FDA News: Issue 30, September 2021

Author: [AUTHOR] Published on 9/24/2021 5:00:00 AM

FDA Approves EXKIVITY (Mobocertinib) for the Treatment of Adult Patients with Locally Advanced or Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Whose Disease Has Progressed on or After Platinum-Based Chemotherapy

On September 15, 2021, the US Food and Drug Administration (FDA) approved EXKIVITY (mobocertinib) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

The approved recommended dosage of EXKIVITY is 160 mg orally once daily with or without food until disease progression or unacceptable toxicity. Swallow EXKIVITY capsules whole. Do not open, chew, or dissolve the contents of the capsules. 

EXKIVITY can cause life-threatening heart rate-corrected QT (QTc) prolongation, including Torsades de Pointes, which can be fatal, and requires monitoring of QTc and electrolytes at baseline and periodically during treatment. Increase monitoring frequency in patients with risk factors for QTc prolongation.

Avoid use of concomitant drugs which are known to prolong the QTc interval and use of strong or moderate CYP3A inhibitors with EXKIVITY, which may further prolong the QTc. 

Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of QTc prolongation. 

Additional information regarding dosage and administration as well as warnings and precautions about QTc prolongation and Torsades de Pointes, interstitial lung disease/pneumonitis, cardiac toxicity, diarrhea, or embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)
MOA: Mobocertinib is an EGFR kinase inhibitor that irreversibly binds to and inhibits EGFR exon 20 insertion mutations at lower concentrations than wild type EGFR.

General PK: After single- and multiple-dose administration, combined molar Cmax and AUC0-24h 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 at the approved recommended dosage.

Absorption: The median (min, max) Tmax of mobocertinib is 4 hours (1, 8 hours). The mean (%CV) absolute bioavailability is 37% (50%).

Distribution: The mean (SD) 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 mean (%CV) apparent volume of distribution of mobocertinib was 3,509 L (38%) at steady-state. 

Elimination: The mean (%CV) plasma elimination half-life of mobocertinib, AP32960, AP32914 were 18 hours (21%), 24 hours (20%), 18 hours (21%) at steady-state, respectively. The mean (%CV) apparent clearance of mobocertinib, AP32960, AP32914 were 138 L/hr (47%), 149 L/hr (36%), 159 L/hr (52%) at steady-state, respectively. 

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.

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. 

Drug Interactions
Strong or Moderate CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors with EXKIVITY. If concomitant use of moderate CYP3A inhibitors cannot be avoided, reduce the EXKIVITY dose and monitor the QTc interval more frequently with ECGs. Coadministration of EXKIVITY with strong or moderate CYP3A inhibitors increased mobocertinib plasma concentrations, which may increase the risk of adverse reactions, including QTc interval prolongation.

Strong or Moderate CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers with EXKIVITY. Coadministration of EXKIVITY with strong or moderate CYP3A inducers decreased mobocertinib plasma concentrations, which may reduce EXKIVITY anti-tumor activity.

CYP3A Substrates: Avoid concomitant use of hormonal contraceptives with EXKIVITY. Avoid concomitant use of EXKIVITY with other CYP3A substrates where minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with the approved product Prescribing Information. Coadministration of EXKIVITY with CYP3A substrates may decrease plasma concentrations of CYP3A substrates, which may reduce the efficacy of these substrates.

Drugs that Prolong the QTc Interval: Avoid concomitant use of other medications known to prolong the QTc interval with EXKIVITY. If concomitant use is unavoidable, monitor the QTc interval more frequently with ECGs. EXKIVITY can cause QTc interval prolongation. Coadministration of EXKIVITY with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.

Use in Specific Populations
No clinically meaningful differences in the PK 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), or mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST)-to-moderate (total bilirubin ≥ 1.5 to 3 times ULN and any AST) hepatic impairment. The effect of severe (eGFR > 3 times ULN and any AST) hepatic impairment on mobocertinib PK is unknown.

Efficacy and Safety
Efficacy of EXKIVITY was evaluated in a pooled subset of patients with EGFR exon 20 insertion mutation-positive metastatic or locally advanced NSCLC whose disease had progressed on or after platinum-based chemotherapy enrolled in an international, open-label, multicohort clinical trial. The major efficacy outcome measure was ORR according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by blinded independent central review (BICR). Additional information regarding efficacy trial can be found in the full prescribing information linked below.

The most common (> 20%) adverse reactions are 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.

Full prescribing information is available at https://go.usa.gov/xMBxH.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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