Rybrevant

RYBREVANT (amivantamab) injection for intravenous infusion is a sterile, preservative-free, colorless to pale yellow solution in single-dose vials. The pH is 5.7.
Each RYBREVANT vial contains 350 mg/7 mL (50 mg/mL) amivantamab.
Amivantamab is a low-fucose human immunoglobulin G1-based bispecific antibody directed against the EGF and MET receptors, produced by mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology that has a molecular weight of approximately 148 kDa.
Excipients/Inactive Ingredients: Each RYBREVANT vial contains EDTA disodium salt dihydrate (0.14 mg), L-histidine (2.3 mg), L-histidine hydrochloride monohydrate (8.6 mg), L-methionine (7 mg), polysorbate 80 (4.2 mg), sucrose (595 mg), and water for injection, USP.

Pharmacology: Mechanism of Action: Amivantamab is a bispecific antibody that binds to the extracellular domains of EGFR and MET.
In in vitro and in vivo studies, amivantamab was able to disrupt EGFR and MET signaling functions in mutation models of exon 19 deletions, exon 21 L858R substitutions, and exon 20 insertions through blocking ligand binding or degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.
Immunogenicity: The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described as follows with the incidence of anti-drug antibodies in other studies, including those of amivantamab or amivantamab products.
During treatment in studies CHRYSALIS, CHRYSALIS-2, PAPILLON, MARIPOSA, and MARIPOSA-2 (up to 39 months), 4 of the 1862 (0.2%) patients who received RYBREVANT as a single agent or in combination developed a treatment-emergent anti-amivantamab antibodies. Given the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, safety or efficacy of RYBREVANT is unknown.
Pharmacodynamics: The exposure-response relationship and time-course of pharmacodynamic response of amivantamab have not been fully characterized in patients with NSCLC with EGFR mutations.
Clinical Studies: Previously Treated NSCLC Patients with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations - MARIPOSA-2: The efficacy of RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 (NCT04988295), a randomized, open-label, multicenter trial. Eligible patients were required to have locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations and progressive disease on or after receiving osimertinib. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll. Patients were randomized (1:2:2) to receive RYBREVANT in combination with carboplatin and pemetrexed (RYBREVANT-CP, N=131), carboplatin and pemetrexed (CP, N=263), or RYBREVANT as part of another combination regimen. The evaluation of efficacy for metastatic NSCLC relied upon comparison between: RYBREVANT in combination with carboplatin and pemetrexed. RYBREVANT was administered 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; Platinum-based chemotherapy with carboplatin and pemetrexed.
For both arms, carboplatin was administered intravenously at area under the concentration-time curve 5 mg/mL per minute (AUC 5) once every 3 weeks, for up to 12 weeks and pemetrexed was administered intravenously at 500 mg/m² once every 3 weeks until disease progression or unacceptable toxicity.
Randomization was stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases (yes or no), and Asian race (yes or no). Tumor assessments were performed every 6 weeks for the first 12 months and every 12 weeks thereafter.
The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Overall survival (OS) and overall response rate (ORR) as assessed by BICR were key secondary outcome measures.
A total of 394 patients were randomized between the two arms, 131 to the RYBREVANT-CP arm and 263 to the CP arm. The median age was 62 (range: 31 to 85) years, with 38% of patients ≥65 years of age; 60% were female; and 48% were Asian and 46% were White, 1% were American Indian or Alaska Native, 1% were Black or African American, 0.5% were multiple races and 2.8% were race not reported or race unknown; 8% were Hispanic or Latino. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (40%) or 1 (60%); 65% never smoked; 45% had history of brain metastasis, and 99.7% had Stage IV cancer at study enrollment.
The trial demonstrated a statistically significant improvement in PFS by BICR for RYBREVANT in combination with carboplatin and pemetrexed compared to carboplatin and pemetrexed.
Efficacy results are summarized in Table 1. (See Table 1 and Figure 1.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

At the prespecified second interim analysis of OS, with 85% of the deaths needed for the final analysis, there was no statistically significant difference in OS. The median OS was 17.7 months (95% CI: 16.0, 22.4) in the ACP arm and 15.3 months (95% CI: 13.7, 16.8) in the CP arm, with a hazard ratio of 0.73 (95% CI: 0.54, 0.99).
Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to be randomized in MARIPOSA-2. Baseline disease assessment, including brain magnetic resonance imaging (MRI) was performed at treatment initiation. All patients underwent serial brain MRI during the trial.
Pre-specified secondary analyses of intracranial ORR by BICR in the subset of 91 (23%) patients with baseline intracranial disease were performed. Data were only available for intracranial complete responses and not available for intracranial partial responses. Intracranial ORR was 20% (95% CI: 8, 39) in the 30 patients with baseline intracranial disease in the ACP arm and 7% (95% CI: 1.8, 16) in the 61 patients with baseline intracranial disease in the CP arm.
First-Line Treatment of NSCLC with Exon 20 Insertion Mutations - PAPILLON: The efficacy of RYBREVANT was evaluated in PAPILLON (NCT04538664), in a randomized, open-label, multicenter study. Eligible patients were required to have previously untreated locally advanced or metastatic NSCLC with EGFR Exon 20 insertion mutations measurable disease per RECIST v1.1, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1, and adequate organ and bone marrow function. Patients with brain metastases at screening were eligible for participation once they were definitively treated, clinically stable, asymptomatic, and off corticosteroid treatment for at least 2 weeks prior to randomization. Patients with a medical history of interstitial lung disease or active ILD were excluded from the clinical study.
A total of 308 patients were randomized 1:1 to receive RYBREVANT in combination with carboplatin and pemetrexed (n=153) or carboplatin and pemetrexed (n=155). 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. Carboplatin was administered intravenously at area under the concentration-time curve 5 mg/mL per minute (AUC 5) once every 3 weeks, for up to 12 weeks. Pemetrexed was administered intravenously at 500 mg/m² on once every 3 weeks until disease progression or unacceptable toxicity. Patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1) and prior brain metastases (yes or no).
The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall response rate (ORR), duration of response (DOR) and overall survival (OS). Cross-over to single agent RYBREVANT was permitted for patients who had confirmed disease progression on carboplatin and pemetrexed.
The median age was 62 (range: 27 to 92) years, with 40% of the patients ≥65 years of age; 58% were female; 61% were Asian and 36% were White, 0.7% were Black or African American and race was not reported in 2.3% of patients; 93% were not Hispanic or Latino. Baseline ECOG performance status was 0 (35%) or 1 (65%); 58% were never smokers; 23% had history of brain metastasis and 84% had Stage IV cancer at initial diagnosis.
PAPILLON demonstrated a statistically significant improvement in progression-free survival for patients randomized to RYBREVANT in combination with carboplatin and pemetrexed compared with carboplatin and pemetrexed.
Efficacy results are summarized in Table 2 and Figure 2. (See Table 2 and Figure 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

While OS results were immature at the current analysis, with 44% of pre-specified deaths for the final analysis reported, no trend towards a detriment was observed. Seventy-five (48%) of the treated patients crossed over from the carboplatin and pemetrexed arm after confirmation of disease progression to receive RYBREVANT as a single agent.
Previously Treated NSCLC with Exon 20 Insertion Mutations - CHRYSALIS: The efficacy of RYBREVANT was evaluated in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in a multicenter, open-label, multi-cohort clinical trial (CHRYSALIS, NCT02609776). The study included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients with untreated brain metastases and patients with a history of ILD requiring treatment with prolonged steroids or other immunosuppressive agents within the last 2 years were not eligible for the study.
In the efficacy population, EGFR exon 20 insertion mutation status was determined by prospective local testing using tissue (94%) and/or plasma (6%) samples. Of the 81 patients with EGFR exon 20 insertion mutations identified by local testing, plasma samples from 78/81 (96%) patients were tested retrospectively using Guardant360 CDx, identifying 62/78 (79%) samples with an EGFR exon 20 insertion mutation; 16/78 (21%) samples did not have an EGFR exon 20 insertion mutation identified.
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. The major efficacy outcome measure was overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by Blinded Independent Central Review (BICR). An additional efficacy outcome measure was duration of response (DOR) by BICR.
The efficacy population included 81 patients with NSCLC with EGFR exon 20 insertion mutation with measurable disease who were previously treated with platinum-based chemotherapy. The median age was 62 (range: 42 to 84) years, 59% were female; 49% were Asian, 37% were White, 2.5% were Black; 74% had baseline body weight <80 kg; 95% had adenocarcinoma; and 46% had received prior immunotherapy. The median number of prior therapies was 2 (range: 1 to 7). At baseline, 67% had Eastern Cooperative Oncology Group (ECOG) performance status of 1; 53% never smoked; all patients had metastatic disease; and 22% had previously treated brain metastases.
Efficacy results are summarized in Table 3. (See Table 3.)

Click on icon to see table/diagram/image

Pharmacokinetics: Amivantamab exposures increased proportionally over a dosage range from 350 to 1750 mg (0.33 to 1.7 times the lowest approved recommended dosage) when RYBREVANT was administered as a single agent. Steady-state concentrations of RYBREVANT were reached by week 13 for both the 3-week and 2-week dosing regimen and the systemic accumulation was 1.9-fold.
Distribution: The amivantamab mean (%CV) volume of distribution is 5 (24%) L.
Elimination: The mean (% CV) linear clearance (CL) is 0.26 L/day (30%) and mean terminal half-life is 14 days (33%).
Specific Populations: No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on age (range: 21-88 years), body weight (31 to 140 kg), sex, race (White, Asian or Black or African American) and ethnicity (Hispanic/Latino or not Hispanic/Latino), mild or moderate renal impairment (eGFR 30 to 89 mL/min) or mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN <total bilirubin ≤1.5 times ULN)]. The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR <15 mL/min) or moderate to severe hepatic impairment (total bilirubin >1.5 times ULN and any AST) on amivantamab-vmjw pharmacokinetics has not been studied.
Body Weight: Increases in body weight increased the volume of distribution and clearance of amivantamab. Amivantamab exposures are 30 to 40% lower in patients who weighed ≥80 kg compared to patients with body weight <80 kg at the same dose. Exposures of amivantamab were comparable between patients who weighed <80 kg and received 1050 mg dose and patients who weighed ≥80 kg and received 1400 mg dose.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: No studies have been performed to assess the potential of amivantamab for carcinogenicity or genotoxicity. Fertility studies have not been performed to evaluate the potential effects of amivantamab. In 6-week and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs.

Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations: RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the 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, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor [see Patient Selection under Dosage & Administration].
First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations: RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by a validated test [see Patient Selection under Dosage & Administration].
Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations: RYBREVANT is indicated as a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by a validated test [see Patient Selection under Dosage & Administration], whose disease has progressed on or after platinum-based chemotherapy.

Important Dosage Information: Administer premedications before each RYBREVANT infusion as recommended [see Recommended Premedications as follows].
Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 11 and 12, with the initial dose as a split infusion on Week 1 on Day 1 and Day 2 [see Administration as follows].
Administer RYBREVANT via peripheral line for Week 1 Day 1 and 2 and Week 2 to reduce the risk of infusion-related reactions [see Administration as follows].
When administering RYBREVANT in combination with carboplatin and pemetrexed, infuse pemetrexed first, carboplatin second, and RYBREVANT last [see Administration as follows].
Patient Selection: Select patients for treatment with RYBREVANT based on the presence of a mutation as detected by a validated test. (See Table 4.)

Click on icon to see table/diagram/image

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 5. (See Table 5.)

Click on icon to see table/diagram/image

The recommended order of administration and regimen for RYBREVANT in combination with carboplatin and pemetrexed are provided in Table 6. (See Table 6.)

Click on icon to see table/diagram/image

Recommended Dosage of RYBREVANT as a Single Agent - Every 2-week dosing: The recommended dosage of RYBREVANT as a single agent, based on baseline body weight, are provided in Table 7. Administer RYBREVANT until disease progression or unacceptable toxicity. (See Table 7.)

Click on icon to see table/diagram/image

Recommended Premedications: Prior to the initial infusion of RYBREVANT (Week 1, Day 1 and 2), administer premedications as described in Table 8 to reduce the risk of infusion-related reactions [see Infusion-Related Reactions under Precautions]. (See Table 8.)
Glucocorticoid administration is required for Week 1, Day 1 and 2 dose only and upon re-initiation after prolonged dose interruptions, then as necessary for subsequent infusions (see Table 8). Administer both antihistamine and antipyretic prior to all infusions.

Click on icon to see table/diagram/image

Dosage Modifications for Adverse Reactions: The recommended dose reductions for adverse reactions for RYBREVANT are listed in Table 9. (See Table 9.)

Click on icon to see table/diagram/image

The recommended dosage modifications and management for adverse reactions for RYBREVANT are provided in Table 10. (See Table 10.)

Click on icon to see table/diagram/image

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 10. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information.
Administration: Administer the diluted RYBREVANT solution [see Preparation under Cautions for Usage] by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer).
Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE.
The administration set with filter, must be primed with either 5% Dextrose Injection or 0.9% 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 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 11. (See Table 11.)
Administer RYBREVANT via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions during initial treatment [see Infusion-Related Reactions under Precautions].
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.

Click on icon to see table/diagram/image

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 12. (See Table 12.)
Administer RYBREVANT via a peripheral line on Week 1 and Week 2, to reduce the risk of infusion-related reactions during initial treatment [see Infusion-Related Reactions under Precautions].
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.

Click on icon to see table/diagram/image

None.

Infusion-Related Reactions: RYBREVANT can cause infusion-related reactions (IRR); 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 Carboplatin and Pemetrexed: Based on the pooled safety population [see Clinical Trials Experience under Adverse Reactions], IRR occurred in 50% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (3.2%) adverse reactions. The incidence of infusion modifications due to IRR was 46%, and 2.8% of patients permanently discontinued RYBREVANT due to IRR.
RYBREVANT as a Single Agent: In CHRYSALIS, [see Clinical Trials Experience under Adverse Reactions], IRR occurred in 66% of patients treated with RYBREVANT as a single agent. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62%, and 1.3% of patients permanently discontinued RYBREVANT due to IRR.
Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT as recommended [see Recommended Premedications under Dosage & Administration]. Administer RYBREVANT via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions [see Administration under Dosage & Administration].
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. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Interstitial Lung Disease/Pneumonitis: RYBREVANT can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.
RYBREVANT with Carboplatin and Pemetrexed: Based on the pooled safety population [see Clinical Trials Experience under Adverse Reactions], ILD/pneumonitis occurred in 2.1% treated with RYBREVANT in combination with carboplatin and pemetrexed with 1.8% of patients experiencing Grade 3 ILD/pneumonitis. 2.1% discontinued RYBREVANT due to ILD/pneumonitis.
RYBREVANT as a Single Agent: In CHRYSALIS, [see Clinical Trials Experience under Adverse Reactions], ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT as a single agent, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) permanently 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 Modifications for Adverse Reactions under Dosage & Administration].
Dermatologic Adverse Reactions: RYBREVANT can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin.
RYBREVANT with Carboplatin and Pemetrexed: Based on the pooled safety population [see Clinical Trials Experience under Adverse Reactions], rash occurred in 82% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (15%) adverse reactions. Rash leading to dose reductions occurred in 14% of patients, and 2.5% permanently discontinued RYBREVANT and 3.1% discontinued pemetrexed.
RYBREVANT as a Single Agent: In CHRYSALIS, [see Clinical Trials Experience under Adverse Reactions], rash occurred in 74% of patients treated with RYBREVANT as a single agent, 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 Clinical Trials Experience under Adverse Reactions].
Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with RYBREVANT as a single agent.
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 (e.g., isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.
When initiating treatment with RYBREVANT, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. 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, reduce the dose, or permanently discontinue RYBREVANT based on severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
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 Carboplatin and Pemetrexed: Based on the pooled safety population [see Clinical Trials Experience under Adverse Reactions], ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed. All events were Grade 1 or 2.
RYBREVANT as a Single Agent: In CHRYSALIS, [see Clinical Trials Experience under Adverse Reactions], 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 with new or worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
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. [See Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation.]
Use in Children: The safety and efficacy of RYBREVANT have not been established in pediatric patients.
Use in the Elderly: Of the 130 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the MARIPOSA-2 study, 40% were ≥65 years of age and 10% were ≥75 years of age.
Of the 151 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the PAPILLON study, 37% were ≥65 years of age and 8% were ≥75 years of age.
Of the 302 patients with locally advanced or metastatic NSCLC treated with RYBREVANT as a single agent in the CHRYSALIS study, 39% were ≥65 years of age and 11% were ≥75 years of age.
No clinically important differences in safety or efficacy were observed between patients who were ≥65 years of age and younger patients.

Pregnancy: Risk Summary: Based on the mechanism of action and findings in animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. There are no available data on the use of RYBREVANT in pregnant women or animal data to assess the risk of RYBREVANT in pregnancy. Disruption or depletion of EGFR in animal models resulted in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR or MET signaling has resulted in embryo lethality, malformations, and post-natal death in animals (see Data as follows). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data: Animal Data: No animal studies have been conducted to evaluate the effects of amivantamab on reproduction and fetal development; however, based on its mechanism of action, RYBREVANT can cause fetal harm or developmental anomalies. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development) and can cause developmental anomalies and early death in surviving fetuses. Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling. Similarly, knock out of MET or its ligand HGF was embryonic lethal due to severe defects in placental development, and fetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab has the potential to be transmitted from the mother to the developing fetus.
Lactation: Risk Summary: There are no data on the presence of amivantamab in human milk, the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions from RYBREVANT in breast-fed children, advise women not to breastfeed during treatment with RYBREVANT and for 3 months after the last dose.
Females and Males of Reproductive Potential: RYBREVANT can cause fetal harm when administered to a pregnant woman [see Pregnancy as previously mentioned].
Pregnancy Testing: Verify pregnancy status of females of reproductive potential prior to initiating RYBREVANT.
Contraception: Females: Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT.

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

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.
Determine the dose required and number of RYBREVANT vials needed based on patient's baseline weight [see Dosage & Administration]. Each vial of RYBREVANT contains 350 mg of amivantamab.
Withdraw and then discard a volume of either 5% Dextrose Injection or 0.9% Sodium Chloride Injection from the 250 mL infusion bag equal to the volume of RYBREVANT to be added (i.e., 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.

Store at 2°C to 8°C. Store in original package in order to protect from light. Do not freeze.

Advise the patient to read the approved patient labeling (Patient Information).
Infusion-Related Reactions: Advise patients that RYBREVANT can cause infusion-related reactions, the majority of which may occur with the first infusion. Advise patients to alert their healthcare provider immediately for any signs or symptoms of infusion-related reactions [see Infusion-Related Reactions under Precautions].
Interstitial Lung Disease/Pneumonitis: Advise patients of the risks of interstitial lung disease (ILD)/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms [see Interstitial Lung Disease/Pneumonitis under Precautions].
Dermatologic Adverse Reactions: Advise patients of the risk of dermatologic adverse reactions. Advise patients to apply alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream to reduce the risk of skin reactions. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. Advise patients to limit direct sun exposure during and for 2 months after treatment, to use broad-spectrum UVA/UVB sunscreen, and to wear protective clothing during treatment with RYBREVANT [see Dermatologic Adverse Reactions under Precautions].
Ocular Toxicity: Advise patients of the risk of ocular toxicity. Advise patients to contact their ophthalmologist if they develop eye symptoms and advise discontinuation of contact lenses until symptoms are evaluated [see Ocular Toxicity under Precautions].
Paronychia/Nail Toxicity: Advise patients of the risk of paronychia. Advise patients to contact their healthcare provider for signs or symptoms of paronychia [see Clinical Trials Experience under Adverse Reactions].
Embryo-Fetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus, to use effective contraception during treatment with RYBREVANT and for 3 months after the last dose, and to inform their healthcare provider of a known or suspected pregnancy. [See Embryo-Fetal Toxicity under Precautions; Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation.]
Lactation: Advise women not to breastfeed during treatment with RYBREVANT and for 3 months after the last dose [see Lactation under Use in Pregnancy & Lactation].

Targeted Cancer Therapy

L01FX18 - amivantamab ; Belongs to the class of other monoclonal antibodies and antibody drug conjugates. Used in the treatment of cancer.

P₁S₁S₃