Hyrnuo Drug Information

HYRNUO is indicated for the treatment of adult patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have HER2 ( ERBB2 ) tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Patient Selection

Select patients for treatment of locally advanced or metastatic non-squamous NSCLC based on the presence of HER2 ( ERBB2 ) TKD activating mutations in tumor specimens. Information on FDA-approved tests is available at http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage

The recommended dosage of HYRNUO is 20 mg orally twice daily with food, until disease progression or unacceptable toxicity. Swallow tablets whole. Do not cut, crush, or chew tablets.

Missed Dose If a dose is missed, take the missed dose as soon as you remember prior to the next scheduled dose. Do not take 2 doses at the same time to make up for the missed dose. Vomited Dose If a dose is vomited, do not take an additional dose.

Resume dosing at the next scheduled time.

Dosage Modifications for Adverse Reactions

The recommended dosage reductions for adverse reactions are provided in Table 1. Table 2: Recommended HYRNUO Interstitial lung disease (ILD)/pneumonitis s for Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce HYRNUO dosage as shown in Table 3.

After the CYP3A inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the HYRNUO dosage that was used prior to initiating the inhibitor. Table 3: Recommended HYRNUO Dosage Modifications for Concomitant Use with Strong CYP3A Inhibitors

Clinical Trial 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 in the WARNINGS AND PRECAUTIONS reflects exposure to HYRNUO at 20 mg orally twice daily in 268 patients with locally advanced or metastatic NSCLC harboring HER2 and/or other mutations from the SOHO-01 study. In this pooled safety population, the most common (>20%) adverse reactions were diarrhea, rash, stomatitis, and paronychia.

The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased potassium, increased lipase, decreased lymphocyte count, decreased sodium, increased amylase, increased ALT, and increased AST. The safety of HYRNUO at 20 mg orally twice daily was evaluated in 136 patients with locally advanced or metastatic NSCLC harboring HER2 activating mutations who had received prior systemic therapy in the SOHO-01 study. The most common adverse reactions (>20%) in patients who received HYRNUO were diarrhea, rash, paronychia, stomatitis, and nausea.

Serious adverse reactions occurred in 31% of patients who received HYRNUO. Permanent discontinuation of HYRNUO due to an adverse reaction occurred in 3.7% of patients. Adverse reactions which resulted in permanent discontinuation were corneal epithelial microcysts, hepatic function abnormal, electrocardiogram QT prolonged, pain in extremity and dyspnea (0.7%, 1 patient each).

Dosage interruptions of HYRNUO due to an adverse reaction occurred in 46% of patients. Adverse reactions which resulted in dosage interruptions in >3% of patients were diarrhea, hypokalemia, nausea, decreased appetite, and pneumonia. Dose reductions of HYRNUO due to adverse reactions occurred in 28% of patients.

Adverse reactions which resulted in dose reductions in >2% of patients were diarrhea, rash, and hypokalemia. Table 4 summarizes the adverse reactions in SOHO-01 (Groups D and E). Table 4: Adverse Reactions (≥10%) in Patients with NSCLC with HER2 Activating Mutations Who Received HYRNUO in SOHO-01 (Groups D and E) Clinically relevant adverse reactions in <10% of patients who received HYRNUO included edema (8%), cardiac arrhythmia (6%; includes arrhythmia, atrioventricular block complete, electrocardiogram QT prolonged, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia) and alopecia (3.7%).

Table 5 summarizes the laboratory abnormalities observed in SOHO-01 (Groups D and E).

Effect of Other Drugs on HYRNUO Table 6 describes drug interactions where concomitant use of another drug affects HYRNUO. Table 6: Drug Interactions that Affect HYRNUO Strong and Moderate CYP3A Inhibitors Prevention or management Strong CYP3A Inhibitors: Avoid concomitant use of HYRNUO with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce HYRNUO dosage.

Moderate CYP3A Inhibitors: Monitor patients for increased HYRNUO-associated adverse reactions. Mechanism and Clinical Effect Sevabertinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inhibitor may increase sevabertinib plasma concentrations, which may increase the risk of HYRNUO-associated adverse reactions.

Concomitant use with a strong or moderate CYP3A inducer may decrease sevabertinib plasma concentrations, which may decrease the effectiveness of HYRNUO.

Effects of HYRNUO on Other Drugs Table 7 describes drug interactions where concomitant use of HYRNUO affects another drug. Table 7: HYRNUO Drug Interactions that Affect Other Drugs Certain CYP3A Substrates Prevention or management Avoid concomitant use of HYRNUO with CYP3A substrates where minimal increases in the concentration may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information of the CYP3A substrate. Mechanism and Clinical Effect Sevabertinib is a weak to moderate CYP3A inhibitor.

Sevabertinib increases exposure of CYP3A substrates, which may increase the risk of adverse reactions related to these substrates. Certain P-gp Substrates Prevention or management Refer to the Prescribing Information for P-gp substrates where minimal increases in the concentration may lead to serious adverse reactions. Mechanism and Clinical Effect Sevabertinib is a P-gp inhibitor.

CYP1A1 Substrates Prevention or management Refer to the Prescribing Information of CYP1A1 substrates. Mechanism and Clinical Impact Sevabertinib is an inhibitor of CYP1A1 in vitro.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, HYRNUO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of HYRNUO in pregnant women to inform a drug-associated risk. In embryo-fetal development studies, oral administration of sevabertinib to pregnant rats during the period of organogenesis resulted in alterations to growth at maternal exposures ≥0.18 times the human exposure based on area under the curve (AUC) at the clinical dose of 20 mg twice daily.

Animal studies with disrupted or depleted HER2/EGFR and in vitro assays have demonstrated that inhibition of HER2 and/or EGFR results in structural abnormalities, alteration to growth, and embryo-fetal and infant mortality (see Data ). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Sevabertinib treatment resulted in maternal toxicity (reduced body weight and body weight gain) and a reduction in fetal weights at ≥6 mg/kg/day (≥0.18 times the human exposure based on AUC at the clinical dose). Additional Nonclinical Data A literature-based assessment of the effects on reproduction in mouse models with disrupted or depleted HER2 / EGFR demonstrated that HER2/EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. In a human-induced pluripotent stem cell-based assay, sevabertinib reduced cardiomyocyte and hepatocyte differentiation markers.

Pediatric Use The safety and effectiveness of HYRNUO have not been established in pediatric patients.