Adagrasib

Adagrasib is a selective, irreversible inhibitor of KRAS G12C, a mutant form of the KRAS protein in which glycine at position 12 is replaced by cysteine. The mutation keeps KRAS locked in its active, GTP-bound form and drives uncontrolled cell growth. Adagrasib is selective for this mutant protein and switches it off.

Mechanism of Action

• Normal KRAS: KRAS works as an on/off switch for cell growth. Binding guanosine triphosphate (GTP) turns it on and activates the MAP kinase pathway; hydrolysis of GTP to guanosine diphosphate (GDP) turns it off.
• KRAS G12C mutation: the glycine-to-cysteine change impairs GTP hydrolysis, so KRAS stays active and keeps signalling, which leads to uncontrolled proliferation and malignant transformation.
• Covalent inhibition: adagrasib binds covalently to the mutant cysteine and locks KRAS G12C in its inactive, GDP-bound conformation, which prevents KRAS-dependent downstream signalling.
• Antitumour effect: it inhibits the growth and viability of tumour cells carrying KRAS G12C and caused regression in KRAS G12C-positive nonclinical tumour models, with minimal off-target activity.
• Cardiac electrophysiology: adagrasib prolongs the QTc interval in a concentration-dependent way. At the mean steady-state maximum concentration with 600 mg twice daily, the mean QTcF change from baseline was about 18 ms (17.93 ms; 90% confidence interval 15.13 to 20.73 ms).

Pharmacokinetics

• Absorption: median time to peak concentration about 6 hours; the absolute oral bioavailability is not known. AUC and Cmax rise in proportion to dose between 400 and 600 mg. At 600 mg twice daily, steady state is reached within 8 days, with about 6-fold accumulation compared with a single dose. A high-fat, high-calorie meal has no clinically significant effect.
• Distribution: plasma protein binding about 99%; apparent volume of distribution about 942 L in healthy subjects.
• Metabolism: mainly by CYP3A4, which adagrasib also inhibits, including its own metabolism. At steady state, other enzymes (CYP2C8, CYP1A2, CYP2B6, CYP2C9 and CYP2D6) contribute to its metabolism.
• Elimination: at steady state in patients, terminal half-life about 29 hours and apparent oral clearance about 25.8 L/h (population analysis). After a single radiolabelled oral dose, about 75% was recovered in faeces (14% as unchanged drug) and 4.5% in urine (2% unchanged).
• Special populations: no clinically meaningful differences in pharmacokinetics were seen with age (19 to 89 years), sex, race, body weight (36 to 139 kg), ECOG performance status (0 or 1) or tumour burden. None are expected in mild to severe renal impairment (creatinine clearance 15 to below 90 mL/min) or mild to severe hepatic impairment (Child-Pugh classes A to C).

Adagrasib is used on its own (monotherapy).

• Advanced non-small cell lung cancer (NSCLC) with a KRAS G12C mutation: adults whose disease has progressed after at least one prior systemic therapy. The KRAS G12C mutation must be confirmed with a validated test before treatment starts.

• Hypersensitivity to adagrasib or to any of the excipients.
• Concomitant use of CYP3A substrates with a narrow therapeutic index (adagrasib is a strong CYP3A4 inhibitor; see Drug Interactions).

The frequencies below come from 821 patients with KRAS G12C-positive solid tumours treated with adagrasib 600 mg twice daily (median duration 5.2 months) in pooled studies. They are all-cause event frequencies, so some events may have other causes such as the disease itself or other medicines. The most common reactions were diarrhoea (65.2%), nausea (59.9%), fatigue (54.3%), vomiting (50.3%), decreased appetite (32.9%), anaemia (32.4%), raised blood creatinine (31.7%), raised AST (29.0%), raised ALT (28.3%), peripheral oedema (23.0%), raised alkaline phosphatase (18.1%), dizziness (17.1%) and hyponatraemia (17.1%).

Very common (≥1/10): anaemia, hyponatraemia, decreased appetite, dizziness (including vertigo), QT prolongation on the electrocardiogram, diarrhoea, nausea, vomiting, raised lipase, raised amylase, hepatotoxicity (a grouped term that includes raised AST, ALT, alkaline phosphatase, GGT and bilirubin, drug-induced liver injury, hepatitis and hepatic failure), raised blood creatinine, fatigue (including asthenia), peripheral oedema.

Common (≥1/100 to <1/10): decreased lymphocyte count (including lymphocytopenia), pneumonitis.

No other reactions are listed in the SmPC frequency table.

The most common severe reactions (grade 3 or higher) were fatigue (9.0%), anaemia (7.2%), raised ALT (6.6%), raised lipase (4.8%), raised AST (4.6%), hyponatraemia (4.0%), decreased lymphocyte count (3.7%) and QT prolongation (3.4%). The most common serious reactions were vomiting (2.8%), acute kidney injury (2.2%), nausea (2.1%), diarrhoea (1.3%) and raised ALT (1.0%). Reactions that led to stopping treatment were pneumonitis, nausea, fatigue, raised ALT and raised AST (each below 1%). The most common reasons for dose reduction or interruption were nausea (14.7%), vomiting (13.4%), diarrhoea (13.3%), fatigue (10.2%), raised ALT (10.2%), raised AST (7.3%), raised blood creatinine (6.9%), anaemia (3.5%) and QT prolongation (3.4%).

Severe cutaneous adverse reactions (Stevens–Johnson syndrome, toxic epidermal necrolysis and DRESS), which can be life-threatening or fatal, have also been reported.

Adagrasib is metabolised mainly by CYP3A4, and it is itself a strong, time-dependent CYP3A4 inhibitor. In vitro it is also a reversible inhibitor of CYP2B6, CYP2C9 and CYP2D6, and it inhibits P-gp, BCRP, MATE-1/MATE-2K, OATP1B1 and OCT1. Interactions therefore run in both directions.

• Strong CYP3A inducers: rifampicin lowered adagrasib Cmax by 88% and AUC by 95%. Avoid.
• Strong CYP3A inhibitors: itraconazole raised adagrasib Cmax 2.4-fold and AUC 4-fold after a single 200 mg dose. Avoid.
• CYP3A substrates with a narrow therapeutic index: contraindicated, because raised levels are linked to serious or life-threatening events. The SmPC names alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, sirolimus, midazolam, triazolam, ticagrelor and tacrolimus. Oral midazolam exposure rose about 21-fold with adagrasib 400 mg twice daily, and about 31-fold is predicted at 600 mg twice daily.
• Other sensitive CYP3A substrates: avoid, unless the substrate’s own SmPC recommends otherwise.
• CYP2C9 substrates (inhibited in vitro): avoid sensitive substrates where small changes in concentration may lead to serious reactions, unless the substrate’s SmPC recommends otherwise.
• CYP2D6 substrates: dextromethorphan exposure rose 1.8-fold with adagrasib 400 mg twice daily, and 2.4-fold is predicted at 600 mg twice daily. Avoid sensitive CYP2D6 substrates where small changes in concentration may lead to serious reactions, unless the substrate’s SmPC recommends otherwise.
• P-gp substrates: a single 600 mg dose raised digoxin Cmax 1.1-fold and AUC 1.4-fold. Avoid P-gp substrates where small changes in concentration may lead to serious reactions, unless the substrate’s SmPC recommends otherwise.
• BCRP and OATP1B1 substrates: no clinically significant difference in rosuvastatin pharmacokinetics.
• QTc-prolonging medicines: the effect of combining them with adagrasib is unknown. Avoid them; if the combination cannot be avoided, periodic ECG monitoring is needed.
• Food: adagrasib can be taken with or without food. A high-fat, high-calorie meal has no clinically significant effect on its pharmacokinetics.

Treatment should be started by a physician experienced in the use of anti-cancer medicinal products. A KRAS G12C mutation must be confirmed with a validated test before the first dose. The tablets are swallowed whole with water, with or without food; taking them with food may improve tolerability.

Recommended Dose

• 600 mg (three 200 mg tablets) twice daily.
• Treatment continues until disease progression or unacceptable toxicity.

Dose Adjustments for Side Effects

• Dose levels: first reduction to 400 mg (two 200 mg tablets) twice daily; second reduction to 600 mg (three 200 mg tablets) once daily.
• General rule: severe (for example grade 3) or intolerable reactions require interruption until sufficient improvement, then dosing is resumed. Grading follows NCI CTCAE version 5.0.
• Nausea, vomiting or diarrhoea despite appropriate supportive care (grade 3 or 4): withhold until recovery to grade 1 or less, or to baseline, then resume at the next lower dose level.
• Hepatotoxicity: for grade 2 AST or ALT (3 to 5 times the upper limit of normal), reduce to the next lower dose level. For grade 3 or 4 (above 5 times the upper limit), withhold until recovery to grade 1 or less, or to baseline, then resume at the next lower dose level. For AST or ALT above 3 times the upper limit with total bilirubin above 2 times the upper limit and no alternative cause, stop permanently.
• QTc prolongation: for grade 3 (QTc 501 ms or more, or a rise of more than 60 ms from baseline), withhold until recovery to grade 1 or less, or to baseline, then resume at the next lower dose level. For grade 4 (ventricular arrhythmia), stop permanently.
• Other grade 3 or 4 reactions: withhold until recovery to grade 1 or less, or to baseline, then resume at the next lower dose level.

Patients Who Cannot Swallow Tablets

Patients who have difficulty swallowing solids may disperse the tablets, without crushing them, in 120 mL of non-carbonated, room-temperature water. No other liquid may be used. Stir until the tablets are dispersed and drink immediately. The mixture may look white with small pieces of tablet, which must not be chewed. Rinse the container with another 120 mL of water and drink that immediately.

Special Populations

• Elderly: no clinically relevant difference between patients older and younger than 65 years; data are limited in patients aged 75 or over. No dose adjustment.
• Hepatic impairment: no dose adjustment in mild, moderate or severe impairment (Child-Pugh classes A to C).
• Renal impairment: no dose adjustment in mild, moderate or severe impairment.
• Children and adolescents: safety and efficacy in children aged 0 to 18 years have not been established; no data are available.

Delayed, Missed or Vomited Dose

• If less than 4 hours have passed since the scheduled time, take the dose as normal.
• If a dose is more than 4 hours late, skip it and take the next dose at the scheduled time.
• If vomiting occurs after a dose, do not take an extra dose; take the next dose as prescribed.

Gastrointestinal Reactions

Diarrhoea, nausea and vomiting can occur. Patients are monitored and treated with supportive care, such as anti-diarrhoeals, antiemetics or fluid replacement. Depending on severity, the dose is reduced, or withheld until recovery to grade 1 or baseline and then resumed at a reduced dose.

Hepatotoxicity

Raised transaminases occurred in treated patients. Liver tests (AST, ALT, alkaline phosphatase and bilirubin) are checked before treatment, monthly for the first 3 months and as clinically indicated, and more often if transaminase or alkaline phosphatase levels rise. Depending on severity, the dose is reduced, withheld and resumed at a reduced dose, or stopped permanently.

QT Prolongation

• Monitoring: a baseline electrocardiogram (ECG) is recommended for all patients before treatment and again during treatment.
• Avoid where possible in patients with congenital long QT syndrome, concurrent QTc prolongation or a past episode of torsades de pointes.
• Extra checks: consider periodic ECGs and electrolyte checks in patients with congestive heart failure or electrolyte abnormalities, or who take medicines known to prolong the QTc interval, and avoid such medicines.
• If QTc prolongation occurs: after correcting any electrolyte disturbance, treatment can continue at a reduced dose, or be interrupted and resumed at a reduced dose. Stop permanently if QTc prolongation comes with signs or symptoms of life-threatening arrhythmia.

CYP3A Substrates

Adagrasib is a strong CYP3A4 inhibitor. Giving it with medicines that depend heavily on CYP3A for clearance, and whose raised levels are linked to serious or life-threatening events, is contraindicated (see Drug Interactions for the examples named in the SmPC).

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including Stevens–Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported and can be life-threatening or fatal. Patients should know the signs and symptoms and are monitored closely for skin reactions. If one is suspected, adagrasib is withheld and the patient is referred to a specialised unit. If Stevens–Johnson syndrome, toxic epidermal necrolysis or DRESS related to adagrasib is confirmed, treatment is stopped permanently.

Pregnancy, Breastfeeding and Fertility

• Contraception: use in women of childbearing potential who are not using contraception is not recommended. Female patients of childbearing potential must use an effective contraceptive method during treatment and for at least 5 days after the last dose.
• Pregnancy: there are no data on its use in pregnant women, and animal studies are insufficient with respect to reproductive toxicity. Adagrasib is not recommended during pregnancy.
• Breastfeeding: it is not known whether adagrasib or its metabolites pass into human milk. A risk to breast-fed newborns and infants cannot be excluded, and adagrasib should not be used during breastfeeding.
• Fertility: no clinical data are available on possible effects on fertility.

Effect on Driving

Adagrasib has a minor influence on the ability to drive and use machines. Dizziness (including vertigo) and fatigue may occur. Patients who are affected should not drive, use machines or take part in activities where this would put themselves or others at risk.

Krazati tablets do not require any special temperature storage conditions. Store them in the original package to protect them from moisture, and keep the bottle tightly closed. Each bottle contains two silica gel desiccant containers. Keep out of the sight and reach of children.

2 years. Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription. Treatment is started by a physician experienced in the use of anti-cancer medicinal products, after a validated test has confirmed the KRAS G12C mutation. Adagrasib is taken at home as tablets, so it is supplied to the patient or to the treating clinic on prescription.