Rybrevant Adverse Reactions

The following adverse reactions are discussed in Precautions: Infusion-Related Reactions; Interstitial Lung Disease/Pneumonitis; Dermatologic Adverse Reactions; Ocular Toxicity.
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.
RYBREVANT in Combination with Carboplatin and Pemetrexed: The pooled safety population described in Precautions also reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed in 281 patients in two studies: MARIPOSA-2 [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions] in 130 patients with previously treated locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after treatment with osimertinib; PAPILLON [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions] in 151 patients with previously untreated, locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.
Patients received RYBREVANT intravenously at 1400 mg (for patients <80 kg) or 1750 mg (for patients ≥80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1750 mg (for patients <80 kg) or 2100 mg (for patients ≥80 kg) starting at Week 7 until disease progression or unacceptable toxicity, in combination with carboplatin at area under the curve AUC 5 once every 3 weeks, for up to 12 weeks, and pemetrexed at 500 mg/m² once every 3 weeks until disease progression or unacceptable toxicity. Among 281 patients who received RYBREVANT in combination with carboplatin and pemetrexed, 65% were exposed for 6 months or longer and 24% were exposed for greater than one year. In the safety population, the most common (≥20%) adverse reactions were rash, nail toxicity, infusion-related reaction, fatigue, nausea, stomatitis, constipation, edema, decreased appetite, musculoskeletal pain, vomiting, and COVID-19. The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased neutrophils, decreased leukocytes, decreased platelets, decreased hemoglobin, decreased potassium, decreased sodium, increased alanine aminotransferase, increased gamma-glutamyl transferase, and decreased albumin.
RYBREVANT as a Single Agent: The data in Precautions also reflect exposure to RYBREVANT as a single agent in CHRYSALIS [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions] in 302 patients with locally advanced or metastatic NSCLC. Patients received RYBREVANT at 1050 mg (for patient baseline body weight <80 kg) or 1400 mg (for patient baseline body weight ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. Among 302 patients who received RYBREVANT as a single agent, 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 increased gamma-glutamyl transferase, decreased sodium, decreased potassium and increased alkaline phosphatase.
Previously Treated Non-Small Cell Lung Cancer (NSCLC) with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations: The safety data described as follows reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Eligible patients had locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations with progressive disease on or after treatment with osimertinib.
Patients with asymptomatic or previously treated and stable intracranial metastases were eligible. Patients received RYBREVANT intravenously at 1400 mg (for patients <80 kg) or 1750 mg (for patients ≥80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1750 mg (for patients <80 kg) or 2100 mg (for patients ≥80 kg) starting at Week 7 until disease progression or unacceptable toxicity, in combination with carboplatin at area under the curve AUC 5 once every 3 weeks, for up to 12 weeks, and pemetrexed at 500 mg/m² once every 3 weeks until disease progression or unacceptable toxicity. Among patients who received RYBREVANT (n=130), 52% were exposed for 6 months or longer and 7% were exposed for greater than one year. The median treatment duration was 6.3 months (range: 0 to 14.7 months).
The median age was 62 years (range: 36 to 84 years); 62% were female; 48% were Asian, 46% were White, 2.3% Black or African American, 1.5% race not reported, 1.5% race unknown, 0.8% Alaska native; 7% were Hispanic or Latino; and 87% had baseline body weight <80 kg.
Serious adverse reactions occurred in 32% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in > 2% of patients included dyspnea (3.1%), thrombocytopenia (3.1%), sepsis (2.3%), and pulmonary embolism (2.3%). Fatal adverse reactions occurred in 2.3% of patients who received RYBREVANT in combination with carboplatin and pemetrexed; these included respiratory failure, sepsis, and ventricular fibrillation (0.8% each).
Permanent discontinuation of RYBREVANT due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions leading to discontinuation of RYBREVANT in ≥5% of patients were infusion-related reactions.
Dose interruptions of RYBREVANT due to an adverse reaction occurred in 60% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 52% of patients. Adverse reactions requiring dose interruption in ≥5% of patients included infusion-related reaction, rash and fatigue.
Dose reductions of RYBREVANT due to an adverse reaction occurred in 17% of patients. Adverse reactions requiring dose reductions in ≥2% of patients included rash.
The most common adverse reactions ≥20% were rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19.
Table 13 summarizes the adverse reactions in MARIPOSA-2. (See Table 13.)

Click on icon to see table/diagram/image

Clinically relevant adverse reactions in <10% of patients who received RYBREVANT in combination with carboplatin and pemetrexed include: abdominal pain, hemorrhoids, dizziness, visual impairment, trichomegaly, keratitis, and interstitial lung disease.
Table 14 summarizes the laboratory abnormalities in MARIPOSA-2. (See Table 14.)

Click on icon to see table/diagram/image

First-line Treatment of Non-Small Cell Lung Cancer (NSCLC) with Exon 20 Insertion Mutations: The safety data described as follows reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed at the recommended dosage in the PAPILLON trial [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions] in 151 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Among patients who received RYBREVANT in combination with carboplatin and pemetrexed the median exposure was 9.7 months (range: 0.0 to 26.9 months). In patients that received carboplatin and pemetrexed alone, the median exposure was 6.7 months (range 0.0 to 25.3).
The median age was 61 years (range: 27 to 86 years); 56% were female; 64% were Asian, 32% were White, 1.3% were Black or African American, race was not reported in 1.3% of patients; 89% were not Hispanic or Latino; 86% had baseline body weight <80 kg.
Serious adverse reactions occurred in 37% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in ≥2% of patients included rash, pneumonia, interstitial lung disease (ILD), pulmonary embolism, vomiting and COVID-19. Fatal adverse reactions occurred in 7 patients (4.6%) due to pneumonia, cerebrovascular accident, cardio-respiratory arrest, COVID-19, sepsis and death not otherwise specified.
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 rash and ILD.
Dose interruptions of RYBREVANT due to an adverse reaction occurred in 64% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 38% of patients. Adverse reactions requiring dose interruption in ≥5% of patients included rash and nail toxicity.
Dose reductions of RYBREVANT due to an adverse reaction occurred in 36% of patients. Adverse reactions requiring dose reductions in ≥5% of patients included rash, and nail toxicity.
The most common adverse reactions (≥20%) were rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, edema, constipation, decreased appetite, nausea, COVID-19, diarrhea, and vomiting. The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased albumin, increased alanine aminotransferase, increased gamma-glutamyl transferase, decreased sodium, decreased potassium, decreased magnesium, and decreases in white blood cells, hemoglobin, neutrophils, platelets, and lymphocytes.
Table 15 summarizes the adverse reactions in PAPILLON. (See Table 15.)

Click on icon to see table/diagram/image

Clinically relevant adverse reactions in <10% of patients who received RYBREVANT in combination with carboplatin and pemetrexed included pulmonary embolism, deep vein thrombosis, skin ulcer, conjunctivitis and interstitial lung disease (ILD)/pneumonitis.
Table 16 summarizes the laboratory abnormalities in PAPILLON. (See Table 16.)

Click on icon to see table/diagram/image

Previously Treated NSCLC Exon 20 Insertion Mutations: The safety data described as follows reflect exposure to RYBREVANT at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in the CHRYSALIS trial [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions], 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 17 summarizes the adverse reactions in CHRYSALIS. (See Table 17.)

Click on icon to see table/diagram/image

Clinically relevant adverse reactions in <10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN).
Table 18 summarizes the laboratory abnormalities in CHRYSALIS. (See Table 18.)

Click on icon to see table/diagram/image