mutations/megabase (Muts/Mb) by a FoundationOne test (n=20) or approved by the TAPUR Molecular Tumor Board for other tests (n=8). A Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16 weeks (wks) (SD16+)), an additional 18 pts are enrolled. If ≥7 of 28 pts have DC, the drug is considered worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight female MBC pts were enrolled from October 2016 to July 2018. Pts received P at 2 mg/kg (n=8) or 200 mg (n=20) IV over 30 minutes, every 3 wks. HTMB ranged from 9 to 37 Muts/Mb. Demographics and outcomes are summarized in Table (N=28). No relationship was observed between #Muts/Mb and PFS or OS. Two grade 3 AEs (weight loss and hypoalbuminemia) and 1 grade 2 SAE (urinary tract infection) were reported as at least possibly related to P. Conclusions: P demonstrated anti-tumor activity in heavily pre-treated MBC pts with HTMB . Additional study of P is warranted in MBC pts with HTMB. Clinical trial information: NCT02693535. [Table: see text]
Triplet therapy (continuous ribociclib, everolimus, exemestane) in HR+/HER2− advanced breast cancer postprogression on a CDK4/6 inhibitor (TRINITI-1): Efficacy, safety, and biomarker results.
Authors: Bardia Aditya , Hurvitz Sara A. , DeMichele Angela , Clark Amy Sanders , Zelnak Amelia Bruce , Yardley Denise A. , Karuturi Meghan Sri , Sanft Tara B. , Blau Sibel , Hart Lowell L. , Ma Cynthia X. , Caria Nicola , Purkayastha D. Das , Mistry Alomi , Moulder Stacy L.
Published: May 2019

1016

Background: The combination of CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) provides consistent improvement in PFS and response rates compared with single-agent ET as first- or subsequent-line therapy in HR+, HER2− advanced breast cancer (ABC), but the optimal regimen postCDK4/6i progression, including the role of continued CDK 4/6 blockade, is unclear. Methods: TRINITI-1 is a Phase I/II, open-label trial (NCT02732119) of triplet therapy: ribociclib (RIB; CDK4/6i) + everolimus (EVE; mTORi) + exemestane (EXE; ET) in men or postmenopausal women with HR+, HER2− ABC that progressed on prior CDK4/6i and up to 3 lines of therapy (≥ 1 ET and ≤ 1 chemotherapy regimen). Phase I determined RP2D; Phase II assessed efficacy/safety of RIB 300 or 200 mg + EVE 2.5 or 5 mg + EXE 25 mg/day. Here we present the first results in the entire patient population who received this triplet regimen and the correlation of biomarkers with outcomes. Results: As of October 24, 2018, 95 patients were evaluable (ET refractory and postCDK4/6i) in Phases I (n = 17) and II (n = 78). Continuous RIB + EVE + EXE demonstrated clinical benefit at week 24 in 39 patients (41.1%), exceeding the predefined primary end point threshold (> 10%). ORR was 8.4% by investigator assessment, median PFS was 5.7 months, and 1-year PFS was 33%. AEs were consistent with known safety profile of RIB, EVE, and EXE. Most common AEs were neutropenia (all grades, 41.7%; grade 3/4, 31.3%), stomatitis (41.7%; 3.1%), and fatigue (35.4%; 1.0%). No grade 3/4 QTc prolongation was noted. ctDNA genotyping revealed patients with certain tumor alterations, eg ESR1, had shorter median PFS vs wild-type: 3.5 vs 6.9 mo (HR 1.76, 95% CI 1.01–3.05). Additional genomic results, including PIK3CA, will be presented. Conclusions: TRINITI-1 met its primary efficacy end point and is the first trial to demonstrate clinical benefit and tolerability of continuous triplet therapy with ET + mTORi + CDK4/6i in patients with ET-refractory HR+, HER2− ABC postCDK4/6i progression. Tumor genomic profile might impact the clinical outcome with triplet therapy and warrants additional research to guide rational therapy selection. Clinical trial information: NCT02732119.
Association of STK11/LKB1 genomic alterations with lack of benefit from the addition of pembrolizumab to platinum doublet chemotherapy in non-squamous non-small cell lung cancer.
Authors: Skoulidis Ferdinandos , Arbour Kathryn Cecilia , Hellmann Matthew David , Patil Pradnya Dinkar , Marmarelis Melina Elpi , Awad Mark M. , Murray Joseph Christopher , Hellyer Jessica , Gainor Justin F. , Dimou Anastasios , Bestvina Christine M. , Shu Catherine A. , Riess Jonathan W. , Blakely Collin Michael , Pecot Chad Victor , Mezquita Laura , Tabbò Fabrizio , Scheffler Matthias , Papadimitrakopoulou Vassiliki , Heymach John
Published: May 2019

102

Background: Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread adoption of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we examine the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy. Methods: 497 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 17 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 377 pts treated with first-line CPP (or > 1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 120 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP. Results: Among 377 CPP-treated pts, STK11/LKB1 genomic alterations (N = 102) were associated with significantly shorter PFS (mPFS 4.8m vs 7.2m, HR 1.5, 95% CI 1.1 to 2.0; P = 0.0063) and shorter OS (mOS 10.6m vs 16.7m, HR 1.58, 95% CI 1.09 to 2.27; P = 0.0083) compared with STK11/LKB1-wt tumors (N = 275). ORR also differed significantly between the two groups (32.6% vs 44.7%, P = 0.049). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N = 333). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not improve PFS (mPFS 4.8m vs 4.3m, HR 1.13, 95% CI 0.83 to 1.54, P = 0.75) or OS (mOS 10.6m vs 10.3m, HR 1.03, 95% CI 0.71 to 1.49, P = 0.79) compared to CP alone. Conclusions: In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.
Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Final overall survival (OS) from the phase III HERITAGE Trial.
Authors: Waller Cornelius F. , Manikhas Aleksei , Pennella Eduardo J. , Bondarenko Igor , Mukhametshina Guzel , Tiambeng Maria Luisa Abesanis , Akewanlop Charuwan , Vynnychenko Ihor , Sriuranpong Virote , Ray Sirshendu , Hernandez-Bronchud Miguel , Herson Jay , Parra Joseph D. , Parra Joseph D. , Nemsadze Gia , Gopalakrishnan Unmesh , Loganathan Subramanian , Muniz Rafael , Barve Abhijit , Rugo Hope S.
Published: May 2019

1021

Background: The multicenter, double-blind, randomized, parallel-group, phase 3 Heritage trial (NCT02472964) evaluated efficacy and safety of trastuzumab-dkst (Ogivri), a trastuzumab biosimilar, vs trastuzumab, plus taxane as first-line therapy for patients with HER2+ metastatic breast cancer. Overall response at week (wk) 24 and progression-free survival (PFS) at wk 48 have been reported (Rugo et al, JAMA 2017; ASCO 2018). Methods: Eligible patients were randomized 1:1 to trastuzumab-dkst or trastuzumab, plus taxane. After 24 wks, patients with responding/stable disease continued monotherapy per randomization. Safety and OS during maintenance, cumulative through 36 months of follow-up from last patient on study, are described. Results: 500 patients were randomized; 343 received monotherapy after 24 wks (trastuzumab-dkst, n = 179; trastuzumab, n = 164). 128 patients discontinued monotherapy (trastuzumab-dkst, n = 63; trastuzumab, n = 65); mean time to discontinuation was 19 months in both groups. Treatment-emergent adverse events (TEAEs) during monotherapy were similar for trastuzumab-dkst (69%) and trastuzumab (73%); most were low grade and serious TEAE rates were 6% in both groups. Cumulative rates of TEAEs of special interest were similar for hypersensitivity, pulmonary, and cardiac events (trastuzumab-dkst, 23%, 16%, and 5%; trastuzumab, 24%, 13%, and 5%). Incidences of left ventricular ejection fraction (LVEF) < 50% ≥1 time postbaseline (trastuzumab-dkst, 5%; trastuzumab, 3%) and LVEF < 50% postbaseline and ≥10% reduction (trastuzumab-dkst, 4%; trastuzumab, 3%) were low. At 36 months, 169 patients had received further lines of therapy, with similar distribution of HER2 treatments, endocrine therapies, and chemotherapies. Final median PFS was 11.1 months in both groups. Median duration of response was 9.9 and 9.8 months and median OS was 35.0 and 30.2 months for trastuzumab-dkst and trastuzumab, respectively: unstratified hazard ratio, 0.9 (95% CI, 0.70-1.17). Conclusions: Long-term safety data with similar median OS compared with originator trastuzumab further support the safety and efficacy profile of trastuzumab-dkst. Clinical trial information: NCT02472964.
mTORC1 activation assessed in metastatic sample to predict outcome in patients with metastatic breast cancer treated with everolimus-exemestan: Results from the SAFIRTOR study.
Authors: Bachelot Thomas Denis , Treilleux Isabelle , Schiffler Camille , Bieche Ivan , Campone Mario , Patsouris Anne , Arnedos Monica , Cottu Paul H. , Jacquin Jean-Philippe , Dalenc Florence , Attignon Valéry , Rouleau Etienne , Morel Alain , Legrand François , Jimenez Marta , Andre Fabrice
Published: May 2019

1024

Background: Using samples from TAMRAD study (Treilleux, Ann Oncol, 2015), we previously reported that p4EBP1, a downstream protein of mTOR, was associated with higher benefit to everolimus (eve). SAFIRTOR study was designed to validate clinical utility of this biomarker. Methods: Patients (pts) with ER+, HER2 negative, AI resistant MBC were prospectively included (NCT02444390). All pts had a biopsy of a metastatic site and were then treated with standard eve + exemestane (exe) combination. The primary end point was to validate that p4EBP1 expression is associated with longer PFS in patients treated with eve. 120 evaluable pts were needed for the pre planed statistical analysis. All samples were collected and processed in a standardized procedure in order to allow phophoproteins IHC staining. In addition to p4EBP1, we explored prognostic value of pS6K, pAkt, PTEN and LKB1, together with genomic alterations assessed by NGS and CGH arrays. Results: 150 pts were included, 30 pts had no adequate sample, and further 13 had missing clinical data, 107 were evaluable for primary objective. Median age was 62, they had previously progressed on AI treatment, either in the adjuvant (22 pts) or the metastatic setting (83 pts). 20 were considered as primary hormone resistant, 87 as secondary resistant. The median Allread score for p4EBP1 was 5.5 (range: 0-6.5). Analysis of the primary endpoint showed that p4EBP1 staining above the median is associated with a longer PFS on eve+exe. (median PFS: 9.3 months, 95CI 6.3-13.1 for high p4EBP1 versus 5.8 months, 95CI 3.7-7.8 for low p4EBP1, p = 0.02). Prognostic value of high pEBP1 remained significant when assessed in a multivariate analysis along classical clinico-biological prognostic factors for MBC (HR 0.57, 95%CI 0.38-0.88, p = 0.01). In this AI resistant population, the tumor of 42 (46%), 33 (35%) and 5 (5.3%) pts carried an activating mutation for ESR1, PIK3CA and AKT1, respectively. None of these mutational statuses were correlated to outcome. Conclusions: This prospective study validates p4EBP1 expression analysis to select patients most likely to benefit from everolimus + exemestane. Clinical trial information: NCT02444390.