May 21, 2021 (HORSHAM, P.A.) -- The Janssen Pharmaceutical Companies of Johnson & Johnson announced today the U.S. Food and Drug Administration (FDA) has granted the accelerated approval of Rybrevant (amivantamab-vmjw) for the treatment of adult 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, whose disease has progressed on or after platinum-based chemotherapy.[1] Rybrevant is the first fully-human, bispecific antibody approved for the treatment of patients with NSCLC that targets EGFR exon 20 insertion mutations, which are the third most prevalent activating EGFR mutation.[1][2] Today’s approval follows the FDA’s decision to grant Breakthrough Therapy Designation (BTD) in March 2020 and to initiate a Priority Review of the Biologics License Application (BLA) in December 2020. This indication is approved under accelerated approval based on overall response rate and duration of response.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.[1]

“Today’s FDA approval is an important development for people living with non-small cell lung cancer with exon 20 insertion mutations who, until now, have had no approved treatment options to target their disease,” said Jill Feldman, co-founder of the EGFR Resisters, an advocacy organization patient group, and a lung cancer patient advocate. “We are excited by the promise this new treatment option brings to people with this particular type of lung cancer and their families.”

Lung cancer is the leading cause of cancer death among both men and women, accounting for almost 25 percent of all cancer deaths.[3] Currently available targeted treatments, like EGFR tyrosine kinase inhibitors (TKI) are generally insensitive in treating NSCLC driven by EGFR exon 20 insertion mutations and are not FDA-approved for these patients.[4],[5],[6] In addition, NSCLC driven by this mutation carries a worse prognosis and shorter survival rates compared with lung cancer driven by more common EGFR mutations, such as exon 19 deletions and L858R substitutions.[7],[8] Patients newly diagnosed with metastatic NSCLC with EGFR exon 20 insertion mutations have a real-world median overall survival (OS) of 16.2 months (95 percent confidence interval [CI], 11.0 – 19.4), which is lower than patients with EGFR exon 19 deletions/L858R mutations, who have a real-world median OS of 25.5 months (95 percent CI, 24.5 – 27.0).[9]

“Lung cancer is a complex disease, and through the study and deeper understanding of genetic alterations like EGFR exon 20 insertion mutations, we are able to target the disease in new ways and improve treatment outcomes for patients,” said Joshua K. Sabari, M.D., New York University Langone’s Perlmutter Cancer Center and study investigator, who presented the latest clinical trial results at the International Association for the Study of Lung Cancer’s (IASLC WCLC) 2020 World Conference on Lung Cancer Singapore. “Amivantamab-vmjw is an innovative bispecific antibody that brings an important new therapeutic approach to physicians caring for patients with this serious and rare type of lung cancer.”

Rybrevant is a fully-human bispecific antibody directed against EGFR and MET receptors.1 Rybrevant binds extracellularly (outside of the cell) inhibiting tumor growth and leading to tumor cell death.1 Today’s accelerated FDA approval is based on positive results from the Phase 1 CHRYSALIS study, a multicenter, open-label, clinical study evaluating Rybrevant as a monotherapy in patients enrolled in the prior platinum containing chemotherapy cohort.1,[10] Initial results from the CHRYSALIS EGFR exon 20 insertion mutation population, which supported the BTD, were presented at the American Society of Clinical Oncology 2020 Virtual Scientific Program, and updated results were presented at the IASLC WCLC 2020.

“The approval of RYBREVANT, along with the companion diagnostic test, addresses high unmet need in the treatment of people with genetically defined non-small cell lung cancer,” said Peter Lebowitz, M.D., Ph.D., Global Therapeutic Area Head, Oncology, Janssen Research & Development, LLC. “At Janssen, we are committed to the development of innovative therapies like RYBREVANT and believe that advancing medicines targeting specific pathways can bring the greatest benefits and improve outcomes for patients with tumor alterations such as EGFR and MET.”

The FDA simultaneously approved Guardant Health’s Guardant360® CDx liquid biopsy blood test as a companion diagnostic for use with Rybrevant.

Next-generation sequencing tests offer an alternative to polymerase chain reaction (PCR)-based tests which fail to identify 50 percent or more of exon 20 insertion mutations.[11] Information on FDA-approved tests for the detection of EGFR genetic alterations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

“Today’s milestone reflects progress and determination in our mission to develop and deliver transformational therapies to improve the lives of people diagnosed with some of the most devastating and complex diseases of our time,” said Mathai Mammen, M.D., Ph.D., Global Head, Janssen Research & Development, Johnson & Johnson. “The approval of Rybrevant, the first lung cancer treatment for Johnson & Johnson, strengthens our commitment to harness science, expertise and scale to dramatically alter the trajectory of lung cancer, and reduce the impact of the world’s leading cause of cancer mortality.”

About Rybrevant

Rybrevant is being studied in a comprehensive clinical development program for people with untreated advanced EGFR-mutated NSCLC, including the Phase 3 MARIPOSA (NCT04487080) trial studying Rybrevant in combination with lazertinib**.[12] Another Phase 3 trial, PAPILLON (NCT04538664), is studying Rybrevant in combination with carboplatin-pemetrexed for people with advanced or metastatic EGFR-mutated NSCLC with exon 20 insertion mutations.[13] Rybrevant received U.S. FDA BTD in March 2020 and Priority Review Designation following the BLA announcement in December 2020.[14],[15] Janssen has filed regulatory submissions for Rybrevant with health authorities in Europe and other markets.

**In 2018, Janssen Biotech, Inc. entered into a license and collaboration agreement with Yuhan Corporation for the development of lazertinib.

About the CHRYSALIS Study

CHRYSALIS (NCT02609776) is a Phase 1 open-label, multicenter, first-in-human study to evaluate the safety, pharmacokinetics and preliminary efficacy of Rybrevant as a monotherapy and in combinations including with lazertinib, a novel third-generation EGFR TKI[16], in adults with advanced NSCLC.10 The study consists of two parts: Rybrevant monotherapy and combination-dose escalations and Rybrevant monotherapy and combination-dose expansions.10

In the ongoing Phase 1 CHRYSALIS study, patients with locally advanced or metastatic NSCLC with EGFR Exon 20 insertion mutations weighing less than 80 kg received RYBREVANTTM 1050 mg and patients weighing at least 80 kg or more received Rybrevant 1400 mg weekly for four weeks, with the initial dose as a split infusion in week 1 on day 1 and day 2, then administered every two weeks thereafter until disease progression or unacceptable toxicity.1 Disease response using overall response rate (ORR), per Response Evaluation Criteria in Solid Tumors Version 1.1* (RECIST v1.1) as evaluated by Blinded Independent Central Review (BICR), was the primary endpoint.1 In the prior-platinum chemotherapy treated cohort (n=81), the confirmed ORR, as assessed by blinded independent central review, was 40 percent (95 percent CI, 29 – 51), with 3.7 percent having complete responses (CR) and 36 percent achieving partial responses (PR).[1]

Permanent discontinuation of Rybrevant due to an adverse reaction (AE) occurred in 11 percent of patients who received Rybrevant.1 AEs resulting in permanent discontinuation of Rybrevant in greater than or equal to one percent of patients were pneumonia, infusion-related reactions (IRR), pneumonitis/interstitial lung disease (ILD) dyspnea, pleural effusion and rash.1 Dose interruptions of Rybrevant due to AEs occurred in 78 percent of patients.[1] IRR requiring infusions interruptions occurred in 59 percent of patients.1 Adverse reactions requiring dose interruption in greater than or equal to five percent of patients included dyspnea, nausea, rash, vomiting, fatigue and diarrhea.1 The most common AEs (greater than or equal to 20 percent) in patients who received Rybrevant were rash (84 percent), IRR (64 percent), paronychia (50 percent), musculoskeletal pain (47 percent), dyspnea (37 percent), nausea (36 percent), fatigue (33 percent), edema (27 percent), stomatitis (26 percent), cough (25 percent), constipation (23 percent) and vomiting (22 percent).[1]

*RECIST (version 1.1) 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.[17]

Access to Rybrevant (amivantamab-vmjw)

Janssen offers comprehensive access and support information and resources to assist patients in gaining access to Rybrevant. Janssen will work closely with payers and providers to ensure Rybrevant is broadly accessible and affordable for people with NSCLC with EGFR exon 20 insertion mutations. Our comprehensive patient support program, Janssen CarePath, helps patients get started on Rybrevant and stay on track. Janssen CarePath helps verify insurance coverage for patients, provides reimbursement information, helps find financial assistance options for eligible patients and provides ongoing support to help patients start and stay on Rybrevant. If patients have commercial or private health insurance and need help paying for Rybrevant™, the Janssen CarePath Savings Program may be able to help. For more information, visit Rybrevant.JanssenCarePathSavings.com. If patients don’t have commercial or private health insurance, Janssen CarePath can provide information about other resources that may help with out-of-pocket medication costs. Learn more at JanssenCarePath.com/Rybrevant or call a Janssen CarePath Care Coordinator at 833-RYBREVANT (833-792-7382).

About Non-Small Cell Lung Cancer (NSCLC)

Worldwide, lung cancer is one of the most common cancers, and NSCLC makes up 80 to 85 percent of all lung cancers.[18],[19] 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 supporting cell growth and division.8 EGFR mutations are present in 10 to 15 percent8,11,[20],[21],[22] of people with NSCLC adenocarcinoma and occur in 40 to 50 percent of Asians.[23],[24] The five-year survival rate for all people with metastatic NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent.[25],[26] EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.2 Patients with EGFR exon 20 insertion mutations have a real-world five-year OS of 8 percent in the frontline setting, which is worse than patients with EGFR exon 19 deletions or L858R mutations, who have a real-world five-year OS of 19 percent.9

RYBREVANT™ IMPORTANT SAFETY INFORMATION1

WARNINGS AND PRECAUTIONS

Infusion Related Reactions1

Rybrevant can cause infusion related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.

Based on the safety population, IRR occurred in 66% of patients treated with Rybrevant. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued Rybrevant due to IRR.

Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse Rybrevant as recommended. Administer Rybrevant via a peripheral line on Week 1 and Week 2. Monitor patients for any signs and symptoms of infusion reactions during Rybrevant infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue Rybrevant based on severity.

Interstitial Lung Disease/Pneumonitis1

Rybrevant™ can cause interstitial lung disease (ILD)/pneumonitis. Based on the safety population, ILD/pneumonitis occurred in 3.3% of patients treated with Rybrevant™, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued Rybrevant™ due to ILD/pneumonitis.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold Rybrevant™ in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

Dermatologic Adverse Reactions1

Rybrevant™ can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population, rash occurred in 74% of patients treated with Rybrevant™, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and Rybrevant™ was permanently discontinued due to rash in 0.7% of patients.

Toxic epidermal necrolysis occurred in one patient (0.3%) treated with Rybrevant™.

Instruct patients to limit sun exposure during and for 2 months after treatment with Rybrevant™. Advise patients to wear protective clothing and use broad spectrum UVA/UVB sunscreen. Alcohol free emollient cream is recommended for dry skin.

If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce or permanently discontinue Rybrevant™ based on severity.

Ocular Toxicity1

RYBREVANT™ can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with Rybrevant™. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue Rybrevant™ based on severity.

Embryo Fetal Toxicity1

Based on its mechanism of action and findings from animal models, Rybrevant™ can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of Rybrevant™.

Adverse Reactions1

The most common adverse reactions (≥20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium.

Please read full Prescribing Information for Rybrevant™.

About the Janssen Pharmaceutical Companies of Johnson & Johnson

At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology and Pulmonary Hypertension.

Learn more at www.janssen.com. Follow us at www.twitter.com/JanssenGlobal and www.twitter.com/JanssenUS. Janssen Biotech, Inc. and Janssen Research & Development LLC are part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

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

Cautions Concerning Forward-Looking Statements
This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding Rybrevant (amivantamab-vmjw). 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 materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, Janssen Biotech, Inc., any of the other Janssen Pharmaceutical companies, and/or 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 behavior 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 January 3, 2021, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in the company’s most recently filed Quarterly Report on Form 10-Q, and the company’s subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

[1] RYBREVANTTM Prescribing Information. Horsham, PA: Janssen Biotech, Inc.
[2] Arcila, M. et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Molecular Cancer Therapeutics. 2013; Feb; 12(2):220-9.
[3] Key Statistics in Lung Cancer. American Cancer Society. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html. Accessed May 2021.
[4] Remon, J et al. EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins. Cancer Treatment Reviews. 90 (2020).
[5] Baraibar I et al. Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC. Critical Reviews in Oncology. 2020.
[6] O’Leary C, Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small-Cell Lung Cancer (NSCLC). Pharmaceuticals. 2020, 13, 273; doi:10.3390/ph13100273/.
[7] Vyse, S., Huang, P.H. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Sig Transduct Target Ther 4, 5 (2019).
[8] 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.
[9] Girard N, BazhenovaL, MinchomA, OuSI, GadgeelSM, Trigo J, 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.
[10] ClinicalTrials.gov. Study of JNJ-61186372, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer. Available at: https://clinicaltrials.gov/ct2/show/NCT02609776. Accessed May 2021.
[11] Bauml, JM, et al. Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real World Datasets. WCLC Poster #3399. January 2021.
[12] 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://clinicaltrials.gov/ct2/show/NCT04487080 . Accessed May 2021.
[13] 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?term=PAPILLON&cond=NSCLC&draw=2&rank=1. Accessed May 2021.
[14] Janssen Announces U.S. FDA Breakthrough Therapy Designation Granted for JNJ-6372 for the Treatment of Non-Small Cell Lung Cancer. https://www.jnj.com/janssen-announces-u-s-fda-breakthrough-therapy-designation-granted-for-jnj-6372-for-the-treatment-of-non-small-cell-lung-cancer. Accessed May 2021.
[15] Janssen Submits Application to U.S. FDA Seeking Approval of Amivantamab for the Treatment of Patients with Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations. https://www.jnj.com/janssen-submits-application-to-u-s-fda-seeking-approval-of-amivantamab-for-the-treatment-of-patients-with-metastatic-non-small-cell-lung-cancer-with-egfr-exon-20-insertion-mutations. Accessed May 2021.
[16] Ahn, J. et al. Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1–2 study. Lancet Oncology. 2019. 20 (12): 1681-1690.
[17] Eisenhauer E.A. et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer. 2009. 45: 228 – 247.
[18] The World Health Organization. Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed May 2021.
[19] American Cancer Society. What is Lung Cancer? https://www.cancer.org/content/cancer/en/cancer/lung-cancer/about/what-is.html. Accessed May 2021.
[20] Riess JW, Gandara DR, Frampton GM, et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J Thorac Oncol. 2018;13(10):1560-1568. doi:10.1016/j.jtho.2018.06.019
[21] 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. 37:97-104.
[22] Burnett H, Emich H, Carroll C, Stapleton N, Mahadevia P, Li T. 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 et al 2016 (Oncotarget, Vol. 7, No. 48) study which estimated prevalence of EGFR mutations across various patient subgroups, including Asians.
[24] Midha 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] Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). 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, Cardarella S, Lydon CA, Dahlberg SE, Jackman DM, Jänne PA, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol. 2016 Apr;11(4):556-65.

Source: Janssen Pharmaceutical Companies of Johnson & Johnson

Posted: May 2021