SUMMARY

• RYBREVANT (amivantamab-vmjw) is a low fucose, fully human immunoglobulin G1 (IgG1)-based bispecific antibody with immune cell-directing activity that targets epidermal growth factor receptor (EGFR) mutations and mesenchymal-epithelial transition (MET) mutations and amplifications in non-small cell lung cancer (NSCLC).¹
• LAZCLUZE (lazertinib) is a third-generation EGFR tyrosine kinase inhibitor (TKI).²
• Inhibition of hepatocyte growth factor, the ligand that activates the MET receptor,³ can result in decreased serum albumin levels based on the role of the hepatocyte growth factor receptor gene in the stimulation of protein synthesis in the liver. A decrease in albumin levels can lead to reduced osmotic pressure, and peripheral edema may result from a shift of fluid into the interstitial spaces.⁴
• MARIPOSA (NCT04487080) is an ongoing, phase 3, randomized study evaluating the efficacy and safety of RYBREVANT and LAZCLUZE combination therapy (open-label, n=429) vs osimertinib (double-blind, n=429) vs LAZCLUZE (double-blind, n=216) as first-line treatment in patients with EGFR-mutated (Exon 19 deletion [Exon19del] or Exon 21 L858R substitution) locally advanced or metastatic NSCLC.^2,5,6
  • Among patients treated with RYBREVANT plus LAZCLUZE, grade ≥3 hypoalbuminemia was reported in 22 (5%) patients and grade ≥3 peripheral edema was reported in 8 (2%) patients (Table: MARIPOSA: Incidence of AEs Related to Peripheral Edema and Decreased Serum Albumin).⁶
  • In the final overall survival (OS) analysis with a median follow-up of 37.8 months (range, 0-48.1), grade ≥3 hypoalbuminemia was reported in 26 (6%) patients and grade ≥3 peripheral edema was reported in 8 (2%) patients treated with RYBREVANT plus LAZCLUZE. (Table: MARIPOSA Final OS Analysis: Incidence of Peripheral Edema and Decreased Serum Albumin).⁷ 
• PAPILLON (NCT04538664) is an ongoing, phase 3, randomized, open-label study designed to compare the efficacy and safety of RYBREVANT plus chemotherapy (carboplatin and pemetrexed; n=153) vs chemotherapy alone (carboplatin and pemetrexed; n=155) in patients with untreated locally advanced or metastatic NSCLC and EGFR Exon 20 insertion (Exon20ins) mutations.^8,9
  • Among patients treated with RYBREVANT plus chemotherapy, grade ≥3 hypoalbuminemia was reported in 6 (4%) patients and grade ≥3 peripheral edema was reported in 2 (1%) patients (Table: PAPILLON: Incidence of AEs Related to Peripheral Edema and Decreased Serum Albumin).⁹
• MARIPOSA-2 (NCT04988295) is an ongoing, phase 3, randomized, open-label study designed to assess the efficacy and safety of RYBREVANT-LAZCLUZE-chemotherapy (pemetrexed and carboplatin; n=263) and RYBREVANT-chemotherapy (pemetrexed and carboplatin; n=131) vs chemotherapy alone (pemetrexed and carboplatin; n=263) in patients with EGFR-mutated (Exon19del or Exon 21 L858R substitution) locally advanced or metastatic NSCLC on or after osimertinib monotherapy.^10,11
  • Among patients treated with RYBREVANT-LAZCLUZE-chemotherapy, grade ≥3 hypoalbuminemia was reported in 12 (5%) patients and grade ≥3 peripheral edema was reported in 1 (0.4%) patient. Among patients treated with RYBREVANT-chemotherapy, grade ≥3 hypoalbuminemia was reported in 3 (2%) patients and grade ≥3 peripheral edema was reported in 2 (2%) patients (Table: MARIPOSA-2: Incidence of TEAEs Related to Peripheral Edema and Decreased Serum Albumin).¹¹
• CHRYSALIS (NCT02609776) is an ongoing, phase 1, open-label, multicenter, dose-escalation and dose-expansion study evaluating the safety, efficacy, and pharmacokinetics of RYBREVANT as monotherapy and in combination with other therapies in adult patients with advanced NSCLC harboring EGFR mutations who had disease progression during or after previous standard of care (SOC) treatment.¹²
  • Among 114 patients in the safety population, grade ≥3 hypoalbuminemia was reported in 3 (3%) patients and grade ≥3 peripheral edema was not reported in any patients. Among all patients treated at the recommended phase 2 dose (RP2D; n=258), grade ≥3 hypoalbuminemia was reported in 4 (2%) patients and grade ≥3 peripheral edema was reported in 2 (1%) patients (Table: CHRYSALIS: Incidence of AEs Related to Peripheral Edema and Decreased Serum Albumin in Patients Treated at the RP2D).¹² Peripheral edema was most commonly managed by concomitant use of diuretic medications (primarily furosemide).¹⁶
  • In a long-term analysis of 114 patients in CHRYSALIS cohort D with a median follow-up of 19.2 months, grade ≥3 hypoalbuminemia was reported in 5 (4%) patients and grade ≥3 peripheral edema was reported in 1 (1%) patient. Among all patients treated at the RP2D (n=474), grade ≥3 hypoalbuminemia was reported in 11 (2%) patients and grade ≥3 peripheral edema was reported in 5 (1%) patients (Table: CHRYSALIS Long-Term Analysis: Incidence of AEs Related to Peripheral Edema and Decreased Serum Albumin in Patients Treated at the RP2D).¹³
• Please refer to RYBREVANT product labeling for complete safety information, including dose modification guidelines for adverse reactions.
• For guidance on preventing and managing peripheral edema and hypoalbuminemia, refer to Prevention and Management of Peripheral Edema and Hypoalbuminemia as Reported in the Literature.
• Please refer to product labeling for carboplatin and/or pemetrexed for complete prescribing information.

PRODUCT LABELING

• RYBREVANT (amivantamab-vmjw) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/RYBREVANT-pi.pdf.
• LAZCLUZE (lazertinib) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/LAZCLUZE-pi.pdf.

BACKGROUND

Hypoalbuminemia, an event that has been identified as a class effect with MET TKIs, may be a potential contributor to the event of peripheral edema. Inhibition of hepatocyte growth factor, the ligand that activates the MET receptor,³ can result in decreased serum albumin levels based on the role of MET in the stimulation of protein synthesis in the liver. As albumin is the predominant protein regulating osmotic pressure, a decrease in albumin levels can lead to reduced osmotic pressure, and peripheral edema may result from a shift of fluid into the interstitial spaces.⁴

CLINICAL DATA

MARIPOSA Study

Study Design/Methods

• Phase 3, ongoing, randomized study designed to assess the efficacy and safety of RYBREVANT plus LAZCLUZE (open-label, n=429) vs osimertinib (double-blind, n=429) vs LAZCLUZE (double-blind, n=216) as first-line treatment in 1074 patients with EGFRmutated (Exon19del or L858R) locally advanced or metastatic NSCLC.^2,5,6
  • RYBREVANT 1050 mg intravenous (IV; 1400 mg IV for body weight ≥80 kg) was administered every week for the first 4 weeks, with the initial dose as a split infusion on cycle 1 day 1 (C1D1) and D2, followed by every 2 weeks thereafter.
  • LAZCLUZE 240 mg was administered orally (PO) once daily.
  • Osimertinib 80 mg PO was administered once daily.

Results

• The median duration of treatment was 18.5 months for RYBREVANT plus LAZCLUZE and 18 months for osimertinib.^2,5,6
• The incidence of adverse events (AEs) related to decreased serum albumin reported in the MARIPOSA study is shown in the table below.

• In the final OS analysis with a median follow-up of 37.8 months (range, 0-48.1), the incidence of peripheral edema and hypoalbuminemia reported are shown in Table: MARIPOSA Final OS Analysis: Incidence of Peripheral Edema and Decreased Serum Albumin.⁷

PAPILLON Study

Study Design/Methods

• Phase 3, ongoing, randomized, open-label study designed to compare the efficacy and safety of RYBREVANT plus chemotherapy (carboplatin and pemetrexed; n=153) vs chemotherapy alone (carboplatin and pemetrexed; n=155) in patients with untreated locally advanced or metastatic NSCLC and EGFR Exon20ins mutations.^8,9
  • RYBREVANT 1400 mg IV (1750 mg IV for body weight ≥80 kg) was administered every week for the first 4 weeks, with the initial dose as a split infusion on C1D1 and D2, followed by RYBREVANT 1750 mg IV (2100 mg IV for body weight ≥80 kg) every 3 weeks starting at week 7 (cycle 3 day 1 [C3D1]) until disease progression.
  • Pemetrexed 500 mg/m² IVwas administered every 3 weeks until disease progression.¹⁵
  • Carboplatin area under the curve (AUC) 5 IV was administered every 3 weeks for up to 4 cycles.

Results

• The median duration of treatment was 9.7 months (range, 0.1-26.9) for RYBREVANT plus chemotherapy and 6.7 months (range, 0-25.3) for chemotherapy alone.^8,9
• The incidence of AEs related to decreased serum albumin reported in the PAPILLON study is shown in the table below.

MARIPOSA-2 Study

Study Design/Methods

• Phase 3, ongoing, randomized, open-label study designed to assess the efficacy and safety of RYBREVANT-LAZCLUZE-chemotherapy (n=263) and RYBREVANT-chemotherapy (n=131) vs chemotherapy alone (n=263) in 657 patients with EGFR-mutated locally advanced or metastatic NSCLC on or after osimertinib monotherapy (as the most recent line of therapy).^10,11
  • RYBREVANT 1400 mg IV (1750 mg IV for body weight ≥80 kg) was administered every week for the first 4 weeks, with the initial dose as a split infusion on C1D1 and D2, followed by 1750 mg IV (2100 mg IV for body weight ≥80 kg) every 3 weeks starting at week 7 (C3D1) until disease progression.
  • LAZCLUZE 240 mg PO was administered once daily.
  • Chemotherapy was administered every 3 weeks at the beginning of each cycle, with carboplatin at AUC 5 IV for the first 4 cycles, and pemetrexed at 500 mg/m² IV until disease progression.
• In the RYBREVANT-LAZCLUZE-chemotherapy arm, patients randomized before November 7, 2022 received LAZCLUZE on C1D1. Due to an increase in hematologic and gastrointestinal toxicities in the arm, the regimen was modified to start LAZCLUZE after carboplatin completion.¹¹
  • An open-label, randomized, extension cohort will evaluate the efficacy and safety of the modified RYBREVANT-LAZCLUZE-chemotherapy regimen vs RYBREVANT-chemotherapy.

Results

• At a median follow-up of 8.7 months, the median duration of treatment was 5.8 months for RYBREVANT-LAZCLUZE-chemotherapy, 6.3 months for RYBREVANT-chemotherapy, and 3.7 months for chemotherapy alone.^10,11
• The incidence of AEs related to decreased serum albumin reported in the MARIPOSA-2 study is shown in the table below.

CHRYSALIS Study

The results of the CHRYSALIS study are also included in the RYBREVANT product labeling. The incidence of adverse reactions described below may vary from that in the RYBREVANT product labeling due to the evaluation of different patient populations for safety analyses, contributing to differences in reported percentages. The summary below describes safety results from patients with metastatic or unresectable NSCLC and EGFR Exon20ins mutations with disease progression during or after platinum-based chemotherapy who received RYBREVANT at the RP2D and all patients treated at the RP2D.

Study Design/Methods

• Phase 1, ongoing, open-label, multicenter, dose-escalation and dose-expansion study evaluating the safety, efficacy, and pharmacokinetics of RYBREVANT as monotherapy and in combination with other therapies in adult patients with advanced NSCLC harboring EGFR mutations who had disease progression during or after previous SOC treatment.¹²
  • RYBREVANT monotherapy was administered at the RP2D: 1050 mg IV (1400 mg IV for body weight ≥80 kg) every week for C1, with the initial dose as a split infusion on C1D1 and D2, and every 2 weeks thereafter until disease progression or unacceptable toxicity.
  • A total of 114 patients with metastatic or unresectable NSCLC and EGFR Exon20ins mutations with disease progression during or after platinum-based chemotherapy were evaluated for safety, and 81 evaluable patients were assessed for efficacy.

Results

• The median follow-up for safety was 5.1 months (range, 0.2-29.3 months).¹²
• The incidence of AEs related to decreased serum albumin reported in the CHRYSALIS study is shown in the table below.
• Peripheral edema was most commonly managed by concomitant use of diuretic medications.¹⁶
  • In the EGFR Exon20ins population with prior chemotherapy and treated at the RP2D, 9 of 22 (40.9%) patients with peripheral edema received diuretic treatment (primarily furosemide) for their event.

• In a long-term analysis of patients in CHRYSALIS cohort D with a median follow-up of
  19.2 months, the incidence of AEs related to decreased serum albumin reported is shown in the table below.¹³

PREVENTION AND Management of Peripheral Edema and Hypoalbuminemia as reported in the literature

The information provided in this section includes guidance on prevention and management of peripheral edema and hypoalbuminemia as reported in the literature.¹⁷ These are not recommendations for individual patient care. Interventions should be based on patient presentation and clinical judgment of the treating physician.

• Consider the following strategies described in Table: Prevention and Management of Peripheral Edema and Hypoalbuminemia

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DerwentDrug File (and/or other resources, including internal/external databases) was conducted on
03 November 2025. The information included in this response is limited to relevant data from the registrational studies for RYBREVANT.