Abstract
BACKGROUND
Optic pathway gliomas (OPG) are low-grade gliomas (LGG) comprising 3-5% of pediatric brain tumors. Morbidity may include visual loss (acuity and visual fields), ...hypothalamic/pituitary dysfunction, and/or impaired motor function. Genomic alterations of MAPK/BRAF are frequent oncogenic drivers in pediatric LGG. Activity of tovorafenib, an investigational, oral, selective, CNS-penetrant, type II RAF inhibitor in OPGs was analyzed.
METHODS
FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib (420 mg/m2 weekly) in patients 6 months–25 years with BRAF-altered recurrent/progressive LGG or solid tumors. Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints.
RESULTS
Of the 77 patients enrolled in arm 1 (measurable disease per RANO-HGG), 42 (55%) had tumors located in the optic pathway. Median age at enrollment was 8 years (range: 2–16); 37 (88%) harbored a BRAF fusion and 5 (12%) a BRAF V600E mutation. The median prior lines of systemic therapy was 3 (range: 1–9), with 69% having received prior MAPK inhibitors. Of the 39 evaluable patients (RANO-HGG), the ORR was 59% (1 CR, 22 PRs) with a median time to response (TTR) of 2.8 months; 14 (36%) had stable disease (SD). Per RANO-LGG (n = 42), the ORR was 43% (5 PRs; 13 MRs) with a median TTR of 4.1 months; 20 (48%) had SD. Visual acuity remained stable in 79% (23) of patients (Cycle 9, n = 29 assessed). The most common treatment-related adverse events (TRAEs) of any grade in this subgroup were hair color changes (81%), increased creatine phosphokinase (55%), anemia (48%), maculopapular rash (45%), and fatigue (41%). Dose modifications occurred in 14 (33%) and discontinuations in 3 (7%) patients due to TRAEs.
CONCLUSIONS
Tovorafenib demonstrated antitumor activity in recurrent/progressive BRAF-altered OPG and was generally well tolerated. Visual acuity remained stable for the majority with OPGs.
Abstract BACKGROUND: Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. The ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) of ...tovorafenib in BRAF-altered pLGG resulted in antitumor activity and manageable safety. Decreased growth velocity (GV) was observed; this is an update on GV changes in skeletally immature children receiving tovorafenib. Methods A planned safety analysis was completed on August 8, 2023 on 137 patients (Arm 1: 77 & Arm 2: 60). Additional follow-up on all cases of decreased GV (an AESI) reported to the global safety database (GSDB) as of January 19, 2024 is provided. Results Overall, 29% had decreased GV from baseline (BL); 19% had ≥50% decrease. Of the 40 with this AESI, 75% had pre-existing neuromuscular or endocrine comorbidities potentially affecting normal growth, including 6 on GnRH-analogues for precocious puberty and 9 with BL heights 2 SDs above/below average for age and sex. Nineteen had on-treatment bone age assessments; none showed bone age advancement from BL or premature growth plate closure. No osteopenia or abnormal fractures reported. All 10 who discontinued or interrupted tovorafenib for ≥3 months for any reason (mean follow-up: 5.8 months), with off-treatment growth measurements available, showed post-treatment annualized GV (AGV) recovery (average AGV: on-treatment, 1.1 cm/y; off-treatment, 8 cm/y), with some exceeding expected average AGV for age. A 4-year-old boy with 1.2 cm/y AGV on-treatment had 12.3 cm/y AGV off-treatment (follow-up: 2 months). Five additional events of decreased GV in patients not on study FIREFLY-1 were reported to the GSDB; 4 of 5 had ≥3 months of off-treatment follow-up, all 4 recovered GV. Conclusions Decreased GV has been observed in patients on tovorafenib. Preliminary follow-up data in those who interrupted treatment show consistent evidence of GV recovery and preservation of growth potential on bone age studies.
Abstract BACKGROUND Pediatric patients with Diffuse Midline Gliomas (DMG), H3K27M altered have a dismal prognosis and novel therapeutic approaches are urgently needed. Factors that drive development ...of pediatric DMG are unknown. METHODS To determine the prevalence of germline pathogenic/likely pathogenic variants (P/LPV) in DMG, we assembled an international cohort of 252 patients with germline whole genome or whole exome sequencing data, including diffuse intrinsic pontine glioma (DIPG; n=153), from Australian, European and North American centres. RESULTS We identified germline P/LPV in cancer predisposition genes in 7.5% (19/252) of patients, mainly homologous recombination (n=9; BRCA1, BRCA2, PALB2) and Fanconi anemia genes (n=4). Germline P/LPV in mismatch repair genes (MSH2, PMS2) were found in two patients. Two patients each had two separate germline P/LPV. The prevalence of germline P/LPV was not significantly different according to age, location of DMG nor H3K27M mutational status. Furthermore, tumor profiles differed, with absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LPV compared to those without (P = 0.023). Knockdown of BRCA1 in DMG cell cultures sensitized tumor cells to PARP inhibition. Reflecting the potential therapeutic relevance of these findings, we describe one H3.3 K27M-mutant DMG patient with a pathogenic germline BRCA2 and FANCE variant and multiple recurrences, who was treated with a PARP inhibitor (olaparib) and immune checkpoint inhibitor, leading to a near complete radiological response after 4 months. CONCLUSION Our study is the largest series to date investigating germline P/LPV in cancer predisposition genes in DMG and provides new therapeutic insights. It is expected that these germline findings will also guide cascade testing for a proband’s relatives. Our data highlight the importance of germline testing in H3K27-altered DMG patients at diagnosis.
Abstract
OBJECTIVE
To evaluate differences in time to recurrence among molecular subgroups of medulloblastoma treated on a single protocol and to identify factors associated with survival after first ...recurrence.
METHODS
Time to recurrence following SJMB03 treatment was compared across methylation subgroups among relapsed patients. Therapies received subsequent to relapse were noted. Kaplan-Meier methods and log-rank tests were used for statistical analyses.
RESULTS
74 of 330 medulloblastoma patients developed recurrence after initial therapy. (38 Standard-Risk; 36 High-Risk). The 2- and 5-year survival after first recurrence was 30.4% and 14.6% respectively. DNA methylation-based subgroups from initial diagnosis were SHH (n=14), Group 3 (n=24), Group 4 (n=26), and unclassified (n=8). None of the pts with WNT MB had recurrent disease. Median time to first recurrence was 1.23, 0.91, and 3.09 years in SHH, Group3, and Group 4 respectively. Group 4 patients had longer post-recurrence survival than others (p-value=0.0169). Clinical risk at diagnosis (p-value=0.337), anaplasia (p-value=0.4032), TP53 (p-value=0.1969), MYC (p-value=0.8967), and MYCN (p value = 0.9404) abnormalities were not associated with post progression survival. Patients who received any therapeutic modality (chemotherapy, re-radiation and second surgery) had longer survival and those who had all three (n=10) had the best outcome (p-value<0.0001).
CONCLUSION
Outcome after recurrence in medulloblastoma is dismal, however, association with subgroups is still present. Group 4 patients had a longer time to recurrence and post progression survival. No other prognostic factor at initial diagnosis was associated with outcome after recurrence. Patients who received all 3 types of conventional therapy had better survival.
Abstract
BACKGROUND
RAF alterations are oncogenic drivers found in most pediatric low-grade gliomas (LGGs). Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II ...pan‑RAF inhibitor.
METHODS
FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the safety and efficacy of tovorafenib monotherapy. Registrational arm 1 enrolled patients with recurrent/progressive LGG harboring an activating BRAF alteration. Patients aged 6 months–25 years who progressed following ≥ 1 prior line of systemic therapy were eligible. Tovorafenib 420 mg/m2 (≤ 600 mg) was administered weekly (tablet or liquid suspension formulation) until progression or for ≥ 26, 28-day cycles. The primary endpoint (arm 1) was overall response rate, as defined by RANO criteria, per independent review.
RESULTS
As of April 14, 2022, 25 patients were enrolled to arm 1 and had ≥ 6 months of follow-up. Median age at enrollment was 8 years (range 3–18). Most patients had astrocytomas (92%), 48% with optic pathway involvement. Patients were heavily pretreated (56% with ≥ 3 prior lines of therapy), and 72% previously received MAPK pathway-targeted agents. Tumors harbored BRAF fusions (84%) or BRAF V600E mutations (16%). Per independent assessment, partial responses (1 unconfirmed) were seen in 14 (64%) of 22 evaluable patients, with 6 additional patients having stable disease, and a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations. Most treatment-emergent adverse events (AEs) were grade 1 or 2 (96%). The most common grade ≥ 3 AEs were anemia (12%), vomiting, increased blood creatinine phosphokinase and maculopapular rash (8% each). Seven patients (28%) required dose modification for treatment-related AEs; no patients discontinued tovorafenib due to AEs. Updated results, including efficacy per RAPNO assessments will be presented.
CONCLUSIONS
Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children with pretreated BRAF-altered LGG.
Abstract
Pediatric cancers have distinct molecular landscapes compared to adult cancers, with low point mutation rates, distinct mutated genes, and a prevalence of structural rearrangements. These ...complex features suggest genomic analyses alone will have limitations for translation into clinical benefit, and a multifaceted approach is therefore needed to maximize the number of patients for whom a therapeutic recommendation can be made. The Zero Childhood Cancer Program (ZERO) aims to assess the feasibility of precision medicine to identify targeted therapeutic agents for patients with high-risk (HR) pediatric malignancies (newly diagnosed, relapsed or refractory, overall expected survival <30%). Comprehensive molecular profiling, involving whole genome sequencing (tumor, germline DNA), whole transcriptome RNA sequencing and methylation profiling (brain tumors and sarcomas), is combined with preclinical drug testing using in vitro high-throughput drug screening (HTS, 125 compound library, single agent) and patient-derived xenograft (PDX) drug efficacy testing. Results are curated and recommendations (targeted therapy, change of diagnosis or genetics referral for a germline cancer predisposition gene mutation) are made by a national Multidisciplinary Tumor Board. Following the successful completion of a 2-year pilot feasibility study (TARGET, 2015-17), results demonstrated high-throughput in vitro drug screening and patient-derived xenografting expanded the therapeutic options and improved clinical outcomes in a cohort of 56 high-risk pediatric patients, with the HTS and PDX providing orthogonal confirmation of targetable molecular aberrations in 21% of patients and unique therapeutic options for 16% of patients. The national multicenter prospective trial (PRISM, 2017-20) is open at all 8 pediatric oncology centers around Australia. PRISM has enrolled 290 patients at January 2020 across the broad spectrum of HR cancers. This unique comprehensive platform has resulted in at least one recommendation (tiered by the level of supportive evidence) being issued for 75% of patients, and a reportable germline finding in 17% of patients. Early clinical response data indicates that 54% of patients who were treated with a recommended therapy demonstrated clinical benefit (complete response, partial response or stable disease >=6 months), with 38% demonstrating an objective response. ZERO demonstrates the feasibility of a comprehensive precision medicine platform to identify treatment recommendations in HR pediatric cancer patients. Plans are underway for subsequent enrolment expansion, introduction of emerging methods and technologies and extension of research projects in immunoprofiling, liquid biopsy, psychosocial impact of pediatric precision medicine, health economics and health implementation.
Citation Format: Michelle Haber, Mark J. Cowley, Paul Ekert, Loretta Lau, Emily Mould, ZCC PRISM Omics Core, ZCC Prelinical Drug Testing Core, Andrew Gifford, Richard B. Lock, Glenn M. Marshall, Murray D. Norris, Tracey O'Brien, Dong Anh Khuong Quang, David Thomas, Toby Trahair, Katherine Tucker, David S. Ziegler, Vanessa Tyrrell. Zero Childhood Cancer: A comprehensive precision medicine platform for children with high-risk cancer in Australia abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr SY09-02.
Abstract
Introduction: Zero Childhood Cancer’s National Precision Medicine for Children with Cancer Study (PRISM) utilizes novel technologies to guide individualized management of children with ...high-risk cancer (expected overall survival less than 30%). Germline DNA is utilized to distinguish cancer-specific somatic variants from constitutional variants or polymorphisms, allowing identification of clinically relevant germline mutations. The prevalence of cancer predisposition syndromes in pediatric cancer may range from 8.5% to as high as 33%. Method PRISM combines molecular genomic analysis (WGS and RNASeq) with in vitro high-throughput drug screening and patient-derived xenograft drug efficacy testing. A Molecular Tumour Board (MTB) of Oncology and Genetics professionals convenes to determine the significance of genomic analysis as curated by bioinformaticians, molecular scientists, and clinicians.
Results: Between September 2017 and June 2019, 218 children aged under 21 years have been recruited in PRISM (37% with central nervous system tumors, 47% with non-CNS solid tumors, and 16% with hematologic malignancies), and results are available for 208 after discussion at MTB meeting. Forty-two reportable germline variants were detected in 35 participants (detection rate: 16.8%), comprising 28 pathogenic and 14 likely pathogenic variants, across 22 cancer predisposition genes. The most frequently affected gene was CHEK2 (n=7), followed by SMARCB1 (n=5) and BRCA2 (n=3) and NF1 (3). In one out of three participants with germline mutations, somatic analysis revealed a double hit in the same gene altered in the germline. Distributions of participants with germline mutation per group were 16% of patients with CNS tumors (12/77), 19% of patients with non-CNS solid tumors (18/96), and 15% of patients with hematologic malignancies (5/34).
Conclusion: Germline mutation detection rate in cancer predisposition genes was higher than expected, 16.8%; however, it may result from selection bias (i.e., cohort of high-risk cancers). Although genomic sequencing has expanded our understanding of pediatric cancer predisposition and presented opportunities for genetics-mediated care, identifying underlying germline mutations with potential clinical implications remains a clinical challenge for pediatric oncologists.
Citation Format: Paulette Barahona, Alexandra Sherstyuk, Mark Cowley, Paul Ekert, Judy Kirk, Dong-Anh Khuong-Quang, Amit Kumar, Loretta Lau, Chelsea Mayoh, Glenn Marshall, Emily Moud, Tracey O’Brien, Mark Pinese, David Thomas, Vanessa Tyrell, David Ziegler, Michelle Haber, Katherine Tucker, Noemi Auxiliadora Fuentes-Bolanos, Meera Warby. Prevalence and spectrum of germline mutations in children with high-risk cancer abstract. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A03.
Abstract
Background/Objectives: The National Zero Childhood Cancer (ZERO) program, the most innovative child cancer research program in Australia, aims to assess the feasibility of a comprehensive ...precision medicine approach to improve outcomes for patients with high-risk pediatric cancer.
Design/Methods: ZERO combines comprehensive molecular profiling analysis (whole-genome sequencing tumor, germline DNA, deep sequencing of a 386-cancer associated gene panel, whole-transcriptome RNASeq, DNA methylation profiling Epic 850K array) with in vitro high-throughput drug screening (124-compound library, single agent) and patient-derived xenograft (PDX) drug efficacy testing. Results are curated and recommendations made through a national Multidisciplinary Tumor Board (MTB). Recommendations consist of targeted therapy, change of diagnosis, or genetics referral for a germline cancer predisposition gene mutation.
Results: The ZERO national trial (PRISM), which opened in September 2017 at all 8 pediatric centers in Australia, has enrolled 213 patients in the first 20 months (36% central nervous system tumors, 29% sarcoma, 15% leukemias/lymphomas, 7% neuroblastoma, 13% other rare or unknown cancers). The unique ZERO testing platform has resulted in at least one recommendation being issued for 70% of patients. 12% of patients have a reportable germline mutation. We have developed an integrated analytical pipeline to interrogate and cross-validate the full range of variants, structural abnormalities, and mutational signatures identified in pediatric cancers, and incorporate the molecular data with in vitro and in vivo drug sensitivity data where possible. The highest yield of reportable variants is derived from the integrated analysis of WGS and RNASeq. The most highly mutated genes/pathways include TP53, MAPK pathway, CDK/cyclin family, and PI3K/mTOR pathway. Mutation signatures and tumor mutation burden assessment support targeted treatment recommendations (e.g., PARP inhibitors or immunotherapy) and contribute to assessment of pathogenicity of some germline variants. Early experience with drug efficacy studies suggests these data may corroborate genomic therapeutic recommendations and may also identify unanticipated drug “vulnerabilities.” Of the first 21 patients who received an MTB-recommended therapy not usually used in the treatment of the respective tumors generally, 33% have a partial or complete response, 24% have stable disease, and 43% have progressive disease.
Conclusion: ZERO demonstrates the feasibility of a comprehensive precision medicine platform to identify treatment recommendations in high-risk pediatric cancer patients. ZERO is also partnering nationally and internationally to conduct parallel research studies in immunoprofiling, liquid biopsy, cancer predisposition, proteomics, health economics, health implementation, psychosocial impact of precision medicine, and improving access to molecularly targeted therapeutic clinical trials.
Citation Format: Paulette Barahona, Jamie Fletcher, Noemi Fuentes-Bolanos, Marie-Emilie Gauthier, Michelle Haber, Richard B. Lock, Glenn M. Marshall, Chelsea Mayoh, Emily Mould, Sumanth Nagabushan, Murray Norris, Tracey O’Brien, Alexandra Sherstyuk, David Thomas, Toby Trahair, Katherine Tucker, Meera Warby, Marie Wong, David S. Ziegler, Vanessa J. Tyrrell, Paul Ekert, Mark J. Cowley, Loretta Lau, Dong-Anh Khuong Quang, Zero Childhood Cancer Program National Consortium. Zero Childhood Cancer (ZERO): A comprehensive precision medicine platform for children with high-risk cancer abstract. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A52.
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2033
Background: Despite increasing evidence of benefit supporting CGP in personalizing cancer therapy, its widespread uptake remains limited. Barriers include low patient ...understanding, unmet patient expectations related to low utility, clinician concerns over cost-effectiveness, perceived value, and discomfort in management of complex genomic results. Methods: This prospective cross-institutional demonstration study was designed to evaluate implementation of CGP in the care of adult and paediatric advanced cancer pts, incorporating pt reported outcomes (PROMs), discrete choice experiment (DCE), ongoing process optimization and clinician evaluations. DNA sequencing of FFPE tumor and matched blood was completed with CGP (PMCC Comprehensive Cancer Panel; 391 genes) via central laboratory. A tumor board reported results weekly with emphasis on therapeutic relevance. Oncologists performed consent and results delivery. Pts completed pre-and post-test surveys, including validated and study-specific questions, DCE and if eligible, semi-structured interviews. Qualitative interviews were undertaken with study clinicians and laboratory staff to evaluate processes. Results: 86% (315) of 365 enrolled pts had successful CGP; of these 63% (199) had relevant therapeutic, diagnostic or germline results. 50 (16%) had treatment change at 6m, 49 (16%) had germline mutations. 293 (88% of adult pts) completed PROMs. 17 of 19 clinicians/laboratory staff approached consented to an interview. At consent pts cited multifaceted value in testing, showed good understanding of basic concepts, but most (69%) overestimated the likelihood of result-led change. Post-test pts remained consistently satisfied with accessing CGP; valuing research contribution, taking opportunities and information for family. 21% struggled with understanding results but there were low levels of decisional regret following participation (89% had nil/mild regret). Pt-elicited preferences (via DCE) indicated priority for high rates of clinical utility and timeliness. Clinicians sited collaboration and communication as critical to delivery of CGP. Conclusions: Pts undergoing CGP are generally satisfied, and derive value on its use beyond potential therapeutic benefit. Our results suggest that to improve test utility and delivery of CGP with value to pts and investing institution, focus must be placed on addressing the additional barriers to its wider implications including efforts to improve process efficiencies, clinician genomic literacy and decision-making support.
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