Asciminib

Caution should be exercised during concomitant administration of asciminib at a total daily dose of 80 mg and medicinal products with known risk of torsades de pointes, including, but not limited to, bepridil, chloroquine, clarithromycin, halofantrine, haloperidol, methadone, moxifloxacin or pimozide.

Concomitant administration of asciminib 200 mg twice daily with medicinal products with a known risk of torsades de pointes should be avoided.

Based on physiologically-based pharmacokinetic (PBPK) modelling, caution should be exercised during concomitant administration of asciminib at all recommended doses with BCRP substrates, including, but not limited to, sulfasalazine, methotrexate and rosuvastatin. No clinical drug interaction study with BCRP was performed.

Co-administration of asciminib at 80 mg once daily with an OATP1B, CYP3A4 and P-gp substrate (atorvastatin) increased atorvastatin AUC_inf and C_max by 14% and 24%, respectively, in healthy subjects. Clinically relevant interactions between asciminib and OATP1B substrates are unlikely to occur.

Co-administration of asciminib with a CYP2C9 substrate (warfarin) increased S-warfarin AUC_inf and C_max by 41% and 8%, respectively, in healthy subjects receiving asciminib 40 mg twice daily.

Caution should be exercised during concomitant administration of asciminib at a total daily dose of 80 mg with CYP2C9 substrates known to have a narrow therapeutic index, including, but not limited to, phenytoin or warfarin. Dose adjustment of asciminib is not required.

Concomitant administration of asciminib at 200 mg twice daily with CYP2C9-sensitive substrates and CYP2C9 substrates known to have a narrow therapeutic index should be avoided and alternative medicines should be considered. If co-administration cannot be avoided, the CYP2C9 substrate dose should be reduced. If co-administration with warfarin cannot be avoided, the frequency of international normalised ratio (INR) monitoring should be increased as the anticoagulant effect of warfarin may be enhanced.

Co-administration of asciminib with a CYP3A4 substrate (midazolam) increased midazolam AUC_inf and C_max by 28% and 11%, respectively, in healthy subjects receiving asciminib 40 mg twice daily.

Caution should be exercised during concomitant administration of asciminib at all recommended doses with CYP3A4 substrates known to have a narrow therapeutic index, including, but not limited to, the CYP3A4 substrates fentanyl, alfentanil, dihydroergotamine or ergotamine. Dose adjustment of asciminib is not required.

Caution should be exercised during concomitant administration of asciminib at all recommended doses with P-gp substrates known to have a narrow therapeutic index, including, but not limited to digoxin, dabigatran and colchicine. Dose adjustment of asciminib is not required.

Caution should be exercised during concomitant administration of asciminib at 200 mg twice daily with strong CYP3A4 inhibitors, including, but not limited to, clarithromycin, telithromycin, troleandomycin, itraconazole, ketoconazole, voriconazole, ritonavir, indinavir, nelfinavir or saquinavir. Dose adjustment of asciminib is not required.

Co-administration of a strong CYP3A4 inducer (rifampicin) decreased asciminib AUC_inf by 15% and increased C_max by 9% in healthy subjects receiving a single asciminib dose of 40 mg. Co-administration of a strong CYP3A4 inducer (phenytoin) decreased asciminib AUC_inf and C_max by 34% and 22%, respectively, in healthy subjects receiving a single asciminib dose of 200 mg.

Caution should be exercised during concomitant administration of asciminib at all recommended doses with strong CYP3A4 inducers, including, but not limited to, carbamazepine, phenobarbital, phenytoin or St. John's wort (Hypericum perforatum), which may result in lower efficacy of asciminib.

No clinical data are available in patients with severe renal impairment at the 200 mg asciminib twice daily dose. Therefore, no recommendations for dose adjustment can be given. Caution should be exercisedin patients with severe renal impairment receiving the 200 mg twice daily dose.

No clinical data are available in patients with severe hepatic impairment at the 200 mg asciminib twice daily dose. Therefore, no recommendations for dose adjustment can be given. Caution should be exercised in patients with severe hepatic impairment receiving the 200 mg twice daily dose.

Reactivation of hepatitis B virus (HBV) has occurred in patients who are chronic carriers of this virus following administration of other BCR::ABL1 tyrosine kinase inhibitors (TKIs). Patients should be tested for HBV infection before the start of treatment with asciminib. HBV carriers who require treatment with asciminib should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.

There are no or limited amount of data from the use of asciminib in pregnant women. Studies in animals have shown reproductive toxicity. Asciminib is not recommended during pregnancy and in women of childbearing potential not using contraception. The patient should be advised of a potential risk to the foetus if asciminib is used during pregnancy or if the patient becomes pregnant while taking asciminib.

It is unknown whether asciminib/metabolites are excreted in human milk. There are no data on the effects of asciminib on the breast-fed newborn/infant or on milk production. Because of the potential for serious adverse reactions in the breast-fed newborn/infant, breast-feeding should be discontinued during treatment and for at least 3 days after stopping treatment with asciminib.

Women of childbearing potential/Contraception

The pregnancy status of women of childbearing potential should be verified prior to starting treatment with asciminib.

Sexually-active women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with asciminib and for at least 3 days after stopping treatment.

Fertility

There are no data on the effect of asciminib on human fertility. In rat fertility studies, asciminib did not affect reproductive function in male and female rats. However, adverse effects on sperm motility and count were observed in rats at doses of 200 mg/kg/day. The relevance for humans is not known.

Asciminib has no or negligible influence on the ability to drive and use machines. However, it is recommended that patients experiencing dizziness, fatigue or other undesirable effects with a potential impact on the ability to drive or use machines safely should refrain from these activities as long as the undesirable effects persist.

Summary of the safety profile

Ph+ CML (ASCEMBL, X2101, ASC4FIRST studies)

The most common adverse reactions of any grade (incidence ≥20%) in patients receiving asciminib were musculoskeletal pain (34.4%), thrombocytopenia (28.1%), fatigue (25.4%), upper respiratory tract infections (24.8%), headache (22.8%), neutropenia (21.8%), arthralgia (20.7%) and diarrhoea (20.7%).

The most common adverse reactions of ≥ grade 3 (incidence ≥5%) in patients receiving asciminib were thrombocytopenia (16.5%), neutropenia (13.8%), increased pancreatic enzymes (9.4%) and hypertension (9.2%).

Serious adverse reactions occurred in 9.9% of patients receiving asciminib. The most frequent serious adverse reactions (incidence ≥1%) were pleural effusion (1.6%), lower respiratory tract infections (1.6%), thrombocytopenia (1.3%), pancreatitis (1.1%) and pyrexia (1.1%).

Ph+ CML-CP with the T315I mutation in patients resistant to, intolerant to or ineligible for ponatinib (X2101 study)

The safety dataset for the 200 mg twice-daily dose is limited to 48 patients, of whom 34 had a treatment intensity of >90%.

The most common adverse reactions of any grade (incidence ≥20%) in patients receiving asciminib were musculoskeletal pain (41.7%), fatigue (35.4%), increased pancreatic enzymes (31.3%), diarrhoea (27.1%), nausea (27.1%), increased hepatic enzymes (25.0%), arthralgia (25.0%), cough (22.9%), thrombocytopenia (20.8%), vomiting (20.8%) and headache (20.8%).

The most common adverse reactions of ≥grade 3 (incidence ≥5%) in patients receiving asciminib were increased pancreatic enzymes (22.9%), thrombocytopenia (16.7%), neutropenia (12.5%), increased hepatic enzymes (10.4%), hypertension (8.3%), anaemia (6.3%), vomiting (6.3%) and abdominal pain (6.3%).

Serious adverse reactions occurred in 12.5% of patients receiving asciminib. The most frequent serious adverse reactions (incidence ≥1%) were abdominal pain (4.2%), vomiting (4.2%), lower respiratory tract infections (4.2%), constipation (2.1%), headache (2.1%), non-cardiac chest pain (2.1%) and pleural effusion (2.1%).

Tabulated list of adverse reactions

The overall safety profile of asciminib has been evaluated in 556 patients with Ph+ CML in chronic (CP) and accelerated (AP) phases in the pivotal phase III study A2301 (ASCEMBL) and the phase I study X2101, and with newly diagnosed Ph+ CML-CP in the pivotal phase III study J12301 (ASC4FIRST). In ASCEMBL (N=156), patients received asciminib as monotherapy at a dose of 40 mg twice daily. In X2101 (N=200), patients received asciminib as monotherapy at doses ranging from 10 to 200 mg twice daily and 80 to 200 mg once daily. Of these patients, 48 with the T315I mutation received asciminib 200 mg twice daily. In ASC4FIRST (N=200), patients received asciminib as monotherapy at a dose of 80 mg once daily. In the pooled dataset, the median duration of exposure to asciminib was 123.29 weeks (range: 0.1 to 439 weeks).

Adverse reactions from clinical studies are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on the following convention: 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).

Adverse reactions observed with asciminib in clinical studies:

¹ Upper respiratory tract infection includes: upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis.
² Lower respiratory tract infections include: pneumonia, bronchitis and tracheobronchitis.
³ Thrombocytopenia includes: thrombocytopenia and platelet count decreased.
⁴ Neutropenia includes: neutropenia and neutrophil count decreased.
⁵ Anaemia includes: anaemia, haemoglobin decreased and normocytic anaemia.
⁶ Hypothyroidism includes hypothyroidism, autoimmune thyroiditis, blood thyroid stimulating hormone increased, autoimmune hypothyroidism and primary hypothyroidism.
⁷ Dyslipidaemia includes: hypertriglyceridaemia, blood cholesterol increased, hypercholesterolaemia, blood triglycerides increased, hyperlipidaemia and dyslipidaemia.
⁸ Hypertension includes: hypertension and blood pressure increased.
⁹ Pancreatic enzymes increased includes: lipase increased, amylase increased and hyperlipasaemia.
¹⁰ Abdominal pain includes: abdominal pain and abdominal pain upper.
¹¹ Pancreatitis includes: pancreatitis and pancreatitis acute.
¹² Hepatic enzymes increased includes: alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, transaminases increased and hypertransaminasaemia.
¹³ Blood bilirubin increased includes: blood bilirubin increased, bilirubin conjugated increased and hyperbilirubinaemia.
¹⁴ Rash includes: rash, rash maculopapular and rash pruritic.
¹⁵ Musculoskeletal pain includes: pain in extremity, back pain, myalgia, bone pain, musculoskeletal pain, neck pain, musculoskeletal chest pain and musculoskeletal discomfort.
¹⁶ Fatigue includes: fatigue and asthenia.
¹⁷ Oedema includes: oedema and oedema peripheral.
¹⁸ Pyrexia includes: pyrexia and body temperature increased.

Description of selected adverse reactions

Myelosuppression

Thrombocytopenia occurred in 28.1% of patients receiving asciminib, with grade 3 and 4 reactions reported in 7% and 9.5% of patients, respectively. Among the patients with thrombocytopenia ≥ grade 3, the median time to first occurrence of reactions was 6 weeks (range: 0.14 to 64.14 weeks), with median duration of any occurring reaction of 1.57 weeks (95% CI, range: 1.14 to 2 weeks). 2% of patients receiving asciminib permanently discontinued due to thrombocytopenia, while asciminib was temporarily withheld in 12.6% of patients due to the adverse reaction.

Thrombocytopenia occurred in 20.8% of patients with the T315I mutation receiving asciminib, with grade 3 and 4 reactions reported in 16.7% of patients. Among the patients with thrombocytopenia ≥ grade 3, the median time to first occurrence of reactions was 8.36 weeks (range: 1.43 to 38.43 weeks), with median duration of any occurring reaction of 4.29 weeks (95% CI, range: 1.71 to 5.71 weeks). 2.1% of patients with the T315I mutation receiving asciminib permanently discontinued due to thrombocytopenia, while asciminib was temporarily withheld in 6.3% of patients due to the adverse reaction.

Neutropenia occurred in 21.8% of patients receiving asciminib, with grade 3 and 4 reactions reported in 7.6% and 6.3% of patients, respectively. Among the patients with neutropenia ≥ grade 3, the median time to first occurrence of reactions was 7.14 weeks (range: 0.14 to 180.14 weeks), with median duration of any occurring reaction of 1.86 weeks (95% CI, range: 1.29 to 2 weeks). 1.3% of patients receiving asciminib permanently discontinued due to neutropenia, while asciminib was temporarily withheld in 9.4% of patients due to the adverse reaction.

Neutropenia occurred in 16.7% of patients with the T315I mutation receiving asciminib, with grade 3 and 4 reactions reported in 12.5% of patients. Among the patients with neutropenia ≥ grade 3, the median time to first occurrence of reactions was 4.14 weeks (range: 0.14 to 16.57 weeks), with median duration of any occurring reaction of 2.86 weeks (95% CI, range: 1.57 to 4.57 weeks). 2.1% of patients with the T315I mutation receiving asciminib permanently discontinued due to neutropenia, while asciminib was temporarily withheld in 2.1% of patients due to the adverse reaction.

Anaemia occurred in 12.9% of patients receiving asciminib, with grade 3 reactions occurring in 4.1% of patients. Among the patients with anaemia ≥ grade 3, the median time to first occurrence of reactions was 24.14 weeks (range: 0.14 to 207 weeks), with median duration of any occurring reaction of 0.86 weeks (95% CI, range: 0.29 to 1.71 weeks). Asciminib was temporarily withheld in 0.5% of patients due to the adverse reaction.

Anaemia occurred in 10.4% of patients with the T315I mutation receiving asciminib, with grade 3 and 4 reactions reported in 6.3% of patients. Among the patients with anaemia ≥ grade 3, the median time to first occurrence of reactions was 38.43 weeks (range: 24.14 to 131 weeks), with median duration of any occurring reaction of 0.86 weeks (95% CI, range: 0.14 to NE [not estimable] weeks).

Pancreatic toxicity

Pancreatitis occurred in 2% of patients receiving asciminib, with grade 3 reactions occurring in 1.1% of patients. 0.5% of patients receiving asciminib permanently discontinued due to pancreatitis, while asciminib was temporarily withheld in 1.1% of patients due to the adverse reaction. Asymptomatic elevations of serum lipase and amylase occurred in 19.8% of patients receiving asciminib, with grade 3 and 4 reactions occurring in 7.4% and 2% of patients, respectively. Of the patients with elevation of pancreatic enzymes, asciminib was permanently discontinued in 2% of patients due to the adverse reaction.

Pancreatitis occurred in 2.1% of patients with the T315I mutation receiving asciminib. Elevations of serum lipase and amylase occurred in 31.3% of patients with the T315I mutation receiving asciminib, with grade 3 and 4 reactions occurring in 22.9% of patients. 2.1% of patients with the T315I mutation receiving asciminib permanently discontinued due to elevation of pancreatic enzymes, while asciminib was temporarily withheld in 16.7% of patients due to the adverse reaction.

QT prolongation

Electrocardiogram QT prolongation occurred in 0.9% of patients receiving asciminib. In the ASCEMBL clinical study, one patient had a prolonged QTcF greater than 500 milliseconds (ms) together with more than 60 ms QTcF increase from baseline, and one patient had prolonged QTcF with more than 60 ms QTcF increase from baseline.

Hypertension

Hypertension occurred in 17.1% of patients receiving asciminib, with grade 3 and 4 reactions reported in 9% and 0.2% of patients, respectively. Among the patients with hypertension ≥ grade 3, the median time to first occurrence of reactions was 40.14 weeks (range: 0.14 to 365 weeks). Asciminib was temporarily withheld in 0.9% of patients due to the adverse reaction.

Hypertension occurred in 14.6% of patients with the T315I mutation receiving asciminib, with grade 3 and 4 reactions reported in 8.3% of patients. Among the patients with hypertension ≥ grade 3, the median time to first occurrence of reactions was 32.64 weeks (range: 11.14 to 277.3 weeks), with median duration of any occurring reaction of 7.57 weeks (95% CI, range: 2.14 to NE weeks).

Laboratory abnormalities

In the ASCEMBL study, decrease in phosphate levels occurred as a laboratory abnormality in 17.9% (all grades) and 7.1% (grade ¾) of 156 patients receiving asciminib at 40 mg twice daily. In the ASC4FIRST study, decrease in phosphate levels based on normal ranges occurred as a laboratory abnormality in 20.5% (all grades) of 200 patients receiving asciminib at 80 mg once daily.

In the X2101 study, decrease in phosphate levels occurred as a laboratory abnormality in 47.9% (all grades) and 8.3% (grade ¾) of 48 patients receiving asciminib at 200 mg twice daily.

Increases in ALT, AST and bilirubin levels occurred as laboratory abnormalities in 50%, 37.5% and 25% (all grades) of 48 patients receiving asciminib at 200 mg twice daily, respectively. Among these patients, increased ALT ≥ grade 3 events and increased AST ≥ grade 3 events were reported in 8.3% and 2.1% of patients, respectively.