Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Blueprint Medicines (Netherlands) B.V., Gustav Mahlerplein 2, 1082 MA Amsterdam, Netherlands
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitor
ATC code: L01EX18
Avapritinib is a Type 1 kinase inhibitor that has demonstrated biochemical in vitro activity on the PDGFRA D842V and KIT D816V mutants associated with resistance to imatinib, sunitinib and regorafenib with half maximal inhibitory concentrations (IC50) of 0.24 nM and 0.27 nM, respectively, and greater potency against clinically relevant KIT exon 11 and KIT exon 17 mutants than against the KIT wild-type enzyme.
The ability of avapritinib to prolong the QT interval was assessed in 27 patients administered AYVAKYT at doses of 300/400 mg once daily in an open-label, single-arm study in patients with GIST. The estimated mean change from baseline in QTcF was 6.55 ms (90% confidence interval [CI]: 1.80 to 11.29) at the observed steady state geometric mean Cmax of 899 ng/mL. No effect on heart rate or cardiac conduction (PR, QRS, and RR intervals) was observed.
The efficacy and safety of AYVAKYT was assessed in a multi-centre, single-arm, open-label clinical trial (BLU-285-1101; NAVIGATOR). Patients with a confirmed diagnosis of GIST and an Eastern Clinical Oncology Group (ECOG) performance status (PS) of 0 to 2 (58% and 3% of patients had ECOG status 1 and 2, respectively) were included in the study. A total of 217 patients received a starting dose of either 300 mg or 400 mg once daily.
Efficacy was assessed on the basis of overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 modified for patients with unresectable or metastatic GIST (mRECIST v1.1) and duration of response (DOR), as evaluated by a Blinded Independent Central Review (BICR).
In addition, a total of 239 patients have received treatment with avapritinib at the relevant starting dose in an ongoing open-label, randomised phase 3 trial (BLU-285-1303; VOYAGER) in which PFS is the primary endpoint. Ninety six additional patients received avapritinib in this trial after disease progression on the regorafenib control treatment (crossover). As of the last data cut-off date, 9th March 2020, the median treatment duration was 8.9 months in patients with GIST harbouring the PDGFRA D842V mutation included in this study, which provides some preliminary comparative safety data.
A total of 38 patients with unresectable or metastatic GIST harbouring the PDGFRA D842V mutation were enrolled and treated with AYVAKYT at a starting dose of either 300 mg or 400 mg once daily. In the NAVIGATOR trial 71% of patients with unresectable or metastatic GIST harbouring the PDGFRA D842V mutation had dose reductions to 200 mg or 100 mg once daily during the course of therapy. Median time to dose reduction was 12 weeks. The GIST patients were required to have unresectable or metastatic disease and have a documented PDGFRA D842V mutation determined by a locally available diagnostic test. At 12 months, 27 patients were still on AYVAKYT with 22% receiving 300 mg once daily, 37% receiving 200 mg once daily and 41% receiving 100 mg once daily.
Baseline demographics and disease characteristics were median age of 64 years (range: 29 to 90 years), 66% male, 66% white, ECOG PS of 0-2 (61% and 5% of patients had ECOG status 1 and 2, respectively), 97% had metastatic disease, largest target lesion was >5 cm for 58%, 90% had prior surgical resection, and median number of prior lines of tyrosine kinase inhibitors of 1 (range: 0 to 5).
Efficacy results from study BLU-285-1101 (NAVIGATOR) for GIST patients harbouring the PDGFRA D842V mutation are summarised in Table 3. The data represent a median duration of follow-up of 26 months across all patients with PDGFRA D842V mutations who were alive, the median OS had not been reached with 74% of patients alive. The median progression free survival was 24 months. Radiographic tumour reductions were observed in 98% of patients.
Table 3. Efficacy results for PDGFRA D842V-Mutantion in GIST patients (NAVIGATOR study):
| Efficacy Parameter | N = 38 |
|---|---|
| mRECIST 1.1 ORR1, () (95 CI) CR PR | 95 (82.3, 99.4) 13 82 |
| DOR (months), median (CI) | 22.1 (14.1, NE) |
Abbreviations: CI=confidence interval; CR=complete response; DOR=duration of response; mRECIST 1.1=Response Evaluation Criteria In Solid Tumours v1.1 modified for patients with unresectable or metastatic GIST; N=number of patients; NE=not estimable; ORR=overall response rate; PR=partial response
1 ORR is defined as patients who achieved a CR or PR (CR + PR)
In patients with PDGFRA D842V-mutant GIST treated at starting doses of 300 or 400 mg once daily the ORR based on central radiology review by mRECIST v1.1 criteria was 95%.
Based on preliminary results from the ongoing phase 3 study BLU-285-1303 (VOYAGER) in a subset of 13 patients with PDGFRA D842V mutations, partial response was reported in 3 out of 7 patients in the avapritinib group (43% ORR) and none of the 6 patients in the regorafenib group (0% ORR). The median PFS there was not estimable in patients with PDGFRA D842V mutations randomized to avapritinib (95% CI: 9.7, NE) compared to 4.5 months in patients receiving regorafenib (95% CI: 1.7, NE).
Forty-two percent of the patients who received AYVAKYT at a starting dose of 300 mg and 400 mg once daily in NAVIGATOR were 65 years or older. No overall differences in efficacy were observed in comparison with younger patients. Only limited data are available from the use of avapritinib in patients aged 75 years or older (8% (3 out of 38)).
The European Medicines Agency has deferred the obligation to submit the results of studies with AYVAKYT in one or more subsets of the paediatric population with a relapsed/refractory solid tumour harbouring mutations in either KIT or PDGFRA (see section 4.2 for information on paediatric use).
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.
Following administration of avapritinib once daily, steady state was reached by 15 days. After a single dose and repeat dosing of avapritinib, systemic exposure of avapritinib was dose-proportional over the dose range of 30 to 400 mg once daily. The geometric mean accumulation ratio after repeat dosing was 3.1 to 4.6.
The steady state geometric mean (CV%) maximum concentration (Cmax) and area under the concentration-time curve (AUC0-tau) of avapritinib at 300 mg once daily was 813 ng/mL (52%) and 15400 h•ng/mL (48%), respectively.
Following administration of single oral doses of avapritinib of 30 to 400 mg, the median time to peak concentration (Tmax) ranged from 2.0 to 4.1 hours postdose. The absolute bioavailability has not been determined.
Avapritinib Cmax and AUCinf were increased by 59% and 27%, respectively, in healthy subjects administered avapritinib after a high fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the Cmax and AUCinf after overnight fasting.
Avapritinib is 98.8% bound to human plasma proteins in vitro and the binding is not concentrationdependent. The blood-to-plasma ratio is 0.95. Following a single 300 mg oral dose of avapritinib, the geometric mean apparent volume of distribution (Vz/F) of avapritinib was 17 L/kg, indicating extensive distribution into tissues from plasma.
In vitro studies demonstrated that oxidative metabolism of avapritinib is predominantly mediated by CYP3A4, CYP3A5 and to a minor extent by CYP2C9. The relative contributions of CYP2C9 and CYP3A to the in vitro metabolism of avapritinib were 15.1% and 84.9%, respectively. The formation of the glucuronide M690 is catalysed mainly by UGT1A3.
Following a single dose of approximately 310 mg (~100 µCi) [14C]avapritinib to healthy subjects, oxidation, glucuronidation, oxidative deamination and N-dealkylation were the primary metabolic pathways. Unchanged avapritinib (49%) and metabolites, M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating radioactive components. Following oral administration of avapritinib 300 mg once daily in patients, the steady state AUC of the constitutive enantiomers of M499, BLU111207 and BLU111208 are approximately 35% and 42% of the AUC of avapritinib. Compared to avapritinib (IC50 = 4 nM), the enantiomers BLU111207 (IC50 = 41.8 nM) and BLU111208 (IC50 = 12.4 nM) are 10.5- and 3.1-fold less potent against KIT D816V in vitro.
In vitro studies demonstrated that avapritinib is a direct inhibitor of CYP3A and a time-dependent inhibitor of CYP3A4, at clinically relevant concentrations (see section 4.5). In vitro, avapritinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.
In vitro, at clinically relevant concentrations, avapritinib induced CYP3A (see section 4.5). In vitro, avapritinib did not induce CYP1A2 or CYP2B6 at clinically relevant concentrations.
Following single doses of AYVAKYT of 30 to 400 mg, the mean plasma elimination half-life of avapritinib was 32 to 57 hours.
Following oral administration of AYVAKYT 300 mg once daily, the steady state geometric mean apparent oral clearance (CL/F) of avapritinib was 19.5 L/h.
Following a single oral dose of approximately 310 mg (~100 µCi) [14C]avapritinib to healthy subjects, 70% of the radioactive dose was recovered in faeces and 18% excreted in urine. Unchanged avapritinib accounted for 11% and 0.23% of the administered radioactive dose excreted in faeces and urine, respectively.
In vitro, avapritinib is not a substrate of P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K and BSEP at clinically relevant concentrations.
Avapritinib is an inhibitor of P-gp, BCRP, MATE1, MATE2-K, and BSEP in vitro (see section 4.5). In vitro, avapritinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2 at clinically relevant concentrations.
Gastric acid reducing active substances
No clinical drug-drug interaction studies have been conducted. Based on both population and noncompartmental pharmacokinetic analyses for patients with GIST taking gastric acid reducing agents, the effect of gastric acid reducing agents on the bioavailability of avapritinib is not clinically relevant.
Population pharmacokinetic analyses indicate that age, race, sex, body weight, and albumin concentration have no clinically meaningful effect on the pharmacokinetics of avapritinib. In clinical studies, no relevant differences in exposure, safety or efficacy were observed between elderly (aged 65 years and above) and younger patients (see also section 4.8 and section 5.1).
As hepatic elimination is a major route of excretion for avapritinib, hepatic impairment may result in increased plasma avapritinib concentrations. Based on a population pharmacokinetic analysis, avapritinib exposures were similar between 53 subjects with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST), 6 subjects with moderate hepatic impairment (total bilirubin >1.5 to 3.0 times ULN and any AST), and 284 subjects with normal hepatic function (total bilirubin and AST within ULN). The pharmacokinetics of avapritinib in patients with severe hepatic impairment (total bilirubin >3.0 times ULN and any AST) has not been studied.
Based on a population pharmacokinetic analysis, avapritinib exposures were similar among 88 subjects with mild renal impairment (CLcr 60-89 mL/min), 24 subjects with moderate renal impairment (CLcr 30-59 mL/min) and 230 subjects with normal renal function (CLcr ≥90 mL/min), suggesting that no dose adjustment is necessary in patients with mild to moderate renal impairment. The pharmacokinetics of avapritinib in patients with severe renal impairment (CLcr 15-29 mL/min) or end-stage renal disease (CLcr <15 mL/min) has not been studied.
Repeat dose studies in dogs indicated haemorrhage and choroid plexus oedema in the brain at ≥0.4 times the human exposure at the clinical dose of 300 mg once daily. Rats manifested convulsions, which was potentially secondary to inhibition of Nav 1.2 at systemic exposures ≥8-fold higher than the exposure in patients at the clinical dose of 300 mg once daily. This effect was not seen in dogs.
Avapritinib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). It was positive in the in vitro chromosome aberration test in cultured human peripheral blood lymphocytes but negative in the rat bone marrow micronucleus test, and thus, overall non-genotoxic. Carcinogenicity studies with avapritinib have not been conducted.
A combined male and female fertility and early embryonic development study was conducted in rats at oral avapritinib doses of 3, 10, and 30 mg/kg/day for males, and 3, 10, and 20 mg/kg/day for females. Male rats were dosed 4 weeks prior to mating and through mating and female rats were dosed 2 weeks prior to mating and to gestation day 7. No effect on male or female fertility was noted. The high dose of 30 mg/kg/day is approximately equivalent to the human recommended dose, based on body surface area.
Avapritinib showed embryotoxic and teratogenic effects (decreases in foetal weights and viability, and increases in visceral and skeletal malformations) in an embryo-foetal development toxicity study in rats.
An in vitro phototoxicity study in 3T3 mouse fibroblasts as well as a phototoxicity study in pigmented rats demonstrated that avapritinib has a slight potential for phototoxicity.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
