SOHO-01 TRIAL DESIGN

Warnings & Precautions

Diarrhea

HYRNUO can cause severe diarrhea that can lead to dehydration and electrolyte imbalances.

In the pooled safety population, diarrhea was reported in 89% of patients who received HYRNUO including 16% Grade 3. The median time to first onset of any grade diarrhea was four days. Dosage interruptions occurred in 15% of patients, and dose reductions occurred in 14% of patients.

At the first sign of diarrhea or increased bowel movement frequency, instruct patients to start an antidiarrheal treatment (e.g., loperamide), and to increase their fluid and electrolyte intake. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity.

Hepatotoxicity

HYRNUO can cause severe hepatotoxicity characterized by elevations of liver function tests.

In the pooled safety population, based on adverse reaction data, hepatotoxicity occurred in 29% of patients treated with HYRNUO, including 3.1% Grade 3 and 0.3% Grade 4.

Based on laboratory data, 41% of patients treated with HYRNUO experienced increased alanine aminotransferase (ALT), including 2.5% Grade 3 and 0.4% Grade 4. Increased aspartate aminotransferase (AST) occurred in 44% of patients treated with HYRNUO, including 2.5% Grade 3. Increased bilirubin occurred in 15% of patients treated with HYRNUO. The median time to first onset of AST or ALT elevation was 1.4 (range: 0.2 to 24.1) months.

HYRNUO was interrupted for an adverse reaction of hepatotoxicity in 4.2% of patients, the dose was reduced in 4.9%, and permanently discontinued in 0.3%.

Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to the first administration of HYRNUO, every 2 weeks for the first month, and then monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity.

Interstitial Lung Disease/Pneumonitis

HYRNUO can cause severe interstitial lung disease (ILD)/pneumonitis.

In the pooled safety population, ILD/pneumonitis occurred in four patients (1.4%) treated with HYRNUO, including 0.3% Grade 3. One patient required interruption of HYRNUO.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Discontinue HYRNUO upon confirmation of ILD/pneumonitis.

Left Ventricular Dysfunction

HYRNUO can cause severe left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has occurred with anti-HER2 therapies, including HYRNUO.

Treatment with HYRNUO has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment. In the pooled safety population, LVEF decrease occurred in one patient (0.3%) treated with HYRNUO. This Grade 3 LVEF decrease required permanent discontinuation of HYRNUO, and the event recovered.

Evaluate LVEF prior to initiation of HYRNUO and monitor at regular intervals during treatment and as clinically indicated. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity.

Ocular Toxicity

HYRNUO can cause ocular toxicity.

In the pooled safety population, ocular toxicity occurred in 17% of patients treated with HYRNUO, including 11% Grade 1, 4.9% Grade 2, and 0.3% Grade 3 (one case of corneal epithelial microcysts with temporary unilateral blindness).

Promptly refer patients presenting with new or worsening eye symptoms to an ophthalmologist. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity.

Pancreatic Enzyme Elevation

HYRNUO can cause elevations of amylase and lipase levels.

In the pooled safety population, based on laboratory data, increased amylase occurred in 39% of patients treated with HYRNUO, including 3.9% Grade 3 and 0.7% Grade 4. Increased lipase occurred in 48% of patients treated with HYRNUO, including 13% Grade 3 and 1.1% Grade 4. Four patients (1.4%) required interruption of HYRNUO due to increased lipase and three (1%) required interruption of HYRNUO due to increased amylase. One patient (0.3%) required dose reduction of HYRNUO due to increased amylase. The median time to onset of increased amylase/lipase was 0.7 months (range: 0.2 to 20.4 months).

Monitor amylase and lipase regularly during treatment with HYRNUO. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity.

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, HYRNUO can cause fetal harm when administered to a pregnant woman. 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.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with HYRNUO and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with HYRNUO and for 1 week after the last dose.

Adverse Reactions

In SOHO-01, serious adverse reactions occurred in 33% of patients who received HYRNUO. Serious adverse reactions in ≥2% of patients were diarrhea (3.7%), dyspnea (3.1%), vomiting (3.7%), pneumonia (2.6%), and pleural effusion (2.1%). A fatal adverse reaction of cerebral infarction occurred in one patient (0.5%) who received HYRNUO.

The most common adverse reactions (>20%) in patients who received HYRNUO were diarrhea (90%), rash (76%), stomatitis (37%), paronychia (36%), nausea (22%) and weight decreased (22%).

The most common (≥2%) Grade 3 or 4 laboratory abnormalities were lipase increased (18%), potassium decreased (18%), phosphate decreased (13%), lymphocyte count decreased (4.6%), sodium decreased (5%), amylase increased (5%), hemoglobin decreased (3.7%), ALT increased (3.2%), and increased AST (2.6%). Laboratory abnormalities in <20% of patients who received HYRNUO include bilirubin increased (19%; all were Grades 1 and 2), platelet count decreased, and neutrophil count decreased (16% each).

Clinically relevant adverse reactions in <15% of patients who received HYRNUO included abdominal pain (14%), cardiac arrhythmia (10%; including arrhythmia, atrial fibrillation, atrial tachycardia, atrioventricular block complete, atrioventricular block first degree, electrocardiogram QT prolonged, sinus arrhythmia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, and ventricular extrasystoles), and alopecia (7%).

Drug Interactions

Effects of Other Drugs on HYRNUO – 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. Monitor patients for increased HYRNUO-associated adverse reactions with moderate CYP3A inhibitors. Avoid concomitant use of HYRNUO with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce HYRNUO dose.

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

Effects of HYRNUO on Other Drugs – 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. 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.

Sevabertinib is a P-gp inhibitor. Sevabertinib increases exposure of P-gp substrates, which may increase the risk of adverse reactions related to these substrates. Refer to the Prescribing Information for P-gp substrates where minimal increases in the concentration may lead to serious adverse reactions.

Sevabertinib is an inhibitor of CYP1A1 in vitro. Sevabertinib may increase exposure of CYP1A1 substrates, which may increase the risk of adverse reactions related to these substrates. Refer to the Prescribing Information of CYP1A1 substrates.

You are encouraged to report side effects or quality complaints of products to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

Please see full Prescribing Information.