4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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

Dose reduction level

Dose

Starting dose

960 mg (four 240 mg tablets) once daily

First dose reduction

480 mg (two 240 mg tablets) once daily

Second dose reduction

240 mg (one 240 mg tablet) once daily

Table 2. Recommended dose modifications for sotorasib

Adverse reaction

Severitya

Dose modification

Hepatotoxicity

Grade 2 AST or ALT with symptoms

or

Grade ≥ 3 AST or ALT

• Stop treatment until recovered to ≤ grade 1 or to baseline grade

• After recovery, resume treatment at the next dose reduction level

AST or ALT > 3 × ULN with total bilirubin > 2 × ULN, in the absence of alternative causes

• Permanently discontinue treatment

Interstitial Lung Disease/(ILD)/pneumonitis

Any Grade

• Stop treatment if ILD/pneumonitis is suspected

• Permanently discontinue if ILD/pneumonitis is confirmed

Nausea or vomiting despite appropriate supportive care (including anti-emetic therapy)

Grade 3 to 4

• Stop treatment until recovered to ≤ grade 1 or to baseline grade

• After recovery, resume treatment at the next dose reduction level

Diarrhoea despite appropriate supportive care (including anti-diarrhoeal therapy)

Grade 3 to 4

• Stop treatment until recovered to ≤ grade 1 or to baseline grade

• After recovery, resume treatment at the next dose reduction level

Other adverse reactions

Grade 3 to 4

• 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

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.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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) (see section 4.8). These elevations improved or resolved with dose modification or permanent discontinuation of treatment and did not result in any cases of liver failure or fatal cases in clinical studies. Cases of liver enzyme increase can be asymptomatic. Liver function tests (ALT, AST, 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 who develop transaminase and/or bilirubin elevations. Based on the severity of the laboratory abnormalities, treatment with LUMYKRAS must be stopped until recovered to ≤ grade 1 or to baseline grade, and the dose must either be modified or permanently discontinue treatment 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). 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 potential 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'.

4.5. Interaction with other medicinal products and other forms of interaction

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 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.

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 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 Cmax 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

Coadministration of LUMYKRAS with digoxin (a P-gp substrate) increased digoxin Cmax by 91% and AUC by 21%.

Avoid coadministration of LUMYKRAS with P-gp substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration 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 Cmax 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.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The safety of LUMYKRAS was evaluated in 359 patients with KRAS G12C‑mutated solid tumours who received 960 mg orally once daily as monotherapy. The median duration of exposure to LUMYKRAS was 4.1 months (range: 0.02 to 21).

The most common adverse reactions were diarrhoea (34%), musculoskeletal pain (31%), nausea (25%), fatigue (21%), hepatotoxicity (19%) and cough (16%). The most common severe (grade ≥ 3) adverse reactions were increased ALT (5%), increased AST (4%), and diarrhoea (4%). The most common adverse reactions leading to permanent discontinuation of treatment were increased ALT (1%), increased AST (1%) and drug-induced liver injury (1%). The most common adverse reactions leading to dose modification were increased ALT (6%), increased AST (6%), and diarrhoea (6%).

The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased haemoglobin, increased AST, decreased calcium, 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

MedDRA system organ class

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Blood and lymphatic system disorders

Anaemia

Nervous system disorders

Headache

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Cougha

Cardiovascular disorders

Hypertension

Gastrointestinal disorders

Diarrhoea

Nausea

Vomiting

Abdominal painb

Constipation

Hepatobiliary Disorders

Hepatotoxicityc

Musculoskeletal and connective tissue disorders

Musculoskeletal paind

General disorders and administration site conditions

Fatigue

Pyrexia

Peripheral oedema

Metabolism and nutrition disorders

Decreased appetite

Hypokalaemia

Hyponatraemia

Hypocalcaemia

Infections

Pneumonia

Urinary tract infection

Skin and subcutaneous tissue disorders

Rash

Investigations

Blood alkaline phosphatase increased

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

Hepatotoxicty

Among 359 patients who received LUMYKRAS in CodeBreaK 100, a total of 17% of patients who received LUMYKRAS had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 6% were Grade 3 and 0.6% were Grade 4. The median time to first onset of increased ALT/AST was 8 weeks (range: 0.3 to 42). Increased ALT/AST leading to dose interruption or reduction occurred in 7% of patients. LUMYKRAS was discontinued due to increased ALT/AST in 1.7% of patients. In addition to dose interruption or reduction, 5% of patients received corticosteroids for the treatment of hepatotoxicity.

Interstitial Lung Disease (ILD)/Pneumonitis

Among 359 patients who received LUMYKRAS in CodeBreaK 100, ILD/pneumonitis occurred in 0.8% of patients, all cases were Grade 3 or 4 at onset. The median time to first onset for ILD/pneumonitis was 2 weeks (range: 2 to 18 weeks). LUMYKRAS was discontinued due to ILD/pneumonitis in 0.6% 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 SchemeWebsite: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.