Trametinib for the treatment of recurrent/progressive pediatric low-grade glioma

Manoharan, Neevika; Choi, Jungwhan John; Chordas, Christine; Zimmerman, Mary Ann; Scully, Jacqueline; Clymer, Jessica; Filbin, Mariella G.; Ullrich, Nicole J.; Bandopadhayay, Pratiti; Susan, N.; Yeo, Kee Kiat

doi:10.1007/s11060-020-03592-8

Cited by 57 publications

(69 citation statements)

References 54 publications

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“…Unlike for selumetinib (reported median time to partial response: 7.54 months [18]) no phase II data on the time to best response after initiation of trametinib treatment in pLGG patients is available. The median time to best response in our cohort was shorter (median: 4, range: 1-19 months) compared to the report of Manoharan et al (9.8; 3.8-22 months) [22]. However, the median time of treatment was shorter (12.5; 2-27 months) in our cohort compared to the study of Manoharan et.al.…”

Section: Discussioncontrasting

confidence: 76%

“…Selumetinib was shown to be active in different genetic backgrounds including KIAA1549:BRAF fusions, BRAF V600E mutation and NF1 mutations in clinical phase 1 and 2 trials [17,18]. However, activity of trametinib in pLGG has only been described in small retrospective case series and case reports [21][22][23][24]31]. We here report on 18 patients with KIAA1549:BRAF-, BRAF V600E-, FGFR1-or NF1-driven progressive pLGG treated with the MEKi trametinib between 2015 and 2019.…”

Section: Discussionmentioning

confidence: 98%

“…However, the median time of treatment was shorter (12.5; 2-27 months) in our cohort compared to the study of Manoharan et.al. (19.2; 3.8-29.8 (11) 0 (0) Abdominal pain 1 (6) 0 (0) Bilirubin elevation 1 (6) 0 (0) Constipation 1 (6) 0 (0) Dermatitis bullosa 1 (6) 1 (6) Infection without causative agent 1 (6) 0 (0) Left ventricular dysfunction 1 (6) 0 (0) Pancreatitis 1 (6) 1 (6) Pneumococcal meningitis 1 (6) 1 (6) Sinus bradycardia 1 (6) 0 (0) Dose limiting toxicity, n (%) 6 (33) Dose reduction, n (%) 6 (33) Adverse event related discontinuation of treatment, n (%) occur after as much as 22 months after initiation of treatment [22], the comparably low median total treatment duration of our cohort may underestimate response rates as well as the time to best response. Moreover, in our cohort duration of treatment was longer in the group of patients who experienced at least MR (16.5 (range 11-27) months) as compared to patients with SD as best overall response (median 9.5 (range: 2-21) months), indicating that treatment duration could be a parameter influencing response rates.…”

Section: Discussionmentioning

confidence: 99%

“…Trametinib is currently being tested in phase I/II clinical trials (NCT02124772) and first limited data is available in abstract format for patients with BRAF fusions [20]. The published data on the activity of trametinib in pLGG is derived from case series [21][22][23][24]. Two case series reported on two and six progressive PA patients with KIAA1549:BRAF-fusion [21,23], with two partial responses (PR) in one study [23], and two partial responses (PR), three minor responses (MR) and one progressive disease (PD) in the second [21].…”

Section: Introductionmentioning

confidence: 99%

“…In these seven tumors treated with trametinib monotherapy, best responses were three PRs, two PD, one SD, and two missing responses due to early treatment stop because of toxicity. The most recently published case series [22] reported on eleven pLGG patients treated with trametinib, four of which had a KIAA1549:BRAF-fusion, four an NF1 mutation, one had an FGFR mutation and one had a CDKN2A loss. The underlying molecular alteration was unknown in one patient.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussioncontrasting

confidence: 76%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Lateralized overgrowth with vascular malformation caused by a somaticPTPN11pathogenic variant: Another piece added to the puzzle of mosaicRASopathies

Mussa

Turchiano

Cardaropoli³

et al. 2022

Genes Chromosomes & Cancer

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Lateralized/segmental overgrowth disorders (LOs) encompass a heterogeneous group of congenital conditions with excessive body tissue growth. Documented molecular alterations in LOs mostly consist of somatic variants in genes of the PI3KCA/AKT/mTOR pathway or of chromosome band 11p15.5 imprinted region anomalies. In some cases, somatic pathogenic variants in genes of the RAS/MAPK pathway have been reported. We present the first case of a somatic pathogenic variant (T507K) in PTPN11 causing a LO phenotype characterized by severe lateralized overgrowth, vascular proliferation, and cerebral astrocytoma. The T507K variant was detected in DNA from overgrown tissue in a leg with capillary malformation. The astrocytoma tissue showed a higher PTPN11 variant allele frequency. A pathogenic variant in FGFR1 was also found in tumor tissue, representing a second hit on the RAS/MAPK pathway. These findings indicate that RAS/MAPK cascade overactivation can cause mosaic overgrowth phenotypes resembling PIK3CA‐related overgrowth disorders (PROS) with cancer predisposition and are consistent with the hypothesis that RAS/MAPK hyperactivation can be involved in the pathogenesis of astrocytoma. This observation raises the issue of cancer predisposition in patients with RAS/MAPK pathway gene variants and expands genotype spectrum of LOs and the treatment options for similar cases through inhibition of the RAS/MAPK oversignaling.

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Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy

Chan

Sabus

Hemenway

et al. 2023

Pediatric Blood & Cancer

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The event-free survival of pediatric low-grade gliomas is poor, and patients often require multiple treatment strategies. While MEK and RAF inhibitors are efficacious in early-phase trials, not all patients respond, and many experience progression following completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. We report our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system tumors. Two of four patients using this combination therapy experienced severe thromboembolic events, necessitating discontinuation of therapy. This combination requires further investigation, and we urge caution if used.

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Trametinib for the treatment of recurrent/progressive pediatric low-grade glioma

Cited by 57 publications

References 54 publications

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

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

Lateralized overgrowth with vascular malformation caused by a somaticPTPN11pathogenic variant: Another piece added to the puzzle of mosaicRASopathies

Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy

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