1. Mann, Janelle E. PharmD, BCOP

Article Content

What is mobocertinib?

Mobocertinib is a novel small-molecule oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor specifically designed to target EGFR exon 20 insertion mutants.


How does mobocertinib work?

Mobocertinib irreversibly binds to and inhibits EGFR exon 20 insertion mutations at lower concentrations than wild-type EGFR. Mobocertinib has two pharmacologically active metabolites, AP32960 and AP32914, which exhibit inhibitory profiles similar to mobocertinib. Additionally, mobocertinib inhibits HER2 and HER4, members of the EGFR family, along with B-lymphocyte kinase activity.


What is this approved for?

Mobocertinib is approved for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have an EGFR exon 20 insertion mutation, detected by an FDA-approved test, and have progressed on or after platinum-based chemotherapy. Mobocertinib received FDA approval through the accelerated approval pathway, based on overall response rate and duration of response. Confirmatory trials are required to verify clinical benefit in order to maintain approval for this indication.


What is the basis for this approval?

Mobocertinib was approved for previously treated EGFR exon 20 insertion mutation NSCLC patients based on results from the Study AP32788-15-101 trial (JAMA Oncol 2021; doi: 10.1001/jamaoncol.2021.4761). The trial was an international, open-label, multi-cohort clinical trial of mobocertinib at 160 mg by mouth daily as monotherapy in patients with locally advanced or metastatic EGFR exon 20 insertion mutated NSCLC. A total of 114 patients were part of the efficacy population.


The primary endpoint was objective response rate. The observed objective response rate was 28 percent (95% CI, 20-37) by blinded independent central review. Key secondary endpoints observed were median duration of response of 17.5 months, median progression-free survival of 7.3 months, and median overall survival of 13 months. Treatment-related adverse events occurred in 99 percent of patients, including Grade 3 or greater at 47 percent.


How do you administer this drug?

Mobocertinib has a starting dose of 160 mg and is administered as 4 x 40 mg capsules taken by mouth daily with or without food. Capsules should be swallowed whole; do not open, chew, or dissolve capsule contents.


No premedications are required for mobocertinib. It is listed as minimal or low (<30%) emetic potential.


What are the common side effects?


* Gastrointestinal: diarrhea (92%), nausea (37%), vomiting (40%), abdominal pain (18%), decreased appetite (39%), dyspepsia (11%), gastroesophageal reflux disease (15%), stomatitis (46%)


* Dermatologic: rash (78%), paronychia (39%), pruritus (24%), xeroderma (32%), alopecia (19%)


* Increased lab values: amylase (40%), lipase (35%), aspartate aminotransferase (21%), alanine aminotransferase (22%), alkaline phosphatase (25%), serum creatinine (52%)


* Neuromuscular & skeletal: asthenia ( 

* Hematologic: anemia (59%), thrombocytopenia (26%), leukopenia (25%), lymphocytopenia (52%)


* Respiratory: cough (24%), dyspnea (15%), rhinorrhea (13%), upper respiratory tract infection (16%)


* Decreased lab values: albumin (23%), magnesium (23%), potassium (29%), sodium (20%)


* Ophthalmic: Ocular toxicity (11%)


* Other: weight loss (21%), fatigue ( 

What are the uncommon side effects?

Cardiovascular toxicities including atrial fibrillation, cardiac failure, edema, prolonged QT interval on ECG, and ventricular arrhythmia have been observed. Palmar-plantar erythrodysesthesia, peripheral neuropathy, acute kidney injury, pleural effusions, pneumonitis, and fever occurred in less than 10 percent of patients on mobocertinib.


Are there any important drug interactions?

Mobocertinib is a major substrate of CYP3A4 and use with strong CYP3A4 or moderate inducers will decrease mobocertinib concentration and effectiveness and should be avoided. Use with strong CYP3A4 inhibitors will increase risk of toxicities with mobocertinib and should be avoided. Mobocertinib is also a weak inducer of CYP3A4 and may decrease concentrations of drugs metabolized via these pathways. Mobocertinib is an inhibitor of P-gp and BCRP, and it can cause QTc interval prolongation. Avoid concomitant use of other medications known to prolong the QTc interval, if use is unavoidable, monitor QTc interval more frequently with ECGs.


How do I adjust the dose in the setting of renal or hepatic insufficiency?

There are no recommended dose adjustments for renal or hepatic impairment.


What should patients know about this drug?

Mobocertinib can cause severe diarrhea. Nearly all patients experienced diarrhea with 20 percent of patients experiencing Grade 3 or greater toxicities. The median time to onset was 5 days, but diarrhea has occurred within 24 hours after administration.


What else should I know about mobocertinib?

A comprehensive medication review is recommended at the start of treatment. If a patient is started on new medications, it is recommended to evaluate for drug-drug interactions as mobocertinib has significant drug interactions with one of the most common CYP pathways, CYP3A4. Additionally, it is recommended to avoid concomitant medications known to prolong the QTc interval.


QTc prolongation and Torsades de Pointes have been reported with mobocertinib. A QTc interval of greater than 500 msec was observed in 1.2 percent of patients and 11 percent had a change of greater than 60 msec from the baseline. Patients were not allowed on the clinical trial if their baseline QTc interval was greater than 470 msec.


Patients should start on an antidiarrheal agent, such as loperamide, at the first sign of diarrhea or increased bowel movements, as well as increase fluid and electrolyte intake. Dose reductions may be warranted or permanently discontinued based on severity of diarrhea.


Significant cardiovascular toxicities (including decreased ejection fraction, cardiomyopathy, and congestive heart failure) have been observed with mobocertinib. Heart failure was seen in 2.7 percent of patients. In addition to causing QTc prolongation, some resulting in Torsades de Pointes, atrial fibrillation, ventricular tachycardia, first degree atrioventricular block has occurred in 1 percent of patients.


What useful resources are available?


* FDA Accelerated Approval:


* Prescribing Information:


Any clinical trials for mobocertinib?

Trials are ongoing for use of mobocertinib in moderate or severe hepatic failure, as well as severe kidney problems. Learn more at


JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/Manager, Clinical Pharmacy Services at Washington University School of Medicine, St. Louis, Mo. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.

Janelle E. Mann, Pha... - Click to enlarge in new windowJanelle E. Mann, PharmD, BCOP. Janelle E. Mann, PharmD, BCOP
Ramaswamy Govindan, ... - Click to enlarge in new windowRamaswamy Govindan, MD. Ramaswamy Govindan, MD