Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome.

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).

Enrollment on upfront high-risk neuroblastoma trials by race, ethnicity, and poverty status: A report from the Children's Oncology Group.

It is not clear whether trial access disparities exist in the Children's Oncology Group (COG). Here, we leverage a cohort of children with high-risk neuroblastoma (HR-NBL) enrolled on the COG ANBL00B1 neuroblastoma biology study to examine subsequent enrollment to upfront COG therapeutic trials by race, ethnicity, and proxied poverty status. Among 1917 children with HR-NBL enrolled on ANBL00B1, 696 (36.3%) subsequently enrolled on an upfront therapeutic trial with no difference by race, ethnicity, or proxied poverty status. In neuroblastoma, trial access disparities are not comparable to adult oncology, and efforts to advance equity should prioritize other mechanisms of survival disparities.

Norepinephrine transporter and vesicular monoamine transporter 2 tumor expression as a predictor of response to 131 I-MIBG in patients with relapsed/refractory neuroblastoma.

BACKGROUND: Prior studies suggest that norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) mediate meta-iodobenzylguanidine (MIBG) uptake and retention in neuroblastoma tumors. We evaluated the relationship between NET and VMAT2 tumor expression and clinical response to 131 I-MIBG therapy in patients with neuroblastoma. METHODS: Immunohistochemistry (IHC) was used to evaluate NET and VMAT2 protein expression levels on archival tumor samples (obtained at diagnosis or relapse) from patients with relapsed or refractory neuroblastoma treated with 131 I-MIBG. A composite protein expression H-score was determined by multiplying a semi-quantitative intensity value (0-3+) by the percentage of tumor cells expressing the protein. RESULTS: Tumor samples and clinical data were available for 106 patients, of whom 28.3% had partial response (PR) or higher. NET H-score was not significantly associated with response (≥PR), though the percentage of tumor cells expressing NET was lower among responders (median 80% for ≥PR vs. 90% for

Reporting and impact of subsequent cycle toxicities in oncology phase I clinical trials.

BACKGROUND/AIMS: As oncology treatments evolve, classic assumptions of toxicity associated with cytotoxic agents may be less relevant, requiring new design strategies for trials intended to inform dosing strategies for agents that may be administered beyond a set number of defined cycles. We describe the overall incidence of dose-limiting toxicities during and after cycle 1, frequency of reporting subsequent cycle toxicities, and the impact of post-cycle 1 dose-limiting toxicities on conclusions drawn from oncology phase 1 clinical trials. METHODS: We conducted a systematic review of subsequent cycle toxicities in oncology phase I clinical trials published in the Journal of Clinical Oncology from 2000 to 2020. We used chi-square tests and multivariate logistic regression to describe predictors of reporting subsequent cycle toxicity data. RESULTS: From 2000 to 2020, we identified 489 articles reporting on therapeutic phase 1 clinical trials. Of these, 421 (86%) reported data regarding cycle 1 dose-limiting toxicities and 170 (35%) reported data on cycle 1 dose modifications. Of the trials that reported cycle 1 dose-limiting toxicities, the median percentage of patients that experienced cycle 1 dose-limiting toxicities was 8.89%. Only 47 (9.6%) publications reported on post-cycle 1 dose-limiting toxicities and only 92 (19%) reported on dose modifications beyond cycle 1. Of the trials that reported post-cycle 1 dose-limiting toxicities, the median percentage of patients that experienced post-cycle 1 dose-limiting toxicities was 14.8%. Among the 371 studies with a recommended phase 2 dose, 89% did not report whether post-cycle 1 toxicities impacted the recommended phase 2 dose. More recent year of publication was independently associated with reduced odds of reporting subsequent cycle toxicity. CONCLUSION: Reporting of subsequent cycle toxicity is uncommon in oncology phase I clinical trial publications and becoming less common over time. Guidelines for reporting of phase I oncology clinical trials should expand to include toxicity data beyond the first cycle.

Systematic review of clinical drug development activities for neuroblastoma from 2011 to 2020.

BACKGROUND: Understanding the landscape of clinical trials for patients with neuroblastoma may inform efforts to improve drug development. PROCEDURE: We evaluated therapeutic trials for patients with neuroblastoma from 2011 to 2020 in our search using clinical trial information from ClinicalTrials.gov, Clinicaltrialregister.eu, PubMed, and American Society of Clinical Oncology (ASCO) annual meeting collection. Trends in trials and treatments over time were evaluated qualitatively. RESULTS: A total of 192 trials met inclusion criteria. A median of 20.5 trials were started per year, which was stable over time. There were 87 (45%) phase 1, 100 (51%) phase 2, and only five (2.6%) phase 3 trials. The median time to completion was 4.9 years for phase 1 and 2 trials (no phase 3 trials reported as completed during the study period). In all, 34% of trials were international, while 20% of trials were intercontinental. Eighty-nine percent of nonmyeloablative trials included at least one novel agent. 48% of these trials studied combination therapies, and 86% of these combinations included conventional chemotherapy. Among 157 trials that included a targeted agent, 78 targets were identified, with GD2 being the primary target under investigation in 16.7% of these trials. Only eight trials were included in regulatory decisions, which led to European Medicines Agency (EMA) or Food and Drug Administration (FDA) approval for neuroblastoma. CONCLUSIONS: The large number of trials initiated per year, the range of targets, and the rate of intercontinental collaboration are encouraging. The paucity of late-stage trials, the prolonged trial duration, and relative lack of combination studies are major causes of concern. This work will inform future drug development for neuroblastoma.

Clinical and biological features prognostic of survival after relapse or progression of INRGSS stage MS pattern neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project.

BACKGROUND: Outcomes for patients with INRGSS metastatic special (MS) metastatic pattern neuroblastoma at initial diagnosis are well described. Prognosis after an initial event (relapse, progression, secondary malignancy) is unclear. METHODS: We investigated characteristics of MS pattern neuroblastoma patients in the International Neuroblastoma Risk Group database who subsequently experienced an event. Post-event overall survival (OS) ± standard error was calculated overall and by diagnosis era: before 2000 versus 2001 or after. Cox models were used to identify factors prognostic of post-event OS. RESULTS: Among 209 patients with an event, 88% were less than 365 days old at diagnosis; tumors were MYCN amplified in 24% and diploid in 33%. The median (range) time from diagnosis to first event was 8.16 months (7 days to 11.24 years). Of 96 patients with known relapse/progression pattern, 75% were metastatic or primary plus metastatic. Five-year post-event OS was 53% ± 3.6% and was higher for 2001 and afterwards (62% ± 5.0%) compared to before 2001 (44% ± 4.9%; p = .0046). In patients diagnosed in 2001 and after, older age, Hispanic ethnicity, MYCN amplification, 1p LOH, diploidy, high Mitotic Karyorrhexis Index, high lactate dehydrogenase (LDH), unfavorable histology, and longer time to first event were prognostic of worse post-event OS. Independent adverse prognostic factors on multivariable testing were non-White race, MYCN amplification, and diploidy. SUMMARY: Patients diagnosed in and after 2001 have substantially better post-event OS compared to before 2001. In those diagnosed in and after 2001, most well-accepted prognostic factors for OS at diagnosis are also prognostic of post-event OS. Future studies may evaluate strategies to improve outcomes in this rare population.

Children's Oncology Group's 2023 blueprint for research: Neuroblastoma.

Neuroblastoma is the most common extra-cranial solid tumor in children and is known for its clinical heterogeneity. A greater understanding of the biology of this disease has led to both improved risk stratification and new approaches to therapy. Outcomes for children with low and intermediate risk disease are excellent overall, and efforts to decrease therapy for such patients have been largely successful. Although survival has improved over time for patients with high-risk disease and treatments evaluated in the relapse setting are now being moved into earlier phases of treatment, much work remains to improve survival and decrease therapy-related toxicities. Studies of highly annotated biobanked samples continue to lead to important insights regarding neuroblastoma biology. Such studies, along with correlative biology studies incorporated into therapeutic trials, are expected to continue to provide insights that lead to new and more effective therapies. A focus on translational science is accompanied by an emphasis on new agent development, optimized risk stratification, and international collaboration to address questions relevant to molecularly defined subsets of patients. In addition, the COG Neuroblastoma Committee is committed to addressing the patient/family experience, mitigating late effects of therapy, and studying social determinants of health in patients with neuroblastoma.

Children's Oncology Group's 2023 blueprint for research: Bone tumors.

The Children's Oncology Group (COG) Bone Tumor Committee is responsible for clinical trials and biological research on localized, metastatic, and recurrent osteosarcoma and Ewing sarcoma (EWS). Results of clinical trials in localized disease completed and published in the past 10 years have led to international standard-of-care chemotherapy for osteosarcoma and EWS. A recent focus on identifying disease subgroups has led to the identification of biological features associated with poor outcomes including the presence of circulating tumor DNA (ctDNA) at diagnosis, and specific genomic alterations-MYC amplification for osteosarcoma and STAG2 and TP53 mutation for EWS. Studies validating these potential biomarkers are under way. Clinical trials evaluating the addition of multitargeted kinase inhibitors, which are active in relapsed bone sarcomas, to standard chemotherapy are under way in osteosarcoma and planned in EWS. In addition, the Committee has data analyses and a clinical trial under way to evaluate approaches to local management of the primary tumor and metastatic sites. Given the rarity of bone sarcomas, we have prioritized international interactions and are in the process of forming an international data-sharing consortium to facilitate refinement of risk stratification and study of rare disease subtypes.

Evaluation of prevalence and outcomes of serial tyrosine kinase inhibitor use in pediatric patients with advanced solid tumors.

PURPOSE: Multitargeted tyrosine kinase inhibitors (mTKIs) are increasingly utilized in the treatment of pediatric sarcomas and other solid tumors. It is unknown whether serial treatment with multiple TKIs provides a benefit and which patients are most likely to benefit from mTKI rechallenge. METHODS: We performed a retrospective cohort study of pediatric cancer patients who received serial mTKI therapy off-study between 2007 and 2020 as either monotherapy or combination therapy. We report patient characteristics, clinical outcomes, dosing patterns, and treatment-associated toxicity. RESULTS: The study cohort included 25 patients. The overall prevalence of serial mTKI therapy among all patients treated for sarcoma at our institution was 3.7%, and the response rate to second mTKI was 9%. Median 6-month progression-free survival (PFS) and overall survival (OS) from start of second mTKI were 42.1% (95% CI: 20.4%-62.5%) and 79.1% (95% CI: 57.0%-90.8%), respectively. Patients who had received 4 months or more (n = 11) of therapy with first mTKI had significantly longer PFS versus those who received less than 4 months (n = 11; p = .001). Thirty-three percent of patients discontinued second mTKI due to toxicity. Six (40%) of 15 patients who discontinued the first mTKI due to progression had either a partial response or stable disease on the second mTKI. CONCLUSIONS: We observed a low response rate to mTKI rechallenge. However, we identified patients who had been treated with first mTKI for  ≥4 months as more likely to have prolonged stable disease with second mTKI. Several patients had a response or stable disease on the second mTKI despite having progressed on the first mTKI. Though toxicity was common, only a minority of patients discontinued the second mTKI due to toxicity.

Phase 1 study of cabozantinib in combination with topotecan-cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma.

PURPOSE: Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma. METHODS: Oral cabozantinib (25 mg/m2 ) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75 mg/m2 ) and cyclophosphamide (250 mg/m2 ) were administered intravenously (IV) on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation. RESULTS: Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (seven with Ewing sarcoma; five with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis, grade 3 transaminitis, and prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease. CONCLUSIONS: The recommended phase 2 doses and schedules for this combination are topotecan 0.75 mg/m2 IV days 1-5, cyclophosphamide 250 mg/m2 IV days 1-5, and cabozantinib 25 mg/m2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity, while allowing for potential disease control.

NUT Carcinoma in Children and Adolescents: The Expert European Standard Clinical Practice Harmonized Recommendations.

BACKGROUND AND AIMS: Nuclear protein of the testis ( NUT ) carcinoma (NC) is a rare and highly aggressive tumor mainly occurring in adolescents and young adults, defined by the presence of a somatic NUTM1 rearrangement. The aim is to establish internationally harmonized consensus recommendations for the diagnosis and treatment of adolescents and young adults with NC in the framework of the European Reference Network for Paediatric Oncology. METHODS: The European Cooperative Study Group for Pediatric Rare Tumors developed recommendations according to the Consensus Conference Standard Operating procedure methodology and reviewed by external "experts." No evidence of level I to II exists. Recommendations were developed based on published prospective (level III), but more frequently retrospective series (level IV), case reports (level V), and personal expertise (level V). In addition, "strength" of recommendations were categorized by grading (grade A to E). RESULTS: Histology is mandatory for the diagnosis of NC, including immunolabeling with anti-NUT antibodies and molecular biology ( NUTM1 rearrangement) (level V; grade A). Treatment of NC usually combines aggressive approaches in multimodal regimens. Chemotherapy should be considered as first-line treatment (neoadjuvant vincristine-adriamycin-ifosfamide/cisplatin-adriamycin-ifsofamide or vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide) for unresectable or metastatic tumor (ie, 3 courses), rapidly followed by local treatment (level IV; grade B). Referral to a specialized surgical oncology center is highly recommended (level V; grade A). In localized NC, a complete microscopic surgical resection should be attempted whenever and as soon as possible, followed by primary irradiation (60 to 70 Gy) and involved lymph nodes area (level IV; grade B). For head and neck tumors, a systematic neck dissection might be considered, even if N0 (level V; grade C). Adjuvant postirradiation chemotherapy is recommended, for a total of 9 to 12 courses (level IV; grade B). For first-line resected tumors, concomitant adjuvant chemotherapy to radiotherapy may be discussed (level IV; grade B). Targeted therapies and immunotherapeutic regimens should be delivered in the setting of prospective trials (level V; grade B). CONCLUSIONS: This project leads to a consensus strategy based on international experience with this very rare disease.

Adverse prognostic impact of the loss of STAG2 protein expression in patients with newly diagnosed localised Ewing sarcoma: A report from the Children's Oncology Group.

BACKGROUND: Ewing sarcoma (EWS) is an aggressive sarcoma with no validated molecular biomarkers. We aimed to determine the frequency of STAG2 protein loss by immunohistochemistry (IHC) and whether loss of expression is associated with outcome. METHODS: We performed a retrospective cohort study of patients with EWS enrolled to Children's Oncology Group studies. We obtained unstained slides from 235 patients and DNA for sequencing from 75 patients. STAG2 expression was tested for association with clinical features and survival was estimated using Kaplan-Meier methods with log-rank tests. RESULTS: In total, 155 cases passed quality control for STAG2 IHC. STAG2 expression in 20/155 cases could not be categorised with the limited available tissue, leaving 135 patients with definitive STAG2 IHC. In localised and metastatic disease, STAG2 was lost in 29/108 and 6/27 cases, respectively. Among patients with IHC and sequencing, 0/17 STAG2 expressing cases had STAG2 mutations, and 2/7 cases with STAG2 loss had STAG2 mutations. Among patients with localised disease, 5-year event-free survival was 54% (95% CI 34-70%) and 75% (95% CI 63-84%) for patients with STAG2 loss vs. expression (P = 0.0034). CONCLUSION: STAG2 loss of expression is identified in a population of patients without identifiable STAG2 mutations and carries a poor prognosis.

Histologic characterization of paediatric mesenchymal neoplasms treated with kinase-targeted therapy.

AIMS: Recurrent alterations involving receptor tyrosine or cytoplasmic kinase genes have been described in soft-tissue neoplasms such as infantile fibrosarcoma (IFS) and inflammatory myofibroblastic tumour (IMT). Recent trials and regulatory approvals for targeted inhibitors against the kinase domains of these oncoproteins have allowed for increased use of targeted therapies. We aimed to characterize the histologic features of paediatric mesenchymal neoplasms with kinase alterations treated with targeted inhibitors. METHODS AND RESULTS: Eight patients with tyrosine kinase-altered mesenchymal neoplasms with pre- and posttreatment samples were identified. Tumours occurred in five females and three males with a median age at presentation of 6.5 years. Tumour sites were bone/somatic soft-tissue (n = 5) and viscera (n = 3). Pretreatment diagnoses were: IMT (n = 3), epithelioid inflammatory myofibroblastic sarcoma (n = 1), and descriptive diagnoses (n = 4) such as "kinase-driven spindle cell tumor." Fusions identified were ETV6::NTRK3 (n = 2), TPM3::NTRK1, SEPT7::BRAF, TFG::ROS1, KLC1::ALK, RANBP2::ALK, and MAP4::RAF1. Patients were treated with larotrectinib (n = 3), ALK or ALK/ROS1 inhibitors (n = 3), and MEK inhibitors (n = 2). Posttreatment tumours exhibited a striking decrease in cellularity (7/8) and the presence of collagenous stroma (7/8) with extensive glassy hyalinization (5/8). In two cases, abundant coarse or psammomatous calcifications were seen and in one case prominent perivascular hyalinization was noted. Residual viable tumour was seen in 3/8 cases (<5% in one case, and >75% in 2/8 cases). CONCLUSION: Mesenchymal neoplasms with tyrosine kinase alterations treated with targeted inhibitors show a pathologic response, which includes decreased cellularity and stromal hyalinization. The presence of these features may be helpful in assessing tumour response after targeted therapy.

68 Ga-DOTATATE PET and functional imaging in pediatric pheochromocytoma and paraganglioma.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors in childhood. Up to 40% of PPGL are currently thought to be associated with a hereditary predisposition. Nuclear medicine imaging modalities such as fluorodeoxyglucose positron emission tomography (18 F-FDG PET), 68 Ga-DOTATATE PET, and 123 I-metaiodobenzylguanidine (123 I-MIBG) scintigraphy play an essential role in the staging, response assessment, and determination of suitability for targeted radiotherapy in patients with PPGL. Each of these functional imaging modalities targets a different cellular characteristic and as such can be complementary to anatomic imaging and to each other. With the recent US Food and Drug Administration approval and increasing use of 68 Ga-DOTATATE for imaging in children, the purpose of this article is to use a case-based approach to highlight both the advantages and limitations of DOTATATE imaging as it is compared to current radiologic imaging techniques in the staging and response assessment of pediatric PPGL, as well as other neuroendocrine malignancies.

Anatomic patterns of relapse and progression following treatment with 131 I-MIBG in relapsed or refractory neuroblastoma.

OBJECTIVES: Patients with metaiodobenzylguanidine (MIBG)-avid relapsed or refractory neuroblastoma after initial therapy may exhibit transient responses to salvage treatment with iodine-131 metaiodobenzylguanidine (131 I-MIBG). It is unclear whether disease progression following 131 I-MIBG treatment occurs in previously involved versus new anatomic sites of disease. Understanding this pattern of relapse will inform the use of consolidation therapy following 131 I-MIBG administration. METHODS: Patients with relapsed or refractory metastatic MIBG-avid neuroblastoma or ganglioneuroblastoma, who received single-agent 131 I-MIBG, had stable or responding disease 6-8 weeks following 131 I-MIBG, but subsequently experienced disease progression were included. MIBG scans were reviewed to establish anatomic and temporal evolution of MIBG-avid disease. RESULTS: A total of 84 MIBG-avid metastatic sites were identified immediately prior to MIBG therapy in a cohort of 12 patients. At first progression, a total of 101 MIBG-avid sites were identified, of which 69 (68%) overlapped with pre-treatment disease sites, while 32 (32%) represented anatomically new disease areas. Eight of 12 patients had one or more new MIBG-avid sites at first progression. Of the 69 involved sites at progression that overlapped with pre-treatment disease, 11 represented relapsed sites that had cleared following MIBG therapy, two were persistent but increasingly MIBG-avid, and 56 were stably persistent. CONCLUSIONS: Previously involved anatomic disease sites predominate at disease progression following 131 I-MIBG treatment. Nevertheless, the majority of patients progressed in at least one new anatomic disease site. This suggests that consolidation focal therapies targeting residual disease sites may be of limited benefit in preventing systemic disease progression following 131 I-MIBG treatment of relapsed or refractory neuroblastoma.

Pattern and predictors of sites of relapse in neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project.

PURPOSE: We sought to analyze biologic, clinical, and prognostic differences according to pattern of failure at the time of first relapse in neuroblastoma. PATIENTS AND METHODS: Children <21 years diagnosed with neuroblastoma between 1989 and 2017 with known site of first relapse (isolated local vs. distant only vs. combined local and distant sites) were identified from the International Neuroblastoma Risk Group (INRG) database. Data were compared between sites of relapse according to clinical features, biologic features, initial treatment, time to first relapse, and overall survival (OS) from time of first relapse. RESULTS: Pattern of first relapse among 1833 children was 19% isolated local; 65% distant only; and 16% combined sites. All evaluated clinical and biologic variables with exception of tumor diagnosis differed statistically by relapse pattern, with patients with isolated local failure having more favorable prognostic features. Patients with stage 3 disease were more likely to have isolated local failure compared to all other stages (49% vs. 16%; p < .001). OS significantly differed by relapse pattern (5-year OS ± SE): isolated local: 64% ± 3%; distant only: 23% ± 2%; and combined: 26% ± 4% (p < .001). After controlling for age, stage, and MYCN status, patients with isolated local failure (adjusted hazard ratio [HR] = 0.46; 95% confidence interval [CI]: 0.33-0.62; p < .001) and distant-only failure (adjusted HR = 0.57; 95% CI: 0.45-0.71; p < .001) remained at decreased risk for death as compared to patients with combined failure. CONCLUSION: Patients with distant-only and combined failures have a higher proportion of unfavorable clinical and biological features, and a lower survival than those with isolated local relapse.

Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.

BACKGROUND: Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS: We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. RESULTS: A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events. CONCLUSIONS: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).

Role of bone marrow biopsy for staging new patients with Ewing sarcoma: A systematic review.

The incidence of bone marrow metastasis (BMM) in newly diagnosed Ewing sarcoma (ES) is variable across studies. An optimal staging strategy for detecting BMM is not defined. While bone marrow (BM) biopsy and/or aspirate (BMBA) have been the gold standard, [F-18]fluorodeoxyglucose positron emission tomography (FDG-PET) to detect BMM may decrease reliance on BMBA. We conducted a systematic review to assess incidence of BMM and the role of FDG-PET. We observed a pooled incidence of BMM by BMBA of 4.8% in all newly diagnosed ES patients and 17.5% among patients with metastatic disease. Only 1.2% of patients had BMM as their sole metastatic site. FDG-PET detection of BMM compared to BMBA demonstrated pooled 100% sensitivity and 96% specificity, positive predictive value of 75%, and negative predictive value of 100%. In the era of FDG-PET imaging, omission of BMBA may be considered in patients with otherwise localized disease after initial staging studies.

Derivation and validation of risk groups in patients with osteosarcoma utilizing regression tree analysis.

BACKGROUND: For patients with osteosarcoma, apart from stage and primary site, we lack reliable prognostic factors for risk stratification at diagnosis. There is a need for further defined, discrete prognostic groups using presenting clinical features. METHODS: We analyzed a cohort of 3069 patients less than 50 years of age, diagnosed with primary osteosarcoma of the bone between 1986 and 2013 from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly split into test and validation cohorts. Optimal cut points for age, tumor size, and grade were identified using classification and regression tree analysis. Manual recursive partitioning was used to identify discrete prognostic groups within the test cohort. These groups were applied to the validation cohort, and overall survival was analyzed using Cox models, Kaplan Meier methods, and log-rank tests. RESULTS: After applying recursive partitioning to the test cohort, our initial model included six groups. Application of these groups to the validation cohort resulted in four final groups. Key risk factors included presence of metastases, tumor site, tumor grade, age, and tumor size. Patients with localized axial tumors were identified as having similar outcomes to patients with metastases. Age and tumor size were only prognostically important in patients with extremity tumors when assessed in the validation cohort. CONCLUSIONS: This analysis supports prior reports that patients with axial tumors are a high-risk group, and demonstrates the importance of age and tumor size in patients with appendicular tumors. Biologic and genetic markers are needed to further define subgroups in osteosarcoma.

Outcome of patients with relapsed or progressive Ewing sarcoma enrolled on cooperative group phase 2 clinical trials: A report from the Children's Oncology Group.

SevenChildren's Oncology Group phase 2 trials for patients with relapsed/progressive solid tumors were analyzed to estimate the event-free survival (EFS) for relapsed/progressive Ewing sarcoma. One hundred twenty-eight Ewing sarcoma patients were enrolled and 124 events occurred. The 6-month EFS was 12.7%, demonstrating the poor outcome of these patients. Only docetaxel achieved its protocol-specified radiographic response rate for activity; however, the EFS for docetaxel was similar to other agents, indicating that a higher radiographic response rate may not translate into superior disease control. This EFS benchmark could be utilized as an additional endpoint in trials for recurrent Ewing sarcoma.