INDICATION

RYBREVANT^® (amivantamab-vmjw) is indicated in combination with LAZCLUZE^® (lazertinib) for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

RYBREVANT^® can cause infusion-related reactions (IRRs) including anaphylaxis; signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. The median time to IRR onset is approximately 1 hour.

RYBREVANT^® with LAZCLUZE^®

In MARIPOSA (n=421), IRRs occurred in 63% of patients, including Grade 3 in 5% and Grade 4 in 1% of patients. IRR-related infusion modifications occurred in 54%, dose reduction in 0.7%, and permanent discontinuation of RYBREVANT^® in 4.5% of patients.

Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT^® as recommended. Administer RYBREVANT^® via a peripheral line on Week 1 and Week 2 to reduce the risk of IRRs. Monitor patients for signs and symptoms of IRRs in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT^® based on severity. If an anaphylactic reaction occurs, permanently discontinue RYBREVANT^®.

Interstitial Lung Disease/Pneumonitis

RYBREVANT^® can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.

RYBREVANT^® with LAZCLUZE^®

In MARIPOSA, ILD/pneumonitis occurred in 3.1% of patients, including Grade 3 in 1.0% and Grade 4 in 0.2% of patients. There was one fatal case (0.2%) of ILD/pneumonitis and 2.9% of patients permanently discontinued RYBREVANT^® and LAZCLUZE^® due to ILD/pneumonitis.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold both drugs in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

Venous Thromboembolic Events with Concomitant Use of RYBREVANT^® and LAZCLUZE^®

RYBREVANT^® in combination with LAZCLUZE^® can cause serious and fatal venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism (PE). Most events occurred during the first four months of therapy.

In MARIPOSA, VTEs occurred in 36% of patients including Grade 3 in 10% and Grade 4 in 0.5% of patients. On-study VTEs occurred in 1.2% of patients (n=5) while receiving anticoagulation therapy. There were two fatal cases of VTE (0.5%), 9% of patients had VTE leading to dose interruptions of RYBREVANT^®, and 7% of patients had VTE leading to dose interruptions of LAZCLUZE^®; 1% of patients had VTE leading to dose reductions of RYBREVANT^®, and 0.5% of patients had VTE leading to dose reductions of LAZCLUZE^®; 3.1% of patients had VTE leading to permanent discontinuation of RYBREVANT^®, and 1.9% of patients had VTE leading to permanent discontinuation of LAZCLUZE^®. The median time to onset of VTEs was 84 days (range: 6 to 777).

Administer prophylactic anticoagulation for the first four months of treatment. The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate.

Withhold RYBREVANT^® and LAZCLUZE^® based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT^® and LAZCLUZE^® at the same dose level at the discretion of the healthcare provider. In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT^® and continue treatment with LAZCLUZE^® at the same dose level at the discretion of the healthcare provider.

Dermatologic Adverse Reactions

RYBREVANT^® can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin.

RYBREVANT^® with LAZCLUZE^®

In MARIPOSA, rash occurred in 86% of patients, including Grade 3 in 26% of patients. The median time to onset of rash was 14 days (range: 1 to 556 days). Rash leading to dose interruptions occurred in 37% of patients for RYBREVANT^® and 30% for LAZCLUZE^®, rash leading to dose reductions occurred in 23% of patients for RYBREVANT^® and 19% for LAZCLUZE^®, and rash leading to permanent discontinuation occurred in 5% of patients for RYBREVANT^® and 1.7% for LAZCLUZE^®.

When initiating treatment with RYBREVANT^®, prophylactic and concomitant medications are recommended to reduce the risk and severity of dermatologic adverse reactions. Instruct patients to limit sun exposure during and for 2 months after treatment. Advise patients to wear protective clothing and use broad spectrum UVA/UVB sunscreen.

If skin reactions develop, administer supportive care including topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. For patients receiving RYBREVANT^® in combination with LAZCLUZE^®, without, reduce the dose, or permanently discontinue both drugs on severity.

Ocular Toxicity

RYBREVANT^® can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus, and uveitis.

RYBREVANT^® with LAZCLUZE^®

In MARIPOSA, ocular toxicity occurred in 16%, including Grade 3 or 4 ocular toxicity in 0.7% of patients. Withhold, reduce the dose, or permanently discontinue RYBREVANT^® and continue LAZCLUZE^® based on severity.

Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT^® based on severity.

Embryo-Fetal Toxicity

Based on animal models, RYBREVANT^® and LAZCLUZE^® can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus.

Advise patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT^®, and for 3 weeks after the last dose of LAZCLUZE^®.

ADVERSE REACTIONS

RYBREVANT^® with LAZCLUZE^®

In MARIPOSA (n=421), the most common adverse reactions (ARs) (≥20%) were rash (86%), nail toxicity (71%), infusion-related reactions (IRRs) (RYBREVANT^®) (63%), musculoskeletal pain (47%), stomatitis (43%), edema (43%), VTE (36%), paresthesia (35%), fatigue (32%), diarrhea (31%), constipation (29%),
COVID-19 (26%), hemorrhage (25%), dry skin (25%), decreased appetite (24%), pruritus (24%), and nausea (21%). The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased albumin (8%), decreased sodium (7%), increased ALT (7%), decreased potassium (5%), decreased hemoglobin
(3.8%), increased AST (3.8%), increased GGT (2.6%), and increased magnesium (2.6%).

Serious ARs occurred in 49% of patients, with those occurring in ≥2% of patients including VTE (11%), pneumonia (4%), ILD/pneumonitis and rash (2.9% each), COVID-19 (2.4%), and pleural effusion and IRRs (RYBREVANT^®) (2.1% each). Fatal ARs occurred in 7% of patients due to death not otherwise specified (1.2%); sepsis and respiratory failure (1% each); pneumonia, myocardial infarction, and sudden death (0.7% each); cerebral infarction, pulmonary embolism (PE), and COVID-19 infection (0.5% each); and ILD/pneumonitis, acute respiratory distress syndrome (ARDS), and cardiopulmonary arrest (0.2% each).

LAZCLUZE^® Drug Interactions

Avoid concomitant use of LAZCLUZE^® with strong and moderate CYP3A4 inducers. Consider an alternate concomitant medication with no potential to induce CYP3A4.

Monitor for adverse reactions associated with a CYP3A4 or BCRP substrate where minimal concentration changes may lead to serious adverse reactions, as recommended in the approved product labeling for the CYP3A4 or BCRP substrate.

Please read full Prescribing Information for RYBREVANT^® and LAZCLUZE^®.

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