Le sujet a fait l’objet de revues de la littérature par Du-Thanh et al161 ou Friedman et
al.162, en ce qui concerne l’immunothérapie et les thérapies ciblées.
En dehors d’analyse en sous-groupes dans des essais cliniques de phase II et III, il existe peu de données sur l’efficacité et la tolérance des thérapies ciblées et de l’immunothérapie dans la population âgée.
1.
ImmunothérapieSelon les registres américains de la FDA (Food and Drugs Administration), les adultes de plus de 65 ans composaient 28% des patients des essais cliniques traités par ipilimumab, 39% des patients traités par nivolumab ou pembrolizumab. De même, 9% des patients traités par nivolumab étaient âgés de 75 ans ou plus.
Une méta analyse incluant 4725 patients traités par immunothérapie pour des cancers pulmonaires, rénaux ou des mélanomes dans des essais de phase II/III a montré une survie globale prolongée chez les patients âgés de plus de 65 ans. Une analyse en sous-groupe a aussi montré une efficacité sur la survie globale pour les anti CTLA-4 chez les patients de plus de 75 ans, mais pas pour les anti PD-1163.
Sileni et al. ont étudié l’efficacité et la tolérance de l’ipilimumab chez des patients de plus de 70 ans : il n’y avait pas de différence en terme de survie globale (8 mois (95% CI 7,2– 10,6) pour ≥70 ans et 7 mois (95% CI 6,1–7,9) pour < 70 ans; p = 0,17); les taux d’effets indésirables étaient similaires dans les 2 groupes164.
Dans l’essai CheckMate 066, le traitement par Nivolumab, comparé à la Dacarbazine, avait un HR de 0,44 (0,24–0,81) chez les patients de 65–75 ans et un HR de 0,25 (0,10–
51
0,61) chez les patients de ≥75 ans53 : il existe donc un bénéfice au traitement par Nivolumab
par comparaison avec la Dacarbazine, y compris pour les populations âgées.
L’incidence des effets indésirables chez les patients plus âgés ne semble pas très différente de la population générale. Dans l’essai Checkmate 069165, le même taux d’EI était
rapporté chez les patients âgés de moins de 65 ans (54%) et de plus de 65 ans (52%) dans le bras associant Nivolumab et Ipilimumab. Une série de patients de plus de 80 ans traités par immunothérapie (pembrolizumab, nivolumab, ipilimumab ou nivolumab+ipilimumab) a fait l’objet d’un résumé à l’ASCO 2016. Parmi les 106 patients, 28% ont nécessité un traitement par corticothérapie systémique pour un effet indésirable166. L’arrêt précoce du traitement pour toxicité était fréquent (31% sous ipilimumab, 20% sous anti PD1, et 50% sous combinaison anti PD1 et antiCTLA 4).
2.
Thérapies cibléesDans l’étude de phase III comparant Vémurafenib et Dacarbazine, 50 patients étaient âgés de plus de 75ans, et 160 de plus de 65 ans (sur 337). Dans le groupe 65-74 ans, le hazard-ratio (HR) dans le groupe Vémurafenib, est de 0,12 (IC 95 %:0,03—0,47), comparable à la population générale, en faveur d’une supériorité de l’inhibiteur de BRAF. Ce résultat n’était pas retrouvé pour les patients de plus de 75 ans, chez lesquels le HR est à 0,60 (IC 95 % : 0,23—1,55), non significativement supérieur au Déticène66.
Pour l’étude pivot concernant le Dabrafenib65, l’âge des patients allait jusqu’à 93 ans (
âge médian 53 ans), mais il n’existait pas de données ni d’analyse par classe d’âge.
Dans l’étude comparant le Vémurafenib seul à l’association Vémurafenib— Cobimetinib 115, 27 % des malades (133/495) avaient plus de 65 ans, soit 26 % (64/247) des malades recevant l’association des deux molécules et 28 % (69/248) de ceux recevant le Vémurafenib seul. Chez ces patients, l’association était bénéfique en termes de survie sans progression et de survie globale, de la même façon que dans la population générale.
Dans l’étude comparant l’association Dabrafenib-Trametinib au Dabrafenib seul116,
l’analyse en sous-groupes montre que si le bénéfice en survie sans progression est en faveur de l’association des deux molécules chez l’ensemble des patients (HR = 0,75 ; IC95 % : 0,57—0,99), celui-ci n’est plus significatif chez les malades de plus de 65 ans (HR = 1,09 ; IC 95 % : 0,63—1,70).
52
Aucun profil de tolérance particulier des sous-groupes de patients âgés n’a été décrit dans les essais. La seule étude concernant la tolérance ayant une comparaison par classe d’âge incluait 3226 patients dans une étude multicentrique ouverte avec le Vémurafenib88. 257 (8%) patients ≥75 ans étaient traités par Vémurafenib. Ces patients avaient plus d’effets indésirables de grade 3 et 4 (59% versus 43%), tels que carcinomes épidermoïdes cutanés (18% versus 6%), kerato-acanthomes (10% versus 6%) et allongement de l’intervalle QT (3% versus <1%).
V. Problématique
Il n’existe donc pas à l’heure actuelle, à notre connaissance, de données de « vraie vie » sur les bénéfices et les effets secondaires des thérapies ciblées dans le mélanome chez les sujets très âgés. En dépit de leur efficacité, ces traitements oraux, avec leurs effets secondaires spécifiques, peuvent être particulièrement bouleversants pour la population âgée et avoir un réel impact sur la qualité de vie. Il est parfois difficile, dans la pratique quotidienne, de déterminer si ces patients bénéficient réellement d’un tel traitement, c’est pourquoi, nous avons, à travers une étude rétrospective et monocentrique au CHU de Bordeaux, étudié le profil de tolérance et d’efficacité des inhibiteurs de BRAF et/ou de MEK dans une cohorte de 36 patients de 80 ans et plus, atteints de mélanome métastatique.
53
ARTICLE
Safety and efficacy of BRAF/MEK targeted therapy in very
elderly patients with metastatic melanoma.
Anouck Lamoureux1, Léa Dousset1, Caroline Dutriaux1, Cécile Mertens2, Emilie Gérard1, Sorilla Prey1, Marie Beylot-Barry1,3, Anne Pham Ledard1,3.
1. Dermatology Department, CHU de Bordeaux, F-33000 Bordeaux, France. 2. Geriatry Department, CHU de Bordeaux, F-33000 Bordeaux, France
3. INSERM U1053, Team 3 oncogenesis of cutaneous lymphoma, Univ. Bordeaux, F-33000 Bordeaux , France
Introduction:
The incidence of melanoma has been multiplied by 4 in the past 30 years. In France, it is the 6th most frequently diagnosed cancer for women, and the 8th for men1. In the United States, more than 40% of melanomas are diagnosed in patients older than 65 years2. In France, incidence rates exceed 25 per 100 000 in men and women older than 65 years compared to 7.6 per 100 000 and 9.5 per 100 000 in men and women of any age, respectively2. Disease specific survival rate is lower in older patients than in younger ones3,4. The management of those patients can be tricky, due to age-related problems including comorbidities and social issues, treatment toxicity and observance of the patient. In the last 10 years, the treatment of metastatic melanoma has changed drastically with the approval of targeted therapy and checkpoint inhibitors, which have modified the prognosis of the disease and the management of patients. Combined BRAF and MEK inhibition, targeting the mitogen-activated protein kinase (MAPK) pathway, is actually a standard therapy in melanoma harboring BRAFV600 mutation since Vemurafenib plus Cobimetinib or Dabrafenib plus Trametinib have been approved. The combination therapy as compared to BRAF inhibition alone increase the treatment efficacy and decrease the cutaneous adverse effects of BRAF inhibitors when they are used alone. In real life setting, we have to treat patients with metastatic melanoma including very elderly patients. One can wonder if potential side effects could be so
54
deleterious that the benefit ratio would not favor treating these patients. There is few data on the safety and efficacy of targeted therapies in the elderly population, outside of subgroup analysis in the pivotal trials5,6. Furthermore, most elderly patients included in these trials were considered to be fit, however they do not represent the entire elderly population.
This prompted us to analyze retrospectively in our center all patients over 80 years with metastatic melanoma treated with targeted therapy (BRAF inhibitor, with or without MEK inhibitor). The primary endpoint was to assess safety of the therapy in this population. Secondary endpoint was to assess efficacy in the cohort.
Material and Methods:
Inclusion criteriaAll patients over 80 years treated in the Dermatology Department (University hospital of Bordeaux, France) with Vemurafenib or Dabrafenib combined or not with Cobimetinib or Trametinib, respectively, during at least one month were identified retrospectively via hospital databases. Patients were included if they were 80 years or over at the time of treatment, including patients who started the treatment before their 80th birthday. Our monocentric retrospective study included all patients meeting the age inclusion criteria treated from January 1, 2011, to July 30, 2017.
Data collected
Data collected at the time of treatment introduction were: age, gender, general condition (comorbidities, Charlson's comorbidities score), biologic data (albumin, lymphocyte count, creatinine), disease characteristics (TNM stage7, LDH, cerebral involvement) and prior therapies. Molecule detail and dosage at the introduction, and during follow up were recorded. Specific AE (AEs) were assessed according to the medical records and graded with the Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 from the US National Cancer Institute. Occurrence of AEs was recorded focusing on the grade, type, time to onset, number and duration of hospitalizations, temporary of definitive discontinuation of treatment, invasive medical procedures, and outcome.
Full dosage for Vemurafenib, Dabrafenib and Trametinib was 960mgx2 per day, 150mgx2 per day and 2mg per day respectively.
55
When realized, pharmacologic plasma concentration of the molecules were retrospectively recorded8. Values usually described in literature for trough plasma concentration of dabrafenib are 25-50ng/ml, and 10-13.6ng/ml for trametinib but no therapeutic range for efficacy has been properly assessed. Up to now there is no recommended plasma concentration for BRAF inhibitors and MEK inhibitors.
We considered overdose for dabrafenib plasma concentration above 50 ng/ml, which goes in the same direction as a recent work indicating that a dabrafenib trough plasma threshold of 48 ng/ml can predict the occurrence of adverse events9. For Trametinib we considered values above 13.6ng/ml, as they were usually the maximal threshold value observed in literature. Underdosage cannot be defined as there is no data for the minimal effective concentration for dabrafenib or trametinib. We considered values below 25ng/ml for dabrafenib, and 10ng/ml for trametinib, as it is the mean minimum threshold value usually found in literature.
Response rate, statistical analysis
Disease response was evaluated with clinical assessment and complete CT scan after 8 weeks and every 8 weeks during therapy until progression, death or until the last follow up (30 July 2017). Overall survival (OS) was defined as the time interval from the date of the first treatment assumption until death or last date of follow-up, in case of censored observations. Progression free survival (PFS) was defined as the time interval from the first treatment assumption to the detection of progression or to death from any cause, whichever occurred first. Last visit date was used in case of censored observations. Survival curves were estimated using the Kaplan-Meier method. Differences between groups were evaluated by Fisher’s exact test for categorical variables and Mann-Whitney=Wilcoxon’s test for continuous variables.
Results :
Patients and treatment regimen
Thirty-six patients met the inclusion criteria. Patients and disease characteristics are detailed in Table 1. Median age was 83.6 years (range: 78-93). Female / male ratio was 1.4/1. M stages were M1C (n=20, 55.5%) including 5 patients with cerebral involvement, M1b (n=4, 11.1%) and M1a (n=8, 22%). Sixteen patients had an asymptomatic disease at the start of the treatment. Most patients were ECOG status 0 and 1 (8 and 16, respectively). Mean Charlson score was 4.5. Four patients had cognitive impairment, 10 had a chronic heart disease and 28 high blood pressure. Mean follow up duration was 17months.
56
One patient had a grade 4 chronic kidney disease (creatinine clearance using MDRD: 18ml/min/1.73m2), 3 had a grade 3 chronic kidney disease (creatinine clearance using MDRD: 43-51ml/min/1.73m2), and 17 had a grade 2 chronic kidney disease (creatinine clearance using MDRD: 62-89ml/min/1.73m2). No patient had hepatic insufficiency.
Among 36 patients, 11 and 19 received Dabrafenib and Vemurafenib as a monotherapy, respectively, and 6 patients received a combination of Dabrafenib and Trametinib. Two patients received Vemurafenib as part of the clinical trial COBRIM10. For 33 patients (91.6%), it was a first line therapy. For the others, targeted therapy was preceded by Dacarbazine (n=2) or by 3 prior treatments including Ipilimumab (n=1).
During treatment, 4 patients switched: from Vemurafenib to Dabrafenib as monotherapy (n=2), from Dabrafenib to Vemurafenib (n=1), from Vemurafenib to Dabrafenib+Trametinib (n=1).
29 patients did not receive a combination therapy including MEK inhibitor: in 19 cases because of the absence of approval in France at the time of treatment, and in 4 cases because of cardiac comorbidity. Other reasons were: refusal from patient (3 cases), acceptable response with monotherapy started before the MEK inhibitor approval in France (3 cases).
Drug combinations
Our patients were taking an average of 5.9 treatments, including 7 patients with anti-epileptic drugs (5 taking levetiracetam, 1 taking gabapentine, 1 taking depakine), and 15 with proton pump inhibitors. Anti-epileptic drugs are CYP2C8 et 3A4 inducers, known to reduce exposure to the treatment in vitro, whereas proton pump inhibitors can reduce absorption of Dabrafenib, although their role does not seem clinically significative in pharmacology studies.
Baseline characteristics No. (%)
Age (years) : Median, range 83.6 (78-93)
Gender: Male / Female 21/15
Histologic subtype -SSM
-lentigo maligna melanoma -nodular -Regressive -desmoplastic -Unknown -NA -not classified Breslow thickness 22 (61) 2 (5.5) 4 (11.1) 1 (2.7) 1 (2.7) 3 (8.3) 2 (5.5) 1 (2.7)
57 -mean -median, range BRAF mutation : -V600E -V600K -V600R -D594N 4.28 3.75 (0.9-10.8) 24 (66,6) 10 (27,7) 1 (2.7) 1 (2.7) M Stage M0 M1a M1b M1c Cerebral metastasis symptomatic asymptomatic 4 (11) 8 (22.2) 4 (11.1) 20 (55.5) 5 (13.8) 1 4 Lactate Dehydrogenase level
< upper limit of normal range > upper limit of normal range NA
9 (25) 18 (50)
9 (25) Previous systemic therapy
Target therapy as first line therapy
Target therapy as second line therapy or more - after PD1 inhibitor - after chemotherapy 33 (91.6) 3 (8.3) 1 2 Type of targeted therapy
-Vemurafenib alone -Dabrafenib alone -Dabrafenib+ trametinib
Including switch of BRAF inhibitor: -Vemurafenib to Dabrafenib -Vemurafenib to Dabrafenib+Trametinib -Dabrafenib to Vemurafenib 20 (52.7) 13 (30.5) 7 (16.6) 4 2 1 1 Geriatric assessment ECOG Status : 0 1 2 ≥3 8 (22) 16 (44) 6 (16) 6 (16) Comorbidities :
Charlson score: mean, range Myocardial infarction
Congestive heart failure Peripheral vascular disease Cerebrovascular disease Dementia
Connective tissue disease Chronic pulmonary disease Peptic ulcer disease
Liver disease Diabetes Renal disease
Other tumor (non-metastatic)
4.5 [3-13] 14 10 7 6 4 2 1 3 0 5 1 8
58 BMI median, range BMI <22 26.7, [17.6-32] 4 Personal situation
With family at home Alone at home Institution 16 (44) 13 (36) 5 (14) Serum albumin (g/L): median, range >35 ≤35 NA Lymphocyte count (G/L) median, range <1G/L <0.5G/l Hemoglobin (g/l) Median,range
Clearance using MDRD ( ml/min/1.73m2) 60-90 30-59 15-29 39, [31.4-58] 26 (72) 3(8.3) 7(19.4) 1.04, [0.3-2.4] 14 1 12.3 (8.2-14.6) 17 3 1
Table 1. Baseline Characteristics of the study group (n=36). BMI: body mass index, NA: not available.
Safety
Specific adverse events (AEs) and outcome
Detailed description of AEs is provided in Table 2. 123 AEs were recorded in thirty-five patients (97%). Fifteen patients (41%) experienced grade 3 events, including 12 infiltrative squamous cell carcinomas, 2 cases of fever (>40°C for less than 24h) and one case of fatigue. Most common AEs were fatigue (72%) and cutaneous disorders (69%) followed by anorexia (36%), weight loss (33%) and arthralgia (33%). Cutaneous AEs were commonly seen with vemurafenib (14 out of 20, 70%), including 9 verrucous papillomas and 7 cutaneous SCC) while fever was experimented with Dabrafenib (4 out of 13, 31%). Fatigue and weight loss were recorded in 69% and 39% of cases of BRAF inhibitor monotherapy, respectively. 85% of patients exposed to the combination therapy Dabrafenib + Trametinib (n=7) experienced AEs including fatigue (n=3), cutaneous disorders (n=3) and fever (n=2).
59
Weight loss after 2 months of treatment was superior to 5% of initial weight for 12 patients (33%), and for 11 patients of those 12 patients after 4 months. Managements of the AEs (other than targeted therapy dose modifications) consisted in pain medication for arthralgias, antipyretic drugs for fever, topical keratolytic for keratodermia, symptomatic treatment with metoclopramide for nausea, racecadotril or diosmectite for diarrhea.
Five patients (14%) were hospitalized due to an AE: 3 for investigations of a persistent fever (consisting in complete CT scan, blood tests and often IV antibiotics) 1 for asthenia and 1 for depressed level of consciousness. Invasive procedures induced by AEs were surgical resection with local anesthesia for infiltrative squamous cell carcinomas or keratoacanthomas in 13 cases.
Patients who experienced grade 2 or over AEs (except cutaneous AE) had not a statistically significative poorer ECOG status (p=0.72, Fisher exact test) or higher Charlson score (6.75 vs 5.31; p=0.12, Mann Withney-Wilcoxon test).
Personal situation (living at home or in institution) of the patients was not modified during treatment course in 34 cases ( 94%). One patient was living alone at home and was transferred to a retirement home following her femoral head fracture during treatment. The other patient was transferred to a retirement home following the initiation of the treatment, because of a general state degradation due to the melanoma.
60 Treatment discontinuation
Thirteen patients interrupted the treatment for at least 15 days. Interruptions for radiotherapy were not taken into account. Reasons for interrupting the treatment were AEs for 7 patients, complete response for 4 patients, concomitant medical disease not related to the treatment in 2 cases (femoral neck fracture, perforative sigmoiditis). Three patients had more than one interruption of treatment because of AEs. AEs that resulted in the interruption were grade 1 and 2 for 5 patients, and 2 had a grade 3 fever. Treatment was stopped at the patient request in 4 cases, due to an alteration of his quality of life, and never because of a potential life-
Adverse events
All
grades Grade 1 Grade 2 Grade 3 Hospitalisation Fatigue 26(72%) 17 (47%) 8(22%) 1(2.7%) 1 Fever 6 (17%) 3 (8.3%) 1 (2.7%) 2 (5.5%) 3 Malaise 2 (5.5%) 1 (2.7%) 1 (2.7%) 0 0 Confusion 1 0 1 0 0 Depressed level of consciousness 1 0 1 0 1 Nausea 4 (11%) 3 (8.3%) 1 (2.7%) 0 0 Diarrhea 6 (17%) 5 (14%) 1 (2.7%) 0 0 Cardiac dysfonction 3 (8.3%) 2 (5.5%) 1 (2.7%) 0 0 QT elongation 1 (2.7%) 1 (2.7%) 0 0 0 Ophtalmic disorder 1 (2.7%) 0 2 (5.5%) 0 0 Anorexia 13 (36%) 8 (22%) 5 (14%) 0 0 Weight loss 12(33%) 8 (22%) 4 (11%) 0 0 Dysgueusia 6 (17%) 6 (17%) 0 0 0 Arthralgia 12(33%) 11 (30.5%) 1 (2.7%) 0 0 Renal dysfonction 2 (5.5%) 2 (5.5%) 0 0 0 Cutaneous disorders 25 (69%) 5(14%) 8(22%) 12 (33%) 0 Total 35 (97%) 35 (97%) 16(44%) 15 (41%) 5 (13.8%)
Table 2: Adverse events associated with targeted therapy (including Vemurafenib, Dabrafenib and Dabrafenib+ Trametinib)
61
threatening AE. Interruptions of treatment induced by AEs lasted for a median of 8.7 weeks (2-69 weeks). Five of the 7 patients had a asymptomatic disease.
Table 3: Characteristics of patient having treatment interruption because of an AEs.
Four patients (11%) stopped definitively the treatment due to AEs. The cause of definitive interruption was: congestive heart failure (grade 1) in 1 case, fever (grade 3) in 1 case, fatigue (grade 2) in 1 case, and diarrhea and arthralgia (grade 1) in the last case. Of them, 3 stopped at their demand, with the physician agreement, and one stopped because of a poor general status and congestive heart failure.
Dose modifications Initial adaptations
An initial dose reduction (BRAF inhibitors and/or MEK inhibitors) was performed for 13 out of 36 patients (36%). In this patient's subgroup, the Charlson comorbidities score was higher than in the other subgroup (mean Charlson 7 vs 5; p=0.0012, Mann Whitney-Wilcoxon test). Twenty-five patients (69%) started the BRAF inhibitor monotherapy at full dosage, 8 at a half dosage, 1 at 75% dosage and 1 at 66% dosage and 1 at 25%. Of the 6 patients receiving trametinib in association with dabrafenib, 3 started at full dose and 3 at half-dosage. Reasons for initial dose reduction was « age » in all cases for the BRAF inhibitors, and « cardiac disease » in all cases for Trametinib. Among them, 3 patients had later increased their treatment dose due to good safety profile.
Patient Age ECOG status Charlson score Reason for interruption Grade Duration of interruption(weeks) 1 84 1 5 fatigue 2 2 2 87 0 7 fever 3 18 3 80 1 4 Plantar keratodermia 1 69/2.57 4 90 0 6 arthralgia 1 8.7/6.8 5 86 1 5 uveitis 1 18 6 83 3 13 arthralgia 1 4.8 7 86 2 10 Fever/arthralgia 3/1 19/10
62
Patients who started with an initial dose reduction did not significantly experience less AEs of grade 2 or over than patients who started with full dosage (53% vs 86%, OR 5.39 95% CI [0.8754; 42.8862, p=0.04, Fisher exact test) (table 4).
All treatments AEs with grade ≥2
All fatigue Weight
loss arthralgia fever
Full dose (n=23) 20 5 4 1 1
Dose reduction
(n=11) 7 4 0 0 2
OR(IC95%) 5.39(0.87-42.8) 0.63(0.10-4.02) x x 0.26(0-5.51)
P value 0.04 0.69 0.27 1 0.53
Table 4: Occurrence of Adverse events grade ≥2 based on initial full dose or initial dose reduction. X=exact confidence levels not possible.
Dose reductions during therapy.
For 25 patients (69%), dose was reduced during the treatment with a median delay before dose reduction of 30 days, due to AEs for 24 patients (66%) or to elevated dosage in 1 patient. With Dabrafenib, a dose reduction occurred for 10 patients (76%), for 12 patients with Vemurafenib (60%), and for 4 patients (57%) with trametinib. In 19 cases (76%), diminution of posology was accompanied by an improvement of AEs.
Four patients who had started with an initial dose reduction had a second dose reduction because of a AEs (4/24, 16%), versus 19 of those with the full initial dose (79%).
63 Initial dose (%) Dose reduction during treatment (%)****
100% 75% 66% 50% 33% 25% No reduction 75% 66% 50% 33% 25% All BRAF inhibitors* (n=36) 25 1 1 8 0 1 11 1 2 16 3 3 Vemurafenib monotherapy (n=19) 15 1 0 2 0 1 5 1 0 10 0 3 Dabrafenib monotherapy (n=11) 6 0 1 4 0 0 3 0 2 4 2 0 Dabrafenib when in combination with Trametinib (n=6)** 4 0 0 2 0 0 3 0 0 2 1 0 Trametinib when in combination with Dabrafenib)** 3 0 0 2 0 1 3 0 0 2 0 1
Table 5: Dose modifications during treatment. 100%=960mgx2 per day for Vemurafenib, 300mg per day for Dabrafenib and 2mg per day for Trametinib. *Independently of a combination or a monotherapy. ** Independently of the dose of Trametinib associated. ***Independently of the dose of Dabrafenib associated.****If multiples reductions during treatment, only the lowest dose was considered here.
Therapeutic drug monitoring
Twenty-three blood samples for BRAF and MEK inhibitors quantification were performed8, regarding 7 patients treated with Dabrafenib (n=2), Dabrafenib then Vemurafenib (n=1) or Dabrafenib and Trametinib (n=4). Only 2 patients were treated with initial full dose and all of the patients had a dose reduction.
Dabrafenib (with or without combination) was dosed 22 times, with a mean trough plasma concentration of 65.14ng/ml, with 7 dosages above 50ng/ml (in 4 patients without renal of liver injury) (53-214ng/ml, mean 94.5ng/ml). Concentrations over 50ng/ml occurred at 33%, 50% and 66% of the full dose. All of them experienced an AE at the time of this dosage
64
(fatigue grade 1-2 or 3, n=3; pyrexia grade 2, arthralgia grade 1), and some required dose reduction (n=4) or definitive treatment interruption (n=2).
Five times, the trough dabrafenib concentration was under 25ng/ml (7-20.5ng/ml), for 3 patients, among them one patient experienced tumor progression while others had stable disease or PR. “Under dosage” occurred at 33% and 50% of the full dose. Trametinib was