M Raynal1, J-C Alvarez2, P Saiag1, A Beauchet3, C Funck-Brentano4, E Funck-Brentano5. 1. Department of General and Oncologic Dermatology, Ambroise-Paré hospital, AP-HP, 9, avenue Charles de Gaulle, 92100 Boulogne-Billancourt, France; Research Unit EA4340 'Biomarkers and clinical trials in oncology and onco-hematology', Versailles-Saint-Quentin-en-Yvelines University, Paris - Saclay University, 9, avenue Charles de Gaulle, 92100 Boulogne-Billancourt, France. 2. Department of Pharmacology and Toxicology, Versailles Saint-Quentin-en-Yvelines University, Paris-Saclay University, Inserm U-1173, Raymond Poincaré hospital, AP-HP, 104, boulevard Raymond Poincaré, 92380 Garches, France. 3. Department of Bioinformatics, Ambroise Paré Hospital, AP-HP, 9 avenue Charles de Gaulle, 92100 Boulogne-Billancourt, France. 4. Sorbonne Université, INSERM CIC Paris-Est (CIC-1901), AP-HP, Sorbonne Université, ICAN, Pitié-Salpêtrière Hospital, Department of Pharmacology, 47-83, boulevard de l'Hôpital, 75013 Paris, France. 5. Department of General and Oncologic Dermatology, Ambroise-Paré hospital, AP-HP, 9, avenue Charles de Gaulle, 92100 Boulogne-Billancourt, France; Research Unit EA4340 'Biomarkers and clinical trials in oncology and onco-hematology', Versailles-Saint-Quentin-en-Yvelines University, Paris - Saclay University, 9, avenue Charles de Gaulle, 92100 Boulogne-Billancourt, France. Electronic address: elisa.funck-brentano@aphp.fr.
Abstract
BACKGROUND: Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE. METHODS: We analysed PCD/T in patients treated with D+T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results. RESULTS: We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0ng/mL; interquartile range (IQR) [4-945]) and of PCT (median: 8.6ng/mL; IQR [5-39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P=0.06). However, no difference was observed between mean PCD/T of progressing patients (n=21; 125±183ng/mL and 9.3±3.6ng/mL, respectively) and responders (complete, partial or stable response) (n=13; 159±225ng/mL, P=0.58 and 10.6±24.4ng/mL, P=0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n=16) was significantly higher for female subjects (n=18; 11.5±4.8ng/mL) than for male subjects (8.8ng/mL±2.9, P=0.01), but no difference was observed between sex and CPD (P=0.32). CONCLUSION: Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.
BACKGROUND: Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE. METHODS: We analysed PCD/T in patients treated with D+T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results. RESULTS: We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0ng/mL; interquartile range (IQR) [4-945]) and of PCT (median: 8.6ng/mL; IQR [5-39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P=0.06). However, no difference was observed between mean PCD/T of progressing patients (n=21; 125±183ng/mL and 9.3±3.6ng/mL, respectively) and responders (complete, partial or stable response) (n=13; 159±225ng/mL, P=0.58 and 10.6±24.4ng/mL, P=0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n=16) was significantly higher for female subjects (n=18; 11.5±4.8ng/mL) than for male subjects (8.8ng/mL±2.9, P=0.01), but no difference was observed between sex and CPD (P=0.32). CONCLUSION: Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.