Adenocarcinoma of Lung

Featured data include new results from the Phase 3 MARIPOSA study, which has received U.S. FDA Priority Review, and the Phase 1b PALOMA study of subcutaneous amivantamab PRAGUE, March 18, 2024 /PRNewswire/ -- Johnson & Johnson announced today that new data will be featured at this year's European Lung Cancer Congress (ELCC) taking place from March 20 to 23 in Prague, Czech Republic, highlighting the Company's commitment to transform the treatment of lung cancer through the ongoing study of RYBREVANT® (amivantamab)-based regimens in the treatment of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Key data to be featured in four mini-oral presentations include results from an exploratory analysis from the Phase 3 MARIPOSA study evaluating the effect of RYBREVANT® dose interruptions on clinical outcomes, new results confirming the recommended dose for monthly subcutaneous administration of amivantamab from the Phase 1b PALOMA study, and post-progression analyses from the pivotal PAPILLON and MARIPOSA-2 studies, which aim to support the differentiated clinical profile of RYBREVANT® in the treatment of patients with EGFR-mutated NSCLC.1,2,3,4 "The breadth of data being presented at ELCC underscore our commitment to redefine treatment outcomes for patients living with EGFR-mutated NSCLC," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Johnson & Johnson Innovative Medicine. "Following recent regulatory submissions in the U.S. and Europe, we look forward to advancing our transformative portfolio and bringing novel targeted treatment regimens to patients around the world." "The results presented at ELCC reinforce the role RYBREVANT-based treatment regimens may play in improving the standard of care in EGFR-mutated NSCLC," said Henar Hevia, EMEA Therapeutic Area Lead, Oncology, Solid Tumors, Johnson & Johnson Innovative Medicine. "We have made remarkable progress in advancing the science of NSCLC and will continue to evaluate the full potential of RYBREVANT as a treatment for patients through our comprehensive clinical development program." Key presentations include: Insights on the effect of RYBREVANT® plus lazertinib dose interruptions on clinical outcomes from the Phase 3 MARIPOSA study in patients with previously untreated EGFR advanced NSCLC (Abstract #1001). Results from the Phase 1 PALOMA study examining the severity and incidence of infusion-related reactions with subcutaneous amivantamab administration in patients with advanced solid tumor malignancies (Abstract #839). Data from an exploratory analysis of the Phase 3 PAPILLON study evaluating the impact of treatment with RYBREVANT® plus chemotherapy on post-progression secondary endpoints including time-to-treatment discontinuation (TTD) and time to subsequent therapy (TTST) in patients with NSCLC with EGFR exon 20 insertion mutations (Abstract #844). Analysis of post-progression outcomes including TTD, TTST, and progression-free survival after first subsequent therapy (PFS2) from the Phase 3 MARIPOSA-2 study, which is investigating RYBREVANT® plus chemotherapy in patients with EGFR-mutant advanced NSCLC after progression with osimertinib treatment (Abstract #833). The complete list of Company-sponsored abstracts follows: About RYBREVANT® RYBREVANT® (amivantamab-vmjw), a fully-human bispecific antibody targeting EGFR and MET with immune cell-directing activity, is approved in the U.S., Europe, and in other markets around the world as monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.5 RYBREVANT® is also approved in the U.S. in combination with chemotherapy (carboplatin and pemetrexed) for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test. In October 2023, a type II extension of indication application was submitted to the European Medicines Agency (EMA) seeking approval of RYBREVANT® for this indication. In December 2023, Johnson & Johnson submitted an sBLA together with a New Drug Application (NDA) to the U.S. FDA for RYBREVANT® in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations, as detected by an FDA-approved test. This submission is based on the Phase 3 MARIPOSA study and was granted Priority Review in February 2024. A marketing authorization application (MAA) and type II extension of indication application were also submitted to the EMA seeking approval of lazertinib in combination with RYBREVANT® based on the MARIPOSA study. In November 2023, Johnson & Johnson submitted an sBLA to the U.S. FDA for RYBREVANT® in combination with chemotherapy for the treatment of patients with EGFR-mutated NSCLC who progressed on or after osimertinib based on the MARIPOSA-2 study. A type II extension of indication application was also submitted to the EMA seeking approval of RYBREVANT® for this indication. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC§ prefer next-generation sequencing–based strategies over polymerase chain reaction–based approaches for the detection of EGFR exon 20 insertion variants. The NCCN Guidelines include: Amivantamab-vmjw (RYBREVANT®) plus carboplatin and pemetrexed as a preferred (Category 1 recommendation) first-line therapy in treatment-naive patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion mutation-positive advanced NSCLC, or as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.6 †‡ Amivantamab-vmjw (RYBREVANT®) plus chemotherapy as a preferred (Category 1 recommendation) subsequent therapy for patients with locally advanced or metastatic NCSLC with EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression after treatment with osimertinib.6 †‡ Amivantamab-vmjw (RYBREVANT®) as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without an immunotherapy and have EGFR exon 20 insertion mutation-positive NSCLC.6 †‡ RYBREVANT® is being studied in multiple clinical trials in NSCLC, including: The Phase 3 PAPILLON (NCT04538664) study assessing 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. Topline data for this randomized Phase 3 study demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) in patients receiving RYBREVANT®.7 The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT® (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. Topline data for this randomized Phase 3 study demonstrated statistically significant and clinically meaningful improvement in PFS in these patients receiving RYBREVANT® plus chemotherapy with and without lazertinib versus chemotherapy.8 The Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT® 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. Topline data for this randomized Phase 3 study demonstrated statistically significant and clinically meaningful improvement in PFS in patients receiving RYBREVANT® plus lazertinib versus osimertinib.9 The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT® in patients with advanced NSCLC.10 The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT® in combination with lazertinib and lazertinib as a monotherapy in patients with advanced NSCLC with EGFR mutations.11 The 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.12 The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.13 The Phase 3 PALOMA-3 (NCT05388669) study assessing lazertinib with subcutaneous amivantamab compared to intravenous amivantamab in patients with EGFR-mutated advanced or metastatic NSCLC.14 The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT® and capmatinib combination therapy in locally advanced or metastatic NSCLC.15 The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT® and cetrelimab combination therapy in locally advanced or metastatic NSCLC.16 The Phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with RYBREVANT® in combination with lazertinib in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.17 For more information, visit: . 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.18,19 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.20 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.21 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.20,21,22,23,24,25 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.26 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.27,28 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.29 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.30 RYBREVANT® IMPORTANT SAFETY INFORMATION 5 WARNINGS AND PRECAUTIONS The safety population of RYBREVANT® with carboplatin and pemetrexed described in Warnings and Precautions was based on 151 patients in the PAPILLON study. The safety population of RYBREVANT® as a single agent described in Warnings and Precautions was based on 129 patients in the CHRYSALIS study. Infusion-Related Reactions RYBREVANT ® can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. RYBREVANT® with Carboplatin and Pemetrexed RYBREVANT® in combination with carboplatin and pemetrexed can cause infusion-related reactions. Based on the safety population, infusion-related reactions occurred in 42% of patients treated with RYBREVANT® in combination with carboplatin and pemetrexed, including Grade 3 (1.3%) adverse reactions. The incidence of infusion modifications due to IRR was 40%, and 0.7% of patients permanently discontinued RYBREVANT®. RYBREVANT® as a Single Agent 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/Pneumonitis RYBREVANT ® can cause interstitial lung disease (ILD)/pneumonitis. RYBREVANT® with Carboplatin and Pemetrexed Based on the safety population, Grade 3 ILD/pneumonitis occurred in 2.6% of patients treated with RYBREVANT® in combination with carboplatin and pemetrexed. All patients required permanent discontinuation. RYBREVANT® as a Single Agent 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 Reactions RYBREVANT ® can cause rash (including dermatitis acneiform), pruritus and dry skin. RYBREVANT® with Carboplatin and Pemetrexed RYBREVANT® in combination with carboplatin and pemetrexed can cause dermatologic adverse reactions. Based on the safety population, rash occurred in 89% of patients treated with RYBREVANT® in combination with carboplatin and pemetrexed, including Grade 3 (19%) adverse reactions. Rash leading to dose reductions occurred in 19% of patients; 2% permanently discontinued RYBREVANT®, and 1.3% discontinued pemetrexed. RYBREVANT® as a Single Agent 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 ® as a single agent. 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 Toxicity RYBREVANT ® can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. RYBREVANT® with Carboplatin and Pemetrexed Based on the safety population, RYBREVANT® in combination with carboplatin and pemetrexed can cause ocular toxicity including blepharitis, dry eye, conjunctival redness, blurred vision, and eye pruritus. All events were Grade 1-2. RYBREVANT® as a Single Agent 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 Toxicity 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 last dose of RYBREVANT®. Adverse Reactions RYBREVANT® with Carboplatin and Pemetrexed For the 151 patients in the PAPILLON clinical trial who received RYBREVANT® in combination with carboplatin and pemetrexed, the most common adverse reactions (≥20%) were rash (90%), nail toxicity (62%), stomatitis (43%), infusion-related reaction (42%), fatigue (42%), edema (40%), constipation (40%), decreased appetite (36%), nausea (36%), COVID-19 (24%), diarrhea (21%), and vomiting (21%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased albumin (7%), increased alanine aminotransferase (4%), increased gamma-glutamyl transferase (4%), decreased sodium (7%), decreased potassium (11%), decreased magnesium (2%), and decreases in white blood cells (17%), hemoglobin (11%), neutrophils (36%), platelets (10%), and lymphocytes (11%). Serious adverse reactions occurred in 37% of patients who received RYBREVANT® in combination with carboplatin and pemetrexed. Serious adverse reactions in ≥2% of patients included rash, pneumonia, ILD, pulmonary embolism, vomiting, and COVID-19. Fatal adverse reactions occurred in 7 patients (4.6%) due to pneumonia, cerebrovascular accident, cardio-respiratory arrest, COVID-19, sepsis, and death not otherwise specified. RYBREVANT® as a Single Agent For the 129 patients in the CHRYSALIS clinical trial who received RYBREVANT® as a single agent, the most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma-glutamyl transferase (4%), and decreased sodium (4%). Serious adverse reactions occurred in 30% of patients who received RYBREVANT®. Serious adverse reactions in ≥2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in 2 patients (1.5%) due to pneumonia and 1 patient (0.8%) due to sudden death. Please read the full Prescribing Information for RYBREVANT®. About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at or at . Follow us at @JanssenUS and @JNJInnovMed. Janssen Research & Development, LLC, and Janssen Biotech, Inc. are Johnson & Johnson companies. Cautions Concerning Forward-Looking Statements This 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 RYBREVANT® (amivantamab-vmjw) and lazertinib. 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. 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; competition, including technological advances, new products and patents attained by competitors; challenges to patents; 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 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 , or on request from Johnson & Johnson. None of Janssen Research & Development, LLC, Janssen Biotech, Inc. nor Johnson & Johnson undertake to update any forward-looking statement as a result of new information or future events or developments. †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 Campelo et al. Effect of Amivantamab Dose Interruptions on Efficacy and Safety of First-line Amivantamab Plus Lazertinib in EGFR-mutant Advanced NSCLC: Exploratory Analyses from the MARIPOSA study, a Randomized Phase 3 Global Study. European Lung Cancer Congress 2024. March 2024. 2 Leighl et al. Subcutaneous amivantamab administered every 4 weeks (Q4W) in patients with advanced solid malignancies: The phase 1b PALOMA study, a Randomized Phase 1 Global Study. European Lung Cancer Congress 2024. March 2024. 3 Felip et al. Amivantamab Plus Chemotherapy vs Chemotherapy as First-Line Treatment in EGFR Exon 20 Insertion-mutated Advanced NSCLC: Analysis of Post-Progression Endpoints From PAPILLON, a Randomized Phase 3 Global Study. European Lung Cancer Congress 2024. March 2024. 4 Gentzler et al. Amivantamab Plus Chemotherapy vs Chemotherapy in EGFR-mutant Advanced NSCLC After Progression on Osimertinib: A Post-progression Analysis of MARIPOSA-2, a Randomized Phase 3 Global Study. European Lung Cancer Congress 2024. March 21, 2024. 5 RYBREVANT® Prescribing Information. Horsham, PA: Janssen Biotech, Inc. 6 Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.1.2024© 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 March 2024. 7 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: . Accessed March 2024. 8 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: . Accessed March 2024. 9 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: . Accessed March 2024. 10 ClinicalTrials.gov. A Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS). . Accessed March 2024. 11 ClinicalTrials.gov. A Study of Lazertinib as Monotherapy or in Combination With Amivantamab in Participants With Advanced Non-small Cell Lung Cancer (CHRYSALIS-2). . Accessed March 2024. 12 ClinicalTrials.gov. A Study of Amivantamab Subcutaneous (SC) Administration for the Treatment of Advanced Solid Malignancies (PALOMA). Available at: . Accessed March 2024. 13 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). . Accessed March 2024. 14 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). . Accessed March 2024. 15 ClinicalTrials.gov. A Study of Amivantamab and Capmatinib Combination Therapy in Unresectable Metastatic Non-small Cell Lung Cancer (METalmark). . Accessed March 2024. 16 ClinicalTrials.gov. A Study of Combination Therapy With Amivantamab and Cetrelimab in Participants With Metastatic Non-small Cell Lung Cancer (PolyDamas). . Accessed March 2024. 17 ClinicalTrials.gov. Premedication to Reduce Amivantamab Associated Infusion Related Reactions (SKIPPirr). . Accessed March 2024. 18 The World Health Organization. Cancer. . Accessed March 2024. 19 American Cancer Society. What is Lung Cancer? . Accessed March 2024. 20 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. 21 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. 22 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. 23 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. 24 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. 25 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. 26 American Lung Association. EGFR and Lung Cancer. . Accessed March 2024. 27 Howlader N, et al. SEER Cancer Statistics Review, 1975-2016, National Cancer Institute. Bethesda, MD, , based on November 2018 SEER data submission, posted to the SEER web site. 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 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. 30 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. SOURCE Johnson & Johnson

Researchers found a way to screen cancer-linked gene mutations much more easily and quickly than existing approaches, using a variant of CRISPR genome-editing known as prime editing. Tumors can carry mutations in hundreds of different genes, and each of those genes may be mutated in different ways -- some mutations simply replace one DNA nucleotide with another, while others insert or delete larger sections of DNA. Until now, there has been no way to quickly and easily screen each of those mutations in their natural setting to see what role they may play in the development, progression, and treatment response of a tumor. Using a variant of CRISPR genome-editing known as prime editing, MIT researchers have now come up with a way to screen those mutations much more easily. The researchers demonstrated their technique by screening cells with more than 1,000 different mutations of the tumor suppressor gene p53, all of which have been seen in cancer patients. This method, which is easier and faster than any existing approach, and edits the genome rather than introducing an artificial version of the mutant gene, revealed that some p53 mutations are more harmful than previously thought. This technique could also be applied to many other cancer genes, the researchers say, and could eventually be used for precision medicine, to determine how an individual patient's tumor will respond to a particular treatment. "In one experiment, you can generate thousands of genotypes that are seen in cancer patients, and immediately test whether one or more of those genotypes are sensitive or resistant to any type of therapy that you're interested in using," says Francisco Sanchez-Rivera, an MIT assistant professor of biology, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the study. MIT graduate student Samuel Gould is the lead author of the paper, which appears today in Nature Biotechnology. Editing cells The new technique builds on research that Sanchez-Rivera began 10 years ago as an MIT graduate student. At that time, working with Tyler Jacks, the David H. Koch Professor of Biology, and then-postdoc Thales Papagiannakopoulos, Sanchez-Rivera developed a way to use CRISPR genome-editing to introduce into mice genetic mutations linked to lung cancer. In that study, the researchers showed that they could delete genes that are often lost in lung tumor cells, and the resulting tumors were similar to naturally arising tumors with those mutations. However, this technique did not allow for the creation of point mutations (substitutions of one nucleotide for another) or insertions. "While some cancer patients have deletions in certain genes, the vast majority of mutations that cancer patients have in their tumors also include point mutations or small insertions," Sanchez-Rivera says. Since then, David Liu, a professor in the Harvard University Department of Chemistry and Chemical Biology and a core institute member of the Broad Institute, has developed new CRISPR-based genome editing technologies that can generate additional types of mutations more easily. With base editing, developed in 2016, researchers can engineer point mutations, but not all possible point mutations. In 2019, Liu, who is also an author of the Nature Biotechnology study, developed a technique called prime editing, which enables any kind of point mutation to be introduced, as well as insertions and deletions. "Prime editing in theory solves one of the major challenges with earlier forms of CRISPR-based editing, which is that it allows you to engineer virtually any type of mutation," Sanchez-Rivera says. When they began working on this project, Sanchez-Rivera and Gould calculated that if performed successfully, prime editing could be used to generate more than 99 percent of all small mutations seen in cancer patients. However, to achieve that, they needed to find a way to optimize the editing efficiency of the CRISPR-based system. The prime editing guide RNAs (pegRNAs) used to direct CRISPR enzymes to cut the genome in certain spots have varying levels of efficiency, which leads to "noise" in the data from pegRNAs that simply aren't generating the correct target mutation. The MIT team devised a way to reduce that noise by using synthetic target sites to help them calculate how efficiently each guide RNA that they tested was working. "We can design multiple prime-editing guide RNAs with different design properties, and then we get an empirical measurement of how efficient each of those pegRNAs is. It tells us what percentage of the time each pegRNA is actually introducing the correct edit," Gould says. Analyzing mutations The researchers demonstrated their technique using p53, a gene that is mutated in more than half of all cancer patients. From a dataset that includes sequencing information from more than 40,000 patients, the researchers identified more than 1,000 different mutations that can occur in p53. "We wanted to focus on p53 because it's the most commonly mutated gene in human cancers, but only the most frequent variants in p53 have really been deeply studied. There are many variants in p53 that remain understudied," Gould says. Using their new method, the researchers introduced p53 mutations in human lung adenocarcinoma cells, then measured the survival rates of these cells, allowing them to determine each mutation's effect on cell fitness. Among their findings, they showed that some p53 mutations promoted cell growth more than had been previously thought. These mutations, which prevent the p53 protein from forming a tetramer -- an assembly of four p53 proteins -- had been studied before, using a technique that involves inserting artificial copies of a mutated p53 gene into a cell. Those studies found that these mutations did not confer any survival advantage to cancer cells. However, when the MIT team introduced those same mutations using the new prime editing technique, they found that the mutation prevented the tetramer from forming, allowing the cells to survive. Based on the studies done using overexpression of artificial p53 DNA, those mutations would have been classified as benign, while the new work shows that under more natural circumstances, they are not. "This is a case where you could only observe these variant-induced phenotypes if you're engineering the variants in their natural context and not with these more artificial systems," Gould says. "This is just one example, but it speaks to a broader principle that we're going to be able to access novel biology using these new genome-editing technologies." Because it is difficult to reactivate tumor suppressor genes, there are few drugs that target p53, but the researchers now plan to investigate mutations found in other cancer-linked genes, in hopes of discovering potential cancer therapies that could target those mutations. They also hope that the technique could one day enable personalized approaches to treating tumors. "With the advent of sequencing technologies in the clinic, we'll be able to use this genetic information to tailor therapies for patients suffering from tumors that have a defined genetic makeup," Sanchez-Rivera says. "This approach based on prime editing has the potential to change everything."

MUNICH--(BUSINESS WIRE)-- Tubulis today announced that two abstracts with comprehensive preclinical data on their next-generation antibody-drug conjugate (ADC) candidates TUB-030 and TUB-040, have been accepted for poster presentations at the Annual Meeting of the American Association for Cancer Research (AACR), taking place April 5-10, 2024 in San Diego. Tubulis is building a pipeline of uniquely matched ADCs, tailored to respective disease biology by leveraging the company’s proprietary suite of platform technologies to combine the right targeting molecule, conjugation chemistry and payload. TUB-030 is directed against the tumor-associated antigen 5T4 which addresses a wide range of solid tumor indications. TUB-040 targets Napi2b, a well-characterized target in ovarian and lung cancer. Both ADC candidates are optimized for long-lasting, durable tumor engagement and minimal off-target toxicity. “Our novel technologies allow us to push the boundaries of ADC design to fully leverage the biology of well-understood therapeutic targets as well as unlock less-validated ones to create treatments that deliver meaningful patient benefit. The results we will present at the AACR Annual Meeting will highlight the preclinical differentiation of our two lead candidates, TUB-030 and TUB-040. We believe that these two ADC candidates hold great potential to effectively enable durable responses and prolong overall survival in patients with a broad range of solid tumors while maintaining a significant safety and tolerability profile,” said Jonas Helma-Smets, Chief Scientific Officer of Tubulis. “We look forward to further investigating the impact these two candidates can make in the clinic.” Details of the poster presentations: TUB-030 Poster Information Title: Enabling 5T4 for targeted cancer therapy: TUB-030, a novel ADC built with ethynylphosphonamidate conjugation chemistry, shows long-lasting anti-tumor activity via Topoisomerase-I inhibition with an optimized therapeutic index Presenter: Jonas Helma-Smets, CSO of Tubulis Session Category and Title: Immunology - Antibody-Drug Conjugates Session Date and Time: Monday, Apr 8, 2024, 1:30 PM - 5:00 PM PT Location: Poster Section 2 Abstract Number: 2623 The poster will highlight the pre-clinical proof-of-concept data for TUB-030, an ADC that targets the oncofetal 5T4 antigen. 5T4 is a tumor-associated protein that is overexpressed in various types of cancers, including bladder, lung, breast, stomach, esophagus, head and neck, colon, and ovarian cancer. Tubulis’ ADC candidate differs from previous ADCs targeting 5T4 by implementing several layers of differentiation in terms of antibody, payload and conjugation technology. It combines the company’s proprietary P5 conjugation technology with its Tubutecan topoisomerase-I payload platform, resulting in a homogenous DAR (drug-antibody-ratio) of 8. TUB-030 has shown strong cytotoxicity towards cancer cells from different tumor indications with a broad range of 5T4 expression levels. Pharmacokinetic analysis further demonstrated the highly stable pro TUB-030, enabling the efficient delivery of the payload to the tumor. TUB-040 Poster Information Title: TUB-040, a novel Napi2b-targeting ADC built with ethynylphosphonamidate conjugation chemistry, demonstrates high and long-lasting anti-tumor efficacy via Topoisomerase-I inhibition and excellent tolerability predictive of a wide therapeutic window in humans Presenter: Jonas Helma-Smets, CSO of Tubulis Session Category and Title: Immunology - Antibody-Drug Conjugates Session Date and Time: Monday, Apr 8, 2024, 1:30 PM - 5:00 PM PT Location: Poster Section 2 Published Abstract Number: 2622 The poster will provide a detailed overview of the preclinical proof-of-concept for TUB-040. The ADC candidate is directed against Napi2b, an antigen highly overexpressed in ovarian cancer and lung adenocarcinoma. Its IgG1 antibody targeting Napi2b is connected to its payload, the Topoisomerase I inhibitor Exatecan through a cleavable linker system. The company’s P5 conjugation technology was used to build TUB-040 with a homogenous DAR of 8. TUB-040 induces DNA damage and cell death, without causing unspecific uptake and cytotoxicity in healthy, target-negative cells. Moreover, Pharmacokinetic analysis showed that TUB-040 is highly stable, thus efficiently delivering its payload to the tumor while reducing offsite toxicities. The full abstracts will be published on March 22, 2024, in an online-only proceedings supplement to the AACR journal, Cancer Research. The company will issue a press release detailing the full preclinical data following the presentation at AACR. About Tubulis Tubulis generates uniquely matched protein-drug conjugates through the combination of novel proprietary technologies and disease-specific biologic insight. Our goal is to expand the therapeutic potential of antibody-drug conjugates (ADCs) by increasing design flexibility while overcoming constraints of toxicity, efficacy and indication. Tubulis will build new conjugates to fill its growing pipeline and will continue to collaborate with industry partners to usher in a new ADC era and deliver better outcomes for patients. Visit or follow us on LinkedIn and X. View source version on businesswire.com: Contacts For Tubulis Dominik Schumacher, CEO & Co-Founder Phone: + 49 (0) 89 2180 74233 Email: info@tubulis.com Media Requests for Tubulis Trophic Communications Stephanie May, PhD Phone: +49 (0) 171 185 56 82 Email: tubulis@trophic.eu Source: Tubulis View this news release online at: