RYBREVANT® (amivantamab-vmjw) in Combination With Chemotherapy Is the First FDA Approved Therapy for First-line Treatment of Patients With Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations

Approval is based on results from the Phase 3 PAPILLON study, which demonstrated RYBREVANT^® plus chemotherapy reduced the risk of disease progression or death by 61 percent versus chemotherapy alone in patients with previously untreated NSCLC with EGFR exon 20 insertion mutations

National Comprehensive Cancer Network ^® (NCCN ^®) updated its NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ^®) to recommend amivantamab-vmjw (RYBREVANT^®) plus chemotherapy as a preferred first-line regimen for patients with NSCLC with EGFR exon 20 insertion mutations

RARITAN, NJ, USA I March 1, 2024 I Johnson & Johnson (NYSE: JNJ) announced today that following a priority review, the U.S. Food and Drug Administration (FDA) has approved RYBREVANT^® (amivantamab-vmjw) in combination with chemotherapy (carboplatin-pemetrexed) for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations as detected by an FDA-approved test.¹ This FDA action converts the May 2021 accelerated approval of RYBREVANT^® to a full approval based on the confirmatory Phase 3 PAPILLON study.

“When aiming for the best possible treatment outcomes, a targeted approach should be used in the first line for patients with EGFR exon 20 insertion mutations, as this is a commonly applied practice for patients with NSCLC harboring other molecular driver alterations,” said Joshua K. Sabari, M.D.*, an oncologist at NYU Langone’s Perlmutter Cancer Center and study investigator.^* “The results observed in the PAPILLON study showed significant improvement in progression-free survival, supporting the use of this regimen as the potential standard-of-care in the first-line treatment of these patients.”

Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases.^2,3 Alterations in EGFR are the most common actionable driver mutations in NSCLC.⁴ Clinical data show patients with EGFR exon 20 insertion mutations generally experience limited benefits with currently approved third-generation EGFR tyrosine kinase inhibitors and chemotherapy.^5,6 NSCLC driven by EGFR exon 20 insertion mutations carries a worse prognosis and shorter survival rates compared with lung cancer driven by other EGFR driver mutations.⁷

“For patients with lung cancer and their families, each breakthrough in treatment provides not only a new option, but a potential lifeline. The approval of RYBREVANT plus chemotherapy heralds a promising new first-line treatment option for patients newly diagnosed with non-small cell lung cancer where their driver mutation is an EGFR exon 20 insertion,” said Marcia Horn**, Executive Director of the Exon 20 Group and CEO of ICAN, International Cancer Advocacy Network. “This new regimen is a major advance over chemotherapy alone. We’ve seen first-hand the extended survival that Exon 20 Group patients experienced on RYBREVANT plus chemotherapy in the PAPILLON study, and we’re delighted that this historic treatment option, which specifically targets the EGFR exon 20 insertion mutation, has been approved.”

The FDA approval is based on positive results from the randomized, open-label Phase 3 PAPILLON study, which showed RYBREVANT^® plus chemotherapy resulted in a 61 percent reduction in the risk of disease progression or death compared to chemotherapy alone.¹ Results also showed treatment with RYBREVANT^® plus chemotherapy improved objective response rate (ORR) and progression-free survival (PFS).¹ Based on PAPILLON data, the National Comprehensive Cancer Network ^® (NCCN ^®) updated its’ NCCN Clinical Practice Guidelines (NCCN Guidelines^®) to include a category 1 recommendation for amivantamab-vmjw (RYBREVANT^®) plus chemotherapy as a preferred first-line therapy for patients with NSCLC with EGFR exon 20 insertion mutations.^{8 †‡}

“We are redefining care for patients with non-small cell lung cancer by advancing innovative regimens that can be used early, with the goal of extending survival,” said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Johnson & Johnson Innovative Medicine. “RYBREVANT plus chemotherapy is the first targeted approach approved for the first-line treatment of patients with NSCLC with EGFR exon 20 insertion mutations. We look forward to building on this latest milestone as we continue to accelerate our transformative lung cancer portfolio.” 

Warnings and Precautions include Infusion Related Reactions (IRR), Interstitial Lung Disease (ILD)/Pneumonitis, Dermatologic Adverse Reactions, Ocular Toxicity and Embryo-fetal Toxicity. The most common adverse reactions (≥20 percent) were rash, nail toxicity, stomatitis, IRR, fatigue, edema, constipation, decreased appetite, nausea, COVID-19, diarrhea and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥2 percent) were decreased albumin, increased alanine aminotransferase, increased gamma-glutamyl transferase, decreased sodium, decreased potassium, decreased magnesium, and decreases in white blood cells, hemoglobin, neutrophils, platelets, and lymphocytes.¹

About the PAPILLON Study

PAPILLON (NCT04538664) is a randomized, open-label Phase 3 study evaluating the efficacy and safety of RYBREVANT^® in combination with chemotherapy, compared with chemotherapy alone, in newly diagnosed patients with advanced or metastatic NSCLC characterized by EGFR exon 20 insertion 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 ORR, PFS after first subsequent therapy, time to symptomatic progression and overall survival (OS). Patients who received chemotherapy alone were allowed to receive RYBREVANT^® monotherapy in the second-line setting after confirmation of disease progression.¹⁰

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] This indication is approved under accelerated approval based on ORR and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 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 an 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 the 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.^{8 †‡}
• Amivantamab-vmjw (RYBREVANT^®) plus chemotherapy as a preferred (Category 1 recommendation) subsequent therapy for patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression after treatment with osimertinib.^{8 †‡}
• 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.^{8 †‡}

In addition to the Phase 3 PAPILLON study, RYBREVANT^® is being studied in multiple clinical trials in NSCLC, including:

• The Phase 3 MARIPOSA-2 (NCT04988295) study evaluating the efficacy and safety of RYBREVANT^® and chemotherapy in patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC who had disease progression on or after treatment with osimertinib. Data for this randomized Phase 3 study presented at the ESMO 2023 Congress demonstrated statistically significant and clinically meaningful improvement in PFS in patients receiving RYBREVANT^® plus chemotherapy with and without lazertinib versus chemotherapy.^11,12
• The Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT^® in combination with lazertinib, a novel third-generation EGFR TKI, versus osimertinib and versus lazertinib alone in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions (ex19del) or L858R substitution mutations. Data for this randomized Phase 3 study presented at the ESMO 2023 Congress showed statistically significant and clinically meaningful improvement in progression-free survival in patients with EGFR-mutated advanced NSCLC treated with RYBREVANT^® plus lazertinib versus osimertinib.^13,14
• The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT^® in participants with advanced NSCLC.¹⁵
• 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.¹⁶
• The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous (SC) administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab SC delivery.¹⁷
• The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in participants with advanced or metastatic solid tumors including EGFR-mutated NSCLC.¹⁸
• The Phase 3 PALOMA-3 (NCT05388669) study assessing lazertinib with subcutaneous amivantamab compared to intravenous amivantamab in participants with EGFR-mutated advanced or metastatic 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 lazertinib in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.²²
• The Phase 2 COCOON study (NCT06120140) will evaluate enhanced dermatological care to reduce rash and paronychia in patients with EGFR-mutated NSCLC treated first-line with amivantamab plus lazertinib.²³

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.^2,3 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.⁴ 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.^{4,24,25,26,27,28} 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 TKIs is less than 20 percent.^30,31 Patients with EGFR ex19del or L858R mutations have a real-world five-year OS of 19 percent.³²

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 both Johnson & Johnson companies.

*Dr. Sabari has served as a consultant to Johnson & Johnson; he has not been paid for any media work.

**Ms. Horn 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.

§RECIST (v1.1) refers to Response Evaluation Criteria in Solid Tumors, which is a standard way to measure how well solid tumors respond to treatment and is based on whether tumors shrink, stay the same or get bigger.

∥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. RYBREVANT^® Prescribing Information. Horsham, PA: Janssen Biotech, Inc.
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15. 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 September 2023.
16. 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 September 2023.
17. ClinicalTrials.gov. A Study of Amivantamab Subcutaneous (SC) Administration for the Treatment of Advanced Solid Malignancies (PALOMA). https://clinicaltrials.gov/ct2/show/NCT04606381. Accessed September 2023.
18. 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 September 2023.
19. 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 September 2023.
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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 September 2023.
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SOURCE: Johnson & Johnson