Sotorasib

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 effect of the substrate.

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

When sotorasib 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.

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

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

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.

Co-administration of sotorasib with digoxin (a P-glycoprotein [P-gp] substrate) increased digoxin C_max by 1.9-fold and AUC_inf by 1.2-fold of digoxin administered alone. Co-administration of sotorasib 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.

Co-administration of sotorasib with multiple doses of a strong CYP3A4 inducer (rifampicin) decreased sotorasib C_max 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 sotorasib is not recommended because they may decrease sotorasib exposure.

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 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%.

Co-administration of PPIs and H₂ receptor antagonists with sotorasib is not recommended because the impact on sotorasib efficacy is unknown. If treatment with an acid-reducing agent is required, sotorasib should be taken 4 hours before or 10 hours after administration of a local antacid.

There are no data from the use of sotorasib in pregnant women. Studies in animals have shown reproductive toxicity. Sotorasib 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 sotorasib is used during pregnancy, or if the patient becomes pregnant while taking sotorasib.

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

Women of childbearing potential/Contraception

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

Fertility

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

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

Summary of the safety profile

The most common adverse reactions were diarrhoea (34%), nausea (25%), and fatigue (21%). 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%) and increased AST (1%) and DILI (1%). The most common adverse reactions leading to dose modification were increased ALT (6%), diarrhoea (6%), increased AST (6%), nausea (3%), increased blood alkaline phosphatase (3%) and vomiting (2%).

Tabulated list of adverse reactions

Adverse reactions reported in sotorasib clinical studies are displayed in the table 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 sotorasib 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 sotorasib was 4.1 months (range: 0.02 to 21).

Adverse reactions:

^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. Elevations of ALT occurred in 14% of subjects and elevations of AST in 16% of subjects, with a median time to onset of 8 weeks (range: 1 to 42) and 8 weeks (range: 0 to 42), respectively. Elevations of ALT resulted in dose interruption and/or reduction in 6.1% of subjects, and elevations of AST resulted in dose interruption and/or reduction in 6.1% of subjects.

ILD/pneumonitis

In clinical studies, among 359 patients who received sotorasib, 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). Sotorasib was discontinued due to ILD/pneumonitis in 0.6% of patients.

Elderly

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