Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, ATC code: L01XX73
Mechanism of action

Sotorasib is a selective KRAS G12C (Kirsten rat sarcoma viral oncogene homolog) inhibitor, which covalently and irreversibly binds to the unique cysteine of KRAS G12C. Inactivation of KRAS G12C by sotorasib blocks tumour cell signalling and survival, inhibits cell growth, and promotes apoptosis selectively in tumours harbouring KRAS G12C, an oncogenic driver of tumourigenesis.

Clinical efficacy and safety

LUMYKRAS for the treatment of patients with previously treated KRAS G12C-mutated NSCLC (CodeBreaK 100)
The efficacy of LUMYKRAS was studied in a single-arm, open-label, multicentre trial (CodeBreaK 100) that enrolled patients with locally advanced or metastatic KRAS G12C-mutated NSCLC who had disease progression after receiving prior therapy. Key eligibility criteria included progression on an immune checkpoint inhibitor and/or platinum-based chemotherapy and after targeted therapy if actionable oncogenic driver mutations were identified, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, and at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumours (RECIST v1.1). All patients were required to have KRAS G12C- mutated NSCLC prospectively identified in tumour samples using a validated test (Qiagen therascreen® KRAS RGQ PCR Kit) performed in a central laboratory. Patients with renal impairment, hepatic impairment and active brain metastases were excluded.

A total of 126 patients were enrolled and treated with LUMYKRAS 960 mg once daily as monotherapy until disease progression or unacceptable toxicity; 124 patients had at least one measurable lesion at baseline as assessed by Blinded Independent Central Review (BICR) according to RECIST v1.1 and were included in the analysis for response-related efficacy outcomes. The median duration of treatment was 5.5 months (range: 0 to 15) with 48% of patients treated for ≥ 6 months and 33% of patients treated for ≥ 9 months.

The major efficacy outcome measure was objective response rate (ORR) defined as the proportion of patients who achieved CR or PR as evaluated by a BICR according to RECIST v1.1. Additional efficacy outcome measures included duration of response (DOR), disease control rate (DCR) defined as the proportion of patients who achieved CR, PR and stable disease, time to response (TTR), progression-free survival (PFS), and overall survival (OS).

The baseline demographic and disease characteristics of the study population were: median age 64 years (range: 37 to 80); 50% Female; 82% White, 15% Asian, 2% Black; 70% ECOG PS 1; 96% had stage IV disease; 99% with non-squamous histology; 81% former smokers, 12% current smokers, 5% never smokers.

All patients received at least 1 prior line of systemic therapy for metastatic NSCLC; 43% received only 1 prior line of therapy, 35% received 2 prior lines of therapy, 22% received 3 prior lines of therapy, 91% received prior anti-PD-1/PD-L1 immunotherapy, 90% received prior platinum-based chemotherapy, 81% received both platinum-based chemotherapy and anti-PD-1/PD-L1. The sites of known extra-thoracic metastasis included 48% bone, 21% brain, and 21% liver.



Efficacy results are summarised in table 4.

Table 4. Efficacy results in CodeBreaK 100 for patients with KRAS G12C-mutated NSCLC 
Efficacy parameters                                  LUMYKRAS
N = 124
ORR, % (95% CI)a,c                                                 37.1 (28.6, 46.2) Complete response (CR), %                                             2.4 Partial response (PR), %                                             34.7 DORa,d
Number of responders                                                   46 Medianb, months (range)                                         11.1 (6.9, 15.0) Censored, %                                                           39.0 Patients with duration ≥ 6 months, %                                  63.0 CI = confidence interval; DOR = duration of response; ORR = objective response rate a
Response-related efficacy outcome b
Estimated using Kaplan-Meier method c
Based on 01 December 2020 data cut d
Based on 20 June 2021 data cut

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with LUMYKRAS in all subsets of the paediatric population in NSCLC (see section 4.2 for information on paediatric use).

Conditional marketing authorisation

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.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption
Bioavailability of sotorasib has not been investigated in humans. Following an oral, single dose administration, sotorasib was absorbed with median time to achieve peak concentration of 1 hour.

Effect of food
Following administration of sotorasib with a high-fat, high-calorie meal, there was no effect on Cmax, and AUC increased by 38% compared to administration under fasted conditions. Sotorasib can be administered with or without food.

Distribution

The geometric mean apparent volume of distribution after 960 mg PO QD for 8 consecutive days of sotorasib was 211 L (determined using noncompartmental analysis). In vitro, plasma protein binding of sotorasib was 89% and sotorasib bound preferentially to alpha-1-acid glycoprotein in vitro.

Biotransformation

The main metabolic pathways of sotorasib were non-enzymatic conjugation and oxidative metabolism.
In vitro data indicate that sotorasib is metabolised by cytochrome P4502C8, CYP3A4, and CYP3A5, and is a substrate of P-glycoprotein (P-gp). Following single oral administration of a radioactive 
sotorasib dose of 720 mg, a cysteine adduct (formed through hydrolysis of a glutathione adduct) and an oxidative metabolite resulting from CYP3A-mediated cleavage of the piperazine acrylamide moiety were the primary circulating metabolites. Neither of these metabolites were pharmacologically active.

Elimination

The geometric mean apparent clearance after 960 mg PO QD for 8 consecutive days of sotorasib was 26.2 L/hour (determined using noncompartmental analysis). The mean half-life is 5 hours. Steady state was reached within 22 days and remained stable. Sotorasib is primarily eliminated in faeces, with approximately 74% of the dose recovered in faeces and 6% (1% unchanged) recovered in urine.

Linearity/non-linearity

Sotorasib exhibited nonlinear pharmacokinetics over a range of single and multiple oral administration doses studied between 180 to 960 mg QD as Cmax and AUC0-24 hour were less than dose proportional.
The average Cmax and AUC0-24 hour values following multiple doses were similar for all dosing regimens from 180 mg QD to 960 mg QD. Exposure to sotorasib decreases over time following 960 mg QD dosing regimen until steady state is reached. Steady state plasma concentrations were achieved by approximately 3 weeks across the phase 1 and phase 2 clinical studies across all sotorasib doses.

Pharmacokinetics in special populations

Initial results of a population PK analysis suggests no clinically meaningful differences in the pharmacokinetics of sotorasib based on age, sex, race or ethnicity, body weight, line of therapy, ECOG PS, serum albumin, mild renal impairment (CrCL ≥ 60 mL/min), or mild hepatic impairment (AST or ALT < 2.5 × ULN or total bilirubin < 1.5 × ULN). The effect of moderate to severe renal or hepatic impairment on sotorasib pharmacokinetics has not been studied.