sotorasib: prescribing information – dosing, contraindications, interactions, side effects

LUMYKRAS as monotherapy is indicated for the treatment of adults with advanced non-small cell lung cancer (NSCLC) with KRAS G12C-mutation and who have progressed after at least one prior line of systemic therapy.

Treatment with LUMYKRAS must be initiated by a physician experienced in the use of anticancer medicinal products.

The presence of a KRAS G12C-mutation must be confirmed using a validated test prior to initiation of LUMYKRAS therapy.

Posology

The recommended dose is 960 mg sotorasib (eight 120 mg tablets or four 240 mg tablets) once daily, at the same time each day.

Duration of treatment
Treatment with LUMYKRAS is recommended until disease progression or unacceptable toxicity.

Missed doses or vomiting
If less than 6 hours have passed since the scheduled time of dosing, the patient should take the dose as normal. If more than 6 hours have passed since the scheduled time of dosing, the patient must not take the dose. Treatment should be continued as prescribed the next day.

If vomiting occurs after taking LUMYKRAS, the patient must not take an additional dose on the same day, and treatment must be continued as prescribed the next day.

Dose modifications
Dosing should be modified based on LUMYKRAS toxicity. The dose reduction rules outlined in section 4.2 are based on clinical data. Pharmacokinetic (PK) data do suggest a similar exposure at lower sotorasib doses (see section 5.2). Dose reduction levels are summarised in table 1. Dose modifications for adverse reactions are provided in table 2.

A maximum of two dose reductions are recommended for management of an adverse reaction (see table 1). Discontinue LUMYKRAS if an adverse reaction cannot be managed after two dose reductions and patients are unable to tolerate the minimum dose of 240 mg once daily.

Table 1. Recommended sotorasib dose reduction levels

Dose reduction level
Dose
Starting dose
960 mg (eight 120 mg tablets or four 240 mg tablets) once daily
First dose reduction
480 mg (four 120 mg tablets or two 240 mg tablets) once daily
Second dose reduction
240 mg (two 120 mg tablets or one 240 mg tablet) once daily

Table 2. Recommended dose modifications for sotorasib

Adverse reaction
Severitya
Dose modification
Hepatotoxicity
AST or ALT > 3 × and up to
5 × ULN (or > 3 × and up to
5 × baseline if baseline abnormal) with symptoms

or

AST or ALT > 5 × ULN (or
> 5 × baseline if baseline abnormal), in the absence of alternative causes
- Withhold treatment
- Closely monitor liver function until recovered to
≤ 3 × ULN or to
≤ 3 × baseline if baseline abnormal
- After recovery, resume treatment at the next dose reduction level
- Consider initiation of corticosteroids
AST or ALT > 3 × ULN with total bilirubin > 2 × ULN

or

AST or ALT > 3 × ULN and
INR > 1.5 × ULN (for subjects not on anticoagulation therapy), in the absence of alternative causes
- Permanently discontinue treatment if no alternative cause is identified
- If alternative cause is identified, do not resume treatment until
AST/ALT/bilirubin return to baseline

Interstitial lung disease
(ILD)/pneumonitis
Any grade
- Stop treatment if
ILD/pneumonitis is suspected
- Permanently discontinue treatment if ILD/pneumonitis is confirmed and no other cause is identified Nausea, vomiting, or diarrhoea persisting despite supportive care (including anti-emetic or anti-diarrhoeal therapy) Grade ≥ 3
- Stop treatment until recovered to ≤ grade 1 or to baseline grade
- After recovery, resume treatment at the next dose reduction level
Other medicinal product-related toxicity
Grade ≥ 3
- Stop treatment until recovered to ≤ grade 1 or to baseline grade
- After recovery, resume treatment at the next dose reduction level
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal a Grading defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0; INR = International Normalised Ratio

Special populations

Elderly
The limited data on the safety and efficacy of LUMYKRAS in patients aged 75 years and older do not suggest that a dose adjustment is required in elderly patients (see sections 4.8 and 5.2).

Hepatic impairment
No dose adjustment is recommended for patients with mild hepatic impairment.

LUMYKRAS is not recommended for use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment (see section 5.2).

Renal impairment
No dose adjustment is recommended for patients with mild renal impairment (creatine clearance, CrCL ≥ 60 mL/min). LUMYKRAS has not been studied in patients with moderate or severe renal impairment (CrCL < 60 mL/min). Therefore, caution should be exercised when treating patients with moderate, severe and end stage renal impairment (see section 5.2).

Paediatric population
There is no relevant use of LUMYKRAS in the paediatric population in the treatment of non-small cell lung cancer.

Method of administration

LUMYKRAS is for oral use. The tablets must be swallowed whole. There are no data to support the administration of LUMYKRAS if the tablets are chewed, crushed, or split but the tablets can be dispersed in water (see below). The tablets can be taken with or without food.

Administration to patients who have difficulty swallowing solids
Patients should disperse tablets in 120 mL of non-carbonated, room temperature water, without crushing them. Other liquids must not be used. Patients should stir until the tablets are dispersed into small pieces (the tablet will not dissolve completely) and drink it immediately. The appearance of the mixture may range from pale to bright yellow. The container must be rinsed with an additional 120 mL of water, which should be drunk immediately. If it is not drunk immediately, patients must stir again to ensure that the tablets are dispersed. The dispersion must be discarded if it is not drunk within 2 hours.

If administration through a nasogastric (NG) tube or percutaneous endoscopic gastrostomy (PEG) tube is required, follow the process above for the initial dispersion and for the residual rinse of the 120 mg or 240 mg tablets. The dispersed suspension and rinse should be administered as per the NG or PEG tube manufacturer’s instructions with appropriate water flushes. Administer the dispersion within 2 hours of preparation, stored at room temperature.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile

Adverse drug reactions (ADRs) described in table 3 reflect exposure to sotorasib 960 mg once daily as monotherapy in 740 patients with KRAS G12C-mutated solid tumours across multiple clinical studies, including CodeBreaK 200, CodeBreaK 100 phase 2 part A, and CodeBreaK 100 phase 2 part B (dose comparison sub-study) and three phase 1 studies.

The most common adverse reactions in patients treated with LUMYKRAS 960 mg once daily were diarrhoea (36.6%), nausea (24.7%), fatigue (19.1%), vomiting (16.1%), arthralgia (15.3%), and decreased appetite (15.1%). The most common severe (grade ≥ 3) adverse reactions were diarrhoea (6.9%), increased ALT (5.9%) and increased AST (4.6%). The most common adverse reactions leading to permanent discontinuation of treatment were increased ALT (1.5%) and increased AST (1.1%) and DILI (1%). The most common adverse reactions leading to dose modification were diarrhoea (11.4%), increased ALT (5.9%), increased AST (5.7%), nausea (3.8%), increased blood alkaline phosphatase (2.4%) and vomiting (2%).

Tabulated list of adverse reactions

Adverse reactions reported in LUMYKRAS clinical studies are displayed in table 3 below. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), and not known (cannot be estimated from available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

The safety of LUMYKRAS was evaluated in 740 patients with KRAS G12C-mutated solid tumours who received 960 mg orally once daily as monotherapy. The median duration of exposure to LUMYKRAS was 4.2 months (range: 0 to 41).

Table 3. Adverse reactions

MedDRA system organ class
Very common
(≥ 1/10)
Common
(≥ 1/100 to
< 1/10)
Uncommon
(≥ 1/1 000 to
< 1/100)
Blood and lymphatic system disorders
Anaemia

Nervous system disorders

Headache

Respiratory, thoracic and mediastinal disorders
Cough
Dyspnoea
ILD/pneumonitis

Gastrointestinal disorders
Diarrhoea
Nausea
Vomiting
Constipation
Abdominal paina

Hepatobiliary disorders

Drug-induced liver injury
Hepatitis
Renal and urinary disorders

Renal impairment
Renal failure
Chronic kidney disease
Acute kidney injury
Musculoskeletal and connective tissue disorders
Arthralgia
Back pain

General disorders and administration site conditions
Fatigue

Pyrexia

Investigations
Aspartate aminotransferase increased
Alanine aminotransferase increased

Blood alkaline phosphatase increased
Blood bilirubin increased
Gamma- glutamyltransfer ase increased

Metabolism and nutrition disorders
Decreased appetite
Hypokalaemia

a Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower

Description of selected adverse reactions

Elevated liver enzymes
In clinical studies, transient elevations of serum transaminases were observed (see section 4.4).
Among 740 patients who received LUMYKRAS 960 mg once daily as monotherapy, elevations of ALT occurred in 12.8% of patients and elevations of AST in 13.1% of patients, with a median time to onset of 6 weeks (range: 1 to 103) and 6 weeks (range: 0 to 42), respectively. Elevations of ALT resulted in dose interruption and/or reduction in 5.9% of patients, and elevations of AST resulted in dose interruption and/or reduction in 5.7% of patients. Elevated bilirubin occurred in 3.2% of patients and resulted in dose interruption and/or reduction in 0.9% of patients.

ILD/pneumonitis
In clinical studies, among 740 patients who received LUMYKRAS 960 mg once daily as monotherapy, ILD/pneumonitis occurred in 1.9% of patients; ILD/pneumonitis was grade 3 or 4 at onset on 0.8% of patients. A case of fatal ILD occurred in a patient with metastatic NSCLC stage IVB treated with LUMYKRAS in a clinical trial. The patient developed lower respiratory tract infection with a fatal outcome despite steroids and antibiotics treatment. The fatal ILD occurred in a setting of massive disease progression. The median time to first onset for ILD/pneumonitis was 10.6 weeks (range: 2 to 43.3 weeks). LUMYKRAS was discontinued due to ILD/pneumonitis in 0.9% of patients (see sections 4.2 and 4.4).

Elderly
In clinical studies, no overall differences in safety or efficacy were observed between elderly patients (≥ 65 years old) and younger patients (see sections 4.2 and 5.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Hepatotoxicity

Sotorasib can cause hepatotoxicity, which may lead to drug-induced liver injury (DILI) and hepatitis.
Sotorasib has been associated with transient elevations of serum transaminases (ALT and AST), alkaline phosphatase and total bilirubin in 960 mg monotherapy clinical trials. In a total of 740 patients with KRAS G12C-mutated solid tumours who received LUMYKRAS 960 mg monotherapy daily, the incidence for hepatotoxicity is highest in the sub-group of patients with recent (≤ 3 months) immunotherapy (38%) prior to starting LUMYKRAS, as compared to those who started LUMYKRAS either more than 3 months after last dose of immunotherapy (17%) or those who never received immunotherapy (22%). Regardless of time from prior immunotherapy, 87% of elevations improved or resolved with interruption of LUMYKRAS treatment and treatment with corticosteroids.
Elevated liver enzymes led to discontinuation of treatment in 10%, 2% and 0% of patients with prior immunotherapy within ≤ 3 months, with prior immunotherapy within > 3 months and no prior immunotherapy, respectively. Among 740 patients with KRAS G12C-mutated solid tumours who received 960 mg orally once daily, 26% experienced hepatotoxicity and 13% had hepatotoxicity leading to dose interruption and/or dose reduction. Overall, 41% of patients with hepatotoxicity

received concurrent corticosteroids. Cases of liver enzyme increase can be asymptomatic. Patients should be monitored for liver function (ALT, AST, alkaline phosphatase and total bilirubin) prior to the start of LUMYKRAS, every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients with recent immunotherapy and in patients with serious hepatotoxicity events. Based on the severity of the laboratory abnormalities, treatment with LUMYKRAS must be interrupted until recovered to ≤ 3 × ULN or to ≤ 3 baseline (if baseline abnormal) and treatment with corticosteroids considered, and the dose of LUMYKRAS must be either modified or permanently discontinued (see section 4.2).

Interstitial Lung Disease (ILD)/pneumonitis

LUMYKRAS can cause ILD/pneumonitis that can be fatal. ILD/pneumonitis occurred in patients treated with LUMYKRAS with prior exposure to immunotherapy or radiotherapy (see section 4.8).
Recent (≤ 3 months) immunotherapy prior to starting LUMYKRAS may be considered a risk factor for ILD/pneumonitis. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g. dyspnoea, cough, fever). Immediately withhold LUMYKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMYKRAS if no other causes of ILD/pneumonitis are identified (see section 4.2).

Use in population with hepatic impairment

There are no data on the clinical safety and efficacy of multiple doses of LUMYKRAS when administered to patients with moderate and severe hepatic impairment (Child-Pugh B and C). No dose recommendation can be made.

Lactose intolerance

LUMYKRAS contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

In vitro studies indicate that sotorasib is metabolised by cytochrome P450 (CYP) 2C8, CYP3A4, and CYP3A5, and is a substrate of P-glycoprotein (P-gp). Sotorasib was an inducer of CYP3A4, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 in vitro. Sotorasib is an in vitro inhibitor of CYP2C8, CYP2D6, and CYP3A. In vitro studies indicate that sotorasib is an inhibitor of human organic anion transporter (OAT)1/3, OATP1B1, breast cancer resistance protein (BCRP) and P-gp.

Effects of other medicinal products on sotorasib

Acid-reducing agents
Co-administration of sotorasib with a PPI (omeprazole) or an H2 receptor antagonist (famotidine) led to a decrease in sotorasib concentrations.

Under fed conditions (standard-calorie moderate-fat meals), co-administration of multiple doses of omeprazole with a single dose of 960 mg sotorasib decreased sotorasib Cmax by 65% and area under the curve (AUC) by 57%. Co-administration of a single dose of famotidine given 10 hours prior and 2 hours after a single dose of 960 mg sotorasib decreased sotorasib Cmax by 35% and AUC by 38%.

Under fasted conditions, co-administration of multiple doses of omeprazole with a single dose of 960 mg sotorasib decreased sotorasib Cmax by 57% and AUC by 42%. Under fasted conditions, co-administration of repeat doses of omeprazole with a single dose of 960 mg sotorasib and 240 mL of

an acidic beverage (non-diet cola) decreased sotorasib Cmax by 32% and AUC by 23%. The clinical relevance of the decreased sotorasib exposure when co-administered with omeprazole and cola is unclear and efficacy might be reduced.

If co-administration of LUMYKRAS with an acid-reducing agent (such as a PPI or an H2 receptor antagonist) is required, LUMYKRAS should be taken with an acidic beverage (such as cola).
Alternatively, LUMYKRAS should be taken 4 hours before or 10 hours after administration of a local antacid.

CYP3A4 inhibitors
Co-administration of multiple dose itraconazole (a strong CYP3A4 and P-gp inhibitor) did not increase sotorasib exposures to a clinically significant extent. No dose adjustment of LUMYKRAS is recommended when co-administered with CYP3A4 inhibitors.

Strong CYP3A4 inducers
Co-administration of sotorasib with multiple doses of a strong CYP3A4 inducer (rifampicin) decreased sotorasib Cmax by 35% and AUC by 51%. Co-administration of strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John’s wort) with LUMYKRAS is not recommended because they may decrease sotorasib exposure.

Effect of sotorasib on other medicinal products

CYP3A4 substrates
Sotorasib is a moderate CYP3A4 inducer. Co-administration of sotorasib with CYP3A4 substrates led to a decrease in their plasma concentrations, which may reduce the efficacy of these substrates.

Co-administration of sotorasib with midazolam (a sensitive CYP3A4 substrate) decreased midazolam Cmax by 48% and AUC by 53%.

Avoid co-administration of LUMYKRAS with CYP3A4 substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus, tacrolimus, amlodipine and manidipine. If co-administration cannot be avoided, adjust the CYP3A4 substrate dose in accordance with the current summary of product characteristics.

CYP2B6, CYP2C8, CYP2C9 and CYP2C19 substrates
In vitro data indicated that sotorasib may have the potential to induce CYP2B6, CYP2C8, CYP2C9 and CYP2C19; the clinical relevance of these findings is unknown. When sotorasib is co-administered with medicinal products metabolised by these enzymes, appropriate monitoring is recommended.

CYP2D6 substrates
In vitro data indicated that sotorasib may have the potential to inhibit CYP2D6, the clinical relevance of these findings is unknown. When LUMYKRAS is co-administered with CYP2D6 substrates (e.g. flecainide, propafenone, metoprolol), appropriate monitoring is recommended.

BCRP substrates
LUMYKRAS is a weak BCRP inhibitor. Co-administration of LUMYKRAS with a BCRP substrate led to an increase in the plasma concentrations of the BCRP substrate, which may increase the effect of the substrate.

Co-administration of LUMYKRAS with rosuvastatin (a BCRP substrate) increased the rosuvastatin Cmax by 70% and AUC by 34%.

When LUMYKRAS is co-administered with a BCRP substrate, including but not limited to lapatinib, methotrexate, mitoxantrone, rosuvastatin and topotecan, monitor for adverse reactions of the BCRP substrate and reduce the BCRP substrate dose in accordance with its current summary of product characteristics.

Effect of sotorasib on P-gp substrates
Co-administration of sotorasib with digoxin (a P-glycoprotein [P-gp] substrate) increased digoxin Cmax by 1.9-fold and AUCinf by 1.2-fold of digoxin administered alone. Co-administration of LUMYKRAS with P-gp substrates with narrow therapeutic indices is not recommended. If co-administration cannot be avoided, adjust the P-gp substrate dosage in accordance with the current summary of product characteristics.

Women of childbearing potential/Contraception

Women of childbearing potential must be advised to avoid pregnancy while on LUMYKRAS. Female patients of childbearing potential receiving LUMYKRAS must use highly effective contraceptive methods during treatment and for at least 7 days following the last dose of LUMYKRAS.
LUMYKRAS may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method.

Pregnancy

There are no data from the use of sotorasib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). LUMYKRAS is not recommended during pregnancy and in women of childbearing potential not using contraception. Patients must be informed of the potential hazards to the foetus if LUMYKRAS is used during pregnancy, or if the patient becomes pregnant while taking LUMYKRAS.

Breast-feeding

It is unknown if sotorasib or its metabolites are excreted in human milk. A risk to breast-fed newborns/infants cannot be excluded. LUMYKRAS should not be used during breast-feeding.

Fertility

There are no clinical studies to evaluate the effect of sotorasib on fertility.

LUMYKRAS has no or negligible influence on the ability to drive and use machines.

In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. There is no specific antidote for overdose with LUMYKRAS.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, ATC code: L01XX73

Mechanism of action

Sotorasib is a selective KRAS G12C (Kirsten rat sarcoma viral oncogene homologue) 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 phase 2 part A
The efficacy of LUMYKRAS was studied in a single-arm, open-label, multicentre trial (CodeBreaK 100 phase 2 part A) 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.

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 1-2 hours.

In a dose comparison sub-study (CodeBreaK 100 phase 2 part B) in patients receiving sotorasib 240 mg or 960 mg once daily, after 8 daily doses, Cmax and AUC0-24 hour for 240 mg were both 22% lower than 960 mg.

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 vivo, plasma protein binding of sotorasib was 97.6% 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