Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EX14 
Mechanism of action

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS (ROS1), and anaplastic lymphoma kinase (ALK), with IC50 values of 0.1 to 2 nM. The major active metabolite of entrectinib, M5, showed similar in vitro potency and activity against TRK, ROS1, and ALK.

Fusion proteins that include TRK, ROS1 or ALK kinase domains drive tumourigenic potential through hyperactivation of downstream signalling pathways leading to unconstrained cell proliferation.
Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumour types, including subcutaneous and intracranial tumours, harbouring NTRK, ROS1, and ALK fusion genes.

Prior treatments with other drugs that inhibit the same kinases may confer resistance to entrectinib.
Resistance mutations in the TRK kinase domain identified following entrectinib discontinuation include NTRK1 (G595R, G667C) and NTRK3 (G623R, G623E and G623K). Resistance mutations in the ROS1 kinase domain identified following entrectinib discontinuation include G2032R, F2004C and F2004I.

The molecular causes for primary resistance to entrectinib are not known. It is therefore not known if the presence of a concomitant oncogenic driver in addition to an NTRK gene fusion affects the efficacy of TRK inhibition.

Clinical efficacy and safety

NTRK gene fusion-positive solid tumours
Efficacy in adult patients
The efficacy of Rozlytrek was evaluated in a pooled sub-group of adult patients with unresectable or metastatic solid tumours with a NTRK gene fusion enrolled in one of three multicentre single-arm, open-label clinical trials (ALKA, STARTRK-1 and STARTRK-2). To be included in the pooled subgroup, patients were required to have confirmed NTRK gene fusion-positive solid tumours; measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1; at least 12 months of follow-up from the first post-treatment initiation tumour assessment, and no prior therapy with a TRK inhibitor (patients with concomitant driver mutations, where known, were excluded). Patients with primary CNS tumours were assessed separately using Response Assessment in Neuro-Oncology Criteria (RANO). Patients received Rozlytrek 600 mg orally once daily until unacceptable toxicity or disease progression. The primary efficacy endpoints were objective response rate (ORR) and duration of response (DOR) as evaluated by Blinded Independent Central Review (BICR) according to RECIST v1.1.

Efficacy was assessed in 150 adult patients with solid tumours with an NTRK gene fusion enrolled in these trials. The baseline demographic and disease characteristics were: 49.3% males, median age of 59 years (range 21 years to 88 years), 38% and 12% were 65 years or older and 75 years or older respectively, 58.7% white Caucasian, 26% Asian, 5.4% Hispanic or Latino and 63% never smokers.
The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was 0 (41.3%), 1 (50%), or 2 (8.7%). Most patients (95.3%) had metastatic disease [most common sites being lung (60.7%), lymph nodes (54.7%), bone (27.3%), liver (36%) and brain (20%)], 4.7% patients had locally advanced disease. 81.3% and 60.7% of patients had received surgery and radiotherapy for their cancer, respectively. 77.3% patients had received prior systemic therapy for their cancer including 
chemotherapy (69.3%) and 34% patients had no prior systemic therapies for metastatic disease. The most common cancers were sarcoma (21.3%), lung cancer (20.7%), salivary gland tumours (17.3%), thyroid cancer (10.7%) colorectal cancer (7.3%) and breast cancer (6%). Most patients (87.3%) had an NTRK gene fusion detected by next-generation sequencing (NGS) and 12.7% had a NTRK gene fusion detected by other nucleic acid-based tests. The overall median duration of follow-up was 30.6 months.

Efficacy results from patients with NTRK gene fusion-positive solid tumours are summarised in Table 5.

Table 5: Overall efficacy by BICR in adults with NTRK gene fusion-positive solid tumours 
Rozlytrek
Efficacy endpoint
N = 150
Primary endpoints (BICR assessed; RECIST 1.1)
Objective Response Rate
Number of Responses                                                         92/150 ORR% (95% CI)                                                          61.3% (53.0, 69.2) Complete Response, n (%)                                                    25 (16.7%) Partial Response, n (%)                                                     67 (44.7%) Duration of Response*
Number (%) of patients with events                                      50/92 (54.3%) Median, months (95% CI)                                                 20 (13.2, 31.1) 6-month durable response % (95% CI)                                        83% (75, 91) 9-month durable response % (95% CI)                                        77% (68, 86) 12-month durable response % (95% CI)                                       66% (56, 76) Confidence Intervals (CI) calculated using the Clopper-Pearson method.
*Median and percentiles based on Kaplan-Meier estimates

Objective response rate and duration of response by tumour type in adult patients with NTRK gene fusion-positive solid tumours is presented in Table 6 below.



Table 6: Efficacy by tumour type, in adults with NTRK gene fusion-positive solid tumours 
ORR                           DOR
Patients
Tumour type                                                                               Range (N = 150)           n (%)             95% CI
(months)
Sarcoma                                       32            19 (59.4)        (40.6, 76.3)         2.8, 44.6* Non-small cell lung cancer                    31            20 (64.5)        (45.4, 80.8)         3.7, 58.8* Salivary (MASC)                               26            22 (84.6)        (65.1, 95.6 )        2.8, 49.7* Breast cancer (secretory)                      6            5 (83.3)         (35.9, 99.6)         5.5, 53.4* Breast cancer (non-secretory)                  2             NE, PR               NA                  4.2 Breast cancer (NOS)                            1               NE                 NA                  NA Thyroid cancer                                16            10 (62.5)        (35.4, 84.8)         5.6, 44.2* Colorectal cancer                             11            3 (27.3 )         (6.0, 61.0)         1.9*, 20.0 Neuroendocrine cancers                         5            2 (40.0)          (5.3, 85.3)         11.1, 31.1 Head and neck                                  5            3 (60.0)         (14.7, 94.7)         4.0, 32.6* Pancreatic cancer                              4            3 (75.0)         (19.4, 99.4)          7.1, 12.9 Unknown primary cancer                         3            1 (33.3)          (0.8, 90.6)             9.1 Ovarian cancer                                 1           Non CR/PD              NA                  NA Endometrial carcinoma                          1               PR                 NA                 38.2 Cholangiocarcinoma                             1               PR                 NA                  9.3 Gastrointestinal cancer (other)                1               CR                 NA                 30.4 Neuroblastoma                                  1               NE                 NA                  NA Prostate cancer                                1               PD                 NA                  NA Penile cancer                                  1               PD                 NA                  NA Adrenal cancer                                 1               PD                 NA                  NA *Censored
ORR: Objective Response Rate; DOR: Duration of Response; MASC: mammary analogue secretory carcinoma; NA: not applicable due to small number or lack of response; NOS: not otherwise specified; CR: complete response; PR: partial response; PD: progressive disease; NE: not estimable.

Due to the rarity of NTRK gene fusion-positive cancers, patients were studied across multiple tumour types with a limited number of patients in some tumour types, causing uncertainty in the ORR estimate per tumour type. The ORR in the total population may not reflect the expected response in a specific tumour type.

The ORR in 78 patients that had broad molecular characterisation before Rozlytrek treatment was 53.8% [42.2, 65.2]; of those, the ORR in 61 patients who had other genomic alterations in addition to NTRK gene fusion was 47.5% [34.6, 60.7] and the ORR in 17 patients without other genomic alterations was 76.5% [50.1, 93.2].

Intracranial response
A BICR assessment resulted in a subgroup of 22 adult patients with CNS metastases at baseline, including 13 patients with measureable CNS lesions. Intracranial (IC) response assessed by BICR according to RECIST v1.1 was reported in 9 out of these 13 patients (3 CR and 6 PR), for an ORR of 69.2% (95% CI: 38.6, 90.9) and median DOR of 17.2 (7.4, NE). Five of these 13 patients had received intracranial radiotherapy to the brain within 2 months prior to starting Rozlytrek treatment.

Primary CNS tumour
Across the three trials, 12 adult patients with CNS primary tumours were treated with Rozlytrek with a minimum of 12 months of follow-up. One out of the 12 adult patients had an objective response assessed by BICR according to RANO.

Efficacy in paediatric patients
Rozlytrek is not indicated for patients less than 18 years of age.



ROS1-positive NSCLC
The efficacy of Rozlytrek was evaluated in a pooled sub-group of patients with ROS1-positive metastatic NSCLC who received Rozlytrek 600 mg orally once daily and were enrolled in one of three multicentre single-arm, open label clinical trials (ALKA, STARTRK-1 and STARTRK-2). To be included in the pooled sub-group, patients were required to have histologically confirmed, recurrent or metastatic, ROS1-positive NSCLC, ECOG performance status ≤2, measurable disease per RECIST v1.1, ≥6 months of follow-up, and no prior therapy with a ROS1 inhibitor. All patients were assessed for CNS lesions at baseline.

The primary efficacy endpoints were ORR and DOR, as evaluated by BICR according to RECIST v1.1. The secondary efficacy endpoints included PFS, OS, and in patients presenting with CNS metastases at baseline - IC-ORR and IC-DOR, (also evaluated by BICR using RECIST v1.1).

Efficacy was assessed in 161 patients with ROS1-positive NSCLC. The baseline demographic and disease characteristics were: 35.4% males, median age of 54 years (range 20 years to 86 years), 24.2% and 4.3% were older than 65 years and 75 years of age, respectively, 44.1% white Caucasian, 45.3% Asian, 4.3%, Black, 2.6% Hispanic or Latino and 62.7% never smokers. The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was 0 (41%), 1 (49.1%), or 2 (9.9%).
Most patients (98.1%) had metastatic disease [most common sites being lymph nodes (69.6%), lung (50.3%) and brain (32.9%)], 1.9% patients had locally advanced disease and 37.3% patients had no prior systemic therapies for metastatic disease. ROS1 positivity was determined by NGS in 83% of patients, by FISH in 9% of patients, and by RT-PCR in 8% of patients. The overall median duration of follow-up from receipt of the first dose was 15.8 months.

Efficacy results from patients with ROS1-positive NSCLC are summarised in Table 7.

Table 7: Overall efficacy by BICR in patients with ROS1-positive NSCLC 
Rozlytrek
Efficacy endpoint
N = 161
Primary endpoints (BICR-assessed, RECIST 1.1)
Objective Response Rate
Number of Responses                                                    108/161 ORR% (95% CI)                                                    67.1% (59.25, 74.27) Complete Response, n (%)                                               14 (8.7%) Partial Response, n (%)                                               94 (58.4%) Duration of Response*
Number (%) of patients with events                                  48/108 (44.4%) Range (months)                                                        1.8**, 42.3** 6-month durable response % (95% CI)                                   83% (76, 90) 9-month durable response % (95% CI)                                   75% (67, 84) 12-month durable response % (95% CI)                                  63% (53, 73) Secondary endpoints (BICR-assessed, RECIST 1.1)
PFS
Number (%) of patients with events                                  82/161 (50.9%) 6-month PFS % (95% CI)                                               77% (70, 84) 9-month PFS % (95% CI)                                               66% (58, 74) 12-month PFS % (95% CI)                                              55% (47, 64) Overall Survival*
Number (%) of patients with events                                  38/161 (23.6%) 6-month OS % (95% CI)                                                91% (87, 96) 9-month OS % (95% CI)                                                86% (81, 92) 12-month OS % (95% CI)                                               81% (74, 87) 
NE = not estimable.
Confidence Intervals (CI) calculated using the Clopper-Pearson method.
* Event-free rates based on Kaplan-Meier estimates
** Censored

In the ROS1 positive NSCLC efficacy evaluable patients with ≥12 months of follow-up (N = 94), the ORR was 73.4% (95% CI: 63.3, 82), the median DoR was 16.5 months (95% CI: 14.6, 28.6) and median PFS was 16.8 months (95% CI: 12, 21.4).

Intracranial response
A BICR assessment resulted in a subgroup of 46 ROS1-positive NSCLC patients with CNS metastases at baseline including 24 patients with measureable CNS lesions. Intracranial response assessed by BICR according to RECIST v1.1 was reported in 19 of these 24 patients (3 CR and 16 PR) for an ORR of 79.2% (95% CI: 57.8, 92.9). The percentage of patients (95% CI) with DOR ≥6 months, ≥9 months and ≥12 months was 76% (56, 97), 62% (38, 86), and 55% (29, 80), respectively (Kaplan- Meier estimates). Nine of these 24 patients had received intracranial radiotherapy to the brain within 2 months prior to starting Rozlytrek treatment.

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

The pharmacokinetic parameters for entrectinib and its major active metabolite (M5), have been characterized in patients with NTRK gene fusion-positive solid tumours and ROSI-positive NSCLC and healthy subjects. The pharmacokinetics of entrectinib and M5 are linear and are not dose-dependent or time-dependent. Steady state is achieved within one week for entrectinib and two weeks for M5 following daily administration of Rozlytrek.

Entrectinib is a weak P-gp substrate based on in vitro data. The exact in vivo contribution of P-gp is unknown. M5 is a P-gp substrate. Entrectinib is not a substrate of BCRP but M5 is a substrate of BCRP. Entrectinib and M5 are not substrates of OATP 1B1 or OATP1B3.

Absorption

Following a single 600 mg oral administration of Rozlytrek to patients with NTRK gene fusion-positive and ROS1-positive NSCLC under fed conditions, entrectinib was rapidly absorbed reaching time-to-maximum plasma concentration (Tmax) after approximately 4 to 6 hours. Based on population pharmacokinetic analysis, steady-state was achieved within 5 days for entrectinib with 600 mg once daily dosing.

No clinically significant effect of food on entrectinib bioavailability was observed.

Distribution
Entrectinib and its major active metabolite M5 are highly bound to human plasma proteins independent of drug concentrations. In human plasma, entrectinib and M5 had similar protein binding with >99% bound at a clinically relevant concentration.

After a single oral dose of entrectinib, the geometric mean volume of distribution (Vz/F) was 600 L, suggesting extensive distribution of the drug. Entrectinib demonstrated steady-state brain-to-plasma concentration ratios of 0.4 to 2.2 in multiple animal species (mice, rats, and dogs) at clinically relevant systemic exposures.

Biotransformation

Entrectinib is metabolised predominantly by CYP3A4 (~76%). Minor contributions from several other CYPs and UGT1A4 were estimated at <25% in total. The active metabolite M5 (formed by CYP3A4) and the direct N-glucuronide conjugate, M11, (formed by UGT1A4) are the two major circulating metabolites identified.

Elimination

The population PK model estimated mean accumulation at steady-state following 600 mg once daily administration of entrectinib was 1.89 (±0.381) and 2.01 (±0.437) for M5. Following administration of a single dose of [14C]-labelled entrectinib, 83% radioactivity was excreted in faeces (36% of the dose as unchanged entrectinib and 22% as M5) with minimal excretion in urine (3%).

Entrectinib and M5 account for approximately 73% of radioactivity in systemic circulation at Cmax, and approximately half of total radioactivity AUCinf.

Population PK analysis estimated apparent clearance CL/F was 19.6 L/h and 52.4 L/h for entrectinib and M5, respectively. The elimination half-lives of entrectinib and M5 were estimated to be 20 hours and 40 hours, respectively.

Linearity/Non-linearity

Entrectinib has linear pharmacokinetics in the dose range of 100 mg to 600 mg.
Pharmacokinetics in special populations

Paediatric population

Data obtained from population pharmacokinetic analyses show that in paediatric patients 12 years and older, a dose of 400 mg Rozlytrek once daily for BSA range 1.11 m2 to 1.50 m2, and a dose of 600 mg Rozlytrek once daily for BSA range ≥1.51 m2 results in a similar systemic exposure attained in adults treated with 600 mg of Rozlytrek, once daily.

Elderly

No differences in entrectinib exposure were noted in patients older than 65 years and younger adults based on pharmacokinetic analysis.

Renal impairment

Negligible amounts of entrectinib and the active metabolite M5 are excreted unchanged in urine (~3% of the dose) indicating that renal clearance plays a minor role in the elimination of entrectinib.
Based on population pharmacokinetic analyses, the pharmacokinetics of entrectinib are not significantly affected in renal impairment. The impact of severe renal impairment on the pharmacokinetics of entrectinib is unknown.

Hepatic impairment

No clinically significant differences in the pharmacokinetics of entrectinib were observed based on mild hepatic impairment (total bilirubin ≤ 1.5 times ULN). The impact of moderate to severe hepatic impairment on the pharmacokinetics of entrectinib is unknown

Effects of age, body weight, race and gender

No clinically significant differences in the pharmacokinetics of entrectinib were observed based on age (4 years to 86 years), sex, race (Asian, Black and White) and body weight (32 kg to 130 kg).