Johnson & Johnson submits application to the European Medicines Agency seeking approval of subcutaneous formulation of RYBREVANT®▼ (amivantamab) for the treatment of patients with EGFR-mutated non-small cell lung cancer

Submission is supported by data from the Phase 3 PALOMA-3 study featured at the American Society of Clinical Oncology (ASCO) Annual Meeting1New formulation showed non-inferiority to intravenous administration in fourth positive Phase 3 amivantamab study1Longer overall survival, progression-free survival and duration of response shown with subcutaneous amivantamab; featured in Best of ASCO 20241BEERSE, BELGIUM, May 31, 2024 (GLOBE NEWSWIRE) — Janssen-Cilag International NV, a Johnson & Johnson company, announced today the submission of an application for the extension of the RYBREVANT®▼(amivantamab) marketing authorisation (line extension) to the European Medicines Agency (EMA). This application seeks approval for the use of 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 epidermal growth factor receptor (EGFR) exon 19 deletion or L858R mutations, and as a 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 supported by positive data from the Phase 3 PALOMA-3 study (NCT05388669), which demonstrated non-inferior pharmacokinetics and efficacy for SC amivantamab combined with lazertinib compared to intravenous (IV) administration, the currently approved formulation of amivantamab.1 Administration time for SC amivantamab was reduced to approximately five minutes from five hours for the first IV amivantamab infusion (across two days) and showed a five-fold reduction in infusion-related reactions (IRRs).1 These late-breaking results, which are the Company’s fourth positive Phase 3 readout for the amivantamab clinical programme, were featured for the first time as an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #LBA8505) taking place in Chicago, Illinois from 31 May – 4 June 2024.1 These data were also selected for the Best of ASCO 2024 Meetings, which highlight cutting-edge science and reflect leading research in oncology.1“At Johnson & Johnson we constantly strive to transform clinical outcomes for patients and are committed to developing innovative approaches that enhance the treatment experience,” said Henar Hevia, Ph.D, Senior Director, EMEA Therapeutic Area Lead, Oncology, Johnson & Johnson Innovative Medicine. “The positive data presented at ASCO show the potential for improved safety outcomes and added convenience for patients treated with the subcutaneous formulation of amivantamab, and we now look forward to working with the EMA to provide this option to patients who may benefit from it, as soon as possible.”The PALOMA-3 study evaluated the pharmacokinetics (PK), efficacy and safety of SC amivantamab (administered via manual injection) compared to IV amivantamab, both in combination with lazertinib, in patients with EGFR-mutated advanced or metastatic NSCLC after progression on osimertinib and chemotherapy.1 Results showed SC amivantamab was non-inferior to IV amivantamab, meeting both co-primary PK endpoints as measured by amivantamab levels in the blood (Ctrough and area under the serum concentration time curve from day 1 to 15).1At a median follow-up of 7 months, the overall response rate was 30 percent (95 percent confidence interval [CI], 24–37) in the SC arm and 33 percent (95 percent CI, 26–39) for IV (relative risk, 0.92; 95 percent CI, 0.70–1.23; P=0.001), meeting the non-inferiority criteria.1 SC amivantamab also demonstrated longer duration of response (DoR), progression-free survival (PFS) and significant improvement in overall survival (OS) compared to IV administration during this time.1 Specifically, median duration of response was numerically longer for SC amivantamab combined with lazertinib compared to IV (median, 11.2 vs 8.3 months among 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 patients treated with SC amivantamab had significantly longer OS compared with 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 combined with lazertinib were alive compared with 51 percent of those treated with the IV regimen. It is theorised that the efficacy seen with SC amivantamab may be linked to SC absorption, via the lymphatic system, potentially enhancing immune-mediated activity.1 “The PALOMA-3 data show that subcutaneous amivantamab offers shorter infusion times and lower rates of administration-related reactions with pharmacokinetics and efficacy comparable to the current IV administration,” said Dr. Natasha B. Leighl*, medical oncologist at the Princess Margaret Cancer Centre in Toronto, Canada, and the presenting author. “I look forward to seeing how these findings can make a meaningful difference in clinical practice by potentially improving the treatment experience for patients with EGFR-mutated non-small cell lung cancer.” Of particular note, administration time was substantially shorter for SC amivantamab (median less than approximately five minutes) compared to IV administration (up to five hours), with significantly more patients reporting convenience with the SC administration (85 percent with SC amivantamab vs 35 percent with IV administration at end of treatment; P<0.001).1The overall safety profile of SC amivantamab is consistent with the known profile of IV administration. The most common all-Grade adverse events (≥ 20 percent) for SC amivantamab compared to IV were paronychia (54 percent vs 51 percent), hypoalbuminemia (47 percent vs 37 percent) and rash (46 percent vs 43 percent), respectively.1 The rate of infusion-related reactions for patients treated with SC amivantamab combined with lazertinib was shown to be approximately 5-fold lower than that observed with the IV formulation (13 percent vs 66 percent, respectively).1 No Grade 4 or 5 IRRs were reported.1 Preventive blood thinning (prophylactic anticoagulation) was used in most patients and was found to be effective in reducing the rate of venous thromboembolic events (VTE).1 Patients receiving prophylactic anticoagulation had lower rates of VTE (10 percent) than those without prophylaxis (21 percent).1 Furthermore, VTE incidence was numerically lower in the SC arm vs the IV arm (9 percent vs 14 percent) regardless of anticoagulation status.1 Severe bleeding risk was low among patients receiving anticoagulants in the SC (2 percent) and IV (1 percent) arms.1 “We are always exploring innovative approaches to meet the urgent needs of patients living with EGFR-mutated non-small cell lung cancer and these compelling findings reinforce the potential for a new route of administration for amivantamab,” said Yusri Elsayed, M.D., M.H.Sc., Ph.D., Global Therapeutic Area Head, Oncology, Johnson & Johnson Innovative Medicine. “We look forward to pursuing regulatory submissions for this formulation, as we advance our ambition to transform the first-line treatment of EGFR-mutated NSCLC.”#ENDS#About PALOMA-3PALOMA-3 (NCT05388669), which enrolled 418 patients, is a randomised, open-label Phase 3 study evaluating pharmacokinetics (PK), efficacy and safety of subcutaneous amivantamab (administered via manual injection) combined with lazertinib compared to IV 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 on Cycle [C] 2 Day [D] 1 or C4D1) 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 predefined exploratory endpoint. Prophylactic anticoagulation was recommended for the first four months of treatment.4About Amivantamab  Amivantamab is a fully-human EGFR-MET bispecific antibody that acts by targeting tumours with activating and resistance EGFR mutations and MET mutations and amplifications, and by harnessing the immune system.3,4,5,6The European Commission (EC) granted conditional marketing authorisation of 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 for NSCLC.6In November 2023, a Type II extension of indication application was submitted to the European Medicines Agency (EMA) based on the MARIPOSA-2 study seeking 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.7This was followed, in February 2024, with the submission of a Type II extension of indication application 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 provided a positive opinion for 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 studied in multiple clinical trials in NSCLC, including:  The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumours including EGFR-mutated NSCLC.10The 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.11The Phase 3 PAPILLON (NCT04538664) study assessing amivantamab 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.12The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of amivantamab (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.13The Phase 3 MARIPOSA (NCT04487080) study assessing amivantamab 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.14The Phase 1 CHRYSALIS (NCT02609776) study evaluating amivantamab in patients with advanced NSCLC.15The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating amivantamab in combination with lazertinib and lazertinib as a monotherapy in patients with advanced NSCLC with EGFR mutations.16The Phase 1/2 METalmark (NCT05488314) study assessing amivantamab and capmatinib combination therapy in locally advanced or metastatic NSCLC.17The Phase 1/2 PolyDamas (NCT05908734) study assessing amivantamab and cetrelimab combination therapy in locally advanced or metastatic NSCLC.18The Phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with amivantamab in combination with lazertinib in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.19For a full list of adverse events and information on dosage and administration, contraindications and other precautions when using amivantamab, please refer to the Summary of Product Characteristics.6▼ In line with EMA regulations for new medicines, amivantamab is subject to additional monitoring.  About Non-Small Cell Lung CancerIn Europe, it is estimated that 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 biggest cancer killer, with more deaths than breast cancer and prostate cancer combined. 21The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.21 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling 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 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-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 In addition, it has been demonstrated that approximately 50 percent of patients with NSCLC will develop brain metastases which are a substantial contributor to overall cancer mortality.30,31,32 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 www.janssen.com/emea. Follow us at www.linkedin.com/company/jnj-innovative-medicine-emea. Janssen-Cilag International NV is a Johnson & Johnson company.# # #Cautions Concerning Forward-Looking StatementsThis press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of amivantamab. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Janssen-Cilag International NV and Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behaviour and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023, including in 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/, http://www.jnj.com/ or on request from Johnson & Johnson. None of Janssen-Cilag International NV nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.*Dr. Natasha Leighl has served as a consultant to Johnson & Johnson; she has not been paid for any 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. May 31, 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. Accessed May 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). Accessed: 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. Available at: https://www.janssen.com/emea/sites/www_janssen_com_emea/files/janssen_mariposa-2_filing_press_release_2023.pdf. Accessed: May 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. Available at: https://www.janssen.com/emea/sites/www_janssen_com_emea/files/amivantamab_mariposa_ema_filing_release_2024_2.pdf. Accessed: May 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. Available at: https://www.janssen.com/emea/sites/www_janssen_com_emea/files/papillon_chmp_press_release_2024.pdf. Accessed: May 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). Available at: https://clinicaltrials.gov/study/NCT04606381. Accessed May 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). Available at: https://clinicaltrials.gov/ct2/show/NCT04538664. Accessed May 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). Available at: https://classic.clinicaltrials.gov/ct2/show/study/NCT04988295. Accessed May 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). Available at: https://classic.clinicaltrials.gov/ct2/show/NCT04487080. Accessed May 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. Accessed May 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. Accessed May 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. Accessed May 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. Accessed May 2024.19 ClinicalTrials.gov. Premedication to Reduce Amivantamab Associated Infusion Related Reactions (SKIPPirr). https://classic.clinicaltrials.gov/ct2/show/NCT05663866. Accessed May 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: World Conference on Lung Cancer Annual Meeting; January 29, 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 presented at: World Conference on Lung Cancer Annual Meeting; January 29, 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-455616May 2024