567P - Exposure-response analyses of dabrafenib and trametinib in melanoma patients

Background

Dabrafenib (DAB) and trametinib (TRAM) are a BRAF and MEK inhibitor indicated for the treatment of melanoma. At the currently used fixed doses, interpatient variability in exposure is high (84% for DAB and 24% for TRAM). Exposure was associated with efficacy in a previous study with TRAM monotherapy (Ouellet, 2014). Therefore, the aim of this study was to investigate whether exposure to DAB and TRAM is related to efficacy in a real life patient (pt) cohort.

Methods

A prospective observational study was performed. Melanoma pts treated with DAB and TRAM and of whom pharmacokinetic (PK) samples were drawn as routine care were included. Estimated Area Under the concentration-time Curve (AUC_0-∞) was taken as measure of exposure for DAB and trough plasma concentration (C_min) for TRAM. Efficacy endpoint was progression free survival (PFS). Univariable and multivariable exposure-response analyses were performed, taking into account WHO status, prior treatment lines and brain metastases.

Results

In total, 140 pts were included, of whom 468 PK samples were collected. Median DAB AUC per pt was 4608 μg/L*h (IQR 4214 – 5156 μg/L*h) and median TRAM C_min 13.2 μg/L (IQR 10.0 – 18.1 μg/L). For DAB, median PFS was 7.1 vs. 7.7 months (mo) for pts with median AUC < 4608 μg/L*h and ≥ 4608 μg/L*h, respectively (log rank test, p=0.5). Multivariable analysis yielded similar results. For TRAM, the previously proposed threshold of 10.6 μg/L did not discriminate in median PFS (7.1 vs. 8.3 mo, p=0.8). However, when using C_min thresholds of 13.0 – 15.5 μg/L significant and relevant differences in PFS were found. Median PFS in patients with C_min above 15.5 μg/L (n=51) was 12.1 vs. 6.2 mo for those with C_min below this threshold (n=89, p=0.03). Multivariable analysis resulted in a HR of 1.84 (95% CI 1.20 – 2.82, p=0.005). Of the pts with median TRAM C_min < 15.5 μg/L, 9 pts (10%) received a prior dose reduction or interruption due to toxicity (i.e. 90% would be potentially eligible for TRAM dose escalation).

Conclusions

PFS is significantly prolonged in pts with TRAM C_min ≥ 15.5 μg/L, while an exposure-response relationship could not be demonstrated for DAB. Therefore, therapeutic drug monitoring of TRAM could be used to individualize treatment and improve treatment outcomes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

Has not received any funding.

Disclosure

J.V. van Thienen: Advisory/Consultancy: Pfizer; Non-remunerated activity/ies: MSD. J.B.A.G. Haanen: Advisory/Consultancy, Shareholder/Stockholder/Stock options: Neogene; Advisory/Consultancy, Research grant/Funding (institution): MSD Oncology; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (self): Neon Therapeutics; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: AIMM Therapeutics; Advisory/Consultancy: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Gadeta; Advisory/Consultancy, Research grant/Funding (institution): GSK; Advisory/Consultancy: Immunocore; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Celsius Therapeutics. C.U. Blank: Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: MSD Oncology; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: GSK; Advisory/Consultancy: Pfizer; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Lilly; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: GenMab; Advisory/Consultancy: Third Rock Ventures; Shareholder/Stockholder/Stock options: Uniti Cars; Shareholder/Stockholder/Stock options: Forty Seven; Shareholder/Stockholder/Stock options: Neon Therapeutics; Research grant/Funding (institution): NanoString Technologies. J. Beijnen: Honoraria (self), Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: Modra Pharmaceuticals; Research grant/Funding (institution): Several large pharmaceutical companies. N. Steeghs: Research grant/Funding (institution): AstraZeneca/MedImmune; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Blueprint Medicines; Research grant/Funding (institution): AB Science; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Merus; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Pierre Fabre; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Actuate Therapeutics; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Cytovation; Research grant/Funding (institution): InteRNA. All other authors have declared no conflicts of interest.