Safety Profile and Adverse Event Management for Futibatinib, An Irreversible FGFR1-4 Inhibitor: Pooled Safety Analysis of 469 Patients.

PURPOSE: Futibatinib, a covalently-binding inhibitor of fibroblast growth factor receptor (FGFR)1-4 gained approval for the treatment of refractory, advanced intrahepatic cholangiocarcinoma (iCCA) harboring an FGFR2 fusion/other rearrangement. An integrated analysis was performed to evaluate safety and provide guidance on the management of futibatinib-associated adverse events (AEs) in patients with unresectable/metastatic tumors, including iCCA. PATIENTS AND METHODS: Data from three global phase I or II studies of futibatinib (NCT02052778; JapicCTI-142552) were pooled. AEs were graded per NCI CTCAE v4.03, where applicable. Safety was analyzed for patients receiving any futibatinib starting dose (overall population) and in those receiving the approved starting dose of 20 mg once every day. RESULTS: In total, 469 patients with one of 33 known tumor types were analyzed, including 318 patients who received futibatinib 20 mg every day. AEs of clinical interest (AECI; any grade/grade ≥3) in the overall population included hyperphosphatemia (82%/19%), nail disorders (27%/1%), hepatic AEs (27%/11%), stomatitis (19%/3%), palmar-plantar erythrodysesthesia syndrome (PPES; 13%/3%), rash (9%/0%), retinal disorders (8%/0%), and cataract (4%/1%). Median time to onset of grade ≥3 AECIs ranged from 9 days (hyperphosphatemia) to 125 days (cataract). Grade ≥3 hyperphosphatemia, hepatic AEs, PPES, and nail disorders resolved to grade ≤2 within a median of 7, 7, 8, and 28 days, respectively. Discontinuations due to treatment-related AEs were rare (2%), and no treatment-related deaths occurred. AE management included phosphate-lowering medication and dose adjustments. CONCLUSIONS: Futibatinib showed a consistent and manageable safety profile across patients with various tumor types. AECIs were mostly reversible with appropriate clinical management.

Adolescent and parent perspectives on genomic sequencing to inform cancer care.

Next-generation sequencing offers opportunities for targeted cancer therapies and may identify pathogenic germline variants. Adolescents' perception of testing is not well understood. We surveyed 16 adolescents and 59 parents regarding motivations, attitudes, and knowledge related to paired tumor/germline sequencing. Participants generally had a good objective understanding of germline genetics and cancer risk, with parents scoring higher than adolescents. Nearly all participants were motivated by a desire to help other patients and to treat their child/themselves. Most adolescents reported involvement in the decision to enroll in the study. Study findings suggest important similarities and differences between parent and adolescent views.

A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors.

Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects. I6F-MC-JJCD was a multicenter, nonrandomized, open-label, Phase 1b study with 5 separate, parallel dose-escalations in patients with advanced or metastatic cancer from a variety of solid tumors, followed by a dose-confirmation phase in prespecified tumor types. This manuscript reports on 3 of 5 groups. The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). Secondary objectives included evaluation of safety, tolerability, efficacy, and pharmacokinetics. Patients (N = 63) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 12 patients, mostly gastrointestinal (diarrhea, nausea, vomiting). The maximum-tolerated dose of crenigacestat was 25 mg in Part B (LY3023414), 50 mg in Part C (abemaciclib), and not established in Part A (taladegib) due to toxicities. Patients had at least 1 adverse event (AE) and 75.0-82.6% were ≥ Grade 3 all-causality AEs. No patient had complete or partial response. Disease control rates were 18.8% (Part B) and 26.1% (Part C). The study was terminated before dose confirmation cohorts were triggered. This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016.

Accrual Trends for Children's Oncology Group Clinical Trials: A Single Center Experience.

Children's Oncology Group (COG) has been highly successful in improving childhood cancer survival through well-designed multi-institutional clinical trials. However, our center has recognized a decline in the number of enrollments on COG therapeutic clinical trials over recent years. Our single center, retrospective analysis evaluated in detail the patient enrollment rates, annual number of available clinical trials and reason for nonenrollment over the last decade. We found a 61% decrease in enrollment for phase II to III trials of newly diagnosed patients at our center (2011-2018) along a 29% decrease in the number of open COG studies annually. The primary reason for nonenrollment was unavailability of a suitable trial (76%). We also recognized a decrease in number of adolescent and young adult enrollment particularly in the last 8 years (2010-2018); however, the enrollment rate for adolescent and young adults was not substantially different than enrollment of children. The reasons for reduced enrollments are most likely multifactorial and complex. It is imperative that we continue to develop novel clinical studies using a portfolio of federal, investigator-initiated, and industry trials for pediatric oncology patients to continue to advance outcomes, study survivorship, and improve quality of life for these patients.

Mutations predictive of hyperactive Ras signaling correlate with inferior survival across high-risk pediatric acute leukemia.

BACKGROUND: Cancer remains the number one cause of disease-related mortality in children, and despite advances in the molecular understanding of leukemia and targeted therapies, refractory leukemia remains a leading cause of death. It therefore is essential to further define features, e.g., FLT3 alterations and KMT2A rearrangements, associated with inferior survival early to augment or alter therapeutic strategies to improve outcomes. METHODS: To gain insights into the genetic drivers predictive of aggressive clinical behavior among pediatric leukemia patients, we performed comprehensive integrative clinical sequencing (ICS), including paired tumor/normal DNA sequencing and RNA-seq, for pediatric patients who presented at our institution over a period of five years with acute lymphoblastic or myelogenous leukemia (ALL and AML; n=43) and high-risk clinical features (high white blood cell count, extramedullary disease, or refractory and/or relapsed disease). RESULTS: We found that RAS- and Ras-pathway aberrations, including N-RAS, NF1 and PTPN11, are frequent somatic mutations and, importantly, associated with decreased event free and overall survival (OS) (P=0.04, median event free survival 22.8 vs. 5.6 months; P=0.04, median OS 124 vs. 22.5 months). CONCLUSIONS: We thus propose that hyperactive Ras signaling confers inferior survival in high-risk pediatric acute leukemia and that Ras pathways should be molecularly characterized to inform clinical decision making and to identify patients for experimental clinical trials and RAS-targeted therapy.

Hepatosplenic αß T-Cell Lymphoma as Second Malignancy in Young Adult Patient With Previously Undiagnosed Ataxia-Telangiectasia.

Ataxia-telangiectasia is a rare autosomal recessive neurodegenerative disease characterized by ataxia, radiosensitivity, telangiectases, and increased risk for hematologic malignancies. We present a case of a female individual diagnosed with T-cell acute lymphocytic leukemia at 13 years and subsequently with αß subtype of hepatosplenic T-cell lymphoma (HSTCL) at 20 years. During her diagnostic work up for HSTCL, paired tumor-germline sequencing identified a diagnosis of ataxia-telangiectasia. We also describe a very refractory clinical course of her αß HSTCL, including only a brief response to multiagent chemotherapy and an allogenic bone marrow transplant.

Refractory and metastatic infantile fibrosarcoma harboring LMNA-NTRK1 fusion shows complete and durable response to crizotinib.

Infantile fibrosarcoma (IFS) is a rare soft-tissue sarcoma, which classically presents as an aggressive and rapidly enlarging tumor over the distal extremities of children in their first year of life. The presence of ETV6 and NTRK3 gene rearrangement is characteristic of IFS, which can be detected on routine fluorescence in situ hybridization (FISH) testing. Patients with IFS typically respond well to surgical resection and chemotherapy and have an overall survival of ∼90%. In this report, we outline the use of integrative clinical sequencing (ICS) including RNA-seq in a patient with refractory, metastatic IFS to reveal an unusual fusion (LMNA-NTRK1), not detected by routine FISH testing, which was treated with oral crizotinib and resulted in a complete and durable long-term response. This study highlights the utility of ICS in identifying cryptic gene fusions, especially in refractory malignancies, and demonstrates how such information can be used to select targeted therapies in patients with actionable molecular alterations.

Cryptic ETV6-ABL1 Fusion and MLL2 Truncation Revealed by Integrative Clinical Sequencing in Multiply Relapsed Acute Lymphoblastic Leukemia.

The ETV6-ABL1 fusion is a rare genetic aberration classified as Philadelphia chromosome-like high-risk B-cell precursor acute lymphoblastic leukemia. We present the case of a child with multiply relapsed B-cell precursor acute lymphoblastic leukemia in which next-generation sequencing identified this cryptic fusion, undetected by standard testing, resulting in sustained clinical response to targetted therapy with imatinib. Upon subsequent relapse, repeat next-generation sequencing identified an additional aberration, MLL2-ADCY9, as a possible molecular driver conferring resistance to therapy. This report demonstrates the exciting potential of integrative clinical sequencing in identifying previously undetected actionable findings leading to improved outcomes in pediatric oncology patients.

DICER1 Mutations in the Era of Expanding Integrative Clinical Sequencing in Pediatric Oncology.

PURPOSE: DICER1 syndrome is a recently described inherited cancer predisposition syndrome caused by pathogenic variants in DICER1. With the recent increase in integrative clinical sequencing for pediatric patients with cancer, our understanding of the DICER1 syndrome continues to evolve, as new and rare pathogenic variants are reported. As the frequency of integrative clinical sequencing increases, discussions regarding challenges encountered in the interpretation of sequencing results are essential to continue to advance the field of cancer predisposition. The purpose of this work was to identify patients with somatic and/or germline DICER1 variants in our patient population and to discuss sequencing interpretation and the clinical recommendations that result from the integrative clinical sequencing results. METHODS: Patients were enrolled in the PEDS-MIONCOSEQ study. This integrative clinical sequencing study includes paired tumor/normal whole-exome sequencing and tumor transcriptome sequencing. Patients identified as having DICER1 variants were included. RESULTS: We report a DICER1 variant of unknown clinical significance in a patient with a highly unusual response to therapy. Two patients had diagnoses clarified once the integrative clinical sequencing revealing a DICER1 variant was available. We also discovered a patient with low-level DICER1 mosaicism and the challenges encountered in the sequencing interpretation for this patient. In addition to the sequencing data and result interpretation, this work also highlights testing and screening recommendations made to patients with DICER1 variants and their families on the basis of these results. CONCLUSION: This work serves to extend the DICER1 phenotype and advance the utility of clinical integrative sequencing in the fields of pediatric oncology and cancer genetic predisposition.

KRAS mutant tenosynovial giant cell tumor in a pediatric patient: a case report.

Tenosynovial giant cell tumors (TSGCT) are a group of rare, benign soft tissue tumors with common histologic and cytogenetic features, with a median age of diagnosis being 47 years. Generally divided into localized and diffuse subtypes, TSGCTs are typically driven by overexpression of macrophage colony stimulating factor receptor-1 (CSF1R). Treatment of TSGCT is tumor resection, followed by radiation therapy in cases of incomplete resection. Even when the tumor is completely removed, recurrence rates can be as high as 30% in some anatomical locations. Here we report the identification of a previously undescribed KRAS p.G12D activating mutation within a pediatric TSGCT patient, who clinically presented with an enlarging right lower extremity mass pathologically consistent with TSGCT. The patient continues to be in remission three years after complete surgical removal. KRAS mutations are usually found in adult cancers, such as lung and pancreatic, as well as giant cell lesion of the jaw. This case demonstrates the utility of integrative clinical sequencing in identifying lesions with aggressive potential and aiding in complex diagnoses.

Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review.

Severe congenital neutropenia (SCN) is a rare hematologic disorder characterized by defective myelopoiesis and a high incidence of malignant transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). SCN patients who develop MDS/AML have excessive toxicities to traditional chemotherapy, and safer therapies are needed to improve overall survival in this population. In this report, we outline the use of a prospective integrative clinical sequencing trial (PEDS-MIONCOSEQ) in a patient with SCN and AML to help identify oncogenic targets for less toxic agents. Integrative sequencing identified two somatic cis-mutations in the colony stimulating factor 3 receptor (CSF3R) gene, a p.T640N mutation in the transmembrane region and a p.Q768* truncation mutation in the cytoplasmic domain. A somatic mutation p.H105Y, in the runt homology domain (RHD) of runt-related transcription factor 1 (RUNX1), was also identified. In addition, sequencing discovered a unique in-frame EIF4A2-MECOM (MDS1 and ectopic viral integration site 1 complex) chromosomal translocation with high MECOM expression. His mutations in CSF3R served as potential targets for tyrosine kinase inhibition and therefore provided an avenue to avoid more harmful therapy. This study highlights the utility of integrative clinical sequencing in SCN patients who develop leukemia and outlines a strategy on how to approach these patients in a future clinical sequencing trial to improve historically poor outcomes. A thorough review of leukemia in SCN and the role of CSF3R mutations in oncologic therapy are provided to support a new strategy on how to approach MDS/AML in SCN.

Clinically Integrated Sequencing Alters Therapy in Children and Young Adults With High-Risk Glial Brain Tumors.

PURPOSE: Brain tumors have become the leading cause of cancer-related mortality in young patients. Novel effective therapies on the basis of the unique biology of each tumor are urgently needed. The goal of this study was to evaluate the feasibility, utility, and clinical impact of integrative clinical sequencing and genetic counseling in children and young adults with high-risk brain tumors. PATIENTS AND METHODS: Fifty-two children and young adults with brain tumors designated by the treating neuro-oncologist to be high risk (> 25% chance for treatment failure; mean age, 10.2 years; range, 0 to 39 years) were enrolled in a prospective, observational, consecutive case series, in which participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed in a multi-institutional brain tumor precision medicine teleconference. RESULTS: Sequencing revealed a potentially actionable germline or tumor alteration in 25 (63%) of 40 tumors with adequate tissue, of which 21 (53%) resulted in an impact on treatment or change of diagnosis. Platelet-derived growth factor receptor or fibroblast growth factor receptor pathway alterations were seen in nine of 20 (45%) glial tumors. Eight (20%) sequenced tumors harbored an oncogenic fusion isolated on RNA sequencing. Seventeen of 20 patients (85%) with glial tumors were found to have a potentially actionable result, which resulted in change of therapy in 14 (70%) patients. Patients with recurrent brain tumors receiving targeted therapy had a median progression-free survival (from time on therapy) of 4 months. CONCLUSION: Selection of personalized agents for children and young adults with highrisk brain tumors on the basis of integrative clinical sequencing is feasible and resulted in a change in therapy in more than two thirds of children and young adults with high-risk glial tumors.

Integration of Germline Pharmacogenetics Into a Tumor Sequencing Program.

PURPOSE: Evidence-based guidelines inform treatment decisions for patients for whom germline genetic information is available. Our real-time tumor sequencing program, which makes precision treatment decisions for patients with cancer, produces matched germline information, providing a unique opportunity to efficiently implement pharmacogenetics and benefit patients. METHODS: The germline genetic database from the Michigan Oncology Sequencing (MI-Oncoseq) program was searched for 21 clinically actionable polymorphisms in five cancer-relevant genes: TPMT, DPYD, CYP2C19, CYP3A5, and UGT1A1. Residual germ line DNA was sent to an external Clinical Laboratory Improvement Amendments-approved laboratory for confirmatory genotyping. The medical records of MI-Oncoseq patients with actionable phenotypes were searched for receipt of relevant drugs and to determine whether having genetic information at the time of treatment would have led to a treatment recommendation. RESULTS: All nine variants in TPMT, DPYD, and CYP2C19 that were detected in MI-Oncoseq were confirmed by external genotyping. Genotype determinations could not be made for CYP3A5*3, UGT1A1*28, or UGT1A1*80. On the basis of retrospective assessment of 115 adult and pediatric patient records, 4.3% (n = 5) had a potentially clinically actionable phenotype for TPMT, DPYD, or CYP2C19 and received a relevant medication. After accounting for differences in adult and pediatric recommendations, three of these patients could have received a treatment recommendation at the time of prescribing. CONCLUSION: Germline genotype determinations for TPMT, DPYD, and CYP2C19 can be used to make evidence-based treatment recommendations in MI-Oncoseq patients. Although the proportion of patients for whom recommendations can be made is small, this added value to MI-Oncoseq and patient care comes at no additional genotyping cost. Pharmacogenetic assessment should be integrated into tumor sequencing programs that genotype matched germline DNA; however, the complexity and additional cost of implementing pharmacogenetics remain challenging.

Blood-brain barrier-adapted precision medicine therapy for pediatric brain tumors.

Targeted chemotherapeutics provide a promising new treatment option in neuro-oncology. The ability of these compounds to penetrate the blood-brain barrier is crucial for their successful incorporation into patient care. "CNS Targeted Agent Prediction" (CNS-TAP) is a multi-institutional and multidisciplinary translational program established at the University of Michigan for evaluating the central nervous system (CNS) activity of targeted therapies in neuro-oncology. In this report, we present the methodology of CNS-TAP in a series of pediatric and adolescent patients with high-risk brain tumors, for which molecular profiling (academic and commercial) was sought and targeted agents were incorporated. Four of five of the patients had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). We further describe the specific drug properties of each agent chosen and discuss characteristics relevant in their evaluation for therapeutic suitability. Finally, we summarize both tumor and drug characteristics that impact the ability to successfully incorporate targeted therapies into CNS malignancy management.