Mobocertinib ▼

EXKIVITY 40 mg hard capsules

EXKIVITY 40 mg hard capsules

Each capsule contains 40 mg of mobocertinib (as 48.06 mg mobocertinib succinate).

For the full list of excipients, see section 6.1.

Hard capsule.

EXKIVITY 40 mg hard capsules

White, size 2 gelatin hard capsule, imprinted with “MB788” on the cap and “40mg” on the body in black ink.

EXKIVITY as monotherapy is indicated for the treatment of adult patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), who have received prior platinum-based chemotherapy.

Treatment with EXKIVITY should be initiated and supervised by a physician experienced in the use of anticancer therapies.

Select patients with locally advanced or metastatic NSCLC for treatment with EXKIVITY based on the presence of an EGFR exon 20 insertion mutation. EGFR Exon 20 insertion mutation status should be established by an experienced laboratory using a validated test prior to initiation of EXKIVITY therapy (see section 4.4).

Posology

The recommended dosage is 160 mg EXKIVITY once daily. EXKIVITY treatment should be continued until disease progression or is no longer tolerated by the patient.

If a dose is missed by more than 6 hours, the patient should not take a dose on that day but should resume the usual dosing on the following day at the regularly scheduled time.

If a patient vomits after taking a dose, the patient should not repeat the dose but should resume the usual dosing as prescribed on the following day.

Dose adjustments

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability.

EXKIVITY dosage reduction levels for adverse reactions are summarized in Table 1.

Recommended dosage modifications of EXKIVITY and management of adverse reactions are provided in Table 2.

Special populations

Elderly patients

No dose adjustment of EXKIVITY is recommended for patients over 65 years of age based on the results from population pharmacokinetic analyses. Exploratory analysis suggests a higher incidence of ≥ Grade 3 adverse reactions (80% vs 65%), serious adverse reactions (54% vs 42%), and discontinuation of EXKIVITY due to adverse reactions (29% vs 11%) in patients 65 years and older as compared to those younger than 65 years.

Hepatic impairment

No dose adjustment of EXKIVITY is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 to 1.5 times ULN and any AST). The recommended dosage of EXKIVITY in patients with moderate or severe hepatic impairment has not been established. Use in patients with moderate or severe hepatic impairment is not recommended (see section 5.2).

Renal impairment

No dose adjustment of EXKIVITY is recommended for patients with mild or moderate renal impairment (estimated glomerular filtration rate ≥ 30 mL/min). The recommended dosage of EXKIVITY in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min) has not been established. Use in patients with severe renal impairment is not recommended (see section 5.2).

Paediatric population

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

Method of administration

EXKIVITY is for oral use. EXKIVITY can be taken with or without food at approximately the same time each day. Swallow EXKIVITY capsules whole. Do not open, chew or dissolve the contents of the capsules.

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

Co-administration with strong CYP3A inhibitors, grapefruit or grapefruit juice, or St. John's Wort (see section 4.5).

Assessment of EGFR Exon 20 insertion mutation status

When considering using EXKIVITY, it is important that the EGFR Exon 20 insertion mutation status of a patient is determined. A validated test should be performed using either tumour DNA derived from a tissue sample or circulating tumour DNA (ctDNA) obtained from a plasma sample. Only robust, reliable and sensitive tests with demonstrated utility for the determination of EGFR mutation status should be used.

QTc Interval Prolongation

Heart rate-corrected QT (QTc) interval prolongation, including resultant life-threatening arrhythmias such as Torsades de Pointes have occurred in patients treated with EXKIVITY (see section 4.8 and 5.1).

Clinical trials of EXKIVITY did not enrol patients with a prolonged baseline QTc > 450 msec in males or 470 msec in females. Where possible, the use of mobocertinib in patients with congenital long QT syndrome should be avoided. Assess QTc and electrolytes at baseline and correct abnormalities in sodium, potassium, calcium, and magnesium prior to initiating EXKIVITY. Monitor QTc and electrolytes periodically during treatment. Increase monitoring frequency in patients with risk factors for QTc prolongation, such as patients with congenital long QTc syndrome, heart disease, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval (e.g., ondansetron).

Coadministration of strong CYP3A inhibitors with EXKIVITY is contraindicated (see section 4.3). Avoid coadministration of moderate CYP3A inhibitors and medications known to prolong QTc interval with EXKIVITY, as they may further prolong the QTc interval (see section 4.5).

Permanently discontinue EXKIVITY in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia (see section 4.2).

Interstitial Lung Disease/Pneumonitis

Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis have occurred in patients treated with EXKIVITY (see section 4.8).

Patients with a history of interstitial lung disease, dyspnoea at rest, drug-related pneumonitis, radiation pneumonitis that required steroid treatment were excluded from enrolment in the mobocertinib clinical trials.

Withhold EXKIVITY for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnoea, cough, and fever pending diagnostic evaluation and diagnosis confirmation. Permanently discontinue EXKIVITY if ILD/pneumonitis is confirmed and initiate appropriate treatment as necessary (see section 4.2).

Cardiac failure

Severe, life-threatening, and fatal cardiac failure (including congestive cardiac failure, decreased ejection fraction, and cardiomyopathy) have occurred in patients treated with EXKIVITY (see section 4.8).

Patients with a history of significant, uncontrolled, active cardiovascular disease were excluded from enrolment in the mobocertinib clinical trials.

Evaluate cardiac function, including assessment of left ventricular ejection fraction (LVEF) at baseline and periodically during treatment. Patients who develop signs and symptoms consistent with cardiac failure should be treated as clinically indicated. Management of cardiac failure may require permanent discontinuation of EXKIVITY (see section 4.2).

Diarrhoea

In clinical studies, most patients experienced mild to moderate diarrhoea (see section 4.8). In some cases diarrhoea was severe or life threatening. The median time to first onset of diarrhoea was 5 days but could occur as soon as 24 hours after administration of EXKIVITY. Diarrhoea was usually transient and had a median time to resolution of 3 days. Thirty-three percent of patients in the clinical studies experienced recurrent diarrhoea. Prolonged diarrhoea led to dehydration or electrolyte imbalance, with or without renal impairment.

Early and compliant diarrhoea management such as prescribed anti-diarrheal medicinal products (e.g., loperamide), diet, adequate fluid intake (~2L clear liquids per day), and patient education is essential. Patients should be advised to have anti-diarrheal medicinal products (e.g., loperamide) readily available. Begin anti-diarrheal treatment at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. In EXKIVITY clinical studies, the dosage regimen for loperamide was 4 mg at the first bout of diarrhoea and then 2 mg every 2 hours until the patient is diarrhoea-free for at least 12 hours; daily dose of loperamide did not exceed 16 mg. If using loperamide as the antidiarrheal treatment, refer to loperamide product labelling for additional information.

If diarrhoea does not improve or additional signs or symptoms are reported, standard medical practice intervention, including other anti-diarrhoeal medications, are required. Anti-diarrhoeal prophylaxis may be considered as needed. Monitor electrolytes and patients should be advised to increase fluid and electrolyte intake as needed. Withhold, reduce the dose or permanently discontinue EXKIVITY based on the severity (see section 4.2).

Embryo-foetal toxicity

Based on its mechanism of action and data from animal studies, mobocertinib could cause foetal harm when administered to pregnant women. Women of childbearing potential should be advised to use highly effective non-hormonal contraception during treatment with EXKIVITY (see section 4.5) and for 1 month following the final dose. Men with female partners of childbearing potential should be advised to use effective contraception during treatment with EXKIVITY and for 1 week following the final dose of EXKIVITY (see section 4.6).

Drug interactions - Moderate CYP3A inhibitors

The coadministration of moderate CYP3A inhibitors with EXKIVITY should be avoided. If coadministration of moderate CYP3A inhibitors cannot be avoided, the dose of EXKIVITY should be reduced (see section 4.5).

Effect of Other Drugs on EXKIVITY

CYP3A inhibitors

Coadministration of multiple 200 mg twice daily doses of itraconazole (a strong CYP3A inhibitor) with a single 20 mg mobocertinib dose increased combined molar C_max by 186% and AUC_inf by 527% compared to a 20 mg mobocertinib dose administered alone. Coadministration of multiple doses of itraconazole and ketoconazole (strong CYP3A inhibitors) was predicted to increase steady-state combined molar C_max by 306 to 317% and AUC₂₄ by 374 to 419%. The coadministration of strong CYP3A inhibitors with EXKIVITY, including but not limited to certain antivirals (e.g., indinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (e.g., clarithromycin, telithromycin, troleandomycin), antifungals (e.g., ketoconazole, voriconazole), and nefazodone is contraindicated (see section 4.3).

Coadministration of multiple doses of erythromycin and fluconazole (moderate CYP3A inhibitors) was predicted to increase steady-state combined molar C_max by 91 to 106% and AUC₂₄ by 116 to 135%. The coadministration of moderate CYP3A inhibitors (e.g., fluconazole and erythromycin) with EXKIVITY should be avoided. If coadministration of moderate CYP3A inhibitors cannot be avoided, the dose of EXKIVITY should be reduced by approximately 50% (e.g., from 160 mg to 80 mg, 120 mg to 40 mg, or 80 mg to 40 mg) and the QTc interval monitored more frequently. After discontinuation of a moderate CYP3A inhibitor, EXKIVITY should be resumed at the dose that was tolerated prior to the initiation of the moderate CYP3A inhibitor (see section 4.4).

Grapefruit or grapefruit juice are contraindicated as they may also increase plasma concentrations of mobocertinib (see section 4.3).

CYP3A inducers

Coadministration of multiple 600 mg once daily doses of rifampicin (a strong CYP3A inducer) with a single 160 mg mobocertinib dose decreased combined molar C_max by 92% and AUC_inf by 95% compared to a 160 mg mobocertinib dose administered alone. Coadministration of multiple doses of rifampicin was predicted to decrease steady-state combined molar C_max by 88% and AUC₂₄ by 92%. The coadministration of strong CYP3A inducers with EXKIVITY, including but not limited to rifampicin, carbamazepine, phenytoin, rifabutin, and phenobarbital, should be avoided. Coadministration of EXKIVITY with St. John's Wort is contraindicated (see section 4.3).

Coadministration of multiple doses of efavirenz (moderate CYP3A inducer) was predicted to decrease steady-state combined molar C_max by 53% and AUC₂₄ by 58%. The coadministration of moderate CYP3A inducers with EXKIVITY, including but not limited to efavirenz, modafinil, bosentan, etravirine, and nafcillin should be avoided.

Drugs that prolong the QTc interval

Coadministration of EXKIVITY with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole antifungals, 5-HT₃ receptor antagonists) and moderate or strong CYP3A inhibitors that increase plasma concentrations of mobocertinib may increase the risk of QTc interval prolongation, and should be avoided (see section 4.4). If coadministration of EXKIVITY with moderate CYP3A inhibitors or with drugs known to prolong the QTc interval is unavoidable, conduct periodic ECG monitoring (see sections 4.4 and 5.1).

Effect of EXKIVITY on Other Drugs

CYP3A substrates

Coadministration of multiple doses of EXKIVITY 160 mg once daily with oral or intravenous midazolam (a CYP3A substrate) decreased the AUC_inf of midazolam by 32% and 16%, respectively. Mobocertinib may reduce plasma concentrations of coadministered medicinal products that are predominantly metabolised by CYP3A. Therefore, coadministration of EXKIVITY with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of sensitive CYP3A substrates.

EXKIVITY may also induce other enzymes and transporters (e.g., CYP2C, P-gp) via the same mechanisms responsible for induction of CYP3A (e.g., pregnane X receptor activation).

Mobocertinib, AP32960, and AP32914 do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations.

Transporter Systems

Mobocertinib is an inhibitor of P-gp and BCRP in vitro. Based on a physiologically-based pharmacokinetic analysis, coadministration of multiple 160 mg once daily doses of mobocertinib was predicted to result in no clinically meaningful increase in systemic exposures of P-gp (digoxin, dabigatran) and BCRP (sulfasalazine) substrates. Agents that are substrates of BCRP (e.g., sulfasalazine, rosuvastatin) or substrates of P-gp (e.g., digoxin, dabigatran) may have increased exposure when administered with EXKIVITY and should therefore be coadministered with caution.

Mobocertinib is a substrate of P-gp. Given that mobocertinib exhibits high solubility and high permeability in vitro, P-gp inhibitors are unlikely to increase plasma concentrations of mobocertinib.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential being treated with EXKIVITY should be advised to avoid becoming pregnant during treatment. Women of childbearing potential should be advised to use highly effective non-hormonal contraception during treatment with EXKIVITY and for 1 month following the final dose. Men with female partners of childbearing potential should be advised to use effective contraception during treatment with EXKIVITY and for 1 week following the final dose of EXKIVITY.

Pregnancy

EXKIVITY can cause foetal harm when administered to a pregnant woman based on its mechanism of action and data from animal reproduction studies (see section 5.3). There are no clinical data on the use of EXKIVITY in pregnant women. EXKIVITY should not be used during pregnancy unless the clinical condition of the woman requires treatment.

Breast-feeding

It is not known whether mobocertinib or its metabolites are excreted in human milk. Women should discontinue breast-feeding during treatment with EXKIVITY and for 1 week following the final dose.

Fertility

Fertility studies were not conducted in animals with mobocertinib; however, changes were observed in male and female reproductive organs in animal toxicity studies that may indicate the potential for effects on fertility (see section 5.3). The relevance for human fertility is unknown.

EXKIVITY has a minor influence on the ability to drive and use machines. Fatigue has been observed in clinical trials. Patients should be advised not to drive or operate machines if they experience fatigue while taking EXKIVITY.

Summary of the safety profile

The most common adverse reactions (≥ 25%) in patients treated with EXKIVITY were diarrhoea (94%), rash (77%), anaemia (69%), blood creatinine increased (57%), decreased lymphocyte (51%), nausea (49%), stomatitis (47%), amylase increased (42%), decreased appetite (37%), lipase increased (37%), vomiting (37%), paronychia (36%), dry skin (32%), fatigue (31%), hypomagnesaemia (31%), hypokalaemia (30%), decreased platelet count (29%), alanine aminotransferase increased (28%), aspartate aminotransferase increased (28%), and hyponatraemia (28%).

Serious adverse reactions occurred in 47% of patients treated with EXKIVITY. Serious adverse reactions considered to be treatment-related by the study investigator occurred in 17% of patients treated with EKIVITY. The most common serious adverse reactions (≥ 2%) (other than progression of NSCLC) were dyspnoea (6%), diarrhoea (4.8%), vomiting (4.5%), pneumonia (4.1%), acute kidney injury (3.4%), decreased appetite (2.4%), dehydration (2.1%), nausea (2.1%), and respiratory failure (2.1%).

Permanent discontinuation occurred in 18% of patients who received EXKIVITY. Adverse reactions requiring permanent discontinuation of EXKIVITY in at least ≥ 2% of patients were diarrhoea and interstitial lung disease.

Dosage interruptions of EXKIVITY due to an adverse reaction occurred in 66% of patients. Adverse reactions which required dosage interruption in > 5% of patients included diarrhoea, nausea, rash, vomiting, decreased appetite, and stomatitis.

Dose reductions of EXKIVITY due to an adverse reaction occurred in 36% of patients. The adverse reaction requiring dose reduction in > 5% of patients was diarrhoea, nausea, and rash.

Tabulated list of adverse reactions

The safety data described in this section reflect exposure to EXKIVITY in Phase 1/2 clinical trials, at the recommended dose of 160 mg once daily in 290 patients with advanced solid malignancies, including 285 patients with NSCLC.

The median duration of exposure to EXKIVITY was 6.5 months. Among the 290 patients who received EXKIVITY, 52% were exposed for 6 months or longer and 26% were exposed for greater or equal to one year.

The following convention is used for the classification of the frequency of an adverse reaction: 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). Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first.

Description of selected adverse reactions

Interstitial lung disease

In patients treated with EXKIVITY at the recommended dosage of 160 mg once daily, ILD/pneumonitis occurred in 4.5% (13/290) of patients; of these, 0.7% (2/290) were Grade 3 events. The median time to onset of ILD/pneumonitis was 88.5 days and the median time to resolution was 17.0 days. Resolution occurred in 38% (5/13) of patients. ILD/pneumonitis led to dose interruptions and discontinuation of EXKIVITY in 6 (2.1%) and 8 (2.8%) patients, respectively. Fatal cases of respiratory failure occurred in 3 (1.0%) patients. (see section 4.4).

Cardiac failure

In patients treated with EXKIVITY, cardiac failure (including congestive cardiac failure, decreased ejection fraction, and cardiomyopathy) occurred in 3.4% (10/290) of patients. Grade 3 cardiac failure occurred in 1.0% (3/290) of patients. Grade 4 cardiac failure occurred in 1 patient (0.3%). The median time to onset of cardiac failure was 87.5 days and the median time to resolution was 14.5 days. Cardiac failure led to dose reduction, interruptions and discontinuation of EXKIVITY in 1 (0.3%), 3 (1.0%), and 5 (1.7%) patients, respectively. (see section 4.4). Fatal events of cardiac failure occurred in 2 (0.7%) patients.

QTc Interval Prolongation

In patients treated with EXKIVITY, QTc interval prolongation occurred in 12% (35/290) of patients. Grade 3 QTc interval prolongation occurred in 4.5% (13/290) of patients and Grade 4 QTc interval prolongation (Torsades de Pointes) occurred in 1 patient (0.3%). In the 286-patient subset of the pooled EXKIVITY safety population who had scheduled and unscheduled ECGs, 2.8% of patients had a QTc interval > 500 msec and 13% of patients had a change-from-baseline QTc interval > 60 msec. On treatment ECGs were not routinely performed in cycle 1 (first 28 days of treatment). The median time to onset of QTc interval prolongation was 58.0 days and the median time to resolution was 29.0 days. QTc prolongation led to dose interruptions and discontinuation of EXKIVITY in 6 (2.1%) and 1 (0.3%) patients, respectively. (see section 4.4 and 5.1). The incidence of Grade 3 or higher QTc interval prolongation was higher in Asian patients (9% [12/135]) compared to non-Asian patients (1% [2/152]). In the subset of Asian patients who had scheduled and unscheduled ECGs (134/286), 5% of patients had a QTc interval > 500 msec and 17% of patients had a change-from-baseline QTc interval > 60 msec.

Diarrhoea

In clinical studies, 73% of patients experienced Grade 1 or 2 diarrhoea. Grade 3 diarrhoea occurred in 20% (59/290) of patients and Grade 4 diarrhoea occurred in 1 patient (0.3%). The median time to onset of diarrhoea was 5.0 days and the median time to resolution was 3.0 days. Diarrhoea led to dose reduction, interruptions, and discontinuation of EXKIVITY in 44 (15%), 75 (26%), and 10 (3.4%) patients, respectively. (see section 4.4). For Grade 3 or Grade 4 diarrhoea, the incidence was higher in patients ≥ 65 years (26% [30/114]) compared to younger patients (17% [30/176]). The incidence of Grade 3 or Grade 4 diarrhoea was also higher in non-Asian patients (25% [38/152]) compared to Asian patients (16% [22/135]).

Elevated Liver Enzymes

In patients treated with EXKIVITY, elevated liver enzymes (alanine aminotransferase and aspartate aminotransferase) occurred 36% (104/290) of patients. Grade 3 elevated liver enzymes occurred in 3.4% (10/290) of patients. Grade 4 elevated liver enzymes occurred in 1 patient (0.3%). The median time to onset of elevated liver enzymes was 37.5 days and the median time to resolution was 28.0 days. Elevated liver enzymes led to dose reduction and interruptions of EXKIVITY in 6 (2.1%) and 11 (3.8%) patients, respectively.

Elevated Pancreatic Enzymes

In patients treated with EXKIVITY, elevated pancreatic enzymes (amylase and lipase) occurred in 54% (157/290) of patients. Grade 3 elevated pancreatic enzymes occurred in 14% (42/290) of patients. Grade 4 elevated pancreatic enzymes occurred in 4.1% (12/290) of patients. The median time to onset of pancreatic enzymes was 31.0 days and the median time to resolution was 29.0 days, respectively. Elevated pancreatic enzymes led to dose reduction and interruptions of EXKIVITY in 9 (3.1%)and 20 (7%) patients, respectively.

Increased Creatinine

In patients treated with EXKIVITY, increased creatinine occurred 57% (165/290) of patients. Grade 3 increased creatinine occurred in 4.5% (13/290) of patients. Grade 4 increased creatinine occurred in 0.7% (2/290) of patients. The median time to onset of increased creatinine was 30.0 days and the median time to resolution was 30.0 days. Increased creatinine led to dose reduction and interruptions of EXKIVITY in 6 (2.1%) and 12 (4.1%) patients, respectively.

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 the 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 known specific antidote for overdose with EXKIVITY. In the event of an overdose, monitor the patient for adverse reactions (see section 4.8) and provide appropriate supportive care.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: LO1EBXX

Mechanism of action

Mobocertinib is a kinase inhibitor of the EGFR that selectively inhibits and irreversibly binds to EGFR exon 20 insertion mutations at lower concentrations than Wild type (WT)-EGFR. Two pharmacologically-active metabolites, AP32960 and AP32914, with similar inhibitory profiles to mobocertinib, have been identified in the plasma after oral administration of mobocertinib. In vitro, mobocertinib also inhibited the activity of EGFR family members, HER2, HER4, and six additional kinases (BLK, JAK3, TXK, BTK, BMX, and ACK1).

In cultured cells models, mobocertinib inhibits proliferation of cells driven by different EGFR exon 20 insertion mutation variants at 1.5- to 10-fold lower concentrations than WT-EGFR signalling inhibition. Moreover, mobocertinib inhibits proliferation of cells with the common EGFR activating mutations, L858R and exon 19 deletion (DEL19) with or without T790M, and of cells with EGFR uncommon activating mutations including G719X (where X is any other amino acid), S768I, and L861Q/R.

In mouse tumour implantation models, mobocertinib demonstrates tumour regression of human NSCLC xenografts with the EGFR exon 20 insertion [NPH], with EGFR-DEL19 or with EGFR-L858R+T790M. Tumour growth inhibition was observed in an engineered model expressing the EGFR exon 20 insertion mutation [ASV]. Mobocertinib also demonstrated tumour growth inhibition in engineered models expressing the HER2 exon 20 insertion mutations ([FQEA] and [VC]) and the HER2 mutants V659E and S310F.

Cardiac Electrophysiology

A concentration-dependent QTc interval prolongation of approximately 12.7 msec (90% CI: 8.69, 16.8) was observed at the steady-state C_max following mobocertinib 160 mg once daily doses based on a pharmacokinetic/pharmacodynamic analysis of data from 194 patients with advanced solid malignancies. Coadministration of EXKIVITY with moderate or strong CYP3A inhibitors may further prolong the QTc interval from baseline (see sections 4.3, 4.4, and 4.5).

Clinical efficacy and safety

Previously Treated EGFR Exon 20 Insertion Mutation-Positive Metastatic Non-Small Cell Lung Cancer

The efficacy and safety of EXKIVITY for the treatment of patients with EGFR exon 20 insertion mutation-positive locally advanced or metastatic NSCLC was demonstrated in a Phase 1/2 multicentre, single-arm, open-label study (AP32788-15-101). Eligible patients (N=86) with NSCLC who had previously been treated with platinum-based chemotherapy received EXKIVITY at a dose of 160 mg once daily until disease progression or intolerable toxicity. At enrolment, 60 (70%) patients had progressive disease,18 (21%) patients had stable disease, 1 patient (1.2%) had ongoing response to the prior therapy, and 7 (8%) patients had unknown disease status. Eligible patients were required to have histologically or cytologically confirmed locally advanced or metastatic disease (Stage IIIB or IV), a documented EGFR exon 20 insertion mutation by a local test, and adequate organ and bone marrow function. Patients with baseline brain metastases were required to be treated with surgery and/or radiation and be stable, without corticosteroids or evidence of new or enlarging brain metastases, before receiving EXKIVITY. Patients who had disease progression following response to an EGFR-TKI were excluded from the study.

The primary efficacy endpoint was confirmed objective response rate (cORR) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) by an independent review committee (IRC). Additional efficacy endpoints included investigator-assessed cORR, duration of response and time to response.

The study population characteristics were: median age 59 years (range: 27 to 80 years), age 75 years or older (7%), female (63%), White (26%), Asian (72%), never smokers (74%), ECOG performance status 0 (29%) or 1 (71%) and adenocarcinoma histology (99%). Twenty-eight (33%) patients had baseline brain metastases.

The median duration of follow-up was 25.0 months. Efficacy results from this study are summarized in Table 4.

IRC = independent review committee, CI = confidence interval, NE = Not estimable

^a. Kaplan-Meier estimate in confirmed responders only

^b. Based on observed duration of response

Limited intracranial efficacy was observed.

In the earlier dose-finding and expansion parts of the study, 28 patients with EGFR exon 20 insertion mutation-positive NSCLC previously treated with platinum-based chemotherapy received EXKIVITY at a dose of 160 mg once daily until disease progression or intolerable toxicity. The median duration of follow up in this population was 40.7 months. The cORR was 36% (95% CI: 19%, 56%) and 39% (95% CI: 22%, 59%), as determined by IRC and Investigator, respectively. The median cDOR determined by IRC and Investigator was 8.3 months (95% CI: 3.6, 17.5) and 13.9 months (95% CI: 3.9, 27.6), respectively.

The pharmacokinetics of mobocertinib and its active metabolites, AP32960 and AP32914, have been characterized in patients with cancer and in healthy subjects.

In patients receiving 160 mg mobocertinib once daily, the geometric mean (% coefficient of variation) steady-state C_max for mobocertinib, AP32960, and AP32914 was 70.4 (54.8), 40.6 (44.5), and 4.96 (50) ng/mL, respectively. The corresponding AUC₂₄ values at steady-state were 951 (53), 572 (43.1), and 68.1 (53.5) hr•ng/mL, respectively. The geometric mean (% coefficient of variation) C_max and AUC₂₄ values at steady-state for the combined molar exposure of mobocertinib, AP32960, and AP32914 were 202 (48.8) nM and 2760 (47.8) hr•nM, respectively. The steady-state AUC₂₄ of AP32960 and AP32914 was 61.6% and 7.33% of the AUC₂₄ for mobocertinib. After single- and multiple-dose administration, combined molar C_max and AUC₂₄ of mobocertinib, AP32960, and AP32914 was dose-proportional over the dose range of 5 to 180 mg once daily (0.03 to 1.1 times the recommended dosage). The geometric mean accumulation ratio for AUC₂₄ of mobocertinib after multiple-dose administration of 160 mg once daily was 1.03.

Absorption

Following administration of 160 mg EXKIVITY, the median time to peak concentration (T_max) was four hours. The absolute bioavailability of EXKIVITY is 37%.

There was no clinically meaningful effect of a high-fat meal (approximately 900 to 1000 calories with approximately 150, 250, and 500 to 600 calories derived from protein, carbohydrate, and fat, respectively) or low fat-meal (approximately 336 calories with approximately 37, 253, and 46 calories derived from protein, carbohydrate, and fat, respectively) on the combined molar C_max and AUC_inf of mobocertinib, AP32960, and AP32914 compared to administration after an overnight fast.

Distribution

Mobocertinib, AP32960, and AP32914 are 99.3%, 99.5%, and 98.6% bound to human plasma proteins and the binding is not concentration-dependent in vitro. The blood-to-plasma ratios are 0.763, 1.15, and 0.714 for mobocertinib, AP32960, and AP32914, respectively. Based on a population PK analysis, the geometric mean apparent volume of distribution at steady-state for mobocertinib is 3510 L.

Biotransformation

Mobocertinib is primarily metabolized by CYP3A4 in vitro. Following administration of a single 160 mg dose of radiolabelled mobocertinib, oxidation was the major metabolic pathway.

Elimination

Based on a population PK analysis, the geometric mean apparent oral clearance (CL/F) of mobocertinib was 108 L/hr and the geometric mean half-life was 17.6 hours.

Following administration of a single 160 mg dose of radiolabelled mobocertinib, 76% of the administered dose was recovered in faeces (approximately 6% as unchanged mobocertinib) and 3.57% of the administered dose was recovered in urine (approximately 1% as unchanged mobocertinib).

Specific populations

Hepatic impairment

The pharmacokinetics of mobocertinib is similar in patients with normal hepatic function and in patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST). The pharmacokinetics and safety of mobocertinib in patients with moderate or severe hepatic impairment have not been studied.

Renal impairment

The pharmacokinetics of mobocertinib is similar in patients with normal renal function and in patients with mild or moderate renal impairment (estimated glomerular filtration rate ≥ 30 mL/min). The pharmacokinetics and safety of mobocertinib in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min) have not been studied.

Effects of age, body weight, race and sex

Based on a population PK analysis, age, body weight, race, and sex have no clinically meaningful effect on the pharmacokinetics of mobocertinib.

Mobocertinib and its active metabolites demonstrated a low risk for off-target liabilities and for cardiovascular, respiratory, or central nervous system safety pharmacology effects when evaluated in vitro and in single and repeat-dose rat and dog toxicity studies of up to 3 months in duration. Mobocertinib did not show evidence of phototoxicity in a mouse fibroblast in vitro assay.

The main target organ toxicities associated with mobocertinib administration were similar between rats and dogs and were generally reversible. These toxicities included changes in the gastrointestinal (GI) tract (atrophy, single cell necrosis, and mononuclear cell infiltration), reproductive system (atrophy and single cell necrosis), haematological system (acute phase responses), and the squamous epithelium (decreased thickness) in multiple organs, such as the skin and oral cavity. Dose-limiting toxicities were considered GI-related and included weight loss, decreased food consumption and abnormal faecal changes.

Mobocertinib was not genotoxic in two in vitro assays and in an in vivo bone marrow micronucleus assessment in Sprague-Dawley rats. Carcinogenicity studies have not been performed with mobocertinib.

In a preliminary dose range-finding embryo-foetal development study in pregnant rats, at doses of 1.25, 2.5, 5, or 10 mg/kg, daily oral administration of mobocertinib during organogenesis (Days 6 to 20 postcoitum), resulted in maternal and foetal toxicity at 10 mg/kg (exposures approximately 2-fold higher than those achieved in humans at the recommended 160 mg dose). Maternal toxicity was evidenced by an adverse decrease in food consumption and body weight throughout the dosing period. There were adverse effects on embryo-foetal development, including embryo-lethality (embryo-foetal death) and effects on foetal growth (decreased foetal weight), but no clear evidence of teratogenicity (dysmorphogenesis).

Studies of fertility and early embryonic development and pre- and postnatal toxicology were not conducted with mobocertinib; however, an evaluation of the reproductive tract was conducted in the general toxicity studies in rats and dogs. There were changes that included decreases in organ weights affecting multiple reproductive organs (including ovaries, seminal vesicle/prostate gland, epididymis and/or uterus) and microscopic changes of decreased epithelial thickness/inflammation of the cervix/vagina and atrophy of the uterus, prostate gland, or mammary gland (males only) in rats and/or dogs. Based on these findings, mobocertinib may impair fertility in males and females of reproductive potential, although there is some evidence that these effects may be reversible.

EXKIVITY contains no inactive ingredients.

Capsule shell

Gelatin

Titanium dioxide

Printing ink

Shellac

Dehydrated alcohol

Isopropyl alcohol

Butyl alcohol

Propylene glycol

Strong ammonia solution

Black iron oxide

Potassium hydroxide

Purified water

Not applicable.

2 years

Do not store above 30 °C. Do not freeze.

Polychlorotrifluoroethylene (PCTFE)/ polyvinylchloride (PVC) blister with peel-off aluminium foil lidding in a carton, containing 112 capsules.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Takeda UK Limited

1 Kingdom Street, London

W2 6BD

United Kingdom

PLGB 16189/0124

Date of first authorisation: 17 March 2022

Date of Renewal: 04 November 2022

03 January 2023