Rybrevant (Page 3 of 6)

5.2 Interstitial Lung Disease/Pneumonitis

RYBREVANT can cause interstitial lung disease (ILD)/pneumonitis. Based on the safety population [see Adverse Reactions (6.1)] , ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT due to ILD/pneumonitis.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed [see Dosage and Administration (2.4)].

5.3 Dermatologic Adverse Reactions

RYBREVANT can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population [see Adverse Reactions (6.1)] , rash occurred in 74% of patients treated with RYBREVANT, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients [see Adverse Reactions (6.1)].

Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with RYBREVANT.

Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free emollient cream is recommended for dry skin.

If skin reactions develop, start 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. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.4)].

5.4 Ocular Toxicity

RYBREVANT can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population [see Adverse Reactions (6.1)], keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1–2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.4)].

5.5 Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. Administration of other EGFR inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryo lethality, and abortion. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of RYBREVANT. [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere in the labeling:

6.1 Clinical Trials 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 safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT as a single agent in the CHRYSALIS study in 302 patients with locally advanced or metastatic NSCLC who received a dose of 1050 mg (for patients <80 kg) or 1400 mg (for patients ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter. Among 302 patients who received RYBREVANT, 36% were exposed for 6 months or longer and 12% were exposed for greater than one year. In the safety population, the most common (≥ 20%) adverse reactions were rash, infusion-related reaction, paronychia, musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting, and pruritus. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased phosphate, decreased albumin, increased glucose, increased gamma glutamyl transferase, decreased sodium, decreased potassium, and increased alkaline phosphatase.

The data described below reflect exposure to RYBREVANT at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Among patients who received RYBREVANT, 44% were exposed for 6 months or longer and 12% were exposed for greater than one year.

The median age was 62 years (range: 36 to 84 years); 61% were female; 55% were Asian, 35% were White, and 2.3% were Black; and 82% had baseline body weight <80 kg.

Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in ≥ 2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in 2 patients (1.5%) due to pneumonia and 1 patient (0.8%) due to sudden death.

Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of RYBREVANT in ≥1% of patients were pneumonia, IRR, pneumonitis/ILD, dyspnea, pleural effusion, and rash.

Dose interruptions of RYBREVANT due to an adverse reaction occurred in 78% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 59% of patients. Adverse reactions requiring dose interruption in ≥5% of patients included dyspnea, nausea, rash, vomiting, fatigue, and diarrhea.

Dose reductions of RYBREVANT due to an adverse reaction occurred in 15% of patients. Adverse reactions requiring dose reductions in ≥ 2% of patients included rash and paronychia.

The most common adverse reactions (≥ 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased glucose, increased alkaline phosphatase, increased gamma-glutamyl transferase, and decreased sodium.

Table 7 summarizes the adverse reactions in CHRYSALIS.

Table 7: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received RYBREVANT in CHRYSALIS
Adverse Reactions RYBREVANT(N=129)
All Grades (%) Grades 3 or 4 (%)
*
Rash: acne, dermatitis, dermatitis acneiform, eczema, eczema asteatotic, palmar-plantar erythrodysesthesia syndrome, perineal rash, rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular, skin exfoliation, toxic epidermal necrolysis
Fatigue: asthenia, fatigue
Edema: eyelid edema, face edema, generalized edema, lip edema, edema, edema peripheral, periorbital edema, peripheral swelling
§
Pneumonia: atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, and pulmonary sepsis
Musculoskeletal pain: arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain
#
Dyspnea: dyspnea, dyspnea exertional
Þ
Cough: cough, productive cough, upper airway cough syndrome
ß
Stomatitis: aphthous ulcer, cheilitis, glossitis, mouth ulceration, mucosal inflammation, pharyngeal inflammation, stomatitis
à
Abdominal pain: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort
è
Hemorrhage: epistaxis, gingival bleeding, hematuria, hemoptysis, hemorrhage, mouth hemorrhage, mucosal hemorrhage
ð
Peripheral neuropathy: hypoesthesia, neuralgia, paresthesia, peripheral sensory neuropathy
ø
Headache: headache, migraine
Skin and subcutaneous tissue disorders
Rash * 84 3.9
Pruritus 18 0
Dry skin 14 0
General disorders and administration site conditions
Infusion related reaction 64 3.1
Fatigue 33 2.3
Edema 27 0.8
Pyrexia 13 0
Infections and infestations
Paronychia 50 3.1
Pneumonia § 10 0.8
Musculoskeletal and connective tissue disorders
Musculoskeletal pain 47 0
Respiratory, thoracic and mediastinal disorders
Dyspnea # 37 2.3
Cough Þ 25 0
Gastrointestinal disorders
Nausea 36 0
Stomatitis ß 26 0.8
Constipation 23 0
Vomiting 22 0
Diarrhea 16 3.1
Abdominal Pain à 11 0.8
Vascular disorders
Hemorrhage è 19 0
Metabolism and nutrition disorders
Decreased appetite 15 0
Nervous system disorders
Peripheral neuropathy ð 13 0
Dizziness 12 0.8
Headache ø 10 0.8

Clinically relevant adverse reactions in <10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN).

Table 8 summarizes the laboratory abnormalities in CHRYSALIS.

Table 8: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients With Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Whose Disease Has Progressed on or After Platinum-based Chemotherapy and Who Received RYBREVANT in CHRYSALIS
Laboratory Abnormality RYBREVANT *(N=129)
All Grades (%) Grades 3 or 4 (%)
*
The denominator used to calculate the rate was 126 based on the number of patients with a baseline value and at least one post-treatment value.
Chemistry
Decreased albumin 79 8
Increased glucose 56 4
Increased alkaline phosphatase 53 4.8
Increased creatinine 46 0
Increased alanine aminotransferase 38 1.6
Decreased phosphate 33 8
Increased aspartate aminotransferase 33 0
Decreased magnesium 27 0
Increased gamma-glutamyl transferase 27 4
Decreased sodium 27 4
Decreased potassium 26 6
Hematology
Decreased lymphocytes 36 8

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