LUMYKRAS 240 mg film-coated tablets

LUMYKRAS is indicated as monotherapy for the treatment of adult patients with KRAS G12C‑mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), who have progressed on, or are intolerant to, platinum-based chemotherapy and/or anti PD-1/PD-L1 immunotherapy.

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 of LUMYKRAS is 960 mg (four 240 mg tablets) orally once daily, at the same time each day, with or without food.

Duration of treatment

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

Missed doses

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. Additional doses should not be taken in place of a missed dose.

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. Dose reduction levels are summarised in Table 1. Dose modifications for adverse reactions are provided in Table 2.

If toxicity events occur, a maximum of two dose reductions are permitted. LUMYKRAS must be discontinued if patients are unable to tolerate the minimum dose of 240 mg once daily.

Table 1. Recommended sotorasib dose reduction levels

Table 2. Recommended dose modifications for sotorasib

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

Special populations

Elderly

In clinical studies, no overall differences in safety or efficacy were observed between elderly patients (≥ 65 years old) and younger patients. No dose adjustment is recommended in elderly patients (see section 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment (see section 5.2). Dose adjustment should be considered in patients with severe hepatic impairment (Child-Pugh C). There are no data on the clinical safety and efficacy of multiple doses of LUMYKRAS when administered to patients with severe hepatic impairment (Child-Pugh C). LUMYKRAS should be used with caution in patients with severe hepatic impairment.

Renal impairment

Based on population pharmacokinetic analysis, 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) (see section 5.2).

Paediatric population

The safety and efficacy of LUMYKRAS in children and adolescents aged less than 18 years have not been established. No data are available.

Method of administration

LUMYKRAS is for oral use. The tablets should normally be swallowed whole, unless the patient has difficulty swallowing solids, in which case the following instruction should be followed.

Administration to patients who have difficulty swallowing solids

Patients should disperse tablets in 120 mL of non-carbonated, room-temperature water without crushing. Other liquids must not be used. Patients should stir until the tablets are dispersed into small pieces (the tablet will not completely dissolve) 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 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.

Hepatotoxicity

LUMYKRAS can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis. Sotorasib has been associated with transient elevations of serum transaminases (ALT and AST), alkaline phosphatase, and total bilirubin in NSCLC 960 mg monotherapy clinical trials (CodeBreaK 100, CodeBreaK 101, CodeBreaK 105, CodeBreaK 200) (see section 4.8). In a total of 549 patients who received LUMYKRAS 960 mg NSCLC monotherapy, the incidence of hepatotoxicity is highest in the sub-group of patients with recent (≤ 3 months) immunotherapy (40%) prior to starting LUMYKRAS, as compared with those who started LUMYKRAS either more than 3 months after the last dose of immunotherapy (18%) or those who never received immunotherapy (17%). Regardless of time from prior immunotherapy, 90% of ALT/AST elevations improved or resolved following interruption of LUMYKRAS treatment and/or treatment with corticosteroids, where reported. 11%, 2% and 0% of patients with prior immunotherapy within ≤ 3 months, with prior immunotherapy within > 3 months and no prior immunotherapy respectively, discontinued treatment due to elevated liver enzymes. Cases of liver enzyme increase can be asymptomatic. Liver function tests (ALT, AST, alkaline phosphatase and total bilirubin) must be monitored 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. Based on the severity of the laboratory abnormalities, interrupt treatment with LUMYKRAS until recovered to ≤ 3 × ULN or to ≤ 3 × baseline (if baseline abnormal) and consider treatment with corticosteroids, and either modify the dose or permanently discontinue as recommended (see section 4.2).

Interstitial Lung Disease (ILD)/Pneumonitis

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)

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Effects of other medicinal products on sotorasib

Acid-reducing agents

Co-administration of sotorasib with a PPI (e.g omeprazole) or an H2 receptor antagonist (e.g 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 C_max by 65% and 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 C_max 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 C_max 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 C_max 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.

Strong CYP3A4 inducers

Co‑administration of sotorasib with multiple doses of a strong CYP3A4 inducer (e.g rifampicin) decreased sotorasib C_max by 35% and AUC by 51%. Co-administration of strong CYP3A4 inducers with LUMYKRAS is not recommended because the impact on sotorasib efficacy is unknown.

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 C_max by 48% and AUC by 53%.

Avoid co-administration of LUMYKRAS with CYP3A4 substrates with narrow therapeutic indices. If co‑administration cannot be avoided, adjust the CYP3A4 substrate dosage in accordance with the current summary of product characteristics.

Transporter systems

P-glycoprotein (P-gp) Substrates

Co-administration of sotorasib with digoxin (a P-gp substrate) increased digoxin Cmax by 91% and AUC by 21%.

Avoid co-administration of LUMYKRAS with P-gp substrates, for which minimal concentration changes may lead to serious toxicities. If co-administration cannot be avoided, decrease the P-gp substrate dosage in accordance with its Prescribing Information.

Breast Cancer Resistance Protein (BCRP) substrates

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

Co-administration of sotorasib with rosuvastatin (a BCRP substrate) increased rosuvastatin C_max by 70% and AUC by 34%.

When co-administered with LUMYKRAS, monitor for adverse reactions of the BCRP substrate and decrease the BCRP substrate dosage in accordance with the current summary of product characteristics.

Pregnancy

There are no data from the use of sotorasib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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 newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from LUMYKRAS therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

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.

Summary of the safety profile

The safety of LUMYKRAS was evaluated in 740 patients with KRAS G12C‑mutated solid tumours who received 960 mg orally once daily as monotherapy (CodeBreaK 100, CodeBreaK 101, CodeBreaK 105, CodeBreaK 200). The median duration of exposure to LUMYKRAS was 4.2 months (range: 0 to 41).

The most common adverse reactions were diarrhoea (36.6%), musculoskeletal pain (30.1%), nausea (24.7%), fatigue (19.1%), abdominal pain (18.2%), hepatotoxicity (18%), vomiting (16.1%), cough (16.5%). The most common severe (grade ≥ 3) adverse reactions were diarrhoea (6.9%), increased ALT (5.9%), increased AST (4.6%). The most common adverse reactions leading to permanent discontinuation of treatment were increased ALT (1.5%), increased AST (1.1%) and drug-induced liver injury (0.9%). 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 (1.9%). The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased haemoglobin, increased AST, decreased calcium, decreased albumin, increased urine protein, increased ALT, increased alkaline phosphatase, and decreased sodium.

Tabulated list of adverse reactions

Adverse reactions reported in LUMYKRAS clinical studies are displayed in Table 3 below. Frequency is provided by MedDRA category: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 10,000). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

Table 3. Adverse reactions

^a Cough includes cough, productive cough, and upper-airway cough syndrome.

^b Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower

^c Hepatotoxicity includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatitis, hepatotoxicity, liver function test increased, and transaminases increased.

^dMusculoskeletal pain includes arthralgia, myalgia and back pain

Description of selected adverse reactions

Hepatotoxicity

Among 740 patients who received LUMYKRAS 960 mg orally once daily as monotherapy (CodeBreaK 100, CodeBreaK 101, CodeBreaK 105, CodeBreaK 200), a total of 15% of patients who received LUMYKRAS had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 6.9% were Grade ≥3 and 0.4% were Grade ≥4. The median time to first onset of increased ALT/AST was 6.3 weeks (range: 0.4 to 103). Increased ALT/AST leading to dose interruption or reduction occurred in 7.4% of patients. LUMYKRAS was discontinued due to increased ALT/AST in 2.0% of patients. Among patients with hepatotoxicity, 43% received corticosteroids. Elevated bilirubin occurred in 3.2% of patients and resulted in dose interruption and/or reduction in 0.9% of patients.

Interstitial Lung Disease (ILD)/Pneumonitis

Among 740 patients who received LUMYKRAS 960 mg orally once daily as monotherapy (CodeBreaK 100, CodeBreaK 101, CodeBreaK 105, CodeBreaK 200), ILD/pneumonitis occurred in 1.8% of patients; 0.8% were Grade ≥3 and 1 case was fatal. 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: 2.1 to 43.3 weeks). LUMYKRAS was discontinued due to ILD/pneumonitis in 0.9% of patients.

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no clinical experience with overdose with sotorasib. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.

Pharmacotherapeutic group: Antineoplastic agents, ATC code: L01XX73

Mechanism of action

Sotorasib is a potent and highly 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 across multiple cancer types. The potency and selectivity of sotorasib is enhanced through the unique binding to both the P2 pocket and the His95 surface groove, locking the protein in an inactive state that prevents downstream signalling, without affecting wild-type KRAS.

Sotorasib demonstrated in vitro and in vivo inhibition of KRAS^G12C with minimal detectable off-target activity against other cellular proteins and processes. Sotorasib impaired oncogenic signalling and tumour cell survival at clinically relevant exposures in numerous pre-clinical models expressing KRAS^G12C. Sotorasib also enhanced antigen presentation and inflammatory cytokine production only in tumour cells with KRAS^G12C. Sotorasib induced anti-tumour inflammatory responses and immunity, driving permanent and complete tumour regressions in immunocompetent mice implanted with KRAS^G12C expressing tumours.

Clinical efficacy and safety

LUMYKRAS for the treatment of previously treated KRAS G12C-mutated NSCLC (CodeBreaK 100 Phase 2 Part A)

The efficacy of LUMYKRAS was demonstrated 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, 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 performed in a central laboratory.

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 measures were objective response rate (ORR) and duration of response (DOR) as evaluated by a BICR according to RECIST v1.1. Additional efficacy outcome measures included disease control rate (DCR), 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. The ORR was 37% (95% CI: 29, 47). The patients with objective responses had DOR ranging from 1.2 to 11.1 months, and 43% were still on therapy with ongoing response after a median duration of follow-up of 9.6 months. The median TTR was 1.4 months (range: 1.2 to 10.1), with 70% of responses occurring within the first 7 weeks.

Table 4. Efficacy results in CodeBreaK 100 for patients with KRAS G12C-mutated NSCLC (CodeBreaK 100 Phase 2 Part A)

CI = confidence interval; DCR = disease control rate; DOR = duration of response; NE = not estimable; ORR = objective response rate; OS = overall survival; PFS = progression-free survival

^a Response-related efficacy outcome

^b Estimated using Kaplan-Meier method

Cardiac electrophysiology

The effect of sotorasib on the QT interval was assessed in 156 patients administered sotorasib 960 mg once daily in clinical studies. Sotorasib did not prolong the QT interval to any clinically relevant extent. At peak concentrations, the mean change from baseline was less than 5 msec. No patients had a large mean increase in QTc (> 20 msec) in the study.

Paediatric population

The Medicines and Healthcare products Regulatory 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 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 Medicines and Healthcare products Regulatory Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

The pharmacokinetics of sotorasib have been characterised in patients with KRAS G12C-mutated solid tumours, including NSCLC, and healthy subjects.

Absorption

Following an oral, single-dose administration, sotorasib was absorbed with median time to achieve peak concentration of 1-2 hours.

Effect of food

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

Distribution

The mean volume of distribution at steady state of sotorasib was 211 L. In vitro, plasma protein binding of sotorasib was 89%.

Biotransformation

The main metabolic pathways of sotorasib were conjugation and oxidative metabolism.

Elimination

At 960 mg once daily, the steady state apparent clearance is 26.2 L/hr. The mean half-life is 5 hours. Steady state was reached within 22 days and remained stable. No accumulation with multiple dosing was observed. Sotorasib is primarily eliminated in faeces, with approximately 74% of the dose recovered in faeces and 6% (1% unchanged) recovered in urine.

Pharmacokinetics in special populations

No clinically meaningful differences in the pharmacokinetics of sotorasib were observed based on age, sex, race or ethnicity, body weight, line of therapy, ECOG PS or mild renal impairment (CrCL: ≥ 60 mL/min). The effect of moderate to severe renal impairment on sotorasib pharmacokinetics has not been studied

Hepatic Impairment

Compared to subjects with normal liver function, AUC_inf of sotorasib was decreased by 25.4% in subjects with moderate impairment and increased by 3.6% in subjects with severe impairment. The unbound AUC_inf of sotorasib increased by 1.8-fold in subjects with moderate hepatic impairment and by 6.3-fold in subject with severe hepatic impairment.

Mutagenicity

Sotorasib was not mutagenic in a bacterial mutagenicity (Ames) assay. Sotorasib was not genotoxic in the in vivo rat micronucleus and comet assays.

Carcinogenicity

Carcinogenicity studies have not been performed with sotorasib.

Reproductive toxicity

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.

Impairment of fertility

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.

General toxicology

In rats, renal toxicity including minimal to marked histologic tubular degeneration/necrosis and increased kidney weight, urea nitrogen, creatinine, and urinary biomarkers of renal tubular injury were present at doses resulting in exposures approximately ≥ 0.5 times the human AUC at the clinical dose of 960 mg. Increases in cysteine S-conjugate β-lyase pathway metabolism in the rat kidney compared to human may make rats more susceptible to renal toxicity than humans due to local formation of a putative sulphur-containing metabolite..

In the 3-month toxicology study in dogs, sotorasib induced findings in the liver (centrilobular hepatocellular hypertrophy), pituitary gland (hypertrophy of basophils), and thyroid gland (marked follicular cell atrophy, moderate to marked colloid depletion, and follicular cell hypertrophy) at exposures approximately 0.4 times the human exposure based on AUC at the clinical dose of 960 mg. These findings may be due to an adaptive response to hepatocellular enzyme induction and subsequent reduced thyroid hormone levels (i.e. secondary hypothyroidism).

Environmental risk assessment

Environmental risk assessment studies have shown that sotorasib has the potential to be persistent in the environment (see section 6.6). There is no potential for bioaccumulation or toxicity.

Tablet core

Microcrystalline cellulose

Lactose monohydrate

Croscarmellose sodium

Magnesium stearate

Film-coating

Polyvinyl alcohol

Titanium dioxide

Polyethylene glycol

Talc

Iron oxide yellow

None

3 years

This medicinal product does not require any special storage conditions.

LUMYKRAS 240 mg film-coated tablets

PVC/Aclar perforated unit dose blisters with aluminium foil backing containing 8 film-coated tablets. Pack size of 120 film-coated tablets (1 carton with 15 blisters).

Not all pack sizes may be marketed.

This medicinal product may pose a risk to the environment (see section 5.3). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.