Response in a child with a BRAF V600E mutated desmoplastic infantile astrocytoma upon retreatment with vemurafenib

Tilburg, Cornelis M. van; Selt, Florian; Sahm, Felix; Bächli, Heidi; Pfister, Stefan M.; Witt, Olaf; Milde, Till

doi:10.1002/pbc.26893

Cited by 25 publications

(19 citation statements)

References 16 publications

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“…Of note, re-initiation of trametinib treatment in one of the patients from the present cohort patients was able to stop progression and to induce a second disease stabilization (SD). This indicates that the tumor did not develop a bona fide resistance but retained its susceptibility towards the inhibitor, and that re-challenge with the same drug is an option, as has been reported for BRAFi [39]. The phenomenon of occasional rapid progression after MEKi treatment seems to be a class-specific effect, since it was also observed in the present study and is thus not restricted to selumetinib.…”

Section: Discussionsupporting

confidence: 79%

Response to trametinib treatment in progressive pediatric low-grade glioma patients

et al. 2020

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Introduction A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy. Methods In this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity. Results We observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2–4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%). Conclusions Trametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens.

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Section: Discussionsupporting

confidence: 79%

Response to trametinib treatment in progressive pediatric low-grade glioma patients

et al. 2020

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“…36,37 Although its use in pediatric patients has generally been limited, in part due to the difficulty of studying adequate numbers of pediatric PTC patients in clinical trials, 38 there are a number of case reports of children with BRAF V600E-positive tumors whose disease responded to treatment. [39][40][41] One recently FDA-approved agent is larotrectinib, a highly selective small-molecule inhibitor of the tropomyosin receptor kinase (TRK) proteins (encoded by kinase genes NTRK1, NTRK2, and NTRK3), which has demonstrated potent antitumor efficacy in both children and adults with TRK fusion-positive tumors. 42,43 Notably and patients gain experience with these therapies in pediatrics, we anticipate the demand for such treatments will increase for selected patients.…”

Section: Discussionmentioning

confidence: 99%

Integrated DNA and RNA sequencing reveals targetable alterations in metastatic pediatric papillary thyroid carcinoma

Potter

Reuther

Chandramohan

et al. 2020

Pediatric Blood & Cancer

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Background: Pediatric papillary thyroid carcinoma (PTC) is clinically and biologically distinct from adult PTC. We sequenced a cohort of clinically annotated pediatric PTC cases enriched for high-risk tumors to identify genetic alterations of relevance for diagnosis and therapy. Methods: Tumor DNA and RNA were extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation using a custom 124-gene hybridization capture panel and the 75-gene Archer Oncology Research Panel, respectively. NGS libraries were sequenced on an Illumina MiSeq. Results: Thirty-six pediatric PTC cases were analyzed. Metastases were frequently observed to cervical lymph nodes (29/36, 81%), with pulmonary metastases less commonly found (10/36, 28%). Relapsed or refractory disease occurred in 18 patients (18/36, 50%). DNA sequencing revealed targetable mutations in 8 of 31 tumors tested (26%), most commonly BRAF p.V600E (n = 6). RNA sequencing identified targetable fusions in 13 of 25 tumors tested (52%): RET (n = 8), NTRK3 (n = 4), and BRAF. Mutually exclusive targetable alterations were discovered in 15 of the 20 tumors (75%) with

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“…The disease-specific phase 2 component of the study is ongoing. Similarly, early reports of promising vemurafenib activity in children with recurrent BRAF V600E mutant pLGG treated (46, 47) led to the ongoing Pacific Neuro-Oncology Consortium (PNOC) phase I trial of vemurafenib in children with recurrent or refractory gliomas containing the BRAF V600E mutation (NCT01748149).…”

Section: Targeted Treatments For Pediatric Lggmentioning

confidence: 99%

Management of pediatric low-grade glioma

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Bandopadhayay

Haas‐Kogan

et al. 2019

Current Opinion in Pediatrics

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Purpose of review: Pediatric low-grade gliomas have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted therapies to be developed for these diverse tumors. At the same time, technological advances may redefine the late toxicities associated with radiation therapy. Understanding recent developments in pediatric low-grade glioma therapy is essential to the management of these common pediatric tumors. Recent findings: It is now well understood that aberrations of the MAPK pathway are key to oncogenesis in low-grade gliomas. This understanding, along with the development of available targeted agents, have heralded a new era of understanding and treatment for these patients. Promising, sustained responses are now being seen in early phase trials among patients with multiply recurrent/progressive disease. Also, newer and highly conformal radiation approaches such as proton beam radiotherapy maintain efficacy of radiation but limit radiation-associated toxicities. Summary: Novel therapies offer the potential for tumor control with greatly reduced toxicities. However, late effects of these therapies are just now being explored. Improved radiation approaches and targeted agents have the potential to redefine traditional therapy for pediatric low-grade glioma.

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Response in a child with a BRAF V600E mutated desmoplastic infantile astrocytoma upon retreatment with vemurafenib

Cited by 25 publications

References 16 publications

Response to trametinib treatment in progressive pediatric low-grade glioma patients

Response to trametinib treatment in progressive pediatric low-grade glioma patients

Integrated DNA and RNA sequencing reveals targetable alterations in metastatic pediatric papillary thyroid carcinoma

Management of pediatric low-grade glioma

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