Full Press Release Details
Median overall survival not yet reached with projected improvement of more than one year versus osimertinib
RARITAN, N.J. , March 26, 2025 /PRNewswire/ -- Johnson & Johnson (NYSE: JNJ ) today announced results for the gold standard endpoint in cancer treatment of overall survival (OS) from the Phase 3 MARIPOSA study. Head-to-head comparison data versus osimertinib showed RYBREVANT ® (amivantamab-vmjw) plus LAZCLUZE™ (lazertinib) significantly extended OS in the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) exon 19 deletions (ex19del) or L858R substitution mutations. Median OS is projected to exceed one year beyond the median of three years observed with osimertinib and has not yet been reached. This is the first and only study to show a statistically significant and clinically meaningful OS improvement over osimertinib. New compelling data were presented during a proffered paper session at the 2025 European Lung Cancer Congress (ELCC) (Abstract #4O). 1
"The survival curve tells a clear story. RYBREVANT plus LAZCLUZE helps patients live longer, and the benefit keeps growing over time," said trial investigator Professor Nicolas Girard *, M.D., Ph.D., Head of Medical Oncology, Institut Curie, and Professor of Thoracic Oncology and Respiratory Medicine at the Paris-Saclay University, France . "We see the gap between the survival curves continue to widen, which is exactly what we want to see in lung cancer treatment to improve outcomes for patients. These results reinforce that we are entering a new era for EGFR -mutated non-small cell lung cancer; with this evidence in hand, we need to ensure every patient gets the most effective treatment in the first line for the best possible chance at longer survival."
Unlike progression-free survival (PFS), which tracks the time a treatment keeps a patient's cancer from progressing, OS helps patients understand the impact therapy could have on the ability to live longer from the start of treatment. Extending life expectancy is the most meaningful indicator of a treatment's impact.
At a median follow-up of 37.8 months, patients treated with the chemotherapy-free regimen of first-line RYBREVANT ® plus LAZCLUZE™ had a significantly longer OS compared to those receiving osimertinib (hazard ratio [HR], 0.75; 95 percent confidence interval [CI], 0.61-0.92; P<0.005). Median OS for RYBREVANT ® plus LAZCLUZE™ has not yet been reached, indicating that survival benefits continue to extend beyond the measured follow-up period (not reached [NR]; 95 percent CI, 42.9-NR). Comparatively, median OS for osimertinib-treated patients was 36.7 months (95 percent CI, 33.4-41.0) and consistent with prior studies with osimertinib. Fifty-six percent of patients treated with RYBREVANT ® and LAZCLUZE™ were alive at three and a half years compared to 44 percent of patients on osimertinib. Projections based on survival data suggest RYBREVANT ® plus LAZCLUZE™ could extend median OS by at least 12 months compared to osimertinib. 1
The RYBREVANT ® combination also prolonged multiple secondary endpoints vs osimertinib, including intracranial PFS, intracranial duration of response (DOR) and intracranial overall response rate (ORR). Notably, RYBREVANT ® plus LAZCLUZE™ prolonged time to symptomatic progression (TTSP) – the time from treatment randomization to the onset of lung cancer symptoms – by more than 14 months compared to osimertinib (43.6 months vs 29.3 months; HR, 0.69; 95 percent CI, 0.57–0.83; P<0.001). This is a key patient-centered measure, highlighting how long quality of life can be preserved before lung cancer symptoms emerge. 1
"Right now, only twenty percent of patients with EGFR- positive NSCLC survive beyond five years. These MARIPOSA results suggest that RYBREVANT plus LAZCLUZE can change this dire statistic that has been stagnant for far too long," said Joshua Bauml , M.D., Vice President, Lung Cancer Disease Area Stronghold Leader, Johnson & Johnson Innovative Medicine. "This regimen isn't just extending survival, it's offering hope. By using RYBREVANT plus LAZCLUZE first, we're delaying the need for chemotherapy and giving patients and their families more time."
The safety profile of RYBREVANT ® plus LAZCLUZE™ was consistent with the primary analysis, with adverse event (AE) rates comparable to other RYBREVANT ® regimens. No new safety signals were identified with the additional longer-term follow-up. Most AEs occurred early during RYBREVANT ® and LAZCLUZE™ treatment. 1 RYBREVANT ® research findings suggest that implementing prophylactic measures during the first four months of RYBREVANT ® and LAZCLUZE™ treatment may significantly reduce the risk of skin reactions, infusion-related reactions and venous thromboembolic events. 2,3,4
The MARIPOSA study met its primary endpoint in October 2023, showing a statistically significant and clinically meaningful improvement in PFS compared to osimertinib.
RYBREVANT ® plus LAZCLUZE™ is approved in the United States , Europe and other markets around the world for patients with first-line EGFR -mutated NSCLC. These OS results will be shared with health authorities globally.
About the MARIPOSA Study
MARIPOSA ( NCT04487080 ), which enrolled 1,074 patients, is a randomized, Phase 3 study evaluating RYBREVANT ® in combination with LAZCLUZE™ versus osimertinib and versus LAZCLUZE™ alone in first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or substitution mutations. The primary endpoint of the study is PFS (using RECIST v1.1 guidelines**) as assessed by BICR. Secondary endpoints include OS, ORR, DOR, PFS2 and intracranial PFS. 5
About RYBREVANT ®
RYBREVANT ® (amivantamab-vmjw), a fully-human bispecific antibody targeting EGFR and MET with immune cell-directing activity, is approved in the U.S. , Europe and other markets around the world as monotherapy 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. 6
RYBREVANT ® is approved in the U.S. , Europe and other markets around the world in combination with chemotherapy (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.
RYBREVANT ® is approved in the U.S., Europe and other markets around the world in combination with LAZCLUZE™ (lazertinib) for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.
RYBREVANT ® is approved in the U.S. , Europe and other markets around the world in combination with chemotherapy (carboplatin-pemetrexed) for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR TKI.
In February 2025, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of SC amivantamab and LAZCLUZE™ in Europe for the first-line treatment of adult patients with advanced NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, and as a monotherapy for the treatment of adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations after failure of platinum-based therapy.
The National Comprehensive Cancer Network ® (NCCN ® ) Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) for NSCLC § prefer next-generation sequencing–based strategies over polymerase chain reaction–based approaches for the detection of EGFR exon 20 insertion variants. The NCCN Guidelines include:
In addition to the Phase 3 MARIPOSA Study, RYBREVANT ® is being studied in multiple clinical trials in NSCLC, including:
For more information, visit: https://www.RYBREVANT.com .
About LAZCLUZE™
In 2018, Janssen Biotech, Inc., entered into a license and collaboration agreement with Yuhan Corporation for the development of LAZCLUZE™ (marketed as LECLAZA in South Korea ). LAZCLUZE™ is an oral, third-generation, brain-penetrant EGFR TKI that targets both the T790M mutation and activating EGFR mutations while sparing wild-type EGFR . An analysis of the efficacy and safety of LAZCLUZE™ from the Phase 3 LASER301 study was published in The Journal of Clinical Oncology in 2023. 21
About Non-Small Cell Lung Cancer
Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases. 22,23 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. 24 Among the most common driver mutations in NSCLC are alterations in EGFR , which is a receptor tyrosine kinase controlling cell growth and division. 25 EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients. 22,23,26,27,28,29 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations. 30 The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) is less than 20 percent. 31,32 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation. 33 Patients with EGFR exon 20 insertion mutations have a real-world five-year overall survival (OS) of eight percent in the frontline setting, which is worse than patients with EGFR ex19del or L858R mutations, who have a real-world five-year OS of 19 percent. 34
IMPORTANT SAFETY INFORMATION 6,35
WARNINGS AND PRECAUTIONS
Infusion-Related Reactions
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.
RYBREVANT ® with LAZCLUZE™
RYBREVANT ® in combination with LAZCLUZE™ can cause infusion-related reactions. In MARIPOSA (n=421), 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% of patients, 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™.
RYBREVANT ® with Carboplatin and Pemetrexed
Based on the pooled safety population (n=281), IRR occurred in 50% of patients treated with RYBREVANT ® in combination with carboplatin and pemetrexed, including Grade 3 (3.2%) adverse reactions. The incidence of infusion modifications due to IRR was 46%, and 2.8% of patients permanently discontinued RYBREVANT ® due to IRR.
RYBREVANT ® as a Single Agent
In CHRYSALIS (n=302), IRR occurred in 66% of patients treated with RYBREVANT ® . Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued RYBREVANT ® due to IRR.
Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT ® as recommended. Administer RYBREVANT ® via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions. Monitor patients for signs and symptoms of infusion reactions during RYBREVANT ® infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT ® based on severity. If an anaphylactic reaction occurs, permanently discontinue RYBREVANT ® .
Interstitial Lung Disease/Pneumonitis
RYBREVANT ® can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.
RYBREVANT ® with LAZCLUZE™
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 (0.2%) of ILD/pneumonitis and 2.9% of patients permanently discontinued RYBREVANT ® and LAZCLUZE™ due to ILD/pneumonitis.
RYBREVANT ® with Carboplatin and Pemetrexed
Based on the pooled safety population, ILD/pneumonitis occurred in 2.1% treated with RYBREVANT ® in combination with carboplatin and pemetrexed with 1.8% of patients experiencing Grade 3 ILD/pneumonitis. 2.1% discontinued RYBREVANT ® due to ILD/pneumonitis.
RYBREVANT ® as a Single Agent
In CHRYSALIS, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT ® , with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) permanently discontinued RYBREVANT ® due to ILD/pneumonitis.
Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). For patients receiving RYBREVANT ® in combination with LAZCLUZE™, immediately withhold both drugs in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. For patients receiving RYBREVANT ® as a single agent or in combination with carboplatin and pemetrexed, immediately withhold RYBREVANT ® in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.
Venous Thromboembolic (VTE) Events with Concomitant Use of RYBREVANT ® and LAZCLUZE™
RYBREVANT ® in combination with LAZCLUZE™ 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 therapy.
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 two fatal cases of VTE (0.5%), 9% of patients had VTE leading to dose interruptions of RYBREVANT ® , and 7% of patients had VTE leading to dose interruptions of LAZCLUZE™; 1% of patients had VTE leading to dose reductions of RYBREVANT ® , and 0.5% of patients had VTE leading to dose reductions of LAZCLUZE™; 3.1% of patients had VTE leading to permanent discontinuation of RYBREVANT ® , and 1.9% of patients had VTE leading to permanent discontinuation of LAZCLUZE™. The median time to onset of VTEs was 84 days (range: 6 to 777).
Administer prophylactic anticoagulation for the first four months of treatment. 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 LAZCLUZE™ based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT ® and LAZCLUZE™ at the same dose level at the discretion of the healthcare provider. In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT ® and continue treatment with LAZCLUZE™ at the same dose level at the discretion of the healthcare provider.
Dermatologic Adverse Reactions
RYBREVANT ® can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin.
RYBREVANT ® with LAZCLUZE™
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 occurred in 37% of patients for RYBREVANT ® and 30% for LAZCLUZE™, rash leading to dose reductions occurred in 23% of patients for RYBREVANT ® and 19% for LAZCLUZE™, and rash leading to permanent discontinuation occurred in 5% of patients for RYBREVANT ® and 1.7% for LAZCLUZE™.
RYBREVANT ® with Carboplatin and Pemetrexed
Based on the pooled safety population, rash occurred in 82% of patients treated with RYBREVANT ® in combination with carboplatin and pemetrexed, including Grade 3 (15%) adverse reactions. Rash leading to dose reductions occurred in 14% of patients, and 2.5% permanently discontinued RYBREVANT ® and 3.1% discontinued pemetrexed.
RYBREVANT ® as a Single Agent
In CHRYSALIS, rash occurred in 74% of patients treated with RYBREVANT ® as a single agent, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT ® was permanently discontinued due to rash in 0.7% of patients.
Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT ® as a single agent.
Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT ® or LAZCLUZE™ in combination with RYBREVANT ® . Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.
When initiating RYBREVANT ® treatment with or without LAZCLUZE™, administer alcohol-free emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (e.g. use of oral antibiotics) to reduce the risk of dermatologic reactions. If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. For patients receiving RYBREVANT ® in combination with LAZCLUZE™, withhold, reduce the dose, or permanently discontinue both drugs based on severity. For patients receiving RYBREVANT ® as a single agent or in combination with carboplatin and pemetrexed, withhold, dose reduce or permanently discontinue RYBREVANT ® based on severity.
Ocular Toxicity
RYBREVANT ® can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus, and uveitis.
RYBREVANT ® with LAZCLUZE™
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.
RYBREVANT ® with Carboplatin and Pemetrexed
Based on the pooled safety population, ocular toxicity occurred in 16% of patients treated with RYBREVANT ® in combination with carboplatin and pemetrexed. All events were Grade 1 or 2.
RYBREVANT ® as a Single Agent
In CHRYSALIS, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT ® . All events were Grade 1-2.
Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT ® based on severity.
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. 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 ® .
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.
Adverse Reactions
RYBREVANT ® with LAZCLUZE™
For the 421 patients in the MARIPOSA clinical trial who received RYBREVANT ® in combination with LAZCLUZE™, the most common adverse reactions (≥20%) were rash (86%), nail toxicity (71%), infusion-related reactions (RYBREVANT ® , 63%), musculoskeletal pain (47%), stomatitis (43%), edema (43%), VTE (36%), paresthesia (35%), fatigue (32%), diarrhea (31%), constipation (29%), COVID-19 (26%), hemorrhage (25%), dry skin (25%), decreased appetite (24%), pruritus (24%), nausea (21%), and ocular toxicity (16%). The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased albumin (8%), decreased sodium (7%), increased ALT (7%), decreased potassium (5%), decreased hemoglobin (3.8%), increased AST (3.8%), increased GGT (2.6%), and increased magnesium (2.6%).
Serious adverse reactions occurred in 49% of patients who received RYBREVANT ® in combination with LAZCLUZE™. Serious adverse reactions occurring in ≥2% of patients included VTE (11%), pneumonia (4%), ILD/pneumonitis and rash (2.9% each), COVID-19 (2.4%), and pleural effusion and infusion-related reaction (RYBREVANT ® ) (2.1% each). Fatal adverse reactions occurred in 7% of patients who received RYBREVANT ® in combination with LAZCLUZE™ due to death not otherwise specified (1.2%); sepsis and respiratory failure (1% each); pneumonia, myocardial infarction, and sudden death (0.7% each); cerebral infarction, pulmonary embolism (PE), and COVID-19 infection (0.5% each); and ILD/pneumonitis, acute respiratory distress syndrome (ARDS), and cardiopulmonary arrest (0.2% each).
RYBREVANT ® with Carboplatin and Pemetrexed
For the 130 patients in the MARIPOSA-2 clinical trial who received RYBREVANT ® in combination with carboplatin and pemetrexed, the most common adverse reactions (≥20%) were rash (72%), infusion-related reactions (59%), fatigue (51%), nail toxicity (45%), nausea (45%), constipation (39%), edema (36%), stomatitis (35%), decreased appetite (31%), musculoskeletal pain (30%), vomiting (25%), and COVID-19 (21%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased neutrophils (49%), decreased white blood cells (42%), decreased lymphocytes (28%), decreased platelets (17%), decreased hemoglobin (12%), decreased potassium (11%), decreased sodium (11%), increased alanine aminotransferase (3.9%), decreased albumin (3.8%), and increased gamma-glutamyl transferase (3.1%).