Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Amgen Europe B.V., Minervum 7061, 4817 ZK Breda, The Netherlands
Pharmacotherapeutic group: Antineoplastic agents
ATC code: L01XX73
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.
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 G12Cmutated 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 1.1 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
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).
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.
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.
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.
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.
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.
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.
Sotorasib exhibited nonlinear pharmacokinetics over a range of single and multiple oral administration doses studied between 180 to 960 mg QD as Cmax and AUC0-24hour were less than dose proportional. The average Cmax and AUC0-24hour 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.
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.
Sotorasib was not mutagenic in a bacterial mutagenicity (Ames) assay. Sotorasib was not genotoxic in the in vivo rat micronucleus and comet assays.
Carcinogenicity studies have not been performed with sotorasib.
In rat and rabbit embryo-foetal development studies, oral sotorasib was not teratogenic.
In the rat, there were no effects on embryo-foetal development up to the highest dose tested (3.9 times higher than the exposure at the maximum recommended human dose [MRHD] of 960 mg based on area under the curve [AUC]).
In the rabbit, lower foetal body weights and a reduction in the number of ossified metacarpals in foetuses were observed only at the highest dose level tested (2.2 times higher than the exposure at the MRHD of 960 mg based on AUC), which was associated with maternal effects such as decreased body weight gain and food consumption during the dosing phase. Reduced ossification, as evidence of growth retardation associated with reduced foetal body weight, was interpreted as a non-specific effect in the presence of significant maternal toxicity.
Fertility/early embryonic development studies were not conducted with sotorasib. There were no adverse effects on male or female reproductive organs in general toxicology studies conducted in dogs and rats.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:
Environmental risk assessment studies have shown that sotorasib has the potential to be very persistent to the environment (see section 6.6). There is no potential for bioaccumulation or toxicity.
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