Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pierre Fabre Médicament, 45, place Abel Gance, 92100, Boulogne-Billancourt, France
Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor
ATC code: L01XE46
Encorafenib is a potent and highly selective ATP-competitive small molecule RAF kinase inhibitor. The half maximal inhibitory concentration (IC50) of encorafenib against BRAFV600E, BRAF and CRAF enzymes was determined to be 0.35, 0.47 and 0.30 nM, respectively. The encorafenib dissociation half-life was >30 hours and resulted in prolonged pERK inhibition. Encorafenib suppresses the RAF/MEK/ERK pathway in tumour cells expressing several mutated forms of BRAF kinase (V600E, D and K). Specifically, encorafenib inhibits in vitro and in vivo BRAFV600E,DandK mutant melanoma cell growth. Encorafenib does not inhibit RAF/MEK/ERK signalling in cells expressing wild-type BRAF.
Encorafenib and binimetinib (a MEK inhibitor, see section 5.1 of binimetinib SmPC) both inhibit the MAPK pathway, resulting in higher anti-tumour activity. Additionally, the combination of encorafenib and binimetinib prevented the emergence of resistance in BRAF V600E mutant human melanoma xenografts in vivo.
The safety and efficacy of encorafenib in combination with binimetinib were evaluated in a 2-part Phase III, randomised (1:1:1) active-controlled, open-label, multicentre study in patients with unresectable or metastatic BRAF V600 E or K mutant melanoma (Study CMEK162B2301), as detected using a BRAF assay. Patients had histologically confirmed cutaneous or unknown primary melanoma but those with uveal or mucosal melanoma were excluded. Patients were permitted to receive prior adjuvant therapy and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior treatment with BRAF/ MEK inhibitors was not allowed.
In Part 1, patients in the study were randomised to receive encorafenib 450 mg orally daily and binimetinib 45 mg orally twice daily (Combo 450, n=192), encorafenib 300 mg orally daily (Enco 300, n=194), or vemurafenib 960 mg orally twice daily (hereafter referred to as Vem, n=191). Treatment continued until disease progression or unacceptable toxicity. Randomisation was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, vs IVM1c) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1) and prior immunotherapy for unresectable or metastatic disease (yes vs no).
The primary efficacy outcome measure was progression-free survival (PFS) of Combo 450 compared with vemurafenib as assessed by a blinded independent review committee (BIRC). PFS as assessed by investigators (investigator assessment) was a supportive analysis. An additional secondary endpoint included PFS of Combo 450 compared with Enco 300. Other secondary efficacy comparisons between Combo 450 and either vemurafenib or Enco 300 included overall survival (OS), objective response rate (ORR), duration of response (DoR) and disease control rate (DCR) as assessed by BIRC and by investigator assessment.
The median age of patients was 56 years (range 20-89), 58% were male, 90% were Caucasian, and 72% of patients had baseline ECOG performance status of 0. Most patients had metastatic disease (95%) and were Stage IVM1c (64%); 27% of patients had elevated baseline serum lactate dehydrogenase (LDH), and 45% of patients had at least 3 organs with tumour involvement at baseline and 3.5% had brain metastases. 27 patients (5%) had received prior checkpoint inhibitors (anti-PD1/PDL1 or ipilimumab) (8 patients in Combo 450 arm (4%); 7 patients in vemurafenib arm (4%); 12 patients in Enco 300 arm (6%) including 22 patients in the metastatic setting (6 patients in Combo 450 arm; 5 patients in vemurafenib arm; 11 patients in Enco 300 arm) and 5 patients in the adjuvant setting (2 patients in Combo 450 arm; 2 patients in vemurafenib arm; 1 patient in Enco 300 arm). The median duration of exposure was 11.7 months in patients treated with Combo 450, 7.1 months in patients treated with Enco 300 and 6.2 months in patients treated with vemurafenib. The median relative dose intensity (RDI) for Combo 450 was 100% for encorafenib and 99.6% for binimetinib; the median RDI was 86.2% for Enco 300 and 94.5% for vemurafenib.
Part 1 of Study CMEK162B2301 demonstrated a statistically significant improvement in PFS in the patients treated with Combo 450 compared with patients treated with vemurafenib. Table 5 and Figure 1 summarize the PFS and other efficacy results based on central review of the data by a blinded independent radiology committee.
The efficacy results based on investigator assessment were consistent with the independent central assessment. Unstratified subgroup analyses demonstrated point estimates in favour of Combo 450, including LDH at baseline, ECOG performance status and AJCC stage.
Table 5. Study CMEK162B2301, Part 1: Progression-free survival and confirmed overall response results (independent central review):
| Encorafenib + binimetinib n=192 (Combo 450) | Encorafenib n=194 (Enco 300) | Vemurafenib n=191 (Vem) | |
|---|---|---|---|
| Cut-off date: 19 May 2016 | |||
| PFS (primary analysis) | |||
| Number of events (progressive disease(PD)) (%) | 98 (51.0) | 96 (49.5) | 106 (55.5) |
| Median, months (95 % CI) | 14.9 (11.0, 18.5) | 9.6 (7.5,14.8) | 7.3 (5.6, 8.2) |
| HRa (95% CI) (vs Vem) | 0.54 (0.41, 0.71) | ||
| p value (stratified log-rank)b | <0.001 | ||
| HRa (95% CI) (vs. Vem) | 0.68 (0.52, 0.90) | ||
| Nominal p-value | 0.007 | ||
| HRa (95% CI) (vs Enco 300) | 0.75 (0.56, 1.00) | ||
| p value (stratified log-rank)b | 0.051 | ||
| Confirmed overall responses | |||
| Overall response rate, n (%) (95 % CI) | 121 (63.0) (55.8, 69.9) | 98 (50.5) (43.3, 57.8) | 77 (40.3) (33.3, 47.6) |
| CR, n (%) | 15 (7.8) | 10 (5.2) | 11 (5.8) |
| PR, n (%) | 106 (55.2) | 88(45.4) | 66 (34.6) |
| SD, n (%) | 46 (24.0) | 53(27.3) | 73 (38.2) |
| DCR, n (%) (95 % CI) | 177 (92.2) (87.4, 95.6) | 163 (84.0) (78.1, 88.9) | 156 (81.7) (75.4, 86.9) |
| Duration of response | |||
| Median, months (95 % CI) | 16.6 (12.2, 20.4) | 14.9 (11.1, NE) | 12.3 (6.9, 16.9) |
| Updated analysis, cut-off date: 07 November 2017 | |||
| PFS | |||
| Number of events (progressive disease) (%) | 113 (58.9) | 112 (57.7) | 118 (61.8) |
| Median, months (95% CI) | 14.9 (11.0, 20.2) | 9.6 (7.4,14.8) | 7.3 (5.6, 7.9) |
| HRa (95% CI) (vs Vem) | 0.51 (0.39, 0.67) | ||
| Nominal p-value | <0.001 | ||
| HRa (95% CI) (vs Vem) | 0.68 (0.52, 0.88) | ||
| Nominal p-value | 0.0038 | ||
| HRa (95% CI) (vs Enco 300) | 0.77 (0.59,1.00) | ||
| Nominal p-value | 0.0498 | ||
Figure 1. Study CMEK162B2301, Part 1: Kaplan-Meier plot of progression-free survival by independent central review (cut-off date: 19 May 2016):
An interim OS analysis of Study CMEK162B2301 Part 1, (cut-off date 07 November 2017) demonstrated a statistically significant improvement in OS for Combo 450 compared with vemurafenib (see Table 6 and Figure 2).
A similar proportion of patients in each treatment arm received subsequent treatment with checkpoint inhibitors, mainly pembrolizumab, nivolumab and ipilimumab (34.4% Combo 450 arm, 36.1% encorafenib arm, 39.8% vemurafenib arm).
Table 6. Study CMEK162B2301, Part 1: Overall survival interim results (cut-off date: 7 November 2017):
| Encorafenib + binimetinib n=192 (Combo 450) | Encorafenib n=194 (Enco 300) | Vemurafenib n=191 (Vem) | |
|---|---|---|---|
| OS | |||
| Number of Events (%) | 105 (54.7) | 106 (54.6) | 127 (66.5) |
| Median, months (95% CI) | 33.6 (24.4, 39.2) | 23.5 (19.6, 33.6) | 16.9 (14.0, 24.5) |
| Survival at 12 months (95% CI) | 75.5% (68.8, 81.0) | 74.6% (67.6, 80.3) | 63.1% (55.7, 69.6) |
| Survival at 24 months (95% CI) | 57.6% (50.3, 64.3) | 49.1% (41.5, 56.2) | 43.2% (35.9, 50.2) |
| HRa (95% CI) (vs Vem) | 0.61 (0.47, 0.79) | ||
| p-value (stratified log-rank) | <0.0001 | ||
| HRa (95% CI) (vs. Enco 300) | 0.81 (0.61,1.06) | ||
| p-value (stratified log-rank) | 0.061 | ||
Figure 2. Study CMEK162B2301, Part 1: Kaplan-Meier plot of interim overall survival (cut-off date: 7 November 2017):
The Functional Assessment of Cancer Therapy-Melanoma (FACT-M), the European Organisation for Research and Treatment of Cancer’s core quality of life questionnaire (EORTC QLQ-C30) and the EuroQoL-5 Dimension-5 Level examination (EQ-5D-5L) were used to explore patient-reported outcomes (PRO) measures of health-related Quality of Life, functioning, melanoma symptoms, and treatment-related adverse reactions. A definitive 10% deterioration in FACT-M and in EORTC QLQ-C30 was significantly delayed in patients treated with Combo 450 relative to other treatments. The median time to definitive 10% deterioration in the FACT-M score was not reached in the Combo 450 arm and was 22.1 months (95% CI: 15.2, NE) in the vemurafenib arm with a HR for the difference of 0.46 (95% CI: 0.29, 0.72). An analysis of time to definitive 10% deterioration in EORTC QLQ-C30 score provided with similar results.
Patients receiving Combo 450 reported no change or a slight improvement in the mean change from baseline EQ-5D-5L index score at all visits, whilst patients receiving vemurafenib or encorafenib reported decreases at all visits (with statistical significant differences). An evaluation of change over time in score yielded the same trend for EORTC QLQ-C30 and at all visit for FACT-M.
Part 2 of Study CMEK162B2301 was designed to assess the contribution of binimetinib to the encorafenib and binimetinib combination. The PFS for encorafenib 300 mg orally daily used in combination with binimetinib 45 mg orally twice daily (Combo 300, n=258) was compared to the PFS for Enco 300 (n=280, including 194 patients from Part 1 and 86 patients from Part 2). Enrolment in Part 2 started after all Part 1 patients were randomised.
Preliminary Part 2 data, at a cut-off date of 9 November 2016, demonstrated the contribution of binimetinib with an improved median PFS estimate of 12.9 months (95% CI: 10.1, 14.0) for Combo 300 compared to 9.2 months (95% CI: 7.4, 11.0) for Enco 300 (Parts 1 and 2) per independent central review (BIRC). Similar results were observed per Investigator assessment. The confirmed ORR per BIRC was 65.9% (95% CI: 59.8, 71.7) for Combo 300 and 50.4% (95% CI: 44.3, 56.4) for Enco 300 (Parts 1 and 2). Median DOR for confirmed responses per BIRC was 12.7 months [95% CI: 9.3, 15.1] for Combo 300 and 12.9 months [95% CI: 8.9, 15.5] for Enco 300. The median duration of treatment was longer for Combo 300 vs Enco 300, 52.1 weeks vs 31.5 weeks.
In the safety analysis of pooled studies, the incidence of new QTc prolongation >500 ms was 0.7% (2/268) in the encorafenib 450 mg plus binimetinib group, and 2.5% (5/203) in the encorafenib single agent group. QTc prolongation of >60 ms compared to pre-treatment values was observed in 4.9% (13/268) patients in the encorafenib plus binimetinib group, and in 3.4% (7/204) in the encorafenib single agent group (see Sections 4.2 and 4.4).
The European Medicines Agency has deferred the obligation to submit the results of studies with encorafenib in one or more subsets of the paediatric population in melanoma (see section 4.2 for information on paediatric use).
The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumours, including advanced and unresectable or metastatic cutaneous melanoma harbouring a BRAF-V600E or K mutation. The pharmacokinetics of encorafenib have been shown to be approximatively dose linear after single and multiples doses. After repeat once-daily dosing, steady-state conditions were reached within 15 days. The accumulation ratio of approximately 0.5 is likely due to auto-induction of CYP3A4. The inter-subject variability (CV%) of AUC is ranged from 12.3% to 68.9%.
After oral administration, encorafenib is rapidly absorbed with a median Tmax of 1.5 to 2 hours. Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, at least 86% of the encorafenib dose was absorbed. Administration of a single 100 mg dose of encorafenib with a high-fat, high-calorie meal decreased the C max by 36%, while the AUC was unchanged. A drug interaction study in healthy subjects indicated the extent of encorafenib exposure was not altered in the presence of a gastric pH-altering agent (rabeprazole).
Encorafenib is moderately (86.1%) bound to human plasma proteins in vitro. Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, the mean (SD) blood-to-plasma concentration ratio is 0.58 (0.02) and the mean (CV%) apparent volume of distribution (Vz/F) of encorafenib is 226 L (32.7%).
Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, metabolism was found to be the major clearance pathway for encorafenib (approximately 88% of the recovered radioactive dose). The predominant biotransformation reaction of encorafenib was N-dealkylation. Other major metabolic pathways involved hydroxylation, carbamate hydrolysis, indirect glucuronidation and glucose conjugate formation.
Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, radioactivity was eliminated equally in both the faeces and urine (mean of 47.2%). In urine, 1.8% of the radioactivity was excreted as encorafenib. The mean (CV%) apparent clearance (CL/F) of encorafenib was 27.9 L/h (9.15%). The median (range) encorafenib terminal half-life (T½) was 6.32 h (3.74 to 8.09 h).
Encorafenib is metabolised by CYP3A4, CYP2C19 and CYP2D6. In vitro, CYP3A4 was predicted to be the major enzyme contributing to total oxidative clearance of encorafenib in human liver microsomes (~83.3%), followed by CYP2C19 and CYP2D6 (~16.0% and 0.71%, respectively).
In vitro experiments indicate encorafenib is a relatively potent reversible inhibitor of UGT1A1, CYP2B6, CYP2C9 and CYP3A4/5, as well as a time-dependent inhibitor of CYP3A4. Encorafenib induced CYP1A2, CYP2B6, CYP2C9 and CYP3A4 in human primary hepatocytes. Simulations of 450 mg encorafenib co-administered with probe substrates for CYP2B6, CYP1A2, CYP2C9, CYP2C19 and CYP2D6 on Day 1 and Day 15 all indicated no clinically relevant interactions are expected. For co-administration with CYP3A4 and UGT1A1 substrates that undergo gut extraction, a minor to moderate interaction is expected. While binimetinib is a UGT1A1 substrate, it does not undergo gut extraction and therefore no DDI with encorafenib is expected. Additionally, no differences in exposure have been observed clinically when binimetinib is co-administered with encorafenib.
Encorafenib was found to be a substrate of the P-glycoprotein (P-gp) transporters. Inhibition of P-gp is unlikely to result in a clinically important increase in encorafenib concentrations as encorafenib exhibits high intrinsic permeability. The involvement of several uptake transporter families (OCT1, OATP1B1, OATP1B3 and OATPB1) was investigated in vitro using relevant transporter inhibitors. The data suggest that hepatic uptake transporters are not involved in encorafenib distribution into primary human hepatocytes.
In vitro, encorafenib inhibited the hepatic transporter OCT1, but is unlikely to be an effective inhibitor clinically. Based on in vitro studies, there is potential for encorafenib to inhibit renal transporters OCT2, OAT1, OAT3 and hepatic transporters OATP1B1 and OATP1B3 at clinical concentrations. In addition, encorafenib may inhibit P-gp in the gut and BCRP at the expected clinical concentrations.
Based on a population pharmacokinetic analysis, age was found to be a significant covariate on encorafenib volume of distribution, but with high variability. Given the small magnitude of these changes and high variability, these are unlikely to be clinically meaningful, and no dose adjustments are needed for elderly patients.
Based on a population pharmacokinetic analysis gender was not found to be a significant model covariate on clearance or volume of distribution. As a result, no major changes in encorafenib exposure are expected based upon gender.
Based on a population pharmacokinetic analysis, body weight was found to be a significant model covariate on clearance and volume of distribution. However, given the small magnitude of change in clearance and the high variability in the predicted volume of distribution in the model, weight is unlikely to have a clinically relevant influence on the exposition of encorafenib.
There are insufficient data to evaluate potential differences in the exposure of encorafenib by race or ethnicity.
Results from a dedicated clinical study indicate a 25% higher total encorafenib exposures in patients with mild hepatic impairment (Child-Pugh Class A) compared with subjects with normal liver function. This translates into a 55% increase of the unbound encorafenib exposure. The pharmacokinetics of encorafenib has not been evaluated clinically in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. As encorafenib is primarily metabolised and eliminated via the liver, based on PBPK modelling, patients with moderate to severe hepatic impairment may have greater increases in exposure than patients with mild hepatic impairment. No dosing recommendation can be made in patients with moderate or severe hepatic impairment (see sections 4.2 and 4.4).
Encorafenib undergoes minimal renal elimination. No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of encorafenib. In a population pharmacokinetic analysis, no clear trend in encorafenib CL/F was observed in patients with mild (eGFR 60 to 90 mL/min/1.73 m²) or moderate (eGFR 30 to 59 mL/min/1.73 m²) renal impairment compared with subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²). A small decrease in CL/F (≤5%) was predicted for patients with mild and moderate renal impairment, which is unlikely to be clinically relevant. The pharmacokinetics of encorafenib have not been studied in patients with severe renal impairment.
In the 4-week and 13-week rat toxicity studies, clinical signs, reduced body weight reduced epididymides and prostate weights and microscopic findings in testes, epididymides, stomach and skin were noted. Partial reversibility of these findings was noted after a 4-week recovery period. Additionally, in the 13-week rat toxicity study, reversible clinical pathology changes were noted at doses ≥100 mg/kg/d. No NOAEL could be established for the 4-week study. The NOAEL for the 13-week study was at 14- to 32-times human therapeutic exposures.
In the 4-week and 13-week monkey toxicity study, isolated/sporadic episodes of emesis and diarrhoea as well as ophthalmic lesions were observed at slightly above human therapeutic exposures. Ophthalmic lesions were partially reversible and consisted of a separation or detachment in the retina between the outer rods and cones layer and retinal pigmented epithelium at the central macula at the fovea. This observation was similar to that described in humans as central serous-like chorioretinopathy or central serous retinopathy.
Encorafenib was not genotoxic.
Fertility studies were not conducted with encorafenib. In the sub-acute 28-day and sub-chronic 13-week rat toxicology studies, encorafenib treatment at 20 mg/kg/d (dose level approximately 8 times the human exposure at the recommended dose) resulted in decreased testes and epididymis weights with tubular degeneration and oligospermia. In the 13-week study, partial reversibility was noted at the highest dose level (60 mg/kg/d).
The embryo-foetal development study in rats indicated that encorafenib induced foetal toxicity with lower foetal weights and delays in skeletal development. The embryo-foetal development study in rabbits indicated that encorafenib induced foetal toxicity with lower foetal weights and transitory changes in skeletal development. Dilatation of the aortic arc was observed in some foetuses.
Encorafenib was phototoxic in an in vitro 3T3 Neutral Red Uptake Test. Encorafenib was not a sensitiser in the in vivo mouse sensitization assay. Collectively, these data indicate that encorafenib has a risk of phototoxic potential and minimal risk for sensitization at therapeutic doses in patients.
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