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Model based analysis of the heterogeneity in the tumour size dynamics differentiates vemurafenib, dabrafenib and trametinib in metastatic melanoma.

ABSTRACT: PURPOSE:Explore the heterogeneity in dynamics of tumour response to vemurafenib, dabrafenib and trametinib using routinely collected clinical trial imaging data. METHODS:Time-series imaging data from the phase III studies of vemurafenib, dabrafenib and trametinib were collected through a data repository. A mathematical model based on basic mechanisms of tumour growth was placed within a statistical modelling framework to analyse the data. RESULTS:The analysis revealed: (1) existence of homogeneity in drug response and resistance development within a patient; (2) tumour shrinkage rate does not relate to rate of resistance development; (3) vemurafenib and dabrafenib, two BRAF inhibitors, have different variability in tumour shrinkage rates. CONCLUSIONS:Overall these results show how analysis of the dynamics of individual lesions can shed light on the within and between patient differences in tumour shrinkage and resistance rates, which could be used to gain a macroscopic understanding of tumour heterogeneity.

SUBMITTER: Mistry HB

PROVIDER: S-EPMC5778167 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Model based analysis of the heterogeneity in the tumour size dynamics differentiates vemurafenib, dabrafenib and trametinib in metastatic melanoma.

Mistry Hitesh B HB Orrell David D Eftimie Raluca R

Cancer chemotherapy and pharmacology 20171208 2

<h4>Purpose</h4>Explore the heterogeneity in dynamics of tumour response to vemurafenib, dabrafenib and trametinib using routinely collected clinical trial imaging data.<h4>Methods</h4>Time-series imaging data from the phase III studies of vemurafenib, dabrafenib and trametinib were collected through a data repository. A mathematical model based on basic mechanisms of tumour growth was placed within a statistical modelling framework to analyse the data.<h4>Results</h4>The analysis revealed: (1) ...[more]

PMID: 29222604

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Project description:Melanoma is a frequent neoplasm in young adult males in reproductive age, 10% of them degenerating into regional and/or distant metastases (MM). The use of BRAF inhibitors (BRAFi) vemurafenib and dabrafenib is effective in MM patients harboring BRAF V600E/K/D mutations. Despite the increased life expectancy in MM patients treated with BRAFi, concerns are raised by the possible side effects and increased risk of gonado- and/or genotoxicity associated with these drugs. However, these aspects are currently under-investigated. Here we report the different fertility outcome in two cases of MM patients, harboring BRAF V600E mutation, that received vemurafenib and dabrafenib respectively. The first patient, 36 years at recruitment in 2015 and seeking fatherhood, had an history of relapsing melanoma since 2002 and undergone to numerous interventions and chemotherapy cycles. In November 2011, following detection of BRAF V600E mutation, a daily treatment with vemurafenib (1,440 mg) was prescribed with preventive gamete cryopreservation. BRAFi was effective in the clinical stabilization of the disease. In 2015, semen evaluation at follow-up showed sperm parameters within the normal range and no signs of alteration of either sperm function or sperm-DNA. On these bases, no contraindications for fatherhood were given. After a month of free intercourses, the 38-year-old partner achieved spontaneous pregnancy with a regular course, normal male fetal karyotype and a full term birth. The second patient, 39 years at recruitment in 2018 and seeking fatherhood, had an history of melanoma since 2012. In 2018, following the evidence of disease relapse and detection of the BRAF V600E mutation, treatment with dabrafenib/trametinib (300 mg/day/2 mg/day) was initiated together with preventive gamete cryopreservation. In 2019, semen evaluation at follow up showed sperm count and motility below the reference values, associated with increased indexes of sperm aneuploidies and sperm DNA fragmentation. Accordingly, access to assisted reproduction technique with cryopreserved spermatozoa was suggested. Differently from dabrafenib that was associated to damage to spermatogenesis, high-dose vemurafenib showed no association with gonadotoxicity and genotoxicity in humans, even at high doses. Although further confirmation are required, our data represent a valued cue in oncofertility counseling to MM patients in addition to preventive cryopreservation.

Project description:Background:Despite the progress made in the clinical management of metastatic melanoma, a patient's response to treatment cannot be fully predicted, and intrinsic or acquired resistance that is developed in most melanoma patients warrants further research efforts. In addition to genetic factors, microenvironmental input should be considered to explain the diversity of response to treatment among melanoma patients. In this study, we evaluated the impact of insulin on patient-derived BRAFV600E melanoma cells, either untreated or treated with vemurafenib or trametinib, inhibitors of BRAFV600 and MEK1/2, respectively. Methods:Cells were cultured in serum-free conditions, either with or without insulin. The activity of the MAPK/ERK and PI3K/AKT pathways was assessed by Western blotting, cell viability, and percentages of Ki-67- and NGFR-positive cells by flow cytometry. Transcript levels were analyzed using qRT-PCR, and ?-H2AX levels by immunoblotting and confocal microscopy. A luminescence-based assay was used to measure glutathione content. Results:While insulin did not influence the MAPK/ERK pathway activity, it had a strong influence on melanoma cells, in which this pathway was suppressed by either vemurafenib or trametinib. In the presence of insulin, both drugs were much less efficient in 1) inhibiting proliferation and reducing the percentage of Ki-67-positive cells, and 2) inducing apoptosis and phosphorylation of histone H2AX in melanoma cells. Changes induced by vemurafenib and trametinib in glutathione homeostasis and DNA repair gene expression were also attenuated by insulin. Moreover, insulin impaired the combined effects of targeted drugs and doxorubicin in melanoma cells. In addition to insulin-induced PI3K/AKT activity, which was either transient or sustainable depending on the cell line, an insulin-triggered increase in the percentage of cells expressing NGFR, a marker of neural crest stem-like cells, may contribute to the reduced drug efficacy. Conclusion:Our results demonstrate the role of insulin in reducing the efficacy of vemurafenib and trametinib. This needs clinical assessment.

Project description:Background:Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after??36-month follow-up for all living patients. Patients and methods:This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150?mg twice daily) plus trametinib (2?mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results:Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n?=?211) or dabrafenib monotherapy (n?=?212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and?<3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. Conclusions:These data demonstrate that durable (?3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

Dataset Information

Model based analysis of the heterogeneity in the tumour size dynamics differentiates vemurafenib, dabrafenib and trametinib in metastatic melanoma.

Publications

Model based analysis of the heterogeneity in the tumour size dynamics differentiates vemurafenib, dabrafenib and trametinib in metastatic melanoma.

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