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Johnson & Johnson Submits Application to the European Medicines Agency for Approval of the Subcutaneous Formulation of RYBREVANT®▼ (Amivantamab) for the Treatment of Patients

Friday, June 07, 2024

Janssen-Cilag International NV, a Johnson & Johnson company, today announced the submission of an extension application for RYBREVANT ® ▼ (amivantamab) to the European Medicines Agency (EMA). This application seeks approval for a subcutaneous (sc) formulation of amivantamab in combination with lazertinib for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) exon 19 deletion or an L858R mutation, and as monotherapy in adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations after failure of platinum-based therapy.

The application to the EMA is based on positive data from the Phase III PALOMA-3 study ( NCT05388669 ), which demonstrated non-inferior pharmacokinetics and efficacy of SC amivantamab in combination with lazertinib compared to intravenous (IV) administration, the currently approved formulation of amivantamab.1 The  administration time for SC amivantamab was reduced from five hours for the first intravenous amivantamab infusion (over two days) to approximately five minutes and showed a five-fold reduction in infusion-related reactions (IRRs). 1 These breakthrough results, which represent the Company's fourth positive Phase III result for the amivantamab clinical program, were presented for the first time as an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #LBA8505), to be held May 31-June 4, 2024, in Chicago, Illinois . 1  These data were also selected for the “Best of ASCO 2024 Meetings,” which highlight and reflect the cutting-edge research in oncology . 1

"At Johnson & Johnson, we are continually striving to improve clinical outcomes for patients and are committed to developing innovative approaches that enhance the treatment experience," said Dr. Henar Hevia, Executive Director, Oncology Therapeutic Area Leader EMEA, Johnson & Johnson Innovative Medicine. "The positive data presented at ASCO demonstrate the potential for improved safety outcomes and additional convenience for patients treated with the subcutaneous formulation of amivantamab, and we now look forward to working with the EMA to make this option available to patients who can benefit from it as soon as possible."

The PALOMA-3 study evaluated the pharmacokinetics (PK), efficacy and safety of SC amivantamab (administered by manual injection) compared with IV amivantamab, both in combination with lazertinib, in patients with EGFR-mutated advanced or metastatic NSCLC after progression on osimertinib and chemotherapy. 1 The results showed that SC amivantamab was non-inferior to IV amivantamab and met both co-primary PK endpoints as measured by amivantamab blood levels (C trough  and area under the time curve of serum concentration from days 1 to 15). 1

At a median follow-up of 7 months, the overall response rate was 30 percent (95 percent confidence interval [CI], 24–37) in the SC group and 33 percent (95 percent CI, 26–39) for the IV group (relative risk, 0.92; 95 percent CI, 0.70–1.23; p=0.001), meeting noninferiority criteria. 1 SC-administered amivantamab also demonstrated a longer duration of response (DoR), progression-free survival (PFS), and a significant improvement in overall survival (OS) compared with IV administration during this time. 1  Notably, the median duration of response was numerically longer with SC amivantamab in combination with lazertinib compared with IV administration (median 11.2 vs 8.3 months in confirmed responders), as was PFS (median 6.1 vs 4.3 months; hazard ratio [HR], 0.84; 95 percent CI, 0.64-1.10; p=0.20). 1 A pre-specified exploratory endpoint showed that patients treated with SC amivantamab had significantly longer survival than patients treated IV (HR, 0.62; 95 percent CI, 0.42-0.92; nominal p=0.02). 1 At 12 months, 65 percent of patients who received SC amivantamab in combination with lazertinib were still alive, compared with 51 percent of patients treated with the IV regimen. It is suspected that the efficacy observed with SC amivantamab may be related to SC absorption via the lymphatic system, which may enhance immune-mediated activity. 1 

"The PALOMA-3 data demonstrate that subcutaneous administration of amivantamab offers shorter infusion times and a lower rate of administration-related reactions with pharmacokinetics and efficacy comparable to current intravenous administration," said Natasha B. Leighl, MD, medical oncologist at the Princess Margaret Cancer Centre in Toronto, Canada, and presenting author. "I look forward to seeing how these results can make a meaningful difference in clinical practice by improving the treatment experience for patients with EGFR-mutated non-small cell lung cancer." 

Of particular note, administration time for SC amivantamab was significantly shorter (median less than about five minutes) than for IV administration (up to five hours), with significantly more patients reporting that SC administration was more convenient (85 percent with SC amivantamab versus 35 percent with IV administration at the end of treatment; p<0.001). 1

The overall safety profile of SC amivantamab is consistent with the known profile of IV administration. The most common adverse reactions of any grade (≥ 20 percent) for SC amivantamab compared with IV administration were paronychia (54 percent vs. 51 percent), hypoalbuminemia (47 percent vs. 37 percent), and rash (46 percent vs. 43 percent).1 The  rate of infusion-related reactions in patients treated with SC amivantamab in combination with lazertinib was shown to be approximately five-fold lower than with the IV formulation (13 percent vs. 66 percent).1 No Grade 4 or 5 infusion-related reactions (IRRs) were reported. 1 Preventive blood thinning (prophylactic anticoagulation) was used in most patients and was effective in reducing the rate of venous thromboembolic events (VTE). 1 Patients who received prophylactic anticoagulation had a lower rate of VTE (10 percent) than those without prophylaxis (21 percent). 1 In addition, the incidence of VTE was numerically lower in the SC group compared with the IV group (9 percent versus 14 percent), regardless of anticoagulation status. 1 The risk of major bleeding was low in patients receiving anticoagulants in the SC (2 percent) and IV groups (1 percent). 1 

"We are always looking for innovative approaches to meet the urgent needs of patients with EGFR-mutated non-small cell lung cancer, and these compelling results underscore the potential for a new route of administration for amivantamab," said Yusri Elsayed, MD, MHSc., Ph.D., Global Therapeutic Area Head of Oncology, Johnson & Johnson Innovative Medicine. "We look forward to pursuing regulatory submissions for this formulation as we pursue our goal of transforming first-line treatment of EGFR-mutated NSCLC."

About PALOMA-3

PALOMA-3 ( NCT05388669 ), which enrolled 418 patients, is a randomized, open-label Phase III study to evaluate the pharmacokinetics (PK), efficacy, and safety of subcutaneous amivantamab (administered by manual injection) in combination with lazertinib compared with intravenous amivantamab and lazertinib in patients with EGFR-mutated advanced or metastatic NSCLC after progression on osimertinib and chemotherapy.2 The co-primary PK endpoints of the study were trough concentration (Ctrough at cycle [Z]2 day [T] 1  or Z4T1) and C2 area under the curve (AUCD1-D15).4 Key secondary endpoints were objective response rate and progression-free survival (PFS). Overall survival was a pre-specified exploratory endpoint. Prophylactic anticoagulation was recommended for the first four months of treatment. 4

About Amivantamab 

amivantamab is a fully human EGFR-MET bispecific antibody that targets tumors with activating and resistant EGFR mutations as well as MET mutations and amplifications and leverages the immune system. 3,4,5,6

The European Commission (EC) granted conditional approval for amivantamab in December 2021 for the treatment of adult patients with advanced NSCLC with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations after failure of platinum-based therapy. 6  Amivantamab is the first approved treatment in the European Economic Area specifically targeting EGFR exon 20 insertion mutations in NSCLC. 6

In November 2023, a Type II extension application based on the MARIPOSA-2 study was submitted to the European Medicines Agency (EMA) to obtain approval of amivantamab in combination with chemotherapy (carboplatin and pemetrexed) for the treatment of adult patients with advanced NSCLC with EGFR ex19del or L858R substitution mutations after failure of prior therapy including a third-generation EGFR TKI. 7

This was followed in February 2024 by the  submission  of an application for an extension of indication (Type II) to the EMA based on the MARIPOSA study for amivantamab in combination with lazertinib for the first-line treatment of adult patients with advanced NSCLC with common EGFR exon 19 deletions (ex19del) or exon 21 L858R (L858R) substitution mutations. 8  In April 2024, the CHMP issued a positive opinion on the use of amivantamab in combination with carboplatin and pemetrexed chemotherapy for the first-line treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations. 9

In addition to the PALOMA-3 study, amivantamab is being investigated in several clinical trials in non-small cell lung cancer:

  • The Phase II PALOMA-2 trial ( NCT05498428 ) is investigating the subcutaneous administration of amivantamab in patients with advanced or metastatic solid tumors, including EGFR-mutated NSCLC. 10
  • The Phase I PALOMA trial ( NCT04606381 ) is evaluating the feasibility of subcutaneous administration of amivantamab based on safety and pharmacokinetics and is designed to determine a dose, dosing regimen and formulation for subcutaneous administration of amivantamab. 11
  • The phase III PAPILLON study ( NCT04538664 ) is evaluating amivantamab in combination with carboplatin-pemetrexed compared with chemotherapy alone in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. 12
  • The phase III MARIPOSA-2 trial ( NCT04988295 ) is evaluating the efficacy of amivantamab (with or without lazertinib) and carboplatin-pemetrexed compared with carboplatin-pemetrexed alone in patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution after disease progression on or after osimertinib. 13
  • The Phase III MARIPOSA study ( NCT04487080 ) is evaluating amivantamab in combination with lazertinib, compared with osimertinib and lazertinib alone, as first-line treatment for patients with locally advanced or metastatic NSCLC with EGFR-ex19del or L858R substitution mutations. 14
  • The Phase I CHRYSALIS trial ( NCT02609776 ) is investigating amivantamab in patients with advanced NSCLC. 15
  • The Phase I/Ib CHRYSALIS-2 study ( NCT04077463 ) is evaluating amivantamab in combination with lazertinib and lazertinib as monotherapy in patients with advanced NSCLC with EGFR mutations. 16
  • The Phase I/II study METalmark ( NCT05488314 ) is investigating the combination therapy of amivantamab and capmatinib in locally advanced or metastatic NSCLC. 17
  • The phase I/II study PolyDamas ( NCT05908734 ) is investigating the combination therapy of amivantamab and cetrelimab in locally advanced or metastatic NSCLC .18
  • The Phase II SKIPPirr study ( NCT05663866 ) is investigating how to reduce the frequency and/or severity of infusion-related reactions with the first dose of amivantamab in combination with lazertinib in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC. 19

For a full list of side effects, as well as information on dosage and administration, contraindications and other precautions when using amivantamab, see the  Summary of Product Characteristics . 6

▼In line with EMA rules for new medicines, amivantamab is subject to additional monitoring.

About non-small cell lung cancer

In Europe, an estimated 484,306 people were diagnosed with lung cancer in 2022. 20  NSCLC accounts for 85 percent of all lung cancer cases. 21  Lung cancer is Europe's largest cause of cancer death, with more deaths than breast and prostate cancer combined.  21

The major subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.21 The  most common driver mutations in NSCLC include alterations in EGFR, a receptor tyrosine kinase that controls cell growth and division.21,22  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 EGFR ex19del or  EGFR L858R mutations are the most common EGFR mutations.27  The five-year survival rate for all patients with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) is less than 20 percent . 28  Patients with EGFR exon 20 insertion mutations have a real five-year overall survival (OS) rate of eight percent in first-line treatment, which is worse than patients with EGFR Ex19del or L858R mutations, who have a real five-year OS of 19 percent. 29  In addition, approximately 50 percent of patients with NSCLC have been shown to develop brain metastases, which contribute significantly to overall cancer mortality. 30,31,32

About Johnson & Johnson 

At Johnson & Johnson, we believe that health is everything. Our strength in health innovation enables us to create a world where complex diseases are prevented, treated and cured, treatments are smarter and less invasive, and solutions are personal. Our expertise in innovative medicine and MedTech puts us in a unique position to inject innovative solutions today across the spectrum of health that will deliver the breakthroughs of tomorrow, enabling us to have a lasting impact on people's health.

For more information, visit  www.janssen.com/emea . Follow us on  www.linkedin.com/company/jnj-innovative-medicine-emea . Janssen-Cilag International NV is a Johnson & Johnson company.

Cautionary Note Regarding Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment effects of amivantamab. Readers are cautioned not to rely on these forward-looking statements. These statements are based on current expectations about future events. Should underlying assumptions prove incorrect or known or unknown risks or uncertainties materialize, actual results could differ materially from Janssen-Cilag International NV's and Johnson & Johnson's expectations and projections. Risks and uncertainties include, among others: challenges and uncertainties inherent in product research and development, including uncertainty of clinical success and obtaining regulatory approvals; uncertainty of commercial success; difficulties and delays in manufacturing; competition, including technological advances, new products and patents from competitors; challenges to patents; concerns about the effectiveness or safety of products that result in product recalls or regulatory actions; changes in the behavior and spending patterns of purchasers of healthcare products and services; changes in applicable laws and regulations, including global healthcare reform; and trends toward containing healthcare costs. For a further list and description of these risks, uncertainties and other factors, see Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 31, 2023, including the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A Risk Factors" and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at  http://www.sec.gov/ and  http://www.jnj.com/ or upon request from Johnson & Johnson. Neither Janssen-Cilag International NV nor Johnson & Johnson undertakes any obligation to update any forward-looking statements as a result of new information or future events or developments.

* Dr. Natasha Leighl served as a consultant for Johnson & Johnson and was not compensated for her media work. 

1 Leighl N, et al. Subcutaneous amivantamab Plus Lazertinib Vs Intravenous amivantamab Plus Lazertinib In EGFR-mutated, Advanced Non-small Cell Lung Cancer (NSCLC): PALOMA-3, A Phase 3, Global, Randomized, Controlled Trial. 2024 American Society of Clinical Oncology Annual Meeting. 31. Mai 2024.

2 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. Abgerufen im Mai 2024.

3 Grugan KD, et al. Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells. MAbs 2017;9(1):114-126.

4 Moores SL, et al. A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors. Cancer Res 2016;76(13)(suppl 27216193):3942-3953.

5 Yun J, et al. Antitumor Activity of amivantamab (JNJ-61186372), an EGFR–MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion–Driven NSCLC. Cancer Discov 2020;10(8):1194-1209.

6  European Medicines Agency. amivantamab – Summary of Product Characteristics. January 2023. Available at:  Rybrevant, INN-amivantamab (europa.eu).  Retrieved: May 2024.

7 Janssen.com/EMEA. Janssen Submits Application to the European Medicines Agency for RYBREVANT®▼ (amivantamab) in Combination with Chemotherapy for the Treatment of Adult Patients with Advanced EGFR-Mutated Non-Small Cell Lung Cancer After Failure of Prior Therapy. Verfügbar unter: https://www.janssen.com/emea/sites/www_janssen_com_emea/files/janssen_mariposa-2_filing_press_release_2023.pdf. Abgerufen: Mai 2024.

8 Janssen.com/EMEA. Janssen Submits Type II Extension of Indication Application to the European Medicines Agency Seeking Approval of RYBREVANT®▼ (amivantamab), in combination with Lazertinib, for the First-Line Treatment of Patients with EGFR Mutated Non-Small Cell Lung Cancer. Verfügbar unter: https://www.janssen.com/emea/sites/www_janssen_com_emea/files/amivantamab_mariposa_ema_filing_release_2024_2.pdf. Abgerufen: Mai 2024.

9 Janssen.com/EMEA. Johnson & Johnson receives positive CHMP opinion for RYBREVANT®▼ (amivantamab) in combination with chemotherapy for the first-line treatment of patients with advanced non-small cell lung cancer with activating EGFR exon 20 insertion mutations. Verfügbar unter: https://www.janssen.com/emea/sites/www_janssen_com_emea/files/papillon_chmp_press_release_2024.pdf. Abgerufen: Mai 2024.

10 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).

11 ClinicalTrials.gov. A Study of amivantamab Subcutaneous (SC) Administration for the Treatment of Advanced Solid Malignancies (PALOMA). Verfügbar unter: https://clinicaltrials.gov/study/NCT04606381. Abgerufen im Mai 2024.

12 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). Verfügbar unter: https://clinicaltrials.gov/ct2/show/NCT04538664. Abgerufen im Mai 2024.

13 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). Verfügbar unter: https://classic.clinicaltrials.gov/ct2/show/study/NCT04988295. Abgerufen im Mai 2024.

14 ClinicalTrials.gov. A Study of amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA). Verfügbar unter: https://classic.clinicaltrials.gov/ct2/show/NCT04487080. Abgerufen im Mai 2024.

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. Abgerufen im Mai 2024.

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. Abgerufen im Mai 2024.

17 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. Abgerufen im Mai 2024.

18 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. Abgerufen im Mai 2024.

19 ClinicalTrials.gov. Premedication to Reduce amivantamab Associated Infusion Related Reactions (SKIPPirr). https://classic.clinicaltrials.gov/ct2/show/NCT05663866. Abgerufen im Mai 2024.

20  Global Cancer Observatory. Cancer Today. Available at:  https://gco.iarc.fr/en . Accessed: May 2024.

21 Zappa C, et al. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016;5(3):288–300.

22 Wee P, Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers. 2017;9(5):52.

23 Pennell NA, et al. A phase II trial pf adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant non-small cell lung cancer. J Clin Oncol. 2019;37(7);97-104.

24  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: Annual Meeting of the World Conference on Lung Cancer; 29 January 2021; Singapore.

25 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.

26 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.

27  American Lung Association. EGFR and Lung Cancer. Available at:  https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/biomarker-testing/egfr . Accessed May 2024.

28 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.

29 Girard N, et al. Comparative clinical outcomes for patients with NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Abstract vorgestellt auf: World Conference on Lung Cancer Annual Meeting; 29. Januar 2021; Singapore.

30 Shao J et al. The number of brain metastases predicts the survival of non-small cell lung cancer patients with EGFRR mutation status. Cancer Rep (Hoboken). 2022;5(9): e1550.

31 Achrol A et al. Brain metastases. Nat Rev Dis Primers. 2019;17(5): 5.

32 Rangachari D et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 2015;88(1): 108 –

CP-455616

May 2024

Media Contact:
Zayn Qureshi
zqureshi@its.jnj.com
+44 7760 334666

Investor Contact:
Raychel Kruper
investor-relations@its.jnj.com

 

Source: globenewswire.com

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