For APPs & Nurses

Primary Endpoint

For first-line treatment of adult patients with locally advanced or metastatic EGFR+ NSCLC

Superior PFS vs osimertinib with a chemotherapy-sparing combination1

RYBREVANT® + LAZCLUZE™ demonstrated a statistically significant reduction in the risk of progression or death by 30% vs osimertinib1,2

Mariposa trial reduced progression rates for RYBREVANT® (amivantamab) and LAZCLUZE™ patientsRYBREVANT® (amivantamab) and LAZCLUZE™ progression-free rates in the Mariposa trial

7.1-month improvement in mPFS vs osimertinib1

  • 23.7 months (95% CI: 19.1, 27.7) mPFS with RYBREVANT® + LAZCLUZE™ vs 16.6 months (95% CI: 14.8, 18.5) with osimertinib

  • In the non-registrational LAZCLUZE™ arm, median PFS was 18.5 months (95% CI: 14.8, 20.1)2
MARIPOSA study design

PFS results in prespecified subgroups2

Mariposa trial disease progression rates for RYBREVANT® and LAZCLUZE™Mariposa trial disease progression rates for RYBREVANT® and LAZCLUZE™

Methodology

In MARIPOSA, pathogenic alterations were identified using ctDNA by NGS of blood with Guardant360 CDx at baseline. Ex19del and L858R ctDNA in blood was analyzed at baseline with Biodesix ddPCR. This exploratory analysis included all randomized patients who had one or more biomarker assessment. Subgroup analyses of efficacy endpoints were carried out using statistical methods for the primary analysis of the general MARIPOSA population.3

Results

High-risk features at baseline, including detectable ctDNA, TP53 co-mutations, or metastases in the liver or brain, were identified in 89% of patients with baseline ctDNA available for NGS of pathogenic alterations (n=636).2,3

35% reduction

in risk of progression or death in patients with TP53 co-mutations treated with RYBREVANT® + LAZCLUZE™ (n=149) vs osimertinib (n=144) (HR=0.65 [95% CI: 0.48, 0.87])3

  • mPFS of RYBREVANT® + LAZCLUZE™ was 18.2 months (95% CI: 15.3, 22.1) and 12.9 months (95% CI: 11.1, 14.7) with osimertinib
32% reduction

in risk of progression or death in patients with detectable ctDNA at baseline by ddPCR* with RYBREVANT® + LAZCLUZE™ (n=231) vs osimertinib (n=240) (HR=0.68 [95% CI: 0.53, 0.86])3

  • mPFS of RYBREVANT® + LAZCLUZE™ was 20.3 months (95% CI: 16.6, 24.0) and 14.8 months (95% CI: 12.9, 16.5) with osimertinib
42% reduction

in risk of progression or death in patients with liver metastases at baseline treated with RYBREVANT® + LAZCLUZE™ (n=64) vs osimertinib (n=72) (HR=0.58 [95% Cl: 0.37, 0.91])3

  • mPFS of RYBREVANT® + LAZCLUZE™ was 18.2 months (95% CI: 13.1, NE) and 11 months (95% CI: 7.4, 12.8) with osimertinib

This analysis is not included in the Prescribing Information for RYBREVANT® and LAZCLUZE™. This was a post hoc exploratory analysis and was not powered to show statistical significance.

*Consistent results were seen in patients with detectable ctDNA using the NGS assay (HR=0.71 [95% CI: 0.57, 0.89]).

CI, confidence interval; ctDNA, circulating tumor DNA; ddPCR, droplet digital polymerase chain reaction; DNA, deoxyribonucleic acid; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; ex19del, exon 19 deletion; HR, hazard ratio; mPFS, median progression-free survival; NE, not estimable; NGS, next-generation sequencing; NSCLC, non–small cell lung cancer; PFS, progression-free survival.

Other Endpoints

For first-line treatment of adult patients with locally advanced or metastatic EGFR+ NSCLC

OS results were immature at the initial interim analysis (55% of prespecified events); no trend towards detriment was observed. In a longer follow-up (82% of prespecified events), updated OS results were:

RYBREVANT® (amivantamab) with carboplatin and pemetrexed dosing and administration breakdown over timeRYBREVANT® (amivantamab) and LAZCLUZE™ survival rates in Mariposa trial

The final OS analysis has not yet been formally tested.

61% of patients were alive at 36 months with RYBREVANT® + LAZCLUZE™ and 53% with osimertinib2

For first-line treatment of adult patients with locally advanced or metastatic EGFR+ NSCLC

High and durable responses with a chemotherapy-sparing combination1

Overall response rates

RYBREVANT® (amivantamab) response rates in the Mariposa trial for RYBREVANT® and LAZCLUZE™RYBREVANT® and LAZCLUZE™ response rates in Mariposa trial

This was a prespecified analysis and was not powered to show statistical significance.

~1.5X CR with RYBREVANT® + LAZCLUZE™

Duration of response

RYBREVANT® (amivantamab) and LAZCLUZE™ median duration of response bar chartRYBREVANT® (amivantamab) and LAZCLUZE™ median duration of response

This was a prespecified analysis and was not powered to show statistical significance.

~1.5X mDOR with RYBREVANT® + LAZCLUZE™

For first-line treatment of adult patients with locally advanced or metastatic EGFR+ NSCLC

High intracranial ORR with durable intracranial DOR1

Intracranial ORR in subjects with intracranial lesions at baseline

RYBREVANT® and LAZCLUZE™ response rates in Mariposa trialRYBREVANT® (amivantamab) and LAZCLUZE™ response rates in Mariposa trial

This was a prespecified exploratory analysis and was not powered to show statistical significance.

Intracranial DOR in confirmed responders with intracranial lesions at baseline

RYBREVANT® (amivantamab) patients in Mariposa trial maintaining intracranial response bar graphIntracranial response in RYBREVANT® and LAZCLUZE™ bar graph

This was a prespecified exploratory analysis and was not powered to show statistical significance.

CR, complete response; DOR, duration of response; mDOR, median duration of response; ORR, overall response rate; OS, overall survival.

Study Design

For first-line treatment of adult patients with locally advanced or metastatic EGFR+ NSCLC

MARIPOSA: Evaluating the first and only multitargeted combination in first-line EGFR+ mNSCLC vs osimertinib1

MARIPOSA was a randomized, active-controlled, multicenter Phase 3 trial assessing the efficacy of RYBREVANT® in combination with LAZCLUZE™. 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 LAZCLUZE™ (N=429), osimertinib monotherapy (N=429), or LAZCLUZE™ 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® in combination with LAZCLUZE™, and osimertinib.1,2

Serial brain MRIs were conducted for all patients to assess intracranial response and duration2

  • Serial brain MRIs were performed at baseline and either every 8 weeks for the first 30 months and 12 weeks thereafter (for patients with a history of brain metastases) or every 24 weeks (for patients without a history)

The largest Phase 3 trial of patients with EGFR+ disease2,7-16

Mariposa trial study design for RYBREVANT® and LAZCLUZE™Mariposa study design for RYBREVANT® and LAZCLUZE™

LAZCLUZE™ monotherapy arm was included to assess the contribution of the components.2
MARIPOSA was the largest Phase 3 trial that evaluated 1L treatment in patients with EGFR+ mNSCLC as of July 2024.2,7-16

Baseline characteristics were well-balanced across treatment types2

RYBREVANT® (amivantamab) and LAZCLUZE™ Mariposa trial study design characteristics chartMariposa trial study design baseline characteristics

*Other includes American Indian or Alaska Native, Black or African-American, Native Hawaiian or Pacific Islander, multiple, and unknown.

†One patient in the RYBREVANT® + LAZCLUZE™ arm had both ex19del and L858R.

1L, first-line; BICR, blinded independent central review; mNSCLC, metastatic non–small cell lung cancer; RECIST, Response Evaluation Criteria in Solid Tumors.

Safety1

Infusion-Related Reactions (IRRs)

In MARIPOSA, IRRs occurred in 63% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 in 5% and Grade 4 in 1% of patients. The incidence of infusion modifications due to IRR was 54%, and IRRs leading to dose reduction of RYBREVANT® occurred in 0.7% of patients. Infusion-related reactions leading to permanent discontinuation of RYBREVANT® occurred in 4.5% of patients receiving RYBREVANT® in combination with LAZCLUZE™.

Interstitial Lung Disease (ILD)/Pneumonitis

In MARIPOSA, ILD/pneumonitis occurred in 3.1% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 in 1.0% and Grade 4 in 0.2% of patients. There was one fatal case of ILD/pneumonitis and 2.9% of patients permanently discontinued RYBREVANT® and LAZCLUZE™ due to ILD/pneumonitis.

Venous Thromboembolic (VTE) Events With Concomitant Use of RYBREVANT® and LAZCLUZE™

In MARIPOSA, VTEs occurred in 36% of patients receiving RYBREVANT® in combination with LAZCLUZE™, 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 2 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®. 7% of patients had VTE leading to dose interruptions of LAZCLUZE™, 0.5% of patients had VTE leading to dose reductions of LAZCLUZE™, and 1.9% of patients permanently discontinued LAZCLUZE™ due to VTE. The median time to onset of VTEs was 84 days (range: 6 to 777).

Dermatologic Adverse Reactions

In MARIPOSA, rash occurred in 86% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 in 26% of patients. The median time to onset of rash was 14 days (range: 1 to 556 days). Rash leading to dose interruptions of RYBREVANT® occurred in 37% of patients, rash leading to dose reductions of RYBREVANT® occurred in 23% of patients, and rash leading to permanent discontinuation of RYBREVANT® occurred in 5% of patients. Rash leading to dose reduction of LAZCLUZE™ occurred in 19% of patients, rash leading to dose interruption of LAZCLUZE™ occurred in 30% of patients, and LAZCLUZE™ was permanently discontinued due to rash in 1.7% of patients.

Ocular Toxicity

In MARIPOSA, ocular toxicity occurred in 16% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 or 4 ocular toxicity in 0.7% of patients. Withhold, reduce the dose, or permanently discontinue RYBREVANT® and continue LAZCLUZE™ based on severity.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal models, RYBREVANT® and LAZCLUZE™ 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 patients 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®.

Advise females of reproductive potential to use effective contraception during treatment with LAZCLUZE™ and for 3 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LAZCLUZE™ and for 3 weeks after the last dose.

Safety profile of RYBREVANT® + LAZCLUZE™ in the MARIPOSA study1

Majority of ARs were Grades 1 and 2

ARs (≥10%) in patients in MARIPOSA
RYBREVANT® (amivantamab) and LAZCLUZE™ adverse reactions in Mariposa trialRYBREVANT® (amivantamab) and LAZCLUZE™ adverse reactions in Mariposa trial
  • Serious ARs occurred in 49% of patients with RYBREVANT® + LAZCLUZE™ and 33% with osimertinib1,2
  • Serious ARs in ≥2% of patients included VTE (11%), pneumonia (4%), rash (2.9%), ILD/pneumonitis (2.9%), COVID-19 (2.4%), pleural effusion (2.1%), and IRR (2.1%)1
  • Fatal ARs occurred in 7% of patients who received RYBREVANT® + LAZCLUZE™ and 7% with osimertinib1,2
  • The most common ARs (≥20%) were rash, nail toxicity, IRR, musculoskeletal pain, stomatitis, edema, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity1
  • Clinically relevant ARs in <10% of patients who received RYBREVANT® + LAZCLUZE™ included ILD/pneumonitis (3.1%)1

Select laboratory abnormalities that worsened at baseline (≥20%) in MARIPOSA1*

Lab abnormalities observed with RYBREVANT® (amivantamab) and LAZCLUZE™ in Mariposa trialLab abnormalities observed with RYBREVANT® (amivantamab) and LAZCLUZE™ in Mariposa trial

*The denominator used to calculate the rate is the number of patients with a baseline value and at least one post-treatment value for the specific lab test.

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

In the MARIPOSA trial, most IRRs occurred during the first infusion (Week 1, Day 1) and rarely during subsequent infusions.

Mariposa trial IRR per RYBREVANT® infusion chartIRRs per RYBREVANT® infusion in Mariposa trial
  • 92.3% of IRRs were Grades 1 to 2
  • Median time to onset of first IRR was 1 hour (range, 0.05 to 52.5 hours) 
  • Monitor patients for any signs and symptoms of IRRs during RYBREVANT® infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT® based on severity1
  • Signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting1

ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase.

Discontinuation Rates and Dose Modifications

90% of patients treated with RYBREVANT® + LAZCLUZE™ were able to stay on treatment without discontinuation due to treatment-related ARs2

Discontinuation Rates

  • Median duration of treatment was 18.5 months for RYBREVANT® + LAZCLUZE™ and 18 months for osimertinib2
  • Permanent discontinuation of RYBREVANT® due to an AR occurred in 34% of patients. ARs leading to RYBREVANT® discontinuation in ≥1% of patients included rash, IRRs, nail toxicity, VTE, ILD/pneumonitis, pneumonia, edema, hypoalbuminemia, fatigue, paresthesia, and dyspnea1
  • Permanent discontinuation of LAZCLUZE™ due to an AR occurred in 21% of patients. ARs that resulted in permanent discontinuation of LAZCLUZE™ in ≥1% of patients included ILD/pneumonitis, pneumonia, VTE, rash, respiratory failure, and sudden death17

Dose Interruptions

  • Dose interruptions of RYBREVANT® due to an AR occurred in 88% of patients. ARs requiring dose interruption in ≥5% of patients were IRRs, rash, nail toxicity, COVID-19, VTE, increased ALT, edema, and hypoalbuminemia1
  • Dose interruptions of LAZCLUZE™ due to an AR occurred in 72% of patients. ARs requiring dose interruption in ≥5% of patients were rash, nail toxicity, COVID-19, VTE, increased ALT, and increased AST17

Dose Reductions

  • Dose reductions of RYBREVANT® due to AR occurred in 46% of patients. ARs requiring dose reductions in ≥5% of patients were rash and nail toxicity1
  • Dose reductions of LAZCLUZE™ due to an AR occurred in 42% of patients. ARs requiring dose reductions in ≥5% of patients were rash and nail toxicity17

The rate of discontinuations of all agents due to treatment-related ARs was 10% for RYBREVANT® + LAZCLUZE™2

Association of dose interruptions with PFS18*†

Median PFS after 4 months was similar between patients with and without dose interruptions.

  • In this analysis, dose interruption is defined as a skipped dose that is not made up; this population may also include patients that had a dose reduction or drug discontinuation

This analysis is not included in the Prescribing Information for RYBREVANT® + LAZCLUZE™. This was post hoc exploratory analysis.

Key ARs occurred most frequently during the first 4 months and declined over the next 4 months5‡

RYBREVANT® and LAZCLUZE™ adverse reactions observed in Mariposa trialRYBREVANT® (amivantamab) Mariposa trial adverse reactions bar graph

This analysis is not included in the Prescribing Information for RYBREVANT® + LAZCLUZE™. This was post hoc exploratory analysis.

*In this descriptive analysis of PFS, the hazard ratio by multivariable analysis (via multivariate Cox proportional hazards model, only included patients still at risk of PFS at 4 months) adjusted for age, ECOG PS, EGFR mutation type, Asian race, and history of brain metastases was 1.06 (95% CI: 0.73, 1.44).

†To minimize bias, outcomes (such as progression events or deaths, could occur before interruptions leading to outcomes-based selection bias) were evaluated after the first 4 months. Patients who discontinued study, had disease progression, or died in the first 4 months were not evaluated, as they were not in the study by the cutoff timepoint (and the outcome event may occur prior to the interruption).

‡Patients with PFS events or censored in the first 4 months were excluded from this analysis.

AR, adverse reaction.

See Therapy Management for dose modifications

Learn more

References:

  1. RYBREVANT® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.
  2. Cho BC, Lu S, Felip E, et al; MARIPOSA Investigators. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024. doi:10.1056/NEJMoa2403614
  3. Felip E, Cho BC, Alip A, et al. Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA. Ann Oncol. 2024. doi:10.1016/j.annonc.2024.05.541
  4. Gagdeel SM, Cho BC, Lu S, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC: longer follow-up of the MARIPOSA study. Presented at: World Conference on Lung Cancer 2024; September 7-10, 2024; San Diego, California.
  5. Data on file. Janssen Biotech, Inc.
  6. Cho BC, Lu S, Felip E, et al; MARIPOSA Investigators. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. Supplementary Appendix. N Engl J Med. 2024. doi:10.1056/ NEJMoa2403614
  7. Yang JCH, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16(2):141-151.
  8. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:1454-1466. doi:10.1016/S1470-2045(17)30608-3
  9. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239-246. doi:10.1016/S1470-2045(11)70393-X
  10. Nacagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655-1669.
  11. Kawashima Y, Fukuhara T, Saito H, et al. Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Respir Med. 2022;10(1):72-82.
  12. Douillard JY, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014;110(1):55-62.
  13. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957.
  14. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125.
  15. Planchard D, Jänne PA, Cheng Y, et al; FLAURA2 Investigators. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948.
  16. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376(7):629-640.
  17. LAZCLUZE™ [Prescribing Information]. Horsham PA: Janssen Biotech, Inc.
  18. Campelo MRG, Cho BC, Girard N, et al. Effect of amivantamab dose interruptions on efficacy and safety of first-line amivantamab plus lazertinib in EGFR-mutant advanced NSCLC: exploratory analyses from the MARIPOSA study. Presented at: European Lung Cancer Congress 2024; March 20-23, 2024; Prague, Czech Republic.