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ALECENSA Hard capsule (2018)

Active ingredients: Alectinib

Pharmacodynamic properties

Pharmacotherapeutic group: anti-neoplastic agents, protein kinase inhibitor
ATC code: L01XE36

Mechanism of action

Alectinib is a highly selective and potent ALK and RET tyrosine kinase inhibitor. In preclinical studies, inhibition of ALK tyrosine kinase activity led to blockage of downstream signalling pathways including STAT 3 and PI3K/AKT and induction of tumour cell death (apoptosis).

Alectinib demonstrated in vitro and in vivo activity against mutant forms of the ALK enzyme, including mutations responsible for resistance to crizotinib. The major metabolite of alectinib (M4) has shown similar in vitro potency and activity.

Based on preclinical data, alectinib is not a substrate of p-glycoprotein or BCRP, which are both efflux transporters in the blood brain barrier, and is therefore able to distribute into and be retained within the central nervous system.

Clinical efficacy and safety

ALK positive non-small cell lung cancer

Treatment-naïve patients

The safety and efficacy of Alecensa were studied in a global randomised Phase III open label clinical trial (BO28984, ALEX) in ALK-positive NSCLC patients who were treatment naïve. Central testing for ALK protein expression positivity of tissue samples from all patients by Ventana anti-ALK (D5F3) immunohistochemistry (IHC) was required before randomisation into the study.

A total of 303 patients were included in the Phase III trial, 151 patients randomised to the crizotinib arm and 152 patients randomised to the Alecensa arm receiving Alecensa orally, at the recommended dose of 600 mg twice daily.

ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline (yes vs. no) were stratification factors for randomisation. The primary endpoint of the trial was to demonstrate superiority of Alecensa versus crizotinib based on Progression Free survival (PFS) as per investigator assessment using RECIST 1.1. Baseline demographic and disease characteristics for Alecensa were median age 58 years (54 years for crizotinib), 55% female (58% for crizotinib), 55% non-Asian (54% for crizotinib), 61% with no smoking history (65% for crizotinib), 93% ECOG PS of 0 or 1 (93% for crizotinib), 97% Stage IV disease (96% for crizotinib), 90% adenocarcinoma histology (94% for crizotinib), 40% CNS metastases at baseline (38% for crizotinib) and 17% having received prior CNS radiation (14% for crizotinib).

The trial met its primary endpoint at the primary analysis, demonstrating a statistically significant improvement in PFS by investigator. Efficacy data are summarised in Table 4 and the Kaplan-Meier curve for investigator assessed PFS is shown in Figure 1.

Table 4. Summary of efficacy results from study BO28984 (ALEX):

 Crizotinib N=151Alecensa N=152
Median duration of follow-up (months) 17.6 (range 0.3–27.0) 18.6 (range 0.5–29.0)
Primary efficacy parameter
PFS (IΝV)
Number of patients with event n (%) 102 (68%) 62 (41%)
Median (months) 11,1 NE
[95% CI] [9.1; 13.1] [17.7; NE]
HR0.47
[99.7% CI] [0.34, 0.65]
Stratified log-rank p-valuep<0.0001
Secondary efficacy parameters
PFS (IRC)*
Number of patients with event n (%) 92 (61%) 63 (41%)
Median (months) 10.425.7
[95% CI] [7.7; 14.6] [19.9; NE]
HR0.50
[95% CI] [0.36; 0.70]
Stratified log-rank p-value p<0.0001
Time to CNS progression (IRC),*
Number of patients with event n (%) 68 (45%) 18 (12%)
Cause-specific HR0.16
[95% CI] [0.10; 0.28]
Stratified log-rank p-value p<0.0001
12-month cumulative incidence of CNS progression (IRC) 41.4% 9.4%
[95% CI] [5.4; 14.7]
(ORR) (INV),**
Responders n (%) 114 (75.5%) 126 (82,9%)
[95% CI] [67.8; 82.1] [76.0; 88.5]
Overall survival*
Number of patients with event n (%) 40 (27%) 35 (23%)
Median (months) NE NE
[95% CI] [NE; NE] [NE; NE]
HR0.76
[95% CI] [0.48; 1.20]
Duration of response (INV) N=114N=126
Median (months) 11,1 NE
[95% CI] [7.9; 13.0] [NE; NE]
CNS-ORR in patients with measurable CNS metastases at baselineN=22N=21
CNS responders n (%) 11 (50.0%) 17 (81.0%)
[95% CI] [28.2; 71.8] [58.1; 94.6]
CNS-CR n (%) 1 (5%) 8 (38%)
CNS-DOR, Median (months) 5.5 17.3
[95% CI] [2.1, 17.3] [14.8, NE]
CNS-ORR in patients with measurable and non-measurable CNS metastases at baseline (IRC) N=58N=64
CNS responders n (%) 15 (25.9%) 38 (59.4%)
[95% CI] [15.3; 39.0] [46.4; 71.5]
CNS-CR n (%) 5 (9%) 29 (45%)
CNS-DOR, Median (months) 3.7 NE
[95% CI] [3.2, 6.8] [17.3, NE]

* Key secondary endpoints part of the hierarchical testing
** Competing risk analysis of CNS progression, systemic progression and death as competing events
*** 2 patients in the crizotinib arm and 6 patients in the alectinib arm had CR
CI = confidence interval; CNS = central nervous system; CR = complete response; DOR = duration of response; HR = hazard ratio; IRC = Independent Review Committee; INV = investigator; NE = not estimable; ORR = objective response rate; PFS = progression free survival

The PFS benefit was consistent for patients with CNS metastases at baseline (HR = 0.40, 95% CI: 0.25-0.64, median PFS for Alecensa = NE, 95% CI: 9.2-NE, median PFS for crizotinib = 7.4 months, 95%CI: 6.6-9.6) and without CNS metastases at baseline (HR = 0.51, 95% CI: 0.33-0.80, median PFS for Alecensa = NE, 95% CI: NE, NE, median PFS for crizotinib = 14.8 months, 95% CI:10.8-20.3), indicating benefit of Alecensa over crizotinib in both subgroups.

Figure 1. Kaplan Meier Plot of INV Assessed PFS in BO28984 (ALEX):

Crizotinib pre-treated patients

The safety and efficacy of Alecensa in ALK-positive NSCLC patients pre-treated with crizotinib were studied in two Phase I/II clinical trials (NP28673 and NP28761).

NP28673

Study NP28673 was a Phase I/II single arm, multicentre study conducted in patients with ALK-positive advanced NSCLC who have previously progressed on crizotinib treatment. In addition to crizotinib, patients may have received previous treatment with chemotherapy. A total of 138 patients were included in the phase II part of the study and received Alecensa orally, at the recommended dose of 600 mg twice daily.

The primary endpoint was to evaluate the efficacy of Alecensa by Objective Response Rate (ORR) as per central Independent Review Committee (IRC) assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the overall population (with and without prior exposure of cytotoxic chemotherapy treatments). The co-primary endpoint was to evaluate the ORR as per central IRC assessment using RECIST 1.1 in patients with prior exposure of cytotoxic chemotherapy treatments. A lower confidence limit for the estimated ORR above the pre-specified threshold of 35% would achieve a statistically significant result.

Patient demographics were consistent with that of a NSCLC ALK positive population. The demographic characteristics of the overall study population were 67% Caucasian, 26% Asian, 56% females, and the median age was 52 years. The majority of patients had no history of smoking (70%). The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was 0 or 1 in 90.6% of patients and 2 in 9.4% of patients. At the time of entry in the study, 99% of patients had stage IV disease, 61% had brain metastases and in 96% of patients tumours were classified as adenocarcinoma. Among patients included in the study, 20% of the patients had previously progressed on crizotinib treatment only, and 80% had previously progressed on crizotinib and at least one chemotherapy treatment.

Study NP28761

Study NP28761 was a Phase I/II single arm multicentre study conducted in patients with ALK positive advanced NSCLC who have previously progressed on crizotinib treatment. In addition to crizotinib, patients may have received previous treatment with chemotherapy. A total of 87 patients were included in the phase II part of the study and received Alecensa orally, at the recommended dose of 600 mg twice daily.

The primary endpoint was to evaluate the efficacy of Alecensa by ORR as per central IRC assessment using RECIST version 1.1. A lower confidence limit for the estimated ORR above the pre-specified threshold of 35% would achieve a statistically significant result.

Patient demographics were consistent with that of a NSCLC ALK positive population. The demographic characteristics of the overall study population were 84% Caucasian, 8% Asian, 55% females. The median age was 54 years. The majority of patients had no history of smoking (62%). The ECOG performance status at baseline was 0 or 1 in 89.7% of patients and 2 in 10.3% of patients. At the time of entry in the study, 99% of patients had stage IV disease, 60% had brain metastases and in 94% of patients tumours were classified as adenocarcinoma. Among the patients included in the study, 26% of the patients had previously progressed on crizotinib treatment only, and 74% had previously progressed on crizotinib and at least one chemotherapy treatment.

The main efficacy results from studies NP28673 and NP28761 are summarised in Table 5. A summary of pooled analysis of CNS endpoints is presented in Table 6.

Table 5. Efficacy results from studies NP28673 and NP28761:

 NP28673 Alecensa 600 mg twice daily NP28761 Alecensa 600 mg twice daily
Median duration of follow-up (months) 21 (range 1–30) 17 (range 1–29)
Primary efficacy parameters
ORR (IRC) in RE populationN=122aN=67b
Responders N (%) 62 (50.8%) 35 (52.2%)
[95% CI] [41.6%, 60.0%] [39.7%, 64.6%]
ORR (IRC) in patients pre-treated with chemotherapyN=96 
Responders N (%) 43 (44.8%)  
[95% CI] [34.6%, 55.3%]  
Secondary efficacy parameters
DOR (IRC) N=62N=35
Number of patients with events N (%) 36 (58.1%) 20 (57.1%)
Median (months) 15.2 14.9
[95% CI] [11.2, 24.9] [6.9, NE]
PFS (IRC) N=138N=87
Number of patients with events N (%) 98 (71.0%) 58 (66.7%)
Median duration (months) 8.9 8.2
[95% CI] [5.6, 12.8] [6.3, 12.6]

CI = confidence interval; DOR = duration of response; IRC = independent review committee; NE = not estimable; ORR = objective response rate; PFS= progression free survival; RE = response evaluable
a 16 patients did not have measurable disease at baseline according to the IRC and were not included in the IRC response evaluable population.
b 20 patients did not have measurable disease at baseline according to the IRC and were not included in the IRC response evaluable population

ORR results for studies NP28673 and NP28761 were consistent across subgroups of baseline patient characteristics such as age, gender, race, ECOG performance status, Central Nervous System (CNS) metastasis and prior chemotherapy use, especially when considering the small number of patients in some subgroups.

Table 6. Summary of the pooled analysis of CNS endpoints from studies NP28673 and NP28761:

CNS Parameters (NP28673 and NP28761) Alecensa 600 mg twice daily
Patients with measurable CNS lesions at baseline
CNS ORR (IRC) N=50
Responders (%) 32 (64.0%)
[95% CI] [49.2%, 77.1%]
Complete response11 (22.0%)
Partial response21 (42.0%)
CNS DOR (IRC) N=32
Number of patients with events (%) 18 (56.3%)
Median (months) 11.1
[95% CI] [7.6, NE]

CI = confidence interval; DOR = duration of response; IRC = independent review committee; ORR = objective response rate; NE = not estimable

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Alecensa in all subsets of the paediatric population in lung carcinoma (small cell and non-small cell carcinoma) (see section 4.2 for information on paediatric use).

Pharmacokinetic properties

The pharmacokinetic parameters for alectinib and its major active metabolite (M4) have been characterised in ALK-positive NSCLC patients and healthy subjects. Based on population pharmacokinetic analysis, the geometric mean (coefficient of variation %) steady-state Cmax, Cmin and AUC0-12hr for alectinib were approximately 665 ng/mL (44.3%), 572 ng/mL (47.8%) and 7430 ng*h/mL (45.7%), respectively. The geometric mean steady-state Cmax, Cmin and AUC0-12hr for M4 were approximately 246 ng/mL (45.4%), 222 ng/mL (46.6%) and 2810 ng*h/mL (45.9%), respectively.

Absorption

Following oral administration of 600 mg twice daily under fed conditions in ALK-positive NSCLC patients, alectinib was absorbed reaching Tmax after approximately 4 to 6 hours.

Alectinib steady-state is reached within 7 days with continuous 600 mg twice daily dosing. The accumulation ratio for the twice-daily 600 mg regimen was approximately 6-fold. Population PK analysis supports dose proportionality for alectinib across the dose range of 300 to 900 mg under fed conditions.

The absolute bioavailability of alectinib capsules was 36.9% (90% CI: 33.9%, 40.3%) under fed conditions in healthy subjects.

Following a single oral administration of 600 mg with a high-fat, high-calorie meal, alectinib and M4 exposure was increased by around 3-fold relative to fasted conditions (see section 4.2).

Distribution

Alectinib and its major metabolite M4 are highly bound to human plasma proteins (>99%), independent of active substance concentration. The mean in vitro human blood-to-plasma concentration ratios of alectinib and M4 are 2.64 and 2.50, respectively, at clinically relevant concentrations.

The geometric mean volume of distribution at steady state (Vss) of alectinib following IV administration was 475 L, indicating extensive distribution into tissues.

Based on in vitro data, alectinib is not a substrate of P-gp. Alectinib and M4 are not substrates of BCRP or organic anion-transporting polypeptide (OATP) 1B1/B3.

Biotransformation

In vitro metabolism studies showed that CYP3A4 is the main CYP isozyme mediating alectinib and its major metabolite M4 metabolism, and is estimated to contribute 40-50% of alectinib metabolism. Results from the human mass balance study demonstrated that alectinib and M4 were the main circulating moieties in plasma with 76% of the total radioactivity in plasma. The geometric mean Metabolite/Parent ratio at steady state is 0.399.

Metabolite M1b was detected as a minor metabolite from in vitro and in human plasma in healthy subjects. Formation of metabolite M1b and its minor isomer M1a is likely to be catalyzed by a combination of CYP isozymes (including isozymes other than CYP3A) and aldehyde dehydrogenase (ALDH) enzymes.

In vitro studies indicate that neither alectinib nor its major active metabolite (M4) inhibits CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Alectinib did not inhibit OATP1B1/OATP1B3, OAT1, OAT3 or OCT2 at clinically relevant concentrations in vitro.

Elimination

Following administration of a single dose of 14C-labeled alectinib administered orally to healthy subjects the majority of radioactivity was excreted in faeces (mean recovery 97.8%) with minimal excretion in urine (mean recovery 0.46%). In faeces, 84% and 5.8% of the dose was excreted as unchanged alectinib or M4, respectively.

Based on a population PK analysis, the apparent clearance (CL/F) of alectinib was 81.9 L/hour. The geometric mean of the individual elimination half-life estimates for alectinib was 32.5 hours. The corresponding values for M4 were 217 L/hour and 30.7 hours, respectively.

Pharmacokinetics in special populations

Renal impairment

Negligible amounts of alectinib and the active metabolite M4 are excreted unchanged in urine (<0.2% of the dose). Based on a population pharmacokinetic analysis alectinib and M4 exposures were similar in patients with mild and moderate renal impairment and normal renal function. The pharmacokinetics of alectinib has not been studied in patients with severe renal impairment.

Hepatic impairment

As elimination of alectinib is predominantly through metabolism in the liver, hepatic impairment may increase the plasma concentration of alectinib and/or its major metabolite M4. Based on a population pharmacokinetic analysis, alectinib and M4 exposures were similar in patients with mild hepatic impairment and normal hepatic function.

Following administration of a single oral dose of 300 mg alectinib in subjects with severe (Child-Pugh C) hepatic impairment, alectinib Cmax was the same and AUCinf was 2.2-fold higher compared with the same parameters in matched healthy subjects. M4 Cmax and AUCinf was 39% and 34% lower respectively, resulting in a combined exposure of alectinib and M4 (AUCinf) 1.8-fold higher in patients with severe hepatic impairment compared with matched healthy subjects.

The hepatic impairment study also included a group with moderate (Child-Pugh B) hepatic impairment, and a modestly higher alectinib exposure was observed in this group compared with matched healthy subjects. The subjects in the Child Pugh B group however did in general not suffer from abnormal bilirubin, albumin or prothrombin time, indicating that they may not be fully representative of moderately hepatically impaired subjects with decreased metabolic capacity

Effects of age, body weight, race and gender

Age, body weight, race and gender had no clinically meaningful effect on the systemic exposure of alectinib and M4. The range of body weights for patients enrolled in clinical studies is 36.9-123 kg. There are no available data on patients with extreme body weight (>130 kg) (see section 4.2).

Preclinical safety data

Carcinogenicity

Carcinogenicity studies have not been performed to establish the carcinogenic potential of Alecensa.

Mutagenicity

Alectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay but induced a slight increase in numerical aberrations in the in vitro cytogenetic assay using Chinese Hamster Lung (CHL) cells with metabolic activation, and micronuclei in a rat bone marrow micronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity), and not a clastogenic effect on chromosomes.

Impairment of fertility

No fertility studies in animals have been performed to evaluate the effect of Alecensa. No adverse effects on male and female reproductive organs were observed in general toxicology studies. These studies were conducted in rats and monkeys at exposures equal to or greater than 2.6- and 0.5-fold, respectively, of the human exposure, measured by AUC, at the recommended dose of 600 mg twice daily.

Teratogenicity

Alectinib caused embryo-foetal toxicity in pregnant rats and rabbits. In pregnant rats, alectinib caused total embryo-foetal loss (miscarriage) at exposures 4.5-fold of the human AUC exposure and small foetuses with retarded ossification and minor abnormalities of the organs at exposures 2.7-fold of the human AUC exposure. In pregnant rabbits, alectinib caused embryo-foetal loss, small fetuses and increased incidence of skeletal variations at exposures 2.9-fold of the human AUC exposure at the recommended dose.

Other

Alectinib absorbs UV light between 200 and 400 nm and demonstrated a phototoxic potential in an in vitro photosafety test in cultured murine fibroblasts after UVA irradiation.

Target organs in both rat and monkey at clinically relevant exposures in the repeat-dose toxicology studies included, but were not limited to the erythroid system, gastrointestinal tract, and hepatobiliary system.

Abnormal erythrocyte morphology was observed at exposures equal or greater than 10-60% the human exposure by AUC at the recommended dose. Proliferative zone extension in GI mucosa in both species was observed at exposures equal to or greater than 20-120% of the human AUC exposure at the recommended dose. Increased hepatic alkaline phosphatase (ALP) and direct bilirubin as well as vacuolation/degeneration/necrosis of bile duct epithelium and enlargement/focal necrosis of hepatocytes was observed in rats and/or monkeys at exposures equal to or greater than 20-30% of the human exposure by AUC at the recommended dose.

A mild hypotensive effect has been observed in monkeys at around clinically relevant exposures.