Products - Exkivity (mobocertinib)

2.1 Recommended Evaluation and Testing Before Initiating EXKIVITY

Before initiating EXKIVITY, evaluate QTc and electrolytes and correct abnormalities in sodium, potassium, calcium, and magnesium [see Warnings and Precautions (5.1)].

2.2 Patient Selection

Select patients with locally advanced or metastatic NSCLC for treatment with EXKIVITY based on the presence of EGFR exon 20 insertion mutations [see Clinical Studies (14)]. Information on FDAapproved tests is available at: http://www.fda.gov/CompanionDiagnostics.

2.3 Recommended Dosage

The recommended dosage of EXKIVITY is 160 mg orally once daily until disease progression or unacceptable toxicity.

Take EXKIVITY with or without food [see Clinical Pharmacology 12.3], at the same time each day. Swallow EXKIVITY capsules whole. Do not open, chew or dissolve the contents of the capsules.

If a dose is missed by more than 6 hours, skip the dose and take the next dose the following day at its regularly scheduled time.

If a dose is vomited, do not take an additional dose. Take the next dose as prescribed the following day.

2.4 Dosage Modifications for Adverse Reactions

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

Table 1: Recommended EXKIVITY Dose Reductions

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

Table 2: Recommended Dosage Modifications for EXKIVITY Adverse Reactions

ULN = upper limit of normal
^* Graded per Common Terminology Criteria for Adverse Events Version 5.0

2.5 Dosage Modifications for Moderate CYP3A Inhibitors

Avoid concomitant use of moderate CYP3A inhibitors with EXKIVITY. If concomitant use of a moderate CYP3A inhibitor cannot be avoided, reduce the EXKIVITY dose by approximately 50% (i.e., from 160 to 80 mg, 120 to 40 mg, or 80 to 40 mg) and monitor the QTc interval more frequently. After the moderate CYP3A inhibitor has been discontinued for 3 to 5 elimination half-lives, resume EXKIVITY at the dose taken prior to initiating the moderate CYP3A inhibitor [see Drug Interactions (7.1)].

2.6 Dosage Modifications for Patients with Severe Renal Impairment

Reduce the EXKIVITY dose by approximately 50% (i.e., from 160 to 80 mg, 120 to 40 mg, or 80 to 40 mg) and monitor the QTc interval more frequently for patients with severe renal impairment [see Use in Specific Populations (8.6)].

5.1 QTc Prolongation and Torsades de Pointes

EXKIVITY can cause life-threatening heart rate-corrected QT (QTc) prolongation, including Torsades de Pointes, which can be fatal. In the 250 patient subset of the pooled EXKIVITY safety population who had scheduled and unscheduled electrocardiograms (ECGs) [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)], 1.2% of patients had a QTc interval >500 msec and 11% of patients had a change-from-baseline QTc interval >60 msec. Grade 4 Torsades de Pointes occurred in 1 patient (0.4%). Clinical trials of EXKIVITY did not enroll patients with baseline QTc greater than 470 msec.

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 QT syndrome, heart disease, severe renal impairment, or electrolyte abnormalities. Avoid use of concomitant drugs which are known to prolong the QTc interval. Avoid concomitant use of strong or moderate CYP3A inhibitors with EXKIVITY [see Drug Interactions (7.1)], which may further prolong the QTc [see Drug Interactions (7.3)].

Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of the QTc prolongation [see Dosage and Administration (2.4)].

5.2 Interstitial Lung Disease (ILD)/Pneumonitis

EXKIVITY can cause ILD/pneumonitis, which can be fatal. In the pooled EXKIVITY safety population [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 4.3% of patients including 0.8% Grade 3 events and 1.2% fatal events.

Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold EXKIVITY in patients with suspected ILD/pneumonitis and permanently discontinue EXKIVITY if ILD/pneumonitis is confirmed [see Dosage and Administration (2.4)].

5.3 Cardiac Toxicity

EXKIVITY can cause cardiac toxicity (including decreased ejection fraction, cardiomyopathy, and congestive heart failure) resulting in heart failure which can be fatal. In the pooled EXKIVITY safety population [see Adverse Reactions (6.1)], heart failure occurred in 2.7% of patients including 1.2% Grade 3 reactions, 0.4% Grade 4 reactions, and one (0.4%) fatal case of heart failure.

EXKIVITY can cause QTc prolongation resulting in Torsades de Pointes [see Warnings and Precautions (5.1)]. Atrial fibrillation (1.6%), ventricular tachycardia (0.4%), first degree atrioventricular block (0.4%), second degree atrioventricular block (0.4%), left bundle branch block (0.4%), supraventricular extrasystoles (0.4%) and ventricular extrasystoles (0.4%) also occurred in patients receiving EXKIVITY.

Monitor cardiac function, including assessment of left ventricular ejection fraction at baseline and during treatment. Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity [see Dosage and Administration (2.4)].

5.4 Diarrhea

EXKIVITY can cause diarrhea, which can be severe. In the pooled EXKIVITY safety population [see Adverse Reactions (6.1)], diarrhea occurred in 93% of patients, including 20% Grade 3 and 0.4% Grade 4. The median time to first onset of diarrhea was 5 days but diarrhea has occurred within 24 hours after administration of EXKIVITY. In the 48% of patients whose diarrhea resolved, the median time to resolution was 3 days. Diarrhea may lead to dehydration or electrolyte imbalance, with or without renal impairment. Treat diarrhea promptly.

Advise patients to start an antidiarrheal agent (e.g., loperamide) at first sign of diarrhea or increased bowel movement frequency and to increase fluid and electrolyte intake.

Monitor electrolytes and withhold, reduce the dose or permanently discontinue EXKIVITY based on the severity [see Dosage and Administration (2.4)].

5.5 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, EXKIVITY can cause fetal harm when administered to a pregnant woman. Oral administration of mobocertinib to pregnant rats during the period of organogenesis resulted in embryolethality at maternal exposures approximately 1.7 times the human exposure based on area under the curve (AUC) at the 160 mg once daily clinical dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with EXKIVITY [see Drug Interactions (7.2)] and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with EXKIVITY and for 1 week after the last dose of EXKIVITY [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to EXKIVITY as a single agent at a dose of 160 mg orally once daily in 256 patients, including 114 patients with EGFR exon 20 insertion mutation-positive locally advanced or metastatic NSCLC from Study AP32788-15-101, and patients with other solid tumors. Forty-eight percent (48%) were exposed for 6 months or longer and 12% were exposed for greater than one year. The most common (>20%) adverse reactions were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, increased amylase, increased lipase, decreased potassium, decreased hemoglobin, increased creatinine, and decreased magnesium

EGFR Exon 20 Insertion Mutation-Positive Locally Advanced or Metastatic NSCLC Previously Treated with Platinum-Based Chemotherapy

The safety of EXKIVITY was evaluated in a subset of patients in Study AP32788-15-101 with EGFR exon 20 insertion mutation-positive locally advanced or metastatic NSCLC who received prior platinum-based chemotherapy [see Clinical Studies (14)]. Patients with a history of interstitial lung disease, drug-related pneumonitis, radiation pneumonitis that required steroid treatment; significant, uncontrolled, active cardiovascular disease; or prolonged QTc interval were excluded from enrollment in this trial. A total of 114 patients received EXKIVITY 160 mg once daily until disease progression or unacceptable toxicity; 60% were exposed for 6 months or longer and 14% were exposed for greater than 1 year.

Serious adverse reactions occurred in 46% of patients who received EXKIVITY. Serious adverse reactions in ≥2% of patients included diarrhea, dyspnea, vomiting, pyrexia, acute kidney injury, nausea, pleural effusion, and cardiac failure. Fatal adverse reactions occurred in 1.8% of patients who received EXKIVITY, including cardiac failure (0.9%), and pneumonitis (0.9%).

Permanent discontinuation occurred in 17% of patients who received EXKIVITY. Adverse reactions requiring permanent discontinuation of EXKIVITY in at least ≥2% of patients were diarrhea and nausea.

Dosage interruptions of EXKIVITY due to an adverse reaction occurred in 51% of patients. Adverse reactions which required dosage interruption in >5% of patients included diarrhea, nausea and vomiting.

Dose reductions of EXKIVITY due to an adverse reaction occurred in 25% of patients. The adverse reaction requiring dose reduction in >5% of patients was diarrhea.

Table 3 summarizes the adverse reactions in Study AP32788-15-101.

Table 3: Adverse Reactions (≥10%) in Patients with EGFR Exon 20 Insertion Mutation-Positive NSCLC Whose Disease Has Progressed on or after Platinum-Based Chemotherapy in Study AP32788-15-101

^* Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 5)
^** Events of Grade 3 only (no Grade 4 occurred)
^a Stomatitis includes angular cheilitis, aphthous ulcer, cheilitis, mouth ulceration, mucosal inflammation, odynophagia, and stomatitis.
^b Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, and gastrointestinal pain.
^c Rash includes acne, dermatitis, dermatitis acneiform, rash, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, and urticaria.
^d Paronychia includes nail bed tenderness, nail disorder, nail infection, onycholysis, and paronychia.
^e Musculoskeletal pain includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.
^f Fatigue includes asthenia, and fatigue.
^g Cough includes cough, productive cough, and upper-airway cough syndrome.
^h Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, sinusitis, and upper respiratory tract infection.
ⁱ Dyspnea includes dyspnea, and dyspnea exertional.
^j Ocular toxicity includes dry eye, eye pruritus, abnormal sensation in eye, eye discharge, blepharitis, trichiasis, conjunctival hemorrhage, vitreous floaters, blurred vision and corneal edema.
^k QTc interval prolongation includes electrocardiogram QT prolonged, and ventricular arrhythmia.
^l Hypertension includes blood pressure increased, and hypertension.

Clinically relevant adverse reactions in <10% of patients receiving EXKIVITY included edema (9%), acute kidney injury (8%), peripheral neuropathy (7%), palmar-plantar erythrodysesthesia (4.4%), pneumonitis (2.6%) and cardiac failure (2.6%).

Table 4 summarizes the laboratory abnormalities in Study AP32788-15-101.

Table 4: Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients with EGFR Exon 20 Insertion Mutation-Positive NSCLC Whose Disease Has Progressed on or after Platinum-Based Chemotherapy in Study AP32788-15-101

^* Grades per NCI CTCAE v5.0
^** The denominator used to calculate the rate varied from 93 to 113 based on the number of patients with a baseline and at least one post-treatment value. The laboratory abnormalities are values that reflect worsening from baseline.

7.1 Effect of Other Drugs on EXKIVITY

12.1 Mechanism of Action

Mobocertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR) that irreversibly binds to and inhibits 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 other EGFR family members (HER2 and HER4) and one additional kinase (BLK) at clinically relevant concentrations (IC₅₀ values <2 nM).

In cultured cell models, mobocertinib inhibited the proliferation of cells driven by different EGFR exon 20 insertion mutation variants at 1.5- to 10-fold lower concentrations than WT-EGFR signaling inhibition.

In animal tumor implantation models, mobocertinib exhibited anti-tumor activity against xenografts with the EGFR exon 20 insertions NPH or ASV.

12.2 Pharmacodynamics

Cardiac Electrophysiology
The largest mean increase in QTc was 23.0 msec (UCI: 25.5 msec) following administration of EXKIVITY 160 mg once daily. The increase in QTc interval was concentration-dependent.

The largest mean increase in the PR interval was 12.4 msec (UCI: 15.0 msec). PR interval prolongation >220 msec occurred in 5% of patients taking EXKIVITY 160 mg once daily.

12.3 Pharmacokinetics

After single- and multiple-dose administration, combined molar C_max and AUC_0-24h of mobocertinib and its active metabolites, AP32960 and AP32914, was dose-proportional over the dose range of 5 to 180 mg once daily (0.03 to 1.1 times the approved recommended dosage). No clinically meaningful accumulation was observed after administration of EXKIVITY 160 mg once daily based on the AUC ratio of mobocertinib.

Absorption
The median (min, max) time to peak concentration (T_max) of mobocertinib is 4 hours (1, 8 hours). The mean (%CV) absolute bioavailability is 37% (50%).

Effect of Food
No clinically meaningful differences in the combined molar AUC and C_max of mobocertinib, AP32960, and AP32914 were observed following administration of a high-fat meal (approximately 900 to 1000 calories, with 150 calories from protein, 250 calories from carbohydrate and 500 to 600 calories from fat) or a low fat-meal (approximately 336 calories, with 37 calories from protein, 253 calories from carbohydrate, and 46 calories from fat) compared to administration after an overnight fast.

Distribution

Mobocertinib was bound to human plasma proteins in a concentration independent manner in vitro from 0.5 to 5.0 μM. The mean (standard deviation) bound fraction was 99.3% (0.11%) for mobocertinib, 99.5% (0.16%) for AP32960 and 98.6% (0.36%) for AP32914 in vitro.

The blood-to-plasma ratio was 0.76 for mobocertinib, 1.2 for AP32960 and 0.71 for AP32914.

The mean (%CV) apparent volume of distribution (Vss/F) of mobocertinib was 3,509 L (38%) at steady-state.

Elimination

The mean (%CV) plasma elimination half-life of mobocertinib was 18 hours (21%) at steady-state.
The mean apparent oral clearance (CL/F) (%CV) of mobocertinib was 138 L/hr (47%) at steady-state.

The mean (%CV) plasma elimination half-life of AP32960 was 24 hours (20%) at steady-state.
The mean apparent oral clearance (CL/F) (%CV) of AP32960 was 149 L/hr (36%) at steady-state.

The mean (%CV) plasma elimination half-life of AP32914 was 18 hours (21%) at steady-state.
The mean apparent oral clearance (CL/F) (%CV) of AP32914 was 159 L/hr (52%) at steady-state.

Metabolism
Mobocertinib is primarily metabolized by CYP3A. The two active metabolites, AP32960 and AP32914, are equipotent to mobocertinib and account for 36% and 4% of the combined molar AUC, respectively.

Excretion
Following administration of a single 160 mg oral dose of radiolabeled mobocertinib, approximately 76% of the dose was recovered in feces (approximately 6% as unchanged mobocertinib) and approximately 4% was recovered in urine (approximately 1% as unchanged mobocertinib). The percentage of the administered dose recovered in feces and urine for AP32960 was approximately 12% and 1%, respectively. The metabolite AP32914 was below the detection limit in urine and feces.

Specific Populations
No clinically meaningful differences in the pharmacokinetics of mobocertinib were observed based on age (18 to 86 years), race (White, Black, Asian), sex, body weight (37.3 to 132 kg), mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2 by MDRD equation), or mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST)-to-severe (total bilirubin >3 times ULN and any AST) hepatic impairment.

Patients with Renal Impairment
Following administration of a single 80 mg oral dose of EXKIVITY, the unbound combined molar AUC of mobocertinib and its active metabolites was increased by 112% in subjects with severe renal impairment (eGFR <30 mL/min/1.73 m² by MDRD equation) as compared to subjects with normal renal function (eGFR ≥90 mL/min/1.73 m² by MDRD equation).

Drug Interaction Studies
Clinical Studies and Model-Informed Approaches

Effect of CYP3A Inhibitors on Mobocertinib: Coadministration of EXKIVITY with multiple doses of itraconazole or ketoconazole (strong CYP3A inhibitors) is predicted to increase the steady-state combined molar AUC of mobocertinib and its active metabolites by 374 to 419%.

Coadministration of EXKIVITY with multiple doses of a moderate CYP3A inhibitor is predicted to increase the steady-state combined molar AUC of mobocertinib and its active metabolites by approximately 100-200%.

Effect of CYP3A Inducers on Mobocertinib: Coadministration of EXKIVITY with multiple doses of rifampin (a strong CYP3A inducer) is predicted to decrease the steady-state combined molar AUC of mobocertinib and its active metabolites by 92%.

Coadministration of EXKIVITY with multiple doses of efavirenz (a moderate CYP3A inducer) is predicted to decrease the steady-state combined molar AUC of mobocertinib and its active metabolites by 58%.

Effect of Mobocertinib on CYP3A Substrates: Coadministration of EXKIVITY 160 mg once daily with oral or intravenous midazolam (a CYP3A substrate) decreased the AUC of midazolam by 32% and 16%, respectively.

Effect of Mobocertinib on P-gp Substrates: No clinically meaningful differences in the pharmacokinetics of digoxin or dabigatran etexilate (P-gp substrates) are predicted when coadministered with multiple doses of EXKIVITY.

Effect of Mobocertinib on BCRP Substrates: The clinical significance of changes in the pharmacokinetics of a BCRP substrate (e.g., sulfasalazine) when coadministered with multiple doses of EXKIVITY is unknown.

In Vitro Studies

CYP Enzymes: 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. At clinically relevant concentrations, mobocertinib does not inhibit BSEP, MATE1, MATE2-K, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2.

Mobocertinib is a substrate of P-gp. Mobocertinib is not a substrate of BCRP, OATP1B1, and OATP1B3.