Rybrevant

Refer to the lazertinib prescribing information for recommended lazertinib dosing information. Administer RYBREVANT in combination with lazertinib until disease progression or unacceptable toxicity. 4 Recommended Dosage of RYBREVANT in Combination with Carboplatin and Pemetrexed for the Treatment of NSCLC – Every 3-week dosing The recommended dosage of RYBREVANT, administered in combination with carboplatin and pemetrexed is based on baseline body weight is provided in Table 3.

Table 3:

Recommended Dosage for RYBREVANT in Combination with Carboplatin and Pemetrexed Body weight at Baseline Dose adjustment is not required for subsequent body weight changes. Recommended Dose Dosing Schedule Less than 80 kg 1,400 mg Weekly (total of 4 doses) from Weeks 1 to 4 Week 1 - split infusion on Day 1 and Day 2 Weeks 2 to 4 - infusion on Day 1 Weeks 5 and 6 – no dose 1,750 mg Every 3 weeks starting at Week 7 onwards Greater than or equal to 80 kg 1,750 mg Weekly (total of 4 doses) from Weeks 1 to 4 Week 1 - split infusion on Day 1 and Day 2 Weeks 2 to 4 - infusion on Day 1 Weeks 5 and 6 – no dose 2,100 mg Every 3 weeks starting at Week 7 onwards The recommended order of administration and regimen for RYBREVANT in combination with carboplatin and pemetrexed are provided in Table 4.

Table 4:

Order of Administration and Regimen for RYBREVANT in Combination with Carboplatin and Pemetrexed RYBREVANT in Combination with Carboplatin and Pemetrexed Administer the regimen in the following order : pemetrexed first, carboplatin second, and RYBREVANT last.

Drug Dose Duration/Timing of Treatment Pemetrexed Pemetrexed 500 mg/m 2 intravenously Refer to the pemetrexed Full Prescribing Information for complete information. Every 3 weeks, continue until disease progression or unacceptable toxicity.

Carboplatin Carboplatin AUC 5 intravenously Refer to the carboplatin Full Prescribing Information for complete information. Every 3 weeks for up to 12 weeks. RYBREVANT RYBREVANT intravenously See Table 3 . Every 3 weeks, continue until disease progression or unacceptable toxicity.

5 Recommended Premedications to Reduce the Risk of Infusion-Related Reactions Administer premedications as described in Table 5 . After prolonged dose interruptions, restart the following Week 1 Day 1 premedications upon re-initiation: intravenous dexamethasone, diphenhydramine, and acetaminophen.

4) ]. Administer an oral antibiotic (doxycycline or minocycline, 100 mg orally twice daily) starting on Day 1 for the first 12 weeks of treatment. After completion of oral antibiotic treatment, administer antibiotic lotion to the scalp (clindamycin 1% topical once daily) for the next 9 months of treatment.

Administer non-comedogenic skin moisturizer (ceramide-based or other formulations that provide long-lasting skin hydration and exclude drying agents) on the face and whole body (except scalp). Wash hands and feet with 4% chlorhexidine solution once daily.

Limit sun exposure during and for 2 months after treatment. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen to reduce the risk of dermatologic adverse reactions. 3) ]. If there are no signs or symptoms of VTE during the first four months of treatment, consider discontinuation of anticoagulant prophylaxis at the discretion of the healthcare provider.

Refer to the lazertinib prescribing information for information about concomitant medications. 8 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions for RYBREVANT are listed in Table 6.

Table 6:

Dose Reductions for Adverse Reactions for RYBREVANT Dose at which the adverse reaction occurred 1 st Dose Reduction 2 nd Dose Reduction 3 rd Dose Reduction 1,050 mg 700 mg 350 mg Discontinue RYBREVANT 1,400 mg 1,050 mg 700 mg 1,750 mg 1,400 mg 1,050 mg 2,100 mg 1,750 mg 1,400 mg The recommended dosage modifications and management for adverse reactions for RYBREVANT are provided in Table 7.

1) ] Grade 1 to 2 Interrupt RYBREVANT infusion if IRR is suspected and monitor patient until reaction symptoms resolve. Resume the infusion at 50% of the infusion rate at which the reaction occurred. If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Tables 8 and 9 ).

Include corticosteroid with premedications for subsequent dose (see Table 5 ). Grade 3 Interrupt RYBREVANT infusion and administer supportive care medications. Continuously monitor patient until reaction symptoms resolve. Resume the infusion at 50% of the infusion rate at which the reaction occurred.

If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Tables 8 and 9 ). Include corticosteroid with premedications for subsequent dose (see Table 5 ). For recurrent Grade 3, permanently discontinue RYBREVANT.

Grade 4 or any Grade anaphylaxis / anaphylactic reactions Permanently discontinue RYBREVANT. 2) ] Any Grade Withhold RYBREVANT if ILD/pneumonitis is suspected. Permanently discontinue RYBREVANT if ILD/pneumonitis is confirmed. 3) ] Grade 2 or 3 Withhold RYBREVANT and lazertinib.

Administer anticoagulant treatment as clinically indicated. Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose level, at the discretion of the healthcare provider. Grade 4 or recurrent Grade 2 or 3 despite therapeutic level anticoagulation Withhold lazertinib and permanently discontinue RYBREVANT.

Administer anticoagulant treatment as clinically indicated. Once anticoagulant treatment has been initiated, treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider. 4) ] Grade 1 or Grade 2 Initiate supportive care management as clinically indicated.

Reassess after 2 weeks; if rash does not improve, consider dose reduction. Grade 3 Withhold RYBREVANT and initiate supportive care management as clinically indicated. Upon recovery to ≤ Grade 2, resume RYBREVANT at reduced dose. If no improvement within 2 weeks, permanently discontinue treatment.

Grade 4 or Severe bullous, blistering or exfoliating skin conditions (including toxic epidermal necrolysis (TEN)) Permanently discontinue RYBREVANT. 1) ] Grade 3 Withhold RYBREVANT until recovery to ≤ Grade 1 or baseline. Resume at the same dose if recovery occurs within 1 week.

Resume at reduced dose if recovery occurs after 1 week but within 4 weeks. Permanently discontinue if recovery does not occur within 4 weeks. Grade 4 Withhold RYBREVANT until recovery to ≤ Grade 1 or baseline. Resume at reduced dose if recovery occurs within 4 weeks.

Permanently discontinue if recovery does not occur within 4 weeks. Permanently discontinue for recurrent Grade 4 reactions. Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with Lazertinib When administering RYBREVANT in combination with lazertinib, if there is an adverse reaction requiring dose reduction after withholding treatment and resolution, reduce the dose of RYBREVANT first.

Refer to the lazertinib prescribing information for information about dosage modifications for lazertinib. Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with Carboplatin and Pemetrexed When administering RYBREVANT in combination with carboplatin and pemetrexed, modify the dosage of one or more drugs.

Withhold or discontinue RYBREVANT as shown in Table 7. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information. 9 Preparation Dilute and prepare RYBREVANT for intravenous infusion before administration.

Check that the RYBREVANT solution is colorless to pale yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present.

4) ] . Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw. , discard 7 mL diluent from the infusion bag for each RYBREVANT vial). Only use infusion bags made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE).

Withdraw 7 mL of RYBREVANT from each vial and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial. Gently invert the bag to mix the solution. Do not shake. Diluted solutions should be administered within 10 hours (including infusion time) at room temperature 15°C to 25°C (59°F to 77°F).

2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE. 9% Sodium Chloride Injection prior to the initiation of each RYBREVANT infusion. Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents.

RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent Administer RYBREVANT as a single agent infusion every 2 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 8.

1) ]. RYBREVANT may be administered via central line for subsequent weeks. For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.

When given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day.

Table 8:

Infusion Rates of RYBREVANT in Combination with Lazertinib or RYBREVANT as Single Agent Body Weight Less Than 80 kg Week Dose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion Rate In the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance.

Total infusion time is approximately 4–6 hours for day 1 and 6–8 hours for day 2. Subsequent infusion time is approximately 2 hours. (mL/hr) Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 75 Week 1 Day 2 700 mg 50 75 Week 2 1,050 mg 85 Week 3 1,050 mg 125 Week 4 1,050 mg 125 Week 5 1,050 mg 125 Week 6 No dose Week 7 and every 2 weeks thereafter 1,050 mg 125 Body Weight Greater Than or Equal to 80 kg Week Dose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion Rate (mL/hr) Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 75 Week 1 Day 2 1,050 mg 35 50 Week 2 1,400 mg 65 Week 3 1,400 mg 85 Week 4 1,400 mg 125 Week 5 1,400 mg 125 Week 6 No dose Week 7 and every 2 weeks thereafter 1,400 mg 125 RYBREVANT in Combination with Carboplatin and Pemetrexed Administer RYBREVANT in combination with carboplatin and pemetrexed infusions every 3 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 9.

1) ]. RYBREVANT may be administered via central line for subsequent weeks. For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.

Administer the pemetrexed infusion first, carboplatin infusion second, and the RYBREVANT infusion last.

Table 9:

Infusion Rates of RYBREVANT in Combination with Carboplatin and Pemetrexed for Treatment of NSCLC Body Weight Less Than 80 kg Week Dose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion Rate In the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance.

Total infusion time is approximately 4–6 hours for day 1 and 6–8 hours for day 2. Subsequent infusion time is approximately 2 hours. (mL/hr) Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 75 Week 1 Day 2 1,050 mg 33 50 Week 2 1,400 mg 65 Week 3 1,400 mg 85 Week 4 1,400 mg 125 Weeks 5 and 6 No dose Week 7 and every 3 weeks thereafter 1,750 mg 125 Body Weight Greater Than or Equal to 80 kg Week Dose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion Rate (mL/hr) Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 75 Week 1 Day 2 1,400 mg 25 50 Week 2 1,750 mg 65 Week 3 1,750 mg 85 Week 4 1,750 mg 125 Week 5 and 6 No dose Week 7 and every 3 weeks thereafter 2,100 mg 125

1) ] . Patients received RYBREVANT intravenously at 1,050 mg (for patients < 80 kg) or 1,400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5 in combination with lazertinib, 240 mg orally once daily, until disease progression or unacceptable toxicity.

Among 421 patients who received RYBREVANT in combination with lazertinib, 73% were exposed for 6 months or longer and 59% were exposed for greater than one year. The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reaction, edema, musculoskeletal pain, stomatitis, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, dry skin, hemorrhage, decreased appetite, pruritus, and nausea.

The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased albumin, increased ALT, decreased sodium, decreased hemoglobin, increased AST, increased GGT and increased magnesium. 2) ] 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.

3) ] in 151 patients with previously untreated, locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Patients received RYBREVANT intravenously at 1,400 mg (for patients < 80 kg) or 1,750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg (for patients < 80 kg) or 2,100 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/m 2 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.

4) ] in 302 patients with locally advanced or metastatic NSCLC. Patients received RYBREVANT at 1,050 mg (for patient baseline body weight < 80 kg) or 1,400 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 transference, decreased sodium, decreased potassium and increased alkaline phosphatase. 1) ]. Patients received RYBREVANT intravenously at 1,050 mg (for patients < 80 kg) or 1,400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5 in combination with lazertinib, 240 mg orally once daily.

Among the 421 patients who received RYBREVANT in combination with lazertinib, 73% were exposed to RYBREVANT for ≥ 6 months and 59% were exposed to RYBREVANT for > 1 year. 7% were Black or African American, 1% were of unknown or other races; and 13% were Hispanic or Latino, 67% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1, 33% had ECOG PS of 0, 60% had EGFR exon 19 deletions, and 40% had EGFR exon 21 L858R substitution mutations.

Serious adverse reactions occurred in 49% of patients who received RYBREVANT in combination with lazertinib. 1% each). 2% each). Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 34% of patients. Adverse reactions which resulted in permanent discontinuation in ≥ 1% of patients included rash, infusion-related reactions, nail toxicity, VTE, ILD/pneumonitis, pneumonia, edema, hypoalbuminemia, fatigue, paresthesia and dyspnea.

Dosage interruption of RYBREVANT due to an adverse reaction occurred in 88% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients were infusion-related reactions, rash, nail toxicity, COVID-19, VTE, increased ALT, edema, and hypoalbuminemia.

Dose reductions of RYBREVANT due to an adverse reaction occurred in 46% of patients. Adverse reactions requiring dose reductions in ≥ 5% of patients were rash and nail toxicity. The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reaction, musculoskeletal pain, stomatitis, edema, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, and nausea.

The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium. Table 10 summarizes the adverse reactions (≥ 10%) in MARIPOSA.

7 7 0 Psychiatric disorders Insomnia 10 0 11 0 Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT in combination with lazertinib included skin ulcer and ILD/pneumonitis. Table 11 summarizes the laboratory abnormalities in MARIPOSA.

Table 11:

Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA The denominator used to calculate the rate is the number of patients with a baseline value and at least one post-treatment value for the specific lab test.

2) ]. 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 1,400 mg (for patients < 80 kg) or 1,750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg (for patients < 80 kg) or 2,100 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/m 2 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. 7 months). 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.

3%). 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 12 summarizes the adverse reactions in MARIPOSA-2. 2 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, interstitial lung disease, and skin ulcer.

Table 13 summarizes the laboratory abnormalities in MARIPOSA-2. 3) ] in 151 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. 9 months). 3). 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.

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 14 summarizes the adverse reactions in PAPILLON. 0. 7 8 0 Nervous system disorders Dizziness 11 0 12 0 Psychiatric disorders Insomnia 11 0 13 0 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 15 summarizes the laboratory abnormalities in PAPILLON.

Table 15:

Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Who Received RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLON RYBREVANT in Combination with Carboplatin and Pemetrexed The denominator used to calculate the rate varied from 113 to 150 based on the number of patients with a baseline value and at least one post-treatment value.

Carboplatin in Combination with Pemetrexed The denominator used to calculate the rate varied from 119 to 154 based on the number of patients with a baseline value and at least one post-treatment value. 4) ], 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. 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. 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 16 summarizes the adverse reactions in CHRYSALIS. 8 Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN). Table 17 summarizes the laboratory abnormalities in CHRYSALIS.

Table 17:

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 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.

2 Postmarketing Experience The following adverse reactions associated with the use of RYBREVANT were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders:

Infusion-related reactions, including anaphylaxis/anaphylactic reactions

RYBREVANT with Lazertinib RYBREVANT in combination with lazertinib can cause infusion-related reactions. 1) ] , IRRs occurred in 63% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 in 5% and Grade 4 in 1% of patients.

7% of patients. 5% of patients receiving RYBREVANT in combination with lazertinib. 2%) adverse reactions. 8% of patients permanently discontinued RYBREVANT due to IRR. 1) ], IRR occurred in 66% of patients treated with RYBREVANT as a single agent.

1% with subsequent infusions. 4% were Grade 4. 1 to 18 hours) after start of infusion. 3% of patients permanently discontinued RYBREVANT due to IRR. 5) ] . 10) ] . Monitor patients for signs and symptoms of infusion reactions during RYBREVANT infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Interrupt infusion if IRR is suspected. 8) ]. If an anaphylactic reaction occurs, permanently discontinue RYBREVANT. 2 Interstitial Lung Disease/Pneumonitis RYBREVANT can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.

2% of patients. 1) ]. 8% of patients experiencing Grade 3 ILD/pneumonitis. 1% discontinued RYBREVANT due to ILD/pneumonitis. 7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) permanently discontinued RYBREVANT due to ILD/pneumonitis.

, dyspnea, cough, fever). 8) ] . 3 Venous Thromboembolic (VTE) Events with Concomitant Use of RYBREVANT and Lazertinib RYBREVANT in combination with lazertinib can cause serious and fatal venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism.

1) ] . 5% of patients. 2% of patients (n=5) while receiving anticoagulation therapy. 1% of patients had VTE leading to permanent discontinuation of RYBREVANT. The median time to onset of VTEs was 84 days (range: 6 to 777). 7) ]. The use of Vitamin K antagonists is not recommended.

Monitor for signs and symptoms of VTE events and treat as medically appropriate. 8) ] . Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose level at the discretion of the healthcare provider .

In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT. 8) ]. Refer to the lazertinib prescribing information for recommended lazertinib dosage modification. 4 Dermatologic Adverse Reactions RYBREVANT can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin.

1) ] , rash occurred in 86% of patients treated with RYBREVANT in combination with lazertinib, 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 of RYBREVANT occurred in 37% of patients, rash leading to dose reductions of RYBREVANT occurred in 23% of patients, and rash leading to permanent discontinuation of RYBREVANT occurred in 5% of patients.

1) ] , rash occurred in 82% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (15%) adverse reactions. 1% discontinued pemetrexed. 3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days).

1) ]. 3%) treated with RYBREVANT as a single agent. 6) ] . 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.

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.

8) ] . 5 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. 7% of patients. 8) ] .

1) ], ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed. All events were Grade 1 or 2. 3% of patients treated with RYBREVANT. All events were Grade 1–2. Promptly refer patients with new or worsening eye symptoms to an ophthalmologist.

8) ] . 6 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 last dose of RYBREVANT. 3) ] .