Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors
ATC code: L01EX14
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.
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) or the multicentre multi-cohort, open-label clinical trial, TAPISTRY. 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 242 adult patients with solid tumours with an NTRK gene fusion enrolled in these trials. The baseline demographic and disease characteristics were: 47.5% males, median age of 58 years (range 19 years to 92 years), 37.2% and 9.9% were 65 years or older and 75 years or older respectively, 49.4% white Caucasian, 36.5% Asian, 3.3% Hispanic or Latino and 61.9% never smokers. The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was 0 (42.1%), 1 (50%), or 2 (7.9%). Most patients (95.5%) had metastatic disease [most common sites being lung (62.8%), lymph nodes (49.2%), liver (33.1%), bone (31%), and brain (16.5%)], 4.5% patients had locally advanced disease. 76.9% and 52.5% of patients had received surgery and radiotherapy for their cancer, respectively. 71.5% patients had received prior systemic therapy for their cancer including chemotherapy (61.6%) and 37.2% patients had no prior systemic therapies for metastatic disease. The most common cancers were lung cancer (24.8%), sarcoma (19%), salivary gland tumours (15.7%), thyroid cancer (13.6%), colorectal cancer (7%), and breast cancer (7%). The overall median duration of follow-up was 35.1 months.
Efficacy results from patients with NTRK gene fusion-positive solid tumours are summarised in Table 6.
Table 6. Overall efficacy by BICR in adults with NTRK gene fusion-positive solid tumours:
| Efficacy endpoint | Rozlytrek N=242 |
|---|---|
| Primary endpoints (BICR assessed; RECIST 1.1) | |
| Objective Response Rate | |
| Number of Responses | 152/242 |
| ORR% (95% CI*) | 62.8% (56.4, 68.9) |
| Complete Response, n (%) | 41 (16.9%) |
| Partial Response, n (%) | 111 (45.9%) |
| Duration of Response** | |
| Number (%) of patients with events | 86/152 (56.6%) |
| Median, months (95% CI) | 22 (16.6, 30.4) |
| 6-month durable response % (95% CI) | 85% (80, 91) |
| 9-month durable response % (95% CI) | 78% (71, 84) |
| 12-month durable response % (95% CI) | 69% (62, 77) |
* Confidence Intervals (CI) calculated using the Clopper-Pearson method.
** Median and event-free rates 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 7 below.
Table 7. Efficacy by tumour type, in adults with NTRK gene fusion-positive solid tumours:
| Tumour type | Patients (N=242) | ORR | DOR | |
|---|---|---|---|---|
| n (%) | 95% CI | Range (months) | ||
| Sarcoma | 46 | 29 (63) | (47.6, 76.8) | 2.8, 68.6* |
| Non-small cell lung cancer | 60 | 38 (63.3) | (49.9, 75.4) | 3.1, 71.6 |
| Salivary (MASC) | 38 | 32 (84.2) | (68.8, 94) | 2.8, 73.5* |
| Breast cancer (secretory) | 12 | 10 (83.3) | (51.6, 97.9) | 5.5, 69.9* |
| Breast cancer (non-secretory) | 2 | NE, PR | NA | 4.2 |
| Breast cancer (NOS) | 2 | NE, NE | NA | NA |
| Breast cancer (Ductal) | 1 | PD | NA | NA |
| Thyroid cancer | 33 | 20 (60.6) | (42.1, 77.1) | 5.6, 60.7 |
| Colorectal cancer | 17 | 6 (35.3) | (14.2, 61.7) | 5.6*, 24* |
| Neuroendocrine cancers | 8 | 5 (62.5) | (24.5, 91.5) | 7.4, 31.1 |
| Head and neck | 5 | 3 (60.0) | (14.7, 94.7) | 4.0, 56.5* |
| Pancreatic cancer | 6 | 4 (66.7) | (22.3, 95.7) | 5.6*, 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 |
| Gastrointestinal cancer (non-CRC) | 1 | PD | NA | NA |
| 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; CRC: colorectal cancer; 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 122 patients that had broad molecular characterisation before Rozlytrek treatment was 59.8% (95% CI: 50.6, 68.6); of those, the ORR in 97 patients who had other genomic alterations inaddition to NTRK gene fusion was 55.7% (95% CI: 45.2, 65.8) and the ORR in 25 patients without other genomic alterations was 76% (95% CI: 54.9, 90.6).
A BICR assessment resulted in a subgroup of 36 adult patients with CNS metastases at baseline, including 20 patients with measurable CNS lesions. Intracranial (IC) response assessed by BICR according to RECIST v1.1 was reported in 14 out of these 20 patients (7 CR and 7 PR), for an ORR of 70% (95% CI: 45.7, 88.1) and median DOR of 19.7 months (95% CI: 7.4, 26.6). Five of these 20 patients had received intracranial radiotherapy to the brain within 2 months prior to starting Rozlytrek treatment.
Across the three trials, 16 adult patients with primary CNS tumours were treated with Rozlytrek with a minimum of 12 months of follow-up. Two out of the 16 adult patients had an objective response assessed by BICR according to RANO.
Efficacy of Rozlytrek was assessed in 44 paediatric patients with solid tumours that have a NTRK gene fusion enrolled in STARTRK-NG or TAPISTRY.
To be included in the analysis, patients were required to have confirmed NTRK gene fusion-positive solid tumours; at least 6 months of follow-up, no prior therapy with a TRK inhibitor, received at least one dose of entrectinib and presenting with measurable or evaluable disease at baseline. Patients received Rozlytrek doses from 20 mg to 600 mg once daily. The primary efficacy endpoint was confirmed ORR as evaluated by BICR according to RECIST v1.1 for extracranial tumours and according to RANO for primary CNS tumours. The secondary efficacy outcome measures included duration of confirmed response as evaluated by BICR and time to first confirmed objective response (CR or PR).
The baseline demographic and disease characteristics were: 45.5% males, median age of 4 years (range: 2 months to 15 years), 52.3% white Caucasian, 34.1% Asian, and 9.1% Hispanic or Latino, with a median BSA of 0.73 m² (range: 0.2-1.9 m²). At baseline, 23.8% of patients had metastatic disease, 76.2% of patients had locally advanced disease, and 43.2% of patients had no prior systemic therapies for their cancer. The majority of patients had received treatment for their cancer including surgery (n=24), radiotherapy (n=8) and/or systemic therapy (n=25). The sites for metastatic disease included other (4 patients), brain (3 patients), and lung (3 patients). 45.5% of patients had primary CNS tumours. The overall median duration of follow-up was 24.2 months.
Efficacy results from patients with NTRK gene fusion-positive solid tumours are summarised in Table 8.
Table 8. Overall efficacy by BICR in paediatric patients with NTRK gene fusion-positive solid tumours:
| Efficacy endpoints | Rozlytrek n=44 |
|---|---|
| Primary endpoints** | |
| Objective response rate | |
| Number of responses | 32/44 |
| ORR% (95% CI***) | 72.7% (57.21, 85.04) |
| Complete response, n (%) | 20 (45.5%) |
| Partial response, n (%) | 12 (27.3%) |
| Secondary endpoints** | |
| DOR* | |
| Number (%) of patients with events | 6/32 (18.8%) |
| Median, months (95% CI) | NE (25.4, NE) |
| 6-month durable response % (95% CI) | 97% (90, 100) |
| 9-month durable response % (95% CI) | 97% (90, 100) |
| 12-month durable response % (95% CI) | 84% (70, 99) |
NE = not estimable.
* Median and event-free rates based on Kaplan-Meier estimates.
**Includes patients with measurable or evaluable disease. BICR analysis by RECIST v1.1 for solid tumours (24 patients) and by RANO criteria for primary CNS tumours (20 patients).
*** Confidence Intervals (CI) calculated using the Clopper-Pearson method.
Table 9. Efficacy by tumour type in paediatric patients with NTRK gene fusion-positive solid tumours:
| Tumour type | Patients (n=44) | ORR | DOR | |
|---|---|---|---|---|
| n (%) | 95% CI | Range (months) | ||
| Primary CNS | 20 | 10 (50) | (27.2, 72.8) | 5.5, 42.3* |
| Infantile fibrosarcoma | 11 | 10 (90.9) | (58.7, 99.8) | 5.7*, 24* |
| Spindle Cell | 8 | 8 (100.0) | (63.1, 100) | 5.4*, 23* |
| Sarcoma (other) | 2 | PR; Non-CR/Non-PD | NA | 3.7* |
| Melanoma | 1 | CR | NA | 42.4* |
| Kidney cancer | 1 | PR | NA | 9.2* |
| Thyroid cancer | 1 | CR | NA | 11.1* |
* Censored
ORR: Objective Response Rate; DOR: Duration of Response; NA: not applicable due to small number or lack of response; CR: complete response; PR: partial response; PD: progressive disease 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 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 10.
Table 10. Overall efficacy by BICR in patients with ROS1-positive NSCLC:
| Efficacy endpoint | Rozlytrek 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) |
* Event-free rates based on Kaplan-Meier estimates.
** Censored
*** Confidence Intervals (CI) calculated using the Clopper-Pearson method.
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).
A BICR assessment resulted in a subgroup of 46 ROS1-positive NSCLC patients with CNS metastases at baseline including 24 patients with measurable 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.
h2 Conditional approval
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This
means that further evidence on this medicinal product is awaited.
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary
The European Medicines Agency has deferred the obligation to submit the results of studies with Rozlytrek in one or more subsets of the paediatric population in the treatment with NTRK gene fusion-positive locally advanced or metastatic solid tumours (see section 4.2 for information on paediatric use).
The pharmacokinetic parameters for entrectinib and its major active metabolite (M5), have been characterised in patients with NTRK gene fusion-positive solid tumours and ROS1-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.
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.
In healthy adult subjects, the AUC and Cmax of Rozlytrek in the film-coated granule formulation was similar to that of the capsules. Rozlytrek capsules administered as a suspension with water or milk, given orally, or through a gastric or nasogastric tube, results in similar AUC and Cmax as capsules swallowed whole.
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.
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.
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.
Entrectinib has linear pharmacokinetics in the dose range of 100 mg to 600 mg.
The pharmacokinetics of entrectinib have been evaluated in 78 paediatric patients above one month of age. In patients from >1 month to ≤6 months the administered dose was 250 mg/m²; in patients >6 months, the administered dose was 300 mg/m² based on five BSA categories, with a maximum dose of 600 mg for children with ≥1.51 m² body surface area (BSA).
Data obtained from population pharmacokinetic analyses show that in paediatric patients 6 years and older, 300 mg Rozlytrek once daily dose for BSA range 0.81 m² to 1.10 m², 400 mg Rozlytrek once daily dose for BSA range 1.11 m² to 1.50 m², and 600 mg Rozlytrek once daily dose for BSA range ≥1.51 m² results in a similar systemic exposure attained in adults treated with 600 mg Rozlytrek once daily dose.
Data from non-compartmental analysis in patients from 1 month to <6 years demonstrated that systemic exposure of the sum of entrectinib and M5 in paediatric patients receiving 250 mg/m² or 300 mg/m² of Rozlytrek once daily were generally lower than the mean systemic exposure of adult patients treated with 600 mg of Rozlytrek once daily. The recommended dose in this age category is based on available efficacy and safety data.
No differences in entrectinib exposure were noted in patients older than 65 years and younger adults based on pharmacokinetic analysis.
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.
The pharmacokinetics of entrectinib were studied in subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, relative to subjects with normal hepatic function. Following administration of a single oral dose of 100 mg entrectinib, the combined AUClast of entrectinib and M5 showed no relevant change in the hepatic impaired groups compared to the normal function group. The AUClast geometric mean ratio (90% CI) was 1.30 (0.889, 1.89) for the mild, 1.24 (0.886, 1.73) for the moderate, and 1.39 (0.988, 1.95) for the severe hepatic impaired groups compared to the normal hepatic function group. For the unbound entrectinib and M5, the AUClast (fu) geometric mean ratio (90% CI) was 1.91 (1.21, 3.02) for the mild, 1.57 (1.06, 2.31) for the moderate, and 2.34 (1.57, 3.48) for the severe hepatic impaired groups compared to the normal hepatic function group. Although the effect of hepatic impairment on unbound PK parameters generally followed a similar direction as total PK parameters, due to the high non-specific binding in buffer and high variability, results should be interpreted with caution.
In addition, it was also observed that the variability in systemic exposure was high and observed exposures overlapped across all the study groups (see section 4.2).
No clinically significant differences in the pharmacokinetics of entrectinib were observed based on sex, race (Asian, Black and White) and body weight (4 kg to 130 kg).
No carcinogenicity studies have been performed to establish the carcinogenic potential of entrectinib.
Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay but demonstrated a potential for abnormal chromosome segregation (aneugenicity) in cultured human peripheral blood lymphocytes. Entrectinib was not clastogenic or aneugenic in the in vivo micronucleus assay in rats and did not induce DNA damage in a comet assay in rats.
Dedicated fertility studies in animals have not been performed to evaluate the effect of entrectinib. No adverse effects of entrectinib on male and female reproductive organs were observed in the repeat-dose toxicology studies in rats and dogs at approximately 2.4-fold and 0.6-fold, respectively, the human exposure by AUC at the recommended human dose.
In an embryo-foetal developmental study in rats, maternal toxicity (decreased body weight gain and food consumption) and foetal malformations (including body closure defects and malformations of the vertebrae and ribs), were observed at 200 mg/kg/day of entrectinib which represents approximately 2-fold the human exposure by AUC at the recommended dose. Dose-response dependent reduced foetal body weight (low, middle and high dose) and reduced skeletal ossification (middle and high dose) were observed at exposures equivalent to <2 times the human exposure by AUC at the recommended dose.
Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats were observed in the central nervous system (convulsions, abnormal gait, tremors) at ≥0.2 times the human exposures by Cmax at the recommended dose, skin (scabs/sores) and decreased red blood cell parameters at ≥0.1 times the human exposure by AUC at the recommended dose. In adult rats and dogs, effects on liver (increased ALT and hepatocellular necrosis) were observed at ≥0.6 times the human exposure by AUC at the recommended dose. In dogs, diarrhoea at ≥0.1 times the human exposure by AUC at the recommended dose and prolongations of QT/QTc interval at ≥0.1 times the human exposure by Cmax at the recommended dose were also observed.
In a 13-week juvenile rat toxicology study, animals were dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to adulthood in humans). In addition to CNS effects, ptosis and skin effects, decreased RBC parameters and effects on growth and development were observed in the dosing and recovery phases including decreased body weight gain and delayed sexual maturation (at ≥4 mg/kg/day, approximately 0.1 times the human exposure by AUC at the recommended dose). Deficits in neurobehavioural assessments including functional observational battery (decreased landing foot splay, decreased fore and hind limb grip strength that seemed to manifest later in age) and learning and memory (at ≥8 mg/kg/day, approximately 0.2 times the human exposure by AUC at the recommended dose), and decreased femur length (at ≥16 mg/kg/day, approximately 0.3 times the human exposure by AUC at the recommended dose) were observed.
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