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The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours. Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting). Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72–85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred. These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible. Bayer and Loxo Oncology.

Tumour grade, tumour size, resection potential, and extent of disease affect outcome in paediatric non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS), but no risk stratification systems exist and the standard of care is poorly defined. We developed a risk stratification system from known prognostic factors and assessed it in the context of risk-adapted therapy for young patients with NRSTS. In this prospective study, eligible patients enrolled in 159 hospitals in three countries were younger than 30 years, had a Lansky (patients ≤16 years) or Karnofsky (patients >16 years) performance status score of at least 50, and a new diagnosis of a WHO (2002 criteria) intermediate (rarely metastasising) or malignant soft-tissue tumour (apart from tumour types eligible for other Children's Oncology Group studies and tumours for which the therapy in this trial was deemed inappropriate), malignant peripheral nerve sheath tumour, non-metastatic and grossly resected dermatofibrosarcoma protuberans, undifferentiated embryonal sarcoma of the liver, or unclassified malignant soft-tissue sarcoma. Each patient was assigned to one of three risk groups and one of four treatment groups. Risk groups were: low (non-metastatic R0 or R1 low-grade, or ≤5 cm R1 high-grade tumour); intermediate (non-metastatic R0 or R1 >5 cm high-grade, or unresected tumour of any size or grade); or high (metastatic tumour). The treatment groups were surgery alone, radiotherapy (55·8 Gy), chemoradiotherapy (chemotherapy and 55·8 Gy radiotherapy), and neoadjuvant chemoradiotherapy (chemotherapy and 45 Gy radiotherapy, then surgery and radiotherapy boost based on margins with continued chemotherapy). Chemotherapy included six cycles of ifosfamide 3 g/m2 per dose intravenously on days 1–3 and five cycles of doxorubicin 37·5 mg/m2 per dose intravenously on days 1–2 every 3 weeks with sequence adjusted on the basis of timing of surgery or radiotherapy. The primary outcomes were event-free survival, overall survival, and the pattern of treatment failure. Analysis was done per protocol. This study has been completed and is registered with ClinicalTrials.gov, NCT00346164. Between Feb 5, 2007, and Feb 10, 2012, 550 eligible patients were enrolled, of whom 21 were treated in the incorrect group and excluded from this analysis. 529 evaluable patients were included in the analysis: low-risk (n=222), intermediate-risk (n=227), high-risk (n=80); surgery alone (n=205), radiotherapy (n=17), chemoradiotherapy (n=111), and neoadjuvant chemoradiotherapy (n=196). At a median follow-up of 6·5 years (IQR 4·9–7·9), 5-year event-free survival and overall survival were: 88·9% (95% CI 84·0–93·8) and 96·2% (93·2–99·2) in the low-risk group; 65·0% (58·2–71·8) and 79·2% (73·4–85·0) in the intermediate-risk group; and 21·2% (11·4–31·1) and 35·5% (23·6–47·4) in the high-risk group, respectively. Risk group predicted event-free survival and overall survival (p<0·0001). No deaths from toxic events during treatment were reported. Nine patients had unexpected grade 4 adverse events (chemoradiotherapy group, n=2; neoadjuvant chemoradiotherapy group, n=7), including three wound complications that required surgery (all in the neoadjuvant chemoradiotherapy group). Pre-treatment clinical features can be used to effectively define treatment failure risk and to stratify young patients with NRSTS for risk-adapted therapy. Most low-risk patients can be cured without adjuvant therapy, thereby avoiding known long-term treatment complications. Survival remains suboptimal for intermediate-risk and high-risk patients and novel therapies are needed. National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation, American Lebanese Syrian Associated Charities.

A constitutive mutation in a cancer-susceptibility gene can have implications for clinical treatment and genetic counseling of family members. This study involving 1120 children and adolescents showed that 95 (8.5%) had such a mutation. The frequency of germline mutations in cancer-predisposition genes in children and adolescents with cancer and the implications of such mutations are largely unknown. Previous studies have relied mainly on candidate-gene approaches, which are, by design, limited. To better determine the contribution of germline predisposition mutations to childhood cancer, we used next-generation sequencing, including whole-genome and whole-exome sequencing, to analyze the genomes of 1120 children and adolescents with cancer. We describe the prevalence and spectrum of germline variants among 565 cancer-associated genes, with an emphasis on the analysis of 60 genes that have been associated with autosomal dominant cancer-predisposition syndromes. We . . .

Multifocal synchronous or metachronous atypical teratoid rhabdoid tumors (ATRTs) and non-central nervous system malignant rhabdoid tumors (extra-CNS MRTs) are rare cancers. We reviewed the clinical and radiologic characteristics of affected patients seen at our institution. Genotyping and analysis of copy number abnormalities (CNAs) in SMARCB1 were performed in germline and tumor samples. Tumor samples underwent genome-wide DNA methylation and CNA analysis. The median age at diagnosis of 21 patients was 0.6 years. Two-thirds of ATRTs and extra-CNS MRTs were diagnosed synchronously. Although kidney tumors predominated, including two patients with bilateral involvement, at least 30% of cases lacked renal involvement. Histopathologic review confirmed MRTs in all cases and INI1 expression loss in all tumors tested. Fourteen (78%) of 18 patients tested had heterozygous germline SMARCB1 abnormalities. At least one allelic SMARCB1 abnormality was confirmed in 81 and 88% of ATRTs and extra-CNS MRTs, respectively. Unsupervised hierarchical clustering analysis of DNA methylation in 27 tumors and comparison with a reference group of 150 ATRTs classified the CNS tumors ( n  = 14) as sonic hedgehog (64%), tyrosinase (21%), and MYC (14%). The MYC subgroup accounted for 85% of 13 extra-CNS MRTs. Of 16 paired ATRTs and extra-CNS MRTs, the tumors in seven of eight patients showed a different pattern of genome-wide DNA methylation and/or CNAs suggestive of non-clonal origin. CNS and extra-CNS tumors had an identical SMARCB1 amplification ( n  = 1) or very similar DNA methylation pattern ( n  = 1) suggestive of clonal origin. All patients died of tumor progression. The clinical and molecular characteristics of multifocal ATRTs and extra-CNS MRTs are heterogeneous with most patients harboring a cancer predisposition. Although independent tumor origin was confirmed in most cases, metastatic spread was also documented. The recognition of their distinct molecular characteristics is critical in selecting new biologic therapies against these deadly cancers.

Gene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients. This multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion status; had a Karnofsky (≥16 years of age) or Lansky (<16 years of age) performance status score of 50 or more, adequate organ function, and full recovery from the acute toxic effects of all previous anticancer therapy. Following a protocol amendment on Sept 12, 2016, patients with locally advanced infantile fibrosarcoma who would require disfiguring surgery to achieve a complete surgical resection were also eligible. Patients were enrolled to three dose cohorts according to a rolling six design. Larotrectinib was administered orally (capsule or liquid formulation), twice daily, on a continuous 28-day schedule, in increasing doses adjusted for age and bodyweight. The primary endpoint of the phase 1 dose escalation component was the safety of larotrectinib, including dose-limiting toxicity. All patients who received at least one dose of larotrectinib were included in the safety analyses. Reported here are results of the phase 1 dose escalation cohort. Phase 1 follow-up and phase 2 are ongoing. This trial is registered with ClinicalTrials.gov, number NCT02637687. Between Dec 21, 2015, and April 13, 2017, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) with a median age of 4·5 years (IQR 1·3–13·3) were enrolled to three dose cohorts: cohorts 1 and 2 were assigned doses on the basis of both age and bodyweight predicted by use of SimCyp modelling to achieve an area under the curve equivalent to the adult doses of 100 mg twice daily (cohort 1) and 150 mg twice daily (cohort 2); and cohort 3 was assigned to receive a dose of 100 mg/m2 twice daily (maximum 100 mg per dose), regardless of age, equating to a maximum of 173% of the recommended adult phase 2 dose. Among enrolled patients harbouring TRK fusion-positive cancers, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. Adverse events were predominantly grade 1 or 2 (occurring in 21 [88%] of 24 patients); the most common larotrectinib-related adverse events of all grades were increased alanine and aspartate aminotransferase (ten [42%] of 24 each), leucopenia (five [21%] of 24), decreased neutrophil count (five [21%] of 24), and vomiting (five [21%] of 24). Grade 3 alanine aminotransferase elevation was the only dose-limiting toxicity and occurred in one patient without a TRK fusion and with progressive disease. No grade 4 or 5 treatment-related adverse events were observed. Two larotrectinib-related serious adverse events were observed: grade 3 nausea and grade 3 ejection fraction decrease during the 28-day follow-up after discontinuing larotrectinib and while on anthracyclines. The maximum tolerated dose was not reached, and 100 mg/m2 (maximum of 100 mg per dose) was established as the recommended phase 2 dose. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response as per Response Evaluation Criteria In Solid Tumors version 1.1; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. The TRK inhibitor larotrectinib was well tolerated in paediatric patients and showed encouraging antitumour activity in all patients with TRK fusion-positive tumours. The recommended phase 2 dose was defined as 100mg/m2 (maximum 100 mg per dose) for infants, children, and adolescents, regardless of age. Loxo Oncology Inc.

BackgroundNatural killer (NK) cells are one of the main effector populations of immunotherapy with monoclonal antibody and cytokines, used in combination with chemotherapy to treat children with high-risk neuroblastoma on this phase II trial. However, the impact of chemoimmunotherapy on NK cell kinetics, phenotype, and function is understudied.MethodsWe prospectively examined NK cell properties from 63 children with newly diagnosed neuroblastoma enrolled in a phase II trial (NCT01857934) and correlated our findings with tumor volume reduction after 2 courses of chemoimmunotherapy. NK cell studies were conducted longitudinally during chemoimmunotherapy and autologous hematopoietic cell transplantation (autoHCT) with optional haploidentical NK cell infusion and additional immunotherapy.ResultsChemoimmunotherapy led to significant NK cytopenia, but complete NK cell recovery reliably occurred by day 21 of each therapy course as well as after autoHCT. Haploidentical NK cell infusion elevated the NK cell count transiently during autoHCT. NK cell cytotoxicity increased significantly during treatment compared with diagnosis. In addition, NK cells maintained their ability to respond to cytokine stimulation in culture longitudinally. Unsupervised cluster analysis of CD56bright NK cell count and tumor volume at diagnosis and after two courses of chemoimmunotherapy identified two patient groups with distinct primary tumor sizes and therapy responses.ConclusionAfter profound NK cytopenia due to chemoimmunotherapy, endogenously reconstituted NK cells exhibit enhanced NK cytotoxicity compared with pretherapy measurements. Our data suggest a relationship between CD56bright expression and tumor size before and after two courses of chemoimmunotherapy; however, future studies are necessary to confirm this relationship and its predictive significance.Trial registration number NCT01857934.

Background. Mesenchymal chondrosarcoma is an aggressive, uncommon histologic entity arising in bone and soft tissues. We reviewed our institutional experience with this rare diagnosis. Methods. We conducted a retrospective chart review on patients with mesenchymal chondrosarcoma over a 24-year period. Clinicopathologic and radiographic features were reviewed. Results. Twelve patients were identified. Nine were females; median age was 14.5 years (1.2–19.7 years). The most common site was the head/neck (7/12). Disease was localized in 11/12 patients (one with lung nodules). Six with available tissue demonstrated NCOA2 rearrangement by FISH. Six underwent upfront surgical resection, and six received neoadjuvant therapy (2 chemotherapy alone and 4 chemotherapy and radiation). All patients received adjuvant chemotherapy (most commonly ifosfamide/doxorubicin) and/or radiation (median dose 59.4 Gy). At a median follow-up of 4.8 years, 5-year disease-free survival and overall survival were 68.2% (95% CI 39.8%, 96.6%) and 88.9% (95% CI 66.9%, 100%). Two patients had distant recurrences at 15 and 42 months, respectively. Conclusion. Aggressive surgical resection of mesenchymal chondrosarcoma with chemoradiotherapy yields excellent local control and may reduce likelihood of late recurrence. Characterization of downstream targets of the HEY1-NCOA2 fusion protein, xenograft models, and drug screening are needed to identify novel therapeutic strategies.

The survival rate of patients with pediatric cancer has increased considerably due to improved understanding of the biology of cancer subtypes, and the development of targeted therapies. This Review analyzes the recent findings that link pharmacogenomic variations with drug exposure, adverse effects, and efficacy of the emerging new treatments in pediatric oncology. Improvements in protocol-driven clinical trials and supportive care for children and adolescents with cancer have reduced mortality rates by more than 50% over the past three decades. Overall, the 5-year survival rate for patients with pediatric cancer has increased to approximately 80%. Recognition of the biological heterogeneity within specific subtypes of cancer, the discovery of genetic lesions that drive malignant transformation and cancer progression, and improved understanding of the basis of drug resistance will undoubtedly catalyze further advances in risk-directed treatments and the development of targeted therapies, boosting the cure rates further. Emerging new treatments include novel formulations of existing chemotherapeutic agents, monoclonal antibodies against cancer-associated antigens, and molecular therapies that target genetic lesions and their associated signaling pathways. Recent findings that link pharmacogenomic variations with drug exposure, adverse effects, and efficacy should accelerate efforts to develop personalized therapy for individual patients. Finally, palliative care should be included as an essential part of cancer management to prevent and relieve the suffering and to improve the quality of life of patients and their families. Key Points Prophylactic cranial irradiation can be omitted from the treatment of patients with acute lymphoblastic or myeloid leukemia, with the use of effective systemic and intrathecal therapy Vigilant supportive care can reduce morbidity and mortality, and improve event-free survival of acute myeloid leukemia The next generation of treatment for brain tumors will be tailored to specific molecular subtypes of disease to improve the cure rates and reduce the long-term sequela of therapy The cure rates have improved dramatically over the past three decades for patients with localized solid tumors and hematologic cancers Patients with disseminated disease continue to fare poorly and some are now receiving targeted therapies against specific molecular alterations Integration of palliative care into the ongoing care of children with cancer improves the quality of pediatric oncology care

The utility of circulating tumor DNA (ctDNA) analysis has not been well-established for disease detection and monitoring of childhood cancers, especially leukemias. We developed PeCan-Seq, a deep sequencing method targeting diverse somatic genomic variants in cell-free samples in childhood cancer. Plasma samples were collected at diagnosis from 233 children with hematologic, solid and brain tumors. All children with hematologic malignancy (n = 177) had detectable ctDNA at diagnosis. The median ctDNA fraction was 0.77, and 97% of 789 expected tumor variants were identified, including sequence mutations, copy number variations, and structural variations responsible for oncogenic fusions. In contrast, ctDNA was detected in 19 of 38 solid tumor patients and 1 of 18 brain tumor patients. Somatic variants from ctDNA were correlated with minimal residual disease levels as determined by flow cytometry in serial plasma samples from patients with B-cell acute lymphoblastic leukemia (B-ALL). We showcase multi-tumor detection by ctDNA analysis for a patient with concurrent B-ALL and neuroblastoma. In conclusion, PeCan-seq sensitively identified heterogeneous ctDNA alterations from 1 mL plasma for childhood hematologic malignancies and a subset of solid tumors. PeCan-seq provides a robust, non-invasive approach to augment comprehensive genomic profiling at diagnosis and mutation-specific detection during disease monitoring.