RARITAN, N.J., December 16, 2024 – Johnson & Johnson (NYSE:JNJ) today announced the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for the Biologics License Application (BLA) for a fixed combination of amivantamab and recombinant human hyaluronidase for subcutaneous administration (SC amivantamab) in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.
The CRL is related to observations as part of a standard pre-approval inspection at a manufacturing facility. The CRL is unrelated to the product formulation, or the efficacy and safety data submitted in the regulatory application, and the FDA has not requested any additional clinical studies. The currently approved intravenous (IV) formulation of RYBREVANT® (amivantamab-vmjw) is not impacted by the CRL.
“We’re working closely with the FDA to bring SC amivantamab to patients as quickly as possible, and are confident in our path to resolution,” said Yusri Elsayed, M.D., M.H.Sc., Ph.D. Global Therapeutic Area Head, Oncology, Innovative Medicine, Johnson & Johnson. “Backed by interim overall survival data showing a strong favorable trend compared to osimertinib, we believe strongly in the robust efficacy and safety of RYBREVANT – both as a standalone treatment and in combination with LAZCLUZE – for EGFR-mutated advanced lung cancer. We’re proud to have helped so many patients in the front-line setting already with RYBREVANT and look forward to further expanding treatment options with our subcutaneous formulation pending regulatory review and approval.”
The BLA is based on the Phase 3 PALOMA-3 study results presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and published in the Journal of Clinical Oncology. In August 2024, the FDA granted Priority Review for the BLA for SC amivantamab as a treatment for patients with NSCLC with EGFR exon 19 deletions (ex19del) or L858R substitution mutations. RYBREVANT® is currently approved in over 60 countries worldwide.
About the PALOMA-3 Study
PALOMA-3 (NCT05388669), which enrolled 418 patients, is a randomized, open-label Phase 3 study evaluating the pharmacokinetics (PK), efficacy and safety of subcutaneous amivantamab (administered via manual injection) combined with lazertinib compared to IV amivantamab and LAZCLUZE™ (lazertinib) in patients with EGFR-mutated advanced or metastatic NSCLC after progression on osimertinib and chemotherapy. The co-primary PK endpoints of the study were trough concentration (Ctrough on Cycle [C] 2 Day [D] 1 or C4D1) and C2 area under the curve (AUCD1-D15). Descriptive efficacy outcome measures were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Prophylactic anticoagulation was recommended for the first four months of treatment.1
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 L858R 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, ORR, duration of response (DOR), second progression-free survival (PFS2) and intracranial PFS. The combination therapy showed a significant PFS improvement and a favorable OS trend, with a safety profile consistent with known effects of the individual treatments. Overall survival will continue to be assessed with longer term follow-up as a key secondary endpoint.2
About RYBREVANT®
IV 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.3 In the subcutaneous formulation, amivantamab is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE® drug delivery technology.
IV RYBREVANT® is approved in the U.S., Europe and in 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.
IV RYBREVANT® is approved in the U.S. 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 L858R substitution mutations, as detected by an FDA-approved test. In November 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of RYBREVANT® and LAZCLUZE™ in Europe for this indication.
IV RYBREVANT® is approved in the U.S., Europe and in 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.
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:
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Amivantamab-vmjw (IV RYBREVANT®) plus lazertinib (LAZCLUZE™) as a Category 1 recommendation for first-line therapy in patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.4 †‡
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Amivantamab-vmjw (IV RYBREVANT®) plus chemotherapy as a Category 1 recommendation 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.4 †‡
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Amivantamab-vmjw (IV RYBREVANT®) plus chemotherapy as a Category 1 recommendation for first-line therapy in treatment-naive patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion mutation-positive advanced NSCLC.4 †‡
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Amivantamab-vmjw (IV RYBREVANT®) as a 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. 4 †‡
RYBREVANT® is being studied in multiple clinical trials in NSCLC, including:
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The Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT® in combination with LAZCLUZE™ versus osimertinib and versus LAZCLUZE™ alone in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations.2
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The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of IV RYBREVANT® (with or without LAZCLUZE™) and carboplatin-pemetrexed versus carboplatin-pemetrexed alone in patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations after disease progression on or after osimertinib.5
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The Phase 3 PAPILLON (NCT04538664) study assessing IV 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
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The Phase 3 PALOMA-3 (NCT05388669) study assessing LAZCLUZE™ with subcutaneous amivantamab compared to IV RYBREVANT® in patients with EGFR-mutated advanced or metastatic NSCLC.1
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The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.7
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The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for subcutaneous amivantamab delivery.8
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The Phase 1 CHRYSALIS (NCT02609776) study evaluating IV RYBREVANT® in patients with advanced NSCLC.9
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The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating IV RYBREVANT® in combination with LAZCLUZE™ and LAZCLUZE™ as a monotherapy in patients with advanced NSCLC with EGFR mutations.10
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The Phase 1/2 METalmark (NCT05488314) study assessing IV RYBREVANT® and capmatinib combination therapy in locally advanced or metastatic NSCLC.11
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The Phase 1/2 swalloWTail (NCT06532032) study assessing IV RYBREVANT® and docetaxel combination therapy in patients with metastatic NSCLC.12
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The Phase 1/2 PolyDamas (NCT05908734) study assessing IV RYBREVANT® and cetrelimab combination therapy in locally advanced or metastatic NSCLC.13
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The Phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with IV RYBREVANT® in combination with LAZCLUZE™ in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.14
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The Phase 2 COPERNICUS (NCT06667076) study combining developments in treatment administration and prophylactic supportive care in representative US patients with common EGFR-mutated NSCLC treated with subcutaneous amivantamab in combination with LAZCLUZE™ or chemotherapy.15
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The Phase 2 COCOON (NCT06120140) study assessing the effectiveness of a proactive dermatologic management regimen given with first-line RYBREVANT® and LAZCLUZE™ in patients with EGFR-mutated advanced NSCLC.16
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 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.
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.17,18 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.19 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.20 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.17,18,21,22,23,24 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.25 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.26,27 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.28 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.29
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.
Footnotes
†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 ClinicalTrials.gov. A Study of LAZCLUZE™ 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 December 2024.
2 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 December 2024.
3 RYBREVANT® Prescribing Information. Horsham, PA: Janssen Biotech, Inc.
4 Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.9.2024© 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 December 2024.
5 ClinicalTrials.gov. A Study of Amivantamab and LAZCLUZE™ 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 December 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 December 2024.
7 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 December 2024.
8 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 December 2024.
9 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 December 2024.
10 ClinicalTrials.gov. A Study of LAZCLUZE™ 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 December 2024.
11 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 December 2024.
12 ClinicalTrials.gov. A Study of Combination Therapy With Amivantamab and Docetaxel in Participants With Metastatic Non-small Cell Lung Cancer (swalloWTail). https://www.clinicaltrials.gov/study/NCT06532032?term=Swallowtail&intr=amivantamab&rank=1. Accessed December 2024.
13 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 December 2024.
14 ClinicalTrials.gov. Premedication to Reduce Amivantamab Associated Infusion Related Reactions (SKIPPirr). https://classic.clinicaltrials.gov/ct2/show/NCT05663866. Accessed December 2024.
15 ClinicalTrials.gov. A Study of Amivantamab in Combination With Lazertinib, or Amivantamab in Combination With Platinum-Based Chemotherapy, for Common Epidermal Growth Factor Receptor (EGFR)-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) (COPERNICUS). https://www.clinicaltrials.gov/study/NCT06667076?term=COPERNICUS&rank=3. Accessed December 2024.
16 ClinicalTrials.gov. Enhanced Dermatological Care to Reduce Rash and Paronychia in Epidermal Growth Factor Receptor (EGRF)-Mutated Non-Small Cell Lung Cancer (NSCLC) Treated First-line With Amivantamab Plus Lazertinib (COCOON). https://www.clinicaltrials.gov/study/NCT06120140. Accessed December 2024.
17 The World Health Organization. Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed December 2024.
18 American Cancer Society. What is Lung Cancer? https://www.cancer.org/content/cancer/en/cancer/lung-cancer/about/what-is.html. Accessed December 2024.
19 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.
20 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.
21 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.
22 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.
23 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.
24 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.
25 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 December 2024.
26 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.
27 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.
28 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.
29 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.
30 LAZCLUZE™ Prescribing Information. Horsham, PA: Janssen Biotech, Inc.