These Highlights Do Not Include All The Information Needed To Use Rybrevant Safely And Effectively. See Full Prescribing Information For Rybrevant.

RYBREVANT in Combination with Lazertinib

Storage and Handling

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze.

Amivantamab-vmjw 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. RYBREVANT^® (amivantamab-vmjw) 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 (50 mg/mL) amivantamab-vmjw, 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.

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 and Administration (2.3, 2.4)] . Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw.
• 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 (59°F to 77°F).

The safety and efficacy of RYBREVANT have not been established in pediatric patients.

• Of the 421 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with lazertinib in the MARIPOSA study, 45% were ≥ 65 years of age and 12% were ≥ 75 years of age.
• 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.

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 below with the incidence of anti-drug antibodies in other studies, including those of amivantamab-vmjw or amivantamab products.

During treatment in studies CHRYSALIS, CHRYSALIS-2, PAPILLON, MARIPOSA, and MARIPOSA-2 (up to 39 months), 4 of the 1,862 (0.2%) patients who received RYBREVANT as a single agent or in combination developed a treatment-emergent anti-amivantamab-vmjw antibodies. Given the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, safety or efficacy of RYBREVANT is unknown.

• Administer the diluted RYBREVANT solution [see Dosage and Administration (2.9)] 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.

None.

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

The following adverse reactions are discussed elsewhere in the labeling:

• Infusion-Related Reactions [see Warnings and Precautions (5.1)]
• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)]
• Venous Thromboembolic Events [see Warnings and Precautions (5.3)]
• Dermatologic Adverse Reactions [see Warnings and Precautions (5.4)]
• Ocular Toxicity [see Warnings and Precautions (5.5)]

The exposure-response relationship and time-course of pharmacodynamic response of amivantamab-vmjw have not been fully characterized in patients with NSCLC with EGFR mutations.

Amivantamab-vmjw exposures increased proportionally over a dosage range from 350 to 1,750 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.

Select patients for treatment with RYBREVANT based on the presence of a mutation as detected by an FDA-approved test.

RYBREVANT is a bispecific EGF receptor-directed and MET receptor-directed antibody indicated:

• in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test. ( 1, 2.2)
• in combination with carboplatin and pemetrexed for the treatment of adult patients with 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 an EGFR tyrosine kinase inhibitor. ( 1, 2.2)
• in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test. ( 1, 2.2)
• 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 an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. ( 1, 2.2)

Amivantamab-vmjw is a bispecific antibody that binds to the extracellular domains of EGFR and MET.

In in vitro and in vivo studies amivantamab-vmjw 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. Treatment with amivantamab in combination with lazertinib increased in vivo anti-tumor activity compared to either agent alone in a mouse xenograft model of human NSCLC with an EGFR L858R mutation.

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 Use in Specific Populations (8.1, 8.3)] .

• Infusion-Related Reactions (IRR): Interrupt infusion at the first sign of IRRs. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity. ( 2.5, 2.8, 5.1)
• Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening symptoms indicative of ILD. Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. ( 2.8, 5.2)
• Venous Thromboembolic (VTE) Events with Concomitant Use with Lazertinib: Prophylactic anticoagulation is recommended for the first four months of treatment. Monitor for signs and symptoms of VTE and treat as medically appropriate. Withhold RYBREVANT and lazertinib based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose at the discretion of the healthcare provider. Permanently discontinue RYBREVANT and continue lazertinib for recurrent VTE despite therapeutic anticoagulation. ( 2.7, 2.8, 5.3)
• Dermatologic Adverse Reactions: Can cause severe rash including toxic epidermal necrolysis (TEN) and acneiform dermatitis. At treatment initiation, prophylactic and concomitant medications are recommended. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. ( 2.6, 2.8, 5.4)
• Ocular Toxicity: Promptly refer patients with worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. ( 2.8, 5.5)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.6, 8.1, 8.3)

• The recommended dosage of RYBREVANT is based on baseline body weight and administered as an intravenous infusion after dilution. ( 2.3, 2.4)
• Administer prophylactic and concomitant medications as recommended to reduce the risk of dermatologic adverse reactions. ( 2.6)
• Administer via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions. ( 2.10)
• Administer RYBREVANT in combination with lazertinib or RYBREVANT as a single agent weekly for 5 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks starting at Week 7. ( 2.3)
• Administer RYBREVANT in combination with chemotherapy weekly for 4 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 3 weeks starting at Week 7. (2.4)
• When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to reduce the risk of venous thromboembolic (VTE) events for the first four months of treatment. ( 2.7)
• Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 8 and 9. ( 2.9, 2.10)

Injection: 350 mg/7 mL (50 mg/mL) colorless to pale yellow solution in a single-dose vial.

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

Lactation: Advise not to breastfeed. ( 8.2)

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

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.

• To reduce the risk of infusion-related reactions, administer premedications before each RYBREVANT infusion as recommended [see Dosage and Administration (2.5)].
• To reduce the risk of infusion-related reactions, administer RYBREVANT via peripheral line for Week 1 Day 1 and 2 and Week 2 [see Dosage and Administration (2.10)].
• To reduce the risk and severity of dermatologic adverse reactions with RYBREVANT, prophylactic and concomitant medications are recommended [see Dosage and Administration (2.6)].
• To reduce the risk of venous thromboembolic (VTE) events when administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis for the first four months of treatment [see Dosage and Administration (2.7)].
• Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 8 and 9, with the initial dose as a split infusion on Week 1 on Day 1 and Day 2 [see Dosage and Administration (2.10)].
• When administering RYBREVANT in combination with lazertinib, administer lazertinib orally any time before the RYBREVANT infusion [see Dosage and Administration (2.10)].
• When administering RYBREVANT in combination with carboplatin and pemetrexed, infuse pemetrexed first, carboplatin second, and RYBREVANT last [see Dosage and Administration (2.10)].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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

RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the treatment of adult patients with 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 an EGFR tyrosine kinase inhibitor [see Dosage and Administration (2.2)] .

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 an FDA-approved test [see Dosage and Administration (2.2)] , whose disease has progressed on or after platinum-based chemotherapy.

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

NDC 57894-501-01

Rybrevant ^®

(amivantamab-vmjw)

Injection

350 mg/7 mL

(50 mg/mL)

For Intravenous Infusion Only

Dilute Before Use

Rx only

7 mL Vial

janssen

Single-dose vial.

Discard unused portion.

RYBREVANT, in combination with lazertinib, is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)] .

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 an FDA-approved test [see Dosage and Administration (2.2)] .

The recommended dose reductions for adverse reactions for RYBREVANT are listed in Table 6.

The recommended dosage modifications and management for adverse reactions for RYBREVANT are provided in Table 7.

RYBREVANT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

No studies have been performed to assess the potential of amivantamab-vmjw for carcinogenicity or genotoxicity. Fertility studies have not been performed to evaluate the potential effects of amivantamab-vmjw. In 6-week and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs.

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 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. 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 22.

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 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. 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 21 and Figure 4.

Figure 4: Kaplan-Meier Curve of PFS in Previously Untreated NSCLC Patients by BICR Assessment – PAPILLON Study

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.

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.

RYBREVANT in combination with lazertinib can cause serious and fatal venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism. The majority of these events occurred during the first four months of treatment [see Adverse Reactions (6.1)] .

In MARIPOSA [see Adverse Reactions (6.1)], VTEs occurred in 36% of patients receiving RYBREVANT in combination with lazertinib, including Grade 3 in 10% and Grade 4 in 0.5% of patients. On-study VTEs occurred in 1.2% of patients (n=5) while receiving anticoagulation therapy. There were two fatal cases of VTE (0.5%), 9% of patients had VTE leading to dose interruptions of RYBREVANT, 1% of patients had VTE leading to dose reductions of RYBREVANT, and 3.1% of patients had VTE leading to permanent discontinuation of RYBREVANT. The median time to onset of VTEs was 84 days (range: 6 to 777). Administer prophylactic anticoagulation for the first four months of treatment [see Dosage and Administration (2.7)]. The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate.

Withhold RYBREVANT and lazertinib based on severity [see Dosage and Administration (2.8)] . 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. Treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.8)]. Refer to the lazertinib prescribing information for recommended lazertinib dosage modification.

When initiating treatment with RYBREVANT, prophylactic and concomitant medications are recommended to reduce the risk and severity of dermatologic adverse reactions [see Warnings and Precautions (5.4)].

• 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.

The efficacy of RYBREVANT, in combination with lazertinib, was evaluated in MARIPOSA [NCT04487080], a randomized, active-controlled, multicenter trial. Eligible patients were required to have untreated locally advanced or metastatic NSCLC with either exon 19 deletions or exon 21 L858R substitution EGFR mutations identified by local testing, not amenable to curative therapy. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll.

Patients were randomized (2:2:1) to receive RYBREVANT in combination with lazertinib (N=429), osimertinib monotherapy (N=429), or lazertinib monotherapy (an unapproved regimen for NSCLC) until disease progression or unacceptable toxicity. The evaluation of efficacy for the treatment of untreated metastatic NSCLC relied upon comparison between:

• RYBREVANT administered 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 administered at 240 mg orally once daily.
• Osimertinib administered at a dose of 80 mg orally once daily.

Randomization was stratified by EGFR mutation type (exon 19 deletion or exon 21 L858R substitution mutation), Asian race (yes or no), and history of brain metastasis (yes or no). Tumor assessments were performed every 8 weeks for 30 months, and then every 12 weeks until disease progression.

The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR), and duration of response (DOR).

A total of 858 patients were randomized between the two study arms, 429 to the RYBREVANT in combination with lazertinib arm and 429 to the osimertinib arm. The median age was 63 (range: 25–88) years; 61% were female; 58% were Asian, 38% were White, 1.6% were American Indian or Alaska Native, 0.8% were Black or African American, 0.2% were Native Hawaiian or other Pacific Islander, 0.6% were unknown race or multiple races; and 12% were Hispanic or Latino. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and 89% had Stage IV cancer at initial diagnosis. Sixty percent of patients had tumors harboring exon 19 deletions and the remaining 40% had exon 21 L858R substitution mutations.

Among the 858 patients with EGFR exon 19 deletion or L858R substitution mutations that were randomized between the RYBREVANT plus lazertinib arm versus the osimertinib arm, available tissue samples from 544 (63%) patients had evaluable results when tested retrospectively using the cobas EGFR Mutation Test v2. Of the 544 patients with evaluable results, 527 (97%) patients were positive for EGFR exon 19 deletion or L858R substitution mutations, while 17 (3%) patients were negative. Available plasma samples from patients were retrospectively tested using an FDA-approved test to confirm the biomarker status.

The trial demonstrated a statistically significant improvement in PFS by BICR assessment and OS for RYBREVANT in combination with lazertinib compared to osimertinib (see Table 18 and Figures 1 and 2).

Efficacy results for RYBREVANT in combination with lazertinib are provided in Table 18.

Figure 1: Kaplan-Meier Curves of PFS by BICR Assessment in Patients with Previously Untreated NSCLC

Figure 2: Kaplan-Meier Curves of OS in Patients with Previously Untreated NSCLC

Out of all randomized patients (n=858), 367 (43%) had baseline intracranial lesions assessed by BICR using modified RECIST. Results of pre-specified analyses of intracranial ORR and DOR by BICR in the subset of patients with intracranial lesions at baseline for the RYBREVANT in combination with lazertinib arm and the osimertinib arm are summarized in Table 19.

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 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.
• 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 20.

Figure 3: Kaplan-Meier curve of PFS in Previously Treated NSCLC Patients by BICR assessment- MARIPOSA-2

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.

The recommended dosage of RYBREVANT in combination with lazertinib or RYBREVANT as a single agent, based on baseline body weight, are provided in Table 2. Administer RYBREVANT until disease progression or unacceptable toxicity.

When initiating treatment with RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to reduce the risk of venous thromboembolic (VTE) events for the first four months of treatment [see Warnings and Precautions (5.3)]. 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.

The recommended dosage of RYBREVANT, administered in combination with carboplatin and pemetrexed is based on baseline body weight is provided in Table 3.

The recommended order of administration and regimen for RYBREVANT in combination with carboplatin and pemetrexed are provided in Table 4.

RYBREVANT in Combination with Lazertinib

Storage and Handling

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze.

Amivantamab-vmjw 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. RYBREVANT^® (amivantamab-vmjw) 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 (50 mg/mL) amivantamab-vmjw, 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.

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 and Administration (2.3, 2.4)] . Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw.
• 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 (59°F to 77°F).

The safety and efficacy of RYBREVANT have not been established in pediatric patients.

• Of the 421 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with lazertinib in the MARIPOSA study, 45% were ≥ 65 years of age and 12% were ≥ 75 years of age.
• 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.

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 below with the incidence of anti-drug antibodies in other studies, including those of amivantamab-vmjw or amivantamab products.

During treatment in studies CHRYSALIS, CHRYSALIS-2, PAPILLON, MARIPOSA, and MARIPOSA-2 (up to 39 months), 4 of the 1,862 (0.2%) patients who received RYBREVANT as a single agent or in combination developed a treatment-emergent anti-amivantamab-vmjw antibodies. Given the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, safety or efficacy of RYBREVANT is unknown.

• Administer the diluted RYBREVANT solution [see Dosage and Administration (2.9)] 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.

None.

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

The following adverse reactions are discussed elsewhere in the labeling:

• Infusion-Related Reactions [see Warnings and Precautions (5.1)]
• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)]
• Venous Thromboembolic Events [see Warnings and Precautions (5.3)]
• Dermatologic Adverse Reactions [see Warnings and Precautions (5.4)]
• Ocular Toxicity [see Warnings and Precautions (5.5)]

The exposure-response relationship and time-course of pharmacodynamic response of amivantamab-vmjw have not been fully characterized in patients with NSCLC with EGFR mutations.

Amivantamab-vmjw exposures increased proportionally over a dosage range from 350 to 1,750 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.

Select patients for treatment with RYBREVANT based on the presence of a mutation as detected by an FDA-approved test.

RYBREVANT is a bispecific EGF receptor-directed and MET receptor-directed antibody indicated:

• in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test. ( 1, 2.2)
• in combination with carboplatin and pemetrexed for the treatment of adult patients with 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 an EGFR tyrosine kinase inhibitor. ( 1, 2.2)
• in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test. ( 1, 2.2)
• 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 an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. ( 1, 2.2)

Amivantamab-vmjw is a bispecific antibody that binds to the extracellular domains of EGFR and MET.

In in vitro and in vivo studies amivantamab-vmjw 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. Treatment with amivantamab in combination with lazertinib increased in vivo anti-tumor activity compared to either agent alone in a mouse xenograft model of human NSCLC with an EGFR L858R mutation.

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 Use in Specific Populations (8.1, 8.3)] .

• Infusion-Related Reactions (IRR): Interrupt infusion at the first sign of IRRs. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity. ( 2.5, 2.8, 5.1)
• Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening symptoms indicative of ILD. Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. ( 2.8, 5.2)
• Venous Thromboembolic (VTE) Events with Concomitant Use with Lazertinib: Prophylactic anticoagulation is recommended for the first four months of treatment. Monitor for signs and symptoms of VTE and treat as medically appropriate. Withhold RYBREVANT and lazertinib based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose at the discretion of the healthcare provider. Permanently discontinue RYBREVANT and continue lazertinib for recurrent VTE despite therapeutic anticoagulation. ( 2.7, 2.8, 5.3)
• Dermatologic Adverse Reactions: Can cause severe rash including toxic epidermal necrolysis (TEN) and acneiform dermatitis. At treatment initiation, prophylactic and concomitant medications are recommended. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. ( 2.6, 2.8, 5.4)
• Ocular Toxicity: Promptly refer patients with worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. ( 2.8, 5.5)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.6, 8.1, 8.3)

• The recommended dosage of RYBREVANT is based on baseline body weight and administered as an intravenous infusion after dilution. ( 2.3, 2.4)
• Administer prophylactic and concomitant medications as recommended to reduce the risk of dermatologic adverse reactions. ( 2.6)
• Administer via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions. ( 2.10)
• Administer RYBREVANT in combination with lazertinib or RYBREVANT as a single agent weekly for 5 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks starting at Week 7. ( 2.3)
• Administer RYBREVANT in combination with chemotherapy weekly for 4 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 3 weeks starting at Week 7. (2.4)
• When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to reduce the risk of venous thromboembolic (VTE) events for the first four months of treatment. ( 2.7)
• Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 8 and 9. ( 2.9, 2.10)

Injection: 350 mg/7 mL (50 mg/mL) colorless to pale yellow solution in a single-dose vial.

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

Lactation: Advise not to breastfeed. ( 8.2)

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

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.

• To reduce the risk of infusion-related reactions, administer premedications before each RYBREVANT infusion as recommended [see Dosage and Administration (2.5)].
• To reduce the risk of infusion-related reactions, administer RYBREVANT via peripheral line for Week 1 Day 1 and 2 and Week 2 [see Dosage and Administration (2.10)].
• To reduce the risk and severity of dermatologic adverse reactions with RYBREVANT, prophylactic and concomitant medications are recommended [see Dosage and Administration (2.6)].
• To reduce the risk of venous thromboembolic (VTE) events when administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis for the first four months of treatment [see Dosage and Administration (2.7)].
• Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 8 and 9, with the initial dose as a split infusion on Week 1 on Day 1 and Day 2 [see Dosage and Administration (2.10)].
• When administering RYBREVANT in combination with lazertinib, administer lazertinib orally any time before the RYBREVANT infusion [see Dosage and Administration (2.10)].
• When administering RYBREVANT in combination with carboplatin and pemetrexed, infuse pemetrexed first, carboplatin second, and RYBREVANT last [see Dosage and Administration (2.10)].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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

RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the treatment of adult patients with 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 an EGFR tyrosine kinase inhibitor [see Dosage and Administration (2.2)] .

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 an FDA-approved test [see Dosage and Administration (2.2)] , whose disease has progressed on or after platinum-based chemotherapy.

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

NDC 57894-501-01

Rybrevant ^®

(amivantamab-vmjw)

Injection

350 mg/7 mL

(50 mg/mL)

For Intravenous Infusion Only

Dilute Before Use

Rx only

7 mL Vial

janssen

Single-dose vial.

Discard unused portion.

RYBREVANT, in combination with lazertinib, is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)] .

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 an FDA-approved test [see Dosage and Administration (2.2)] .

The recommended dose reductions for adverse reactions for RYBREVANT are listed in Table 6.

The recommended dosage modifications and management for adverse reactions for RYBREVANT are provided in Table 7.

RYBREVANT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

No studies have been performed to assess the potential of amivantamab-vmjw for carcinogenicity or genotoxicity. Fertility studies have not been performed to evaluate the potential effects of amivantamab-vmjw. In 6-week and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs.

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 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. 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 22.

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 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. 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 21 and Figure 4.

Figure 4: Kaplan-Meier Curve of PFS in Previously Untreated NSCLC Patients by BICR Assessment – PAPILLON Study

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.

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.

RYBREVANT in combination with lazertinib can cause serious and fatal venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism. The majority of these events occurred during the first four months of treatment [see Adverse Reactions (6.1)] .

In MARIPOSA [see Adverse Reactions (6.1)], VTEs occurred in 36% of patients receiving RYBREVANT in combination with lazertinib, including Grade 3 in 10% and Grade 4 in 0.5% of patients. On-study VTEs occurred in 1.2% of patients (n=5) while receiving anticoagulation therapy. There were two fatal cases of VTE (0.5%), 9% of patients had VTE leading to dose interruptions of RYBREVANT, 1% of patients had VTE leading to dose reductions of RYBREVANT, and 3.1% of patients had VTE leading to permanent discontinuation of RYBREVANT. The median time to onset of VTEs was 84 days (range: 6 to 777). Administer prophylactic anticoagulation for the first four months of treatment [see Dosage and Administration (2.7)]. The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate.

Withhold RYBREVANT and lazertinib based on severity [see Dosage and Administration (2.8)] . 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. Treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.8)]. Refer to the lazertinib prescribing information for recommended lazertinib dosage modification.

When initiating treatment with RYBREVANT, prophylactic and concomitant medications are recommended to reduce the risk and severity of dermatologic adverse reactions [see Warnings and Precautions (5.4)].

• 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.

The efficacy of RYBREVANT, in combination with lazertinib, was evaluated in MARIPOSA [NCT04487080], a randomized, active-controlled, multicenter trial. Eligible patients were required to have untreated locally advanced or metastatic NSCLC with either exon 19 deletions or exon 21 L858R substitution EGFR mutations identified by local testing, not amenable to curative therapy. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll.

Patients were randomized (2:2:1) to receive RYBREVANT in combination with lazertinib (N=429), osimertinib monotherapy (N=429), or lazertinib monotherapy (an unapproved regimen for NSCLC) until disease progression or unacceptable toxicity. The evaluation of efficacy for the treatment of untreated metastatic NSCLC relied upon comparison between:

• RYBREVANT administered 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 administered at 240 mg orally once daily.
• Osimertinib administered at a dose of 80 mg orally once daily.

Randomization was stratified by EGFR mutation type (exon 19 deletion or exon 21 L858R substitution mutation), Asian race (yes or no), and history of brain metastasis (yes or no). Tumor assessments were performed every 8 weeks for 30 months, and then every 12 weeks until disease progression.

The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR), and duration of response (DOR).

A total of 858 patients were randomized between the two study arms, 429 to the RYBREVANT in combination with lazertinib arm and 429 to the osimertinib arm. The median age was 63 (range: 25–88) years; 61% were female; 58% were Asian, 38% were White, 1.6% were American Indian or Alaska Native, 0.8% were Black or African American, 0.2% were Native Hawaiian or other Pacific Islander, 0.6% were unknown race or multiple races; and 12% were Hispanic or Latino. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and 89% had Stage IV cancer at initial diagnosis. Sixty percent of patients had tumors harboring exon 19 deletions and the remaining 40% had exon 21 L858R substitution mutations.

Among the 858 patients with EGFR exon 19 deletion or L858R substitution mutations that were randomized between the RYBREVANT plus lazertinib arm versus the osimertinib arm, available tissue samples from 544 (63%) patients had evaluable results when tested retrospectively using the cobas EGFR Mutation Test v2. Of the 544 patients with evaluable results, 527 (97%) patients were positive for EGFR exon 19 deletion or L858R substitution mutations, while 17 (3%) patients were negative. Available plasma samples from patients were retrospectively tested using an FDA-approved test to confirm the biomarker status.

The trial demonstrated a statistically significant improvement in PFS by BICR assessment and OS for RYBREVANT in combination with lazertinib compared to osimertinib (see Table 18 and Figures 1 and 2).

Efficacy results for RYBREVANT in combination with lazertinib are provided in Table 18.

Figure 1: Kaplan-Meier Curves of PFS by BICR Assessment in Patients with Previously Untreated NSCLC

Figure 2: Kaplan-Meier Curves of OS in Patients with Previously Untreated NSCLC

Out of all randomized patients (n=858), 367 (43%) had baseline intracranial lesions assessed by BICR using modified RECIST. Results of pre-specified analyses of intracranial ORR and DOR by BICR in the subset of patients with intracranial lesions at baseline for the RYBREVANT in combination with lazertinib arm and the osimertinib arm are summarized in Table 19.

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 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.
• 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 20.

Figure 3: Kaplan-Meier curve of PFS in Previously Treated NSCLC Patients by BICR assessment- MARIPOSA-2

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.

The recommended dosage of RYBREVANT in combination with lazertinib or RYBREVANT as a single agent, based on baseline body weight, are provided in Table 2. Administer RYBREVANT until disease progression or unacceptable toxicity.

When initiating treatment with RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to reduce the risk of venous thromboembolic (VTE) events for the first four months of treatment [see Warnings and Precautions (5.3)]. 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.

The recommended dosage of RYBREVANT, administered in combination with carboplatin and pemetrexed is based on baseline body weight is provided in Table 3.

The recommended order of administration and regimen for RYBREVANT in combination with carboplatin and pemetrexed are provided in Table 4.