RYBREVANT® (amivantamab-vmjw) plus lazertinib is the only chemotherapy-free regimen showing longer progression-free survival versus osimertinib in first-line treatment of patients with high-risk EGFR-mutated non-small cell lung cancer

Investigational chemotherapy-free regimen of RYBREVANT^® plus lazertinib addresses a significant unmet need as most patients with EGFR-mutated NSCLC have high-risk disease

Landmark Phase 3 MARIPOSA data featured in an oral presentation at ASCO 

CHICAGO, IL, USA I May 31, 2024 I Johnson & Johnson today announced new data from the Phase 3 MARIPOSA study demonstrating the benefit of first-line treatment with RYBREVANT^® (amivantamab-vmjw) in combination with lazertinib in patients with high-risk disease or clinical features, which occur in nearly 85 percent of patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Results from the new analysis show the RYBREVANT^® combination consistently and significantly improved progression-free survival (PFS) compared to osimertinib in patients with NSCLC with EGFR exon 19 deletion (ex19del) or L858R mutations. These data were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #8504).¹

“These new data demonstrate the efficacy of RYBREVANT plus lazertinib, showing a significant reduction in the risk of disease progression or death compared to osimertinib in several high-risk subgroups of patients with EGFR-mutated NSCLC,” said Byoung Chul Cho, M.D., Ph.D., medical oncologist and professor in the Division of Medical Oncology at Yonsei Cancer Center, Yonsei University College of Medicine in Seoul, Republic of Korea, and study author.* “These findings support the potential of this combination as an important first-line option for these patients who face significant unmet needs.”

The MARIPOSA study enrolled treatment-naïve patients with EGFR-mutant (ex19del or L858R) advanced NSCLC. Overall, results showed RYBREVANT^® plus lazertinib resulted in a significant reduction in the risk of disease progression or death compared to osimertinib as previously reported. High-risk features, such as liver or brain metastases, baseline TP53 co-mutations, and circulating tumor DNA (ctDNA) shedding are common in patients with EGFR-mutated advanced NSCLC and associated with poor prognoses. In the study, 89 percent of enrolled patients had one or more of these high-risk disease or clinical features at baseline. Specifically, 41 percent had brain metastases, 16 percent had liver metastases, 54 percent had TP53 co-mutations, 70 percent had ctDNA present at baseline and 15 percent continued to shed ctDNA after two cycles of treatment.¹

Results from the analysis showed treatment with RYBREVANT^® plus lazertinib significantly reduced the risk of disease progression or death consistently across all high-risk subgroups¹:

• 31 percent compared to osimertinib in patients with a history of brain metastases (18.3 vs 13.0 months; hazard ratio [HR], 0.69; [95 percent confidence interval [CI], 0.53-0.92]; P=0.010)
• 42 percent compared to osimertinib in patients with liver metastases at baseline (18.2 vs 11.0 months; HR, 0.58 [95 percent CI, 0.37-0.91]; P=0.017)
• 35 percent compared to osimertinib among patients with TP53 co-mutations (18.2 vs 12.9 months; HR, 0.65 [95 percent CI, 0.48-0.87]; P=0.003)
• 32 percent compared to osimertinib in patients with detectable ctDNA at baseline (20.3 vs 14.8 months; HR, 0.68 [95 percent CI, 0.53-0.86]; P=0.002)
• 51 percent compared to osimertinib in patients without cleared ctDNA at C3D1 (16.5 vs 9.1 months; HR, 0.49 [95 percent CI, 0.27-0.87]; P=0.015)

As reported at the European Society for Medical Oncology (ESMO) 2023 Congress, the safety profile of the combination of RYBREVANT^® and lazertinib was consistent with the safety profiles of the individual treatments, with mostly Grade 1 or 2 adverse events (AEs). Toxicity was largely manageable with dose interruptions and reductions, along with supportive care measures commonly used in the treatment of patients with NSCLC. The most common Grade 3 or higher treatment-related AEs were rash and paronychia. RYBREVANT^® plus lazertinib had higher rates of EGFR- and MET-related AEs (hypoalbuminemia and peripheral edema) and venous thromboembolism compared to osimertinib, with higher rates of diarrhea being observed with osimertinib. The rate of discontinuation of all study treatments due to treatment-related AEs for the RYBREVANT^® combination was 10 percent. The rate of interstitial lung disease (including pneumonitis) was less than three percent in both arms.²

“With the majority of patients with EGFR-mutated lung cancer having high-risk disease and clinical features, ensuring that all patients receive the most appropriate treatment in the first-line setting is critical. The results presented at ASCO suggest RYBREVANT plus lazertinib offer a new standard of care in this patient population,” said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Johnson & Johnson Innovative Medicine. “These new findings continue to demonstrate how RYBREVANT-based regimens are transforming treatment for patients with EGFR-mutated non-small cell lung cancer and add to the growing body of evidence that supports the promise of this chemotherapy-free approach.”

About the MARIPOSA Study

MARIPOSA (NCT04487080), which enrolled 1,074 patients, is a randomized, Phase 3 study evaluating RYBREVANT^® in combination with lazertinib versus osimertinib and versus lazertinib 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 overall survival (OS), overall response rate (ORR), duration of response (DOR), second progression-free survival (PFS2) and intracranial PFS.³

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.⁴

RYBREVANT^® is also 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 October 2023, a type II extension of indication application was submitted to the European Medicines Agency (EMA) seeking approval of RYBREVANT^® for this indication.

In December 2023, Johnson & Johnson submitted a supplemental Biologics Lincense Application (sBLA) together with a New Drug Application (NDA) to the U.S. FDA for RYBREVANT^® in combination with lazertinib 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. This submission is based on the Phase 3 MARIPOSA study and was granted Priority Review in February 2024. A marketing authorization application (MAA) and type II extension of indication application were also submitted to the EMA seeking approval of lazertinib in combination with RYBREVANT^® based on the MARIPOSA study.

In November 2023, Johnson & Johnson submitted an sBLA 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.

The 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 carboplatin and pemetrexed as a preferred (Category 1 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.^5 †‡
• Amivantamab-vmjw (RYBREVANT^®) plus chemotherapy as a preferred (Category 1 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.^{5 †‡}
• 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.^{5 †‡}

RYBREVANT^® is being studied in multiple clinical trials in NSCLC, including:

• 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.⁶
• The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT^® (with or without lazertinib) 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.⁷
• The Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT^® in combination with lazertinib versus osimertinib and versus lazertinib alone in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations.³
• The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT^® in patients with advanced NSCLC.⁸
• The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT^® in combination with lazertinib and lazertinib as a monotherapy in patients with advanced NSCLC with EGFR mutations.⁹
• 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.¹⁰
• The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.¹¹
• The Phase 3 PALOMA-3 (NCT05388669) study assessing lazertinib with subcutaneous amivantamab compared to intravenous amivantamab in patients with EGFR-mutated advanced or metastatic NSCLC.¹²
• The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT^® and capmatinib combination therapy in locally advanced or metastatic NSCLC.¹³
• The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT^® and cetrelimab combination therapy in locally advanced or metastatic NSCLC.¹⁴
• 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 lazertinib in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.¹⁵

For more information, visit: https://www.RYBREVANT.com.

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.^16,17 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.¹⁸ Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.¹⁹ 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.^{18,19,20,21,22,23} EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.²⁴ 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.^25,26 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.²⁷ 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.²⁸

Please read the full Prescribing Information for RYBREVANT^®.  

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. 

*Prof. Byoung Chul Cho 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.

¹ 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.
² Cho BC, et al. Amivantamab Plus Lazertinib vs Osimertinib as First-line Treatment in Patients With EGFR-mutated, Advanced Non-small Cell Lung Cancer (NSCLC): Primary Results From MARIPOSA, a Phase 3, Global, Randomized, Controlled Trial. 2023 European Society for Medical Oncology. October 23, 2023.
³ ClinicalTrials.gov. A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA). Available at: https://classic.clinicaltrials.gov/ct2/show/NCT04487080. Accessed May 2024.
⁴ RYBREVANT^® Prescribing Information. Horsham, PA: Janssen Biotech, Inc.
⁵ 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 March 2024.
⁶ 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). Available at: https://clinicaltrials.gov/ct2/show/NCT04538664. Accessed May 2024.
⁷ 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). Available at: https://classic.clinicaltrials.gov/ct2/show/study/NCT04988295. Accessed May 2024.
⁸ 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 May 2024.
9 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 May 2024.
¹⁰ ClinicalTrials.gov. A Study of Amivantamab Subcutaneous (SC) Administration for the Treatment of Advanced Solid Malignancies (PALOMA). Available at: https://clinicaltrials.gov/study/NCT04606381. Accessed May 2024.
¹¹ 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 May 2024.
¹² 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 May 2024.
¹³ 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 May 2024.
¹⁴ 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 May 2024.
¹⁵ ClinicalTrials.gov. Premedication to Reduce Amivantamab Associated Infusion Related Reactions (SKIPPirr). https://classic.clinicaltrials.gov/ct2/show/NCT05663866. Accessed May 2024.
¹⁶ The World Health Organization. Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed May 2024.
¹⁷ American Cancer Society. What is Lung Cancer? https://www.cancer.org/content/cancer/en/cancer/lung-cancer/about/what-is.html. Accessed May 2024.
¹⁸ 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.
¹⁹ 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.
²⁰ 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.
²¹ 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.
²² 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.
²³ 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.
²⁴ 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 May 2024.
²⁵ 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.
²⁶ 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.
²⁷ 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.
²⁸ 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