RYBREVANT® plus LAZCLUZE™ is the first and only chemotherapy-free regimen showing superior progression-free survival versus osimertinib
Following Priority Review, approval is based on Phase 3 MARIPOSA results showing RYBREVANT® plus LAZCLUZE™ reduced the risk of disease progression or death by 30 percent versus osimertinib, with a nine-month-longer median duration of response
RARITAN, NJ, USA I August 20, 2024 I Johnson & Johnson (NYSE: JNJ) announced today that the U.S. Food and Drug Administration (FDA) approved RYBREVANT® (amivantamab-vmjw) plus LAZCLUZE™ (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
With this milestone, RYBREVANT® plus LAZCLUZE™ becomes the first and only multitargeted, chemotherapy-free combination regimen with demonstrated superiority versus osimertinib approved for the first-line treatment of patients with EGFR-mutated NSCLC.1,2 RYBREVANT® is an EGFR- and MET*-directed bispecific antibody that engages the immune system, and LAZCLUZE™ is a highly selective, brain-penetrant, third-generation oral EGFR TKI**. RYBREVANT® plus LAZCLUZE™ is the only multitargeted regimen targeting both the common EGFR mutations directly.1,2
“This approval is a crucial development for patients with EGFR-mutated NSCLC, who have faced significant unmet needs for far too long,” said Jill Feldman†, lung cancer survivor and co-founder of the EGFR Resisters, a patient advocacy group. “Having witnessed firsthand the remarkable evolution in lung cancer treatment, this profoundly important milestone brings a novel therapeutic approach to patients and their families. I’m thrilled that more patients can now experience the progression-free survival benefits seen in the MARIPOSA study.”
Lung cancer is the leading cause of cancer mortality worldwide, resulting in 1.8 million deaths each year, with NSCLC accounting for 80 to 85 percent of all cases.3,4 Of patients with EGFR-mutated NSCLC, between 25 and 39 percent never receive second-line therapy, due to disease progression and lack of treatment options.5,6,7 The five-year survival rate is less than 20 percent for all people with advanced EGFR-mutated NSCLC treated with current standard of care TKI monotherapy.8,9 Acquired resistance mechanisms after TKI monotherapy makes subsequent treatment more difficult.8,9
“The unique combination of RYBREVANT and LAZCLUZE demonstrated superior efficacy in the first-line treatment of certain patients with EGFR-mutated advanced NSCLC as shown with the MARIPOSA study,” said Alexander Spira‡, M.D., Ph.D., FACP, Director, Virginia Cancer Specialists Research Institute, and study investigator. “Patients will now have the option of a potential new first-line standard of care with significant clinical benefits over osimertinib. This first-line therapy uses a targeted approach aiming to achieve the best possible patient outcomes while reserving chemotherapy for later stages of treatment when resistance becomes more complex.”
The FDA approval is based on positive results from the Phase 3 MARIPOSA study, which showed RYBREVANT® plus LAZCLUZE™ reduced the risk of disease progression or death by 30 percent compared to osimertinib (median progression-free survival [PFS]: 23.7 months versus 16.6 months) in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations.1,2 The median duration of response (DOR) was nine months longer with RYBREVANT® plus LAZCLUZE™ versus osimertinib (25.8 months versus 16.7 months), a secondary endpoint of the study.
“Building on more than three decades of oncology innovation, we are uniquely positioned to build best-in-class treatments where survival rates have remained stagnant for years,” said Jennifer Taubert, Executive Vice President, Worldwide Chairman, Innovative Medicine, Johnson & Johnson. “RYBREVANT plus LAZCLUZE establishes a new benchmark in the advanced first-line setting, and we look forward to bringing this new chemotherapy-free treatment regimen to patients.”
“Johnson & Johnson is deeply committed to setting new standards of care for people living with some of the most devastating and complex diseases of our time,” said John Reed, M.D., Ph.D., Executive Vice President, Innovative Medicine, R&D, Johnson & Johnson. “Today’s FDA approval of chemotherapy-free RYBREVANT plus LAZCLUZE in the first line is an incredible step towards our goal of altering the trajectory of lung cancer and reducing the impact of the world’s leading cause of cancer mortality.”
The safety profile of RYBREVANT® plus LAZCLUZE™ was consistent with the profiles of the individual treatments. Venous thromboembolic events (VTE) were observed with the combination. Adverse event (AE) rates were consistent in this arm as compared to other RYBREVANT® regimens.
MARIPOSA Publications & Presentations
Results from MARIPOSA were first presented at the European Society of Medical Oncology 2023 Congress and recently published in The New England Journal of Medicine. Results presented at the 2024 American Society of Clinical Oncology annual meeting and published in Annals of Oncology demonstrated the combination’s significant benefit for patients who have at least one high-risk feature, which represents 85 percent of all EGFR-mutated NSCLC cases.10
Longer-term follow-up data from MARIPOSA will be presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Congress on Lung Cancer (WCLC) in September.
Regulatory Milestones
This approval marks the second new indication this year for RYBREVANT®, following the March 1, 2024, U.S. FDA approval of RYBREVANT® in combination with chemotherapy (carboplatin-pemetrexed) for the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, based on the Phase 3 PAPILLON study.1
On June 17, Johnson & Johnson announced the submission of a Biologics License Application (BLA) to the U.S. FDA for a fixed combination of amivantamab and recombinant human hyaluronidase for subcutaneous administration (SC amivantamab) for all currently approved or submitted indications of intravenous (IV) RYBREVANT®. This application is based on the Phase 3 PALOMA-3 study, with preliminary results showing a five-fold reduction in infusion-related reactions (IRR) with a five-minute administration of SC amivantamab.11 Longer overall survival (OS), PFS and DOR were also observed with SC amivantamab.11 On August 14, the U.S. FDA designated this application for Priority Review.
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 exon 19 deletions or substitution mutations. The primary endpoint of the study is PFS (using RECIST v1.1 guidelines) as assessed by blinded independent central review (BICR). Secondary endpoints include OS, overall response rate (ORR), DOR, second progression-free survival (PFS2) and intracranial PFS.12
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 in 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.1 In the subcutaneous formulation, amivantamab is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE® drug delivery technology.
RYBREVANT® is approved in the U.S. 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. In April 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA)recommended the approval of RYBREVANT® in Europe for this indication.
RYBREVANT® is approved in the U.S. in combination with LAZCLUZE™ for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations, as detected by an FDA-approved test. A marketing authorization application (MAA) and type II extension of indication application were submitted to the EMA seeking approval of LAZCLUZE™ in combination with RYBREVANT® based on the MARIPOSA study.
In November 2023, Johnson & Johnson submitted a supplemental BLA to the U.S. FDA for RYBREVANT® in combination with chemotherapy for the treatment of patients with EGFR-mutated NSCLC who progressed on or after osimertinib based on the MARIPOSA-2 study. A type II extension of indication application was also submitted to the EMA seeking approval of RYBREVANT® for this indication.
In June 2024, Johnson & Johnson submitted a BLA to the U.S. FDA for the subcutaneous formulation of RYBREVANT® in combination with LAZCLUZE™ for all currently approved or submitted indications of intravenous (IV) RYBREVANT® in certain patients with NSCLC. In August 2024, the U.S. FDA designated this application for Priority Review.
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:
- Amivantamab-vmjw (RYBREVANT®) plus chemotherapy as a preferred (Category 1 preferred recommendation) subsequent therapy for patients with locally advanced or metastatic NCSLC with EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression after treatment with osimertinib.13 §¶
- Amivantamab-vmjw (RYBREVANT®) plus carboplatin and pemetrexed as a preferred (Category 1 preferred recommendation) first-line therapy in treatment-naive patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion mutation-positive advanced NSCLC, or as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.13 §¶
- Amivantamab-vmjw (RYBREVANT®) as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without an immunotherapy and have EGFR exon 20 insertion mutation-positive NSCLC.13 §¶
In addition to MARIPOSA, RYBREVANT® is being studied in multiple clinical trials in NSCLC, including:
- The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT® (with or without LAZCLUZE™) and carboplatin-pemetrexed versus carboplatin-pemetrexed alone in patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC after disease progression on or after osimertinib.14
- The Phase 3 PAPILLON (NCT04538664) study assessing RYBREVANT® in combination with carboplatin-pemetrexed versus chemotherapy alone in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.15
- The Phase 3 PALOMA-3 (NCT05388669) study assessing LAZCLUZE™ with subcutaneous amivantamab compared to intravenous amivantamab in patients with EGFR-mutated advanced or metastatic NSCLC.11
- The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT® in patients with advanced NSCLC.16
- The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT® in combination with LAZCLUZE™ and LAZCLUZE™ as a monotherapy in patients with advanced NSCLC with EGFR mutations.17
- The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab subcutaneous delivery.18
- The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.19
- The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT® and capmatinib combination therapy in locally advanced or metastatic NSCLC.20
- The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT® and cetrelimab combination therapy in locally advanced or metastatic NSCLC.21
- The Phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with RYBREVANT® in combination with LAZCLUZE™ in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.22
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™ (lazertinib, marketed as LACLAZA in 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.
Access to RYBREVANT® and LAZCLUZE™️
J&J offers comprehensive access and support information and resources to assist patients in gaining access to RYBREVANT® and LAZCLUZE™. Our patient support program, J&J withMe, is available to provide personalized support to help patients start and stay on their J&J medicines. J&J withMe offers providers help supporting their patients by verifying patients’ insurance coverage, providing information on Prior Authorization and Appeals processes and educating on reimbursement processes. Patients can connect to RYBREVANT withMe to receive cost support, regardless of insurance type, free, personalized one-on-one support from a Care Navigator, and resources and community connections. Learn more at RYBREVANTwithMe.com or by calling 833-JNJ-wMe1 (833-565-9631).♠
About Non-Small Cell Lung Cancer (NSCLC)
Lung cancer is one of the most common cancers worldwide, with NSCLC making up 80 to 85 percent of all cases.3,4 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.23 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.24 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.23,24,25,26,27,28 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.29 The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors is less than 20 percent.8,9 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.30 Patients with EGFR exon 20 insertion mutations have a real-world five-year 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.31
Please read full Prescribing Information for RYBREVANT®.
Please read full Prescribing Information for LAZCLUZE™.
About Johnson & Johnson
At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at https://www.jnj.com/ or at www.janssen.com/johnson-johnson-innovative-medicine. Follow us at @JanssenUS and @JNJInnovMed. Janssen Research & Development, LLC, and Janssen Biotech, Inc., are Johnson & Johnson companies.
* Mesenchymal-epithelial transition
** Tyrosine kinase inhibitor
‡ Dr. Alexander Spira has provided consulting, advisory, and speaking services to Johnson & Johnson; he has not been paid for any media work.
§ See the NCCN Guidelines for detailed recommendations, including other treatment options.
¶ The NCCN Guidelines for NSCLC provide recommendations for certain individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories.
# The NCCN content does not constitute medical advice and should not be used in place of seeking professional medical advice, diagnosis or treatment by licensed practitioners. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
♠ The patient support and resources provided by J&J withMe are not intended to provide medical advice, replace a treatment plan from the patient’s doctor or nurse, provide case management services, or serve as a reason to prescribe a J&J medicine.
1 RYBREVANT® Prescribing Information. Horsham, PA: Janssen Biotech, Inc.
2 LAZCLUZE™ Prescribing Information. Horsham, PA: Janssen Biotech, Inc.
3 The World Health Organization. Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed June 2024.
4 American Cancer Society. What is Lung Cancer? https://www.cancer.org/content/cancer/en/cancer/lung-cancer/about/what-is.html. Accessed June 2024.
5 Lee JY, Mai V, Garcia M, et al. Treatment patterns and outcomes of first-line osimertinib-treated advanced EGFR mutated NSCLC patients: a real-world study [IASLC abstract EP08.02-082]. Presented at: IASLC 2022 World Lung Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria.
6 Nieva J, Karia PS, Okhuoya P, et al. A real-world (rw) observational study of long-term survival (LTS) and treatment patterns after first-line (1L) osimertinib in patients (pts) with epidermal growth factor receptor (EGFR) mutation-positive (m) advanced non-small cell lung cancer [ESMO abstract 1344P]. Ann Oncol. 2023;34(suppl 2):S774.
7 Girard N, Leighl NB, Ohe Y, et al. Mortality among EGFR-mutated advanced NSCLC patients after starting frontline osimertinib treatment: a real-world, US attrition analysis. Presented at: the European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Poster 19P.
8 Howlader N, et al. SEER Cancer Statistics Review, 1975-2016, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, posted to the SEER web site.
9 Lin JJ, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol. 2016 Apr;11(4):556-65.
10 Felip E, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: A secondary analysis from the phase 3 MARIPOSA study. 2024 American Society for Clinical Oncology Annual Meeting. May 31, 2024.
11 ClinicalTrials.gov. A Study of Lazertinib With Subcutaneous Amivantamab Compared With Intravenous Amivantamab in Participants With Epidermal Growth Factor Receptor (EGFR)-Mutated Advanced or Metastatic Non-small Cell Lung Cancer (PALOMA-3). https://clinicaltrials.gov/ct2/show/NCT05388669. Accessed June 2024.
12 ClinicalTrials.gov. A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA). https://classic.clinicaltrials.gov/ct2/show/NCT04487080. Accessed June 2024.
13 Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.1.2024© National Comprehensive Cancer Network, Inc. All rights reserved. To view the most recent and complete version of the guideline, go online to NCCN.org. Accessed June 2024.
14 ClinicalTrials.gov. A Study of Amivantamab and Lazertinib in Combination With Platinum-Based Chemotherapy Compared With Platinum-Based Chemotherapy in Patients With Epidermal Growth Factor Receptor (EGFR)-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer After Osimertinib Failure (MARIPOSA-2). https://classic.clinicaltrials.gov/ct2/show/study/NCT04988295. Accessed June 2024.
15 ClinicalTrials.gov. A Study of Combination Amivantamab and Carboplatin-Pemetrexed Therapy, Compared With Carboplatin-Pemetrexed, in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Characterized by Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions (PAPILLON). https://clinicaltrials.gov/ct2/show/NCT04538664. Accessed June 2024.
16 ClinicalTrials.gov. A Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS). https://clinicaltrials.gov/ct2/show/NCT02609776. Accessed June 2024.
17 ClinicalTrials.gov. A Study of Lazertinib as Monotherapy or in Combination With Amivantamab in Participants With Advanced Non-small Cell Lung Cancer (CHRYSALIS-2). https://clinicaltrials.gov/ct2/show/NCT04077463. Accessed June 2024.
18 ClinicalTrials.gov. A Study of Amivantamab Subcutaneous (SC) Administration for the Treatment of Advanced Solid Malignancies (PALOMA). https://clinicaltrials.gov/study/NCT04606381. Accessed June 2024.
19 ClinicalTrials.gov. A Study of Amivantamab in Participants With Advanced or Metastatic Solid Tumors Including Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small Cell Lung Cancer (PALOMA-2). https://clinicaltrials.gov/ct2/show/NCT05498428. Accessed June 2024
20 ClinicalTrials.gov. A Study of Amivantamab and Capmatinib Combination Therapy in Unresectable Metastatic Non-small Cell Lung Cancer (METalmark). https://clinicaltrials.gov/ct2/show/NCT05488314. Accessed June 2024.
21 ClinicalTrials.gov. A Study of Combination Therapy With Amivantamab and Cetrelimab in Participants With Metastatic Non-small Cell Lung Cancer (PolyDamas). https://www.clinicaltrials.gov/study/NCT05908734?term=polydamas&rank=1. Accessed June 2024.
22 ClinicalTrials.gov. Premedication to Reduce Amivantamab Associated Infusion Related Reactions (SKIPPirr). https://classic.clinicaltrials.gov/ct2/show/NCT05663866. Accessed June 2024.
23 Oxnard JR, et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol. 2013 Feb;8(2):179-84. doi: 10.1097/JTO.0b013e3182779d18
24 Bauml JM, et al. Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real World Datasets. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore.
25 Pennell NA, et al. A phase II trial of adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant non-small cell lung cancer. J Clin Oncol. 37:97-104.
26 Burnett H, et al. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore.
27 Zhang YL, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985-78993.
28 Midha A, et al. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity. Am J Cancer Res. 2015;5(9):2892-2911.
29 American Lung Association. EGFR and Lung Cancer. https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/biomarker-testing/egfr. Accessed June 2024.
30 Arcila, M. et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013 Feb; 12(2):220-9.
31 Girard N, et al. Comparative clinical outcomes for patients with NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore.
SOURCE: Johnson & Johnson
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RYBREVANT® plus LAZCLUZE™ is the first and only chemotherapy-free regimen showing superior progression-free survival versus osimertinib
Following Priority Review, approval is based on Phase 3 MARIPOSA results showing RYBREVANT® plus LAZCLUZE™ reduced the risk of disease progression or death by 30 percent versus osimertinib, with a nine-month-longer median duration of response
RARITAN, NJ, USA I August 20, 2024 I Johnson & Johnson (NYSE: JNJ) announced today that the U.S. Food and Drug Administration (FDA) approved RYBREVANT® (amivantamab-vmjw) plus LAZCLUZE™ (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
With this milestone, RYBREVANT® plus LAZCLUZE™ becomes the first and only multitargeted, chemotherapy-free combination regimen with demonstrated superiority versus osimertinib approved for the first-line treatment of patients with EGFR-mutated NSCLC.1,2 RYBREVANT® is an EGFR- and MET*-directed bispecific antibody that engages the immune system, and LAZCLUZE™ is a highly selective, brain-penetrant, third-generation oral EGFR TKI**. RYBREVANT® plus LAZCLUZE™ is the only multitargeted regimen targeting both the common EGFR mutations directly.1,2
“This approval is a crucial development for patients with EGFR-mutated NSCLC, who have faced significant unmet needs for far too long,” said Jill Feldman†, lung cancer survivor and co-founder of the EGFR Resisters, a patient advocacy group. “Having witnessed firsthand the remarkable evolution in lung cancer treatment, this profoundly important milestone brings a novel therapeutic approach to patients and their families. I’m thrilled that more patients can now experience the progression-free survival benefits seen in the MARIPOSA study.”
Lung cancer is the leading cause of cancer mortality worldwide, resulting in 1.8 million deaths each year, with NSCLC accounting for 80 to 85 percent of all cases.3,4 Of patients with EGFR-mutated NSCLC, between 25 and 39 percent never receive second-line therapy, due to disease progression and lack of treatment options.5,6,7 The five-year survival rate is less than 20 percent for all people with advanced EGFR-mutated NSCLC treated with current standard of care TKI monotherapy.8,9 Acquired resistance mechanisms after TKI monotherapy makes subsequent treatment more difficult.8,9
“The unique combination of RYBREVANT and LAZCLUZE demonstrated superior efficacy in the first-line treatment of certain patients with EGFR-mutated advanced NSCLC as shown with the MARIPOSA study,” said Alexander Spira‡, M.D., Ph.D., FACP, Director, Virginia Cancer Specialists Research Institute, and study investigator. “Patients will now have the option of a potential new first-line standard of care with significant clinical benefits over osimertinib. This first-line therapy uses a targeted approach aiming to achieve the best possible patient outcomes while reserving chemotherapy for later stages of treatment when resistance becomes more complex.”
The FDA approval is based on positive results from the Phase 3 MARIPOSA study, which showed RYBREVANT® plus LAZCLUZE™ reduced the risk of disease progression or death by 30 percent compared to osimertinib (median progression-free survival [PFS]: 23.7 months versus 16.6 months) in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations.1,2 The median duration of response (DOR) was nine months longer with RYBREVANT® plus LAZCLUZE™ versus osimertinib (25.8 months versus 16.7 months), a secondary endpoint of the study.
“Building on more than three decades of oncology innovation, we are uniquely positioned to build best-in-class treatments where survival rates have remained stagnant for years,” said Jennifer Taubert, Executive Vice President, Worldwide Chairman, Innovative Medicine, Johnson & Johnson. “RYBREVANT plus LAZCLUZE establishes a new benchmark in the advanced first-line setting, and we look forward to bringing this new chemotherapy-free treatment regimen to patients.”
“Johnson & Johnson is deeply committed to setting new standards of care for people living with some of the most devastating and complex diseases of our time,” said John Reed, M.D., Ph.D., Executive Vice President, Innovative Medicine, R&D, Johnson & Johnson. “Today’s FDA approval of chemotherapy-free RYBREVANT plus LAZCLUZE in the first line is an incredible step towards our goal of altering the trajectory of lung cancer and reducing the impact of the world’s leading cause of cancer mortality.”
The safety profile of RYBREVANT® plus LAZCLUZE™ was consistent with the profiles of the individual treatments. Venous thromboembolic events (VTE) were observed with the combination. Adverse event (AE) rates were consistent in this arm as compared to other RYBREVANT® regimens.
MARIPOSA Publications & Presentations
Results from MARIPOSA were first presented at the European Society of Medical Oncology 2023 Congress and recently published in The New England Journal of Medicine. Results presented at the 2024 American Society of Clinical Oncology annual meeting and published in Annals of Oncology demonstrated the combination’s significant benefit for patients who have at least one high-risk feature, which represents 85 percent of all EGFR-mutated NSCLC cases.10
Longer-term follow-up data from MARIPOSA will be presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Congress on Lung Cancer (WCLC) in September.
Regulatory Milestones
This approval marks the second new indication this year for RYBREVANT®, following the March 1, 2024, U.S. FDA approval of RYBREVANT® in combination with chemotherapy (carboplatin-pemetrexed) for the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, based on the Phase 3 PAPILLON study.1
On June 17, Johnson & Johnson announced the submission of a Biologics License Application (BLA) to the U.S. FDA for a fixed combination of amivantamab and recombinant human hyaluronidase for subcutaneous administration (SC amivantamab) for all currently approved or submitted indications of intravenous (IV) RYBREVANT®. This application is based on the Phase 3 PALOMA-3 study, with preliminary results showing a five-fold reduction in infusion-related reactions (IRR) with a five-minute administration of SC amivantamab.11 Longer overall survival (OS), PFS and DOR were also observed with SC amivantamab.11 On August 14, the U.S. FDA designated this application for Priority Review.
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 exon 19 deletions or substitution mutations. The primary endpoint of the study is PFS (using RECIST v1.1 guidelines) as assessed by blinded independent central review (BICR). Secondary endpoints include OS, overall response rate (ORR), DOR, second progression-free survival (PFS2) and intracranial PFS.12
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 in 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.1 In the subcutaneous formulation, amivantamab is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE® drug delivery technology.
RYBREVANT® is approved in the U.S. 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. In April 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA)recommended the approval of RYBREVANT® in Europe for this indication.
RYBREVANT® is approved in the U.S. in combination with LAZCLUZE™ for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations, as detected by an FDA-approved test. A marketing authorization application (MAA) and type II extension of indication application were submitted to the EMA seeking approval of LAZCLUZE™ in combination with RYBREVANT® based on the MARIPOSA study.
In November 2023, Johnson & Johnson submitted a supplemental BLA to the U.S. FDA for RYBREVANT® in combination with chemotherapy for the treatment of patients with EGFR-mutated NSCLC who progressed on or after osimertinib based on the MARIPOSA-2 study. A type II extension of indication application was also submitted to the EMA seeking approval of RYBREVANT® for this indication.
In June 2024, Johnson & Johnson submitted a BLA to the U.S. FDA for the subcutaneous formulation of RYBREVANT® in combination with LAZCLUZE™ for all currently approved or submitted indications of intravenous (IV) RYBREVANT® in certain patients with NSCLC. In August 2024, the U.S. FDA designated this application for Priority Review.
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:
- Amivantamab-vmjw (RYBREVANT®) plus chemotherapy as a preferred (Category 1 preferred recommendation) subsequent therapy for patients with locally advanced or metastatic NCSLC with EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression after treatment with osimertinib.13 §¶
- Amivantamab-vmjw (RYBREVANT®) plus carboplatin and pemetrexed as a preferred (Category 1 preferred recommendation) first-line therapy in treatment-naive patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion mutation-positive advanced NSCLC, or as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.13 §¶
- Amivantamab-vmjw (RYBREVANT®) as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without an immunotherapy and have EGFR exon 20 insertion mutation-positive NSCLC.13 §¶
In addition to MARIPOSA, RYBREVANT® is being studied in multiple clinical trials in NSCLC, including:
- The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT® (with or without LAZCLUZE™) and carboplatin-pemetrexed versus carboplatin-pemetrexed alone in patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC after disease progression on or after osimertinib.14
- The Phase 3 PAPILLON (NCT04538664) study assessing RYBREVANT® in combination with carboplatin-pemetrexed versus chemotherapy alone in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.15
- The Phase 3 PALOMA-3 (NCT05388669) study assessing LAZCLUZE™ with subcutaneous amivantamab compared to intravenous amivantamab in patients with EGFR-mutated advanced or metastatic NSCLC.11
- The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT® in patients with advanced NSCLC.16
- The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT® in combination with LAZCLUZE™ and LAZCLUZE™ as a monotherapy in patients with advanced NSCLC with EGFR mutations.17
- The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab subcutaneous delivery.18
- The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.19
- The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT® and capmatinib combination therapy in locally advanced or metastatic NSCLC.20
- The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT® and cetrelimab combination therapy in locally advanced or metastatic NSCLC.21
- The Phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with RYBREVANT® in combination with LAZCLUZE™ in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.22
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™ (lazertinib, marketed as LACLAZA in 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.
Access to RYBREVANT® and LAZCLUZE™️
J&J offers comprehensive access and support information and resources to assist patients in gaining access to RYBREVANT® and LAZCLUZE™. Our patient support program, J&J withMe, is available to provide personalized support to help patients start and stay on their J&J medicines. J&J withMe offers providers help supporting their patients by verifying patients’ insurance coverage, providing information on Prior Authorization and Appeals processes and educating on reimbursement processes. Patients can connect to RYBREVANT withMe to receive cost support, regardless of insurance type, free, personalized one-on-one support from a Care Navigator, and resources and community connections. Learn more at RYBREVANTwithMe.com or by calling 833-JNJ-wMe1 (833-565-9631).♠
About Non-Small Cell Lung Cancer (NSCLC)
Lung cancer is one of the most common cancers worldwide, with NSCLC making up 80 to 85 percent of all cases.3,4 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.23 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.24 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.23,24,25,26,27,28 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.29 The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors is less than 20 percent.8,9 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.30 Patients with EGFR exon 20 insertion mutations have a real-world five-year 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.31
Please read full Prescribing Information for RYBREVANT®.
Please read full Prescribing Information for LAZCLUZE™.
About Johnson & Johnson
At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at https://www.jnj.com/ or at www.janssen.com/johnson-johnson-innovative-medicine. Follow us at @JanssenUS and @JNJInnovMed. Janssen Research & Development, LLC, and Janssen Biotech, Inc., are Johnson & Johnson companies.
* Mesenchymal-epithelial transition
** Tyrosine kinase inhibitor
‡ Dr. Alexander Spira has provided consulting, advisory, and speaking services to Johnson & Johnson; he has not been paid for any media work.
§ See the NCCN Guidelines for detailed recommendations, including other treatment options.
¶ The NCCN Guidelines for NSCLC provide recommendations for certain individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories.
# The NCCN content does not constitute medical advice and should not be used in place of seeking professional medical advice, diagnosis or treatment by licensed practitioners. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
♠ The patient support and resources provided by J&J withMe are not intended to provide medical advice, replace a treatment plan from the patient’s doctor or nurse, provide case management services, or serve as a reason to prescribe a J&J medicine.
1 RYBREVANT® Prescribing Information. Horsham, PA: Janssen Biotech, Inc.
2 LAZCLUZE™ Prescribing Information. Horsham, PA: Janssen Biotech, Inc.
3 The World Health Organization. Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed June 2024.
4 American Cancer Society. What is Lung Cancer? https://www.cancer.org/content/cancer/en/cancer/lung-cancer/about/what-is.html. Accessed June 2024.
5 Lee JY, Mai V, Garcia M, et al. Treatment patterns and outcomes of first-line osimertinib-treated advanced EGFR mutated NSCLC patients: a real-world study [IASLC abstract EP08.02-082]. Presented at: IASLC 2022 World Lung Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria.
6 Nieva J, Karia PS, Okhuoya P, et al. A real-world (rw) observational study of long-term survival (LTS) and treatment patterns after first-line (1L) osimertinib in patients (pts) with epidermal growth factor receptor (EGFR) mutation-positive (m) advanced non-small cell lung cancer [ESMO abstract 1344P]. Ann Oncol. 2023;34(suppl 2):S774.
7 Girard N, Leighl NB, Ohe Y, et al. Mortality among EGFR-mutated advanced NSCLC patients after starting frontline osimertinib treatment: a real-world, US attrition analysis. Presented at: the European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Poster 19P.
8 Howlader N, et al. SEER Cancer Statistics Review, 1975-2016, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, posted to the SEER web site.
9 Lin JJ, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol. 2016 Apr;11(4):556-65.
10 Felip E, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: A secondary analysis from the phase 3 MARIPOSA study. 2024 American Society for Clinical Oncology Annual Meeting. May 31, 2024.
11 ClinicalTrials.gov. A Study of Lazertinib With Subcutaneous Amivantamab Compared With Intravenous Amivantamab in Participants With Epidermal Growth Factor Receptor (EGFR)-Mutated Advanced or Metastatic Non-small Cell Lung Cancer (PALOMA-3). https://clinicaltrials.gov/ct2/show/NCT05388669. Accessed June 2024.
12 ClinicalTrials.gov. A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA). https://classic.clinicaltrials.gov/ct2/show/NCT04487080. Accessed June 2024.
13 Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.1.2024© National Comprehensive Cancer Network, Inc. All rights reserved. To view the most recent and complete version of the guideline, go online to NCCN.org. Accessed June 2024.
14 ClinicalTrials.gov. A Study of Amivantamab and Lazertinib in Combination With Platinum-Based Chemotherapy Compared With Platinum-Based Chemotherapy in Patients With Epidermal Growth Factor Receptor (EGFR)-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer After Osimertinib Failure (MARIPOSA-2). https://classic.clinicaltrials.gov/ct2/show/study/NCT04988295. Accessed June 2024.
15 ClinicalTrials.gov. A Study of Combination Amivantamab and Carboplatin-Pemetrexed Therapy, Compared With Carboplatin-Pemetrexed, in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Characterized by Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions (PAPILLON). https://clinicaltrials.gov/ct2/show/NCT04538664. Accessed June 2024.
16 ClinicalTrials.gov. A Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS). https://clinicaltrials.gov/ct2/show/NCT02609776. Accessed June 2024.
17 ClinicalTrials.gov. A Study of Lazertinib as Monotherapy or in Combination With Amivantamab in Participants With Advanced Non-small Cell Lung Cancer (CHRYSALIS-2). https://clinicaltrials.gov/ct2/show/NCT04077463. Accessed June 2024.
18 ClinicalTrials.gov. A Study of Amivantamab Subcutaneous (SC) Administration for the Treatment of Advanced Solid Malignancies (PALOMA). https://clinicaltrials.gov/study/NCT04606381. Accessed June 2024.
19 ClinicalTrials.gov. A Study of Amivantamab in Participants With Advanced or Metastatic Solid Tumors Including Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small Cell Lung Cancer (PALOMA-2). https://clinicaltrials.gov/ct2/show/NCT05498428. Accessed June 2024
20 ClinicalTrials.gov. A Study of Amivantamab and Capmatinib Combination Therapy in Unresectable Metastatic Non-small Cell Lung Cancer (METalmark). https://clinicaltrials.gov/ct2/show/NCT05488314. Accessed June 2024.
21 ClinicalTrials.gov. A Study of Combination Therapy With Amivantamab and Cetrelimab in Participants With Metastatic Non-small Cell Lung Cancer (PolyDamas). https://www.clinicaltrials.gov/study/NCT05908734?term=polydamas&rank=1. Accessed June 2024.
22 ClinicalTrials.gov. Premedication to Reduce Amivantamab Associated Infusion Related Reactions (SKIPPirr). https://classic.clinicaltrials.gov/ct2/show/NCT05663866. Accessed June 2024.
23 Oxnard JR, et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol. 2013 Feb;8(2):179-84. doi: 10.1097/JTO.0b013e3182779d18
24 Bauml JM, et al. Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real World Datasets. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore.
25 Pennell NA, et al. A phase II trial of adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant non-small cell lung cancer. J Clin Oncol. 37:97-104.
26 Burnett H, et al. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore.
27 Zhang YL, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985-78993.
28 Midha A, et al. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity. Am J Cancer Res. 2015;5(9):2892-2911.
29 American Lung Association. EGFR and Lung Cancer. https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/biomarker-testing/egfr. Accessed June 2024.
30 Arcila, M. et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013 Feb; 12(2):220-9.
31 Girard N, et al. Comparative clinical outcomes for patients with NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore.
SOURCE: Johnson & Johnson
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