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RYBREVANT®

(amivantamab-vmjw)

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RYBREVANT® (amivantamab-vmjw)
Medical Information

Safety Information for RYBREVANT - Cardiac Adverse Events

Last Updated: 04/30/2026

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
  • MARIPOSA (NCT04487080) is an ongoing, phase 3, randomized study evaluating 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 patients with EGFR-mutated (Exon 19 deletion [Exon19del] or Exon 21 L858R substitution) locally advanced or metastatic NSCLC.2-4
  • 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
  • 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.11,12
  • 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.14
  • Please refer to RYBREVANT product labeling for complete safety information, including dose modification guidelines for adverse reactions.
  • Please refer to product labeling for carboplatin and/or pemetrexed for complete prescribing information.

PRODUCT LABELING

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.2-4
    • 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

  • At a median follow-up of 22 months, the median duration of treatment was 18.5 months for RYBREVANT plus LAZCLUZE and 18 months for osimertinib.4
  • The incidence of cardiac AEs in the MARIPOSA study is shown in the table below.
  • The incidence of serious cardiac AEs in the MARIPOSA study is shown in the table below.

MARIPOSA: Incidence of Cardiac AEsa,5   
AEs, n (%)
RYBREVANT + LAZCLUZE
(n=421)
Osimertinib
(n=428)
All Grade 5
Myocardial infarction
3 (1)b
0
Pericardial effusion
1 (<1)
1 (<1)
Arteriosclerosis coronary artery
1 (<1)
0
Cardiopulmonary failure
1 (<1)
0
Cerebral infarction
1 (<1)
0
Circulatory collapse
1 (<1)
0
Coronary artery disease
1 (<1)c
0
Ischemic cerebral infarction
1 (<1)
0
Myocardial rupture
1 (<1)
0
Cardiac failure
0
1 (<1)
Cerebral hemorrhage
0
1 (<1)
Cerebrovascular accident
0
1 (<1)
Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event. aThe safety population included all the patients who had undergone randomization and received ≥1 dose of any trial treatment. All grade 5 AEs correspond to TEAEs leading to death and vice versa.bTwo events in the RYBREVANT + LAZCLUZE group were deemed related to any study treatment by the investigator.cDeemed as related to any study treatment by the investigator.

MARIPOSA: Incidence of Serious Cardiac AEsa,5  
SAEs, n (%)
RYBREVANT + LAZCLUZE
(n=421)
Osimertinib
(n=428)
Pericardial effusion
4 (1)
5 (1)
Cardiac failure
1 (<1)
5 (1)
Abbreviations: AE, adverse event; SAE, serious adverse event. aThe safety population included all the patients who had undergone randomization and received ≥1 dose of any trial treatment.
  • In the final OS analysis, with a median follow-up of 37.8 months, the median duration of treatment was 27 months for RYBREVANT plus LAZCLUZE and 22.4 months for osimertinib.6 
  • The incidence of serious cardiac AEs in the final OS analysis of the MARIPOSA study is shown in the table below.

MARIPOSA Final OS Analysis: Incidence of Serious Cardiac AEs7 
SAEs, n (%)
RYBREVANT + LAZCLUZE
(n=421)
Osimertinib
(n=428)
Pericardial effusion
4 (1)
5 (1)
Cerebral infarction
3 (1)
5 (1)
Cardiac failure
2 (<1)
5 (1)
Abbreviations: AE, adverse event; OS, overall survival; SAE, serious adverse event.  

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. 
    • Carboplatin area under the curve (AUC) 5 IV was administered every 3 weeks for up to 4 cycles.

Results

  • At a median follow-up of 14.9 months, the median duration of treatment was 9.7 months for RYBREVANT plus chemotherapy and 6.7 months for chemotherapy alone.9
  • The incidence of treatment-emergent cardiac AEs in the PAPILLON study is shown in the table below.

PAPILLON: Incidence of Treatment-Emergent Cardiac AEsa,10 
TEAEs, n (%)
RYBREVANT + Chemotherapy
(n=151)
Chemotherapy
(n=155)
All Grade 5
Cardiorespiratory arrestb
1 (1)c
0
Cerebrovascular accident
1 (1)c
0
Acute myocardial infarction
0
1 (1)
Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event. aThe safety population included all the patients who had undergone randomization and received ≥1 dose of any study treatment. All grade 5 AEs correspond to TEAEs leading to death and vice versa.bDeath due to cardiorespiratory arrest occurred in the setting of tumor infiltration of heart and was also deemed related to RYBREVANT.cDenoting the TEAEs leading to death within 30 days of the last dose that occurred within 90 days after the first dose.

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).11,12
    • 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.12
    • 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.12,13
  • The incidence of cardiac AEs in the MARIPOSA-2 study is shown in the table below.
  • The incidence of treatment-emergent serious cardiac AEs in the MARIPOSA-2 study is shown in the table below.

MARIPOSA-2: Incidence of Cardiac AEsa,13 
AEs, n (%)
RYBREVANT-LAZCLUZE-Chemotherapy
(n=263)
RYBREVANT-Chemotherapy
(n=130)
Chemotherapy
(n=243)
All Grade 5
Atrial fibrillation
1 (0.4)
0
0
Cardiac arrest
1 (0.4)
0
0
Cardiac failure
1 (0.4)
0
0
Ventricular fibrillation
0
1 (1)b
0
Abbreviation: AE, adverse event. aThe safety population included all the patients who had undergone randomization and received ≥1 dose of any study treatment.bDeemed as related to any study treatment.

MARIPOSA-2: Incidence of Treatment-Emergent Serious Cardiac AEsa,13 
Treatment-Emergent SAEs, n (%)
RYBREVANT-LAZCLUZE-Chemotherapy
(n=263)
RYBREVANT-Chemotherapy
(n=130)
Chemotherapy
(n=243)
All Grade 5
Supraventricular tachycardia
1 (0.4)
2 (2)
0
Abbreviations: AE, adverse event; SAE, serious adverse event. aThe safety population included all the patients who had undergone randomization and received ≥1 dose of any study treatment.

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 recommended phase 2 dose (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.14
    • 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

  • At a median safety follow-up of 5.1 months, the median duration of treatment was 3.7 months for the safety population.14
  • The incidence of serious cardiac AEs in the CHRYSALIS study is shown in the table below.

CHRYSALIS: Incidence of Serious Cardiac AEs15 
SAEs, n (%)
Safety Population
(n=114)
Acute coronary syndrome
1 (1)
Atrial flutter
1 (1)
Cardio-respiratory distress
1 (1)
Abbreviations: AE, adverse event; SAE, serious adverse event.

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and DerwentDrug File (and/or other resources, including internal/external databases) was conducted on
29 April 2026. The information included in this response is limited to relevant data from the registrational studies for RYBREVANT.

 

References

Show
1 Moores SL, Chiu ML, Bushey BS, et al. A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors. Cancer Res. 2016;76(13):3942-3953.  
2 Cho BC, Felip E, Hayashi H, et al. MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer. Future Oncol. 2022;18(6):639-647.  
3 Janssen Research & Development, LLC. A phase 3, randomized study of amivantamab and lazertinib combination therapy versus osimertinib versus lazertinib as first-line treatment in patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2026 April 29]. Available from: https://clinicaltrials.gov/study/NCT04487080 NLM Identifier: NCT04487080.  
4 Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498.  
5 Cho BC, Lu S, Felip E, et al. Supplement to: Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498.  
6 Yang JCH, Lu S, Hayashi H, et al. Overall survival with amivantamab-lazertinib in EGFR-mutated advanced NSCLC. N Engl J Med. 2025;393(17):1681-1693.  
7 Yang JCH, Lu S, Hayashi H, et al. Supplement to: Overall survival with amivantamab-lazertinib in EGFR-mutated advanced NSCLC. N Eng J Med. 2025;393(17):1681-1693.  
8 Janssen Research & Development, LLC. A randomized, open-label phase 3 study of combination amivantamab and carboplatin-pemetrexed therapy, compared with carboplatin-pemetrexed, in patients with EGFR exon 20ins mutated locally advanced or metastatic non-small cell lung cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2026 April 29]. Available from: https://clinicaltrials.gov/study/NCT04538664 NLM Identifier: NCT04538664.  
9 Zhou C, Tang KJ, Cho BC, et al. Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. N Engl J Med. 2023;389(22):2039-2051.  
10 Zhou C, Tang KJ, Cho BC, et al. Supplement to: Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. N Engl J Med. 2023;389(22):2039-2051.  
11 Janssen Research & Development, LLC. A phase 3, open-label, randomized study of amivantamab and lazertinib in combination with platinum-based chemotherapy compared with platinum-based chemotherapy in patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer after osimertinib failure. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2026 April 29]. Available from: https://clinicaltrials.gov/study/NCT04988295 NLM Identifier: NCT04988295.  
12 Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90.  
13 Passaro A, Wang J, Wang Y, et al. Supplement to: Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase 3 MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90.  
14 Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J Clin Oncol. 2021;39(30):3391-3402.  
15 Park K, Haura EB, Leighl NB, et al. Supplement to: Amivantamab in EGFR exon 20 insertion-mutated non-small cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J Clin Oncol. 2021;39(30):3391-3402.