Istituto Europeo di Oncologia SRL

PARIS--( BUSINESS WIRE )-- Cure51 , a techbio company seeking to unlock the biological mechanisms responsible for exceptional cancer survivors patients, today announces the UK launch of the Rosalind study, a groundbreaking initiative already underway in other parts of Europe. The UK phase, in collaboration with Cambridge University Hospitals and seven other top UK-based institutions was recently approved by the NHS Health Research Authority (HRA) and aims to decode the biological factors behind long-term cancer survival and unlock insights that could pave the way for more effective cancer treatments. The Rosalind study will focus on three of the most aggressive cancer types: extensive stage small cell lung cancer, brain cancer glioblastoma, and metastatic pancreatic ductal adenocarcinoma. Researchers intend to gather tumor samples from over 1,000 exceptional responder patients, who are among the top 3% of patients in these indications in terms of cancer survival. The aim is to identify the biological factors that underpin exceptional survival. Cure51 has developed a multi-layered data hub to analyze the biological features of these cancer super-survivors, to discover novel therapeutic targets on which to base potentially transformative new treatments. Nicolas Wolikow, CEO and Co-Founder of Cure51 , said “ This is a pivotal step in the Rosalind study , as our first and largest partnership in the UK, advancing our mission to identify what sets cancer survivors apart. This work is made possible due to the support of the eight leading UK hospitals and institutions, all united in the goal of defeating cancer.” Dr. Thankammah Ajithkummar , Consultant Clinical Oncologist at Cambridge University Hospitals , added: “ With nearly 400,000 new cancer diagnoses annually in the UK, understanding why some patients achieve remarkable survival is critical. Patients who appear superficially similar in terms of their age and health, and the type and stage of their cancer, can have remarkably different responses to the same treatment. The Rosalind study represents a promising new approach to investigat ing the biology of cancer survivors, aiming to uncover insights that could improve outcomes for all patients. ” “ At Cure51, we are reverse engineering the cure for cancer. By leveraging technology, data and our dedicated team of computational biologists, we aim to uncover the hidden biology of miraculous survivors, to develop therapies that could one day make cancer a manageable disease for all. We are honored to have the support of eight of the world’s most influential hospitals in cancer research,” noted Simon Istolainen, Chief Strategy & Scientific Network Officer, Co-Founder of Cure51 . Cure51 raised €15 million Seed funding in March 2024 led by Sofinnova Partners. The Company partnered with 10xGenomics to deploy its Visium HD precision technology in October 2024, transforming how cancer is diagnosed, treated and ultimately cured. *** About Cure 51 Cure51 is a French 'TechBio' company founded by Nicolas Wolikow and Simon Istolainen, alongside seasoned entrepreneurs and four world-renowned oncology centres: Gustave Roussy Cancer Campus (IGR, Paris - France), Leon Bérard Center (CLB, Lyon - France), Charité Universitätsmedizin (Berlin - Germany), and Istituto Europeo di Oncologia (Milan - Italy). The collaboration between the private and public sectors is at the core of the Cure51 project, led by a passionate team with expertise in computing, medicine, and biology, and partnered with principal investigators across its network of over 50 leading oncology centres worldwide. Cure51's exclusive data collection system, based on partnerships, enables the creation of a unique multimodal and multiomics database of Outliers. Using its discovery platform powered by computational modeling, Cure51 aims to understand the biological mechanisms responsible for this exceptional survival by identifying and validating targets that can act on these interactions, leading to first in class treatments. This research involves the use of all relevant models (in silico, in vitro, in vivo, ex vivo) and the integration of existing literature and available databases, along with the engagement of Cure51's KOL community. Ultimately, drug design will be subject to collaboration contracts with the industry. Further information can be found at www.cure51.com

A hallmark of cancer cells is aneuploidy, when a cell has too few or too many chromosomes. This happens during cell division, when chromosomes can get left behind and not incorporated into the nucleus of a new daughter cell. In 2022, on the alpine shores of Lake Maggiore in northern Italy, longtime friends Samuel Bakhoum, M.D., Ph.D., and Stefano Santaguida, Ph.D., were catching up. Pandemic restrictions had prevented the two from seeing each other for years, but, at a small conference in the lakeside town of Stresa, they seized the opportunity to share what they’d been working on recently—the collapse of micronuclei in cancer cells.“We were so happy and excited to be together in real life,” Santaguida, a molecular biologist at the European Institute of Oncology and the University of Milan, told Fierce Biotech in an interview. “We were working on two separate aspects at the very beginning, without knowing of each other’s work.”Teaming up to tackle the problem has now resulted in two papers published Aug. 29 in the journal Science. The studies explain in mechanistic detail how micronuclei rupture and collapse in cancer cells, an important process that drives cancer progression. By getting tangled with mitochondria, micronuclei are exposed to reactive oxygen species that alter the behavior of a key repair protein and over-activate a protein-destroying pathway. A hallmark of cancer cells is aneuploidy, when a cell has too few or too many chromosomes. This happens during cell division, when chromosomes can get left behind and not incorporated into the nucleus of a new daughter cell. A stranded chromosome forms a shoddy nuclear membrane around itself, which is much smaller and less functional than the main nuclear envelope that surrounds the nucleus. These micronuclei can then break apart, leaving the chromosome exposed to the cellular elements.“That rupture process underlies a lot of the means by which micronuclei seem to drive cancer progression,” Bakhoum, a cell biologist at Memorial Sloan Kettering Cancer Center in New York City, told Fierce in an interview.Enzymes in the cytoplasm break chunks off the free-floating DNA, leading to mutations that can spur new cancer traits or alter how genes are expressed. And the cell can also confuse the loose chromosome for a virus, sparking inflammation that can lead the tumor to evolve immune resistance.Melody Di Bona, Ph.D., a cancer biologist working in Bakhoum’s group, was observing cervical cancer cells under the microscope when she noticed that micronuclei tended to get tangled up with mitochondria. “My hypothesis when I started to look at cells was that mitochondria were actually entering the micronucleus,” Di Bona told Fierce in a joint interview with Santaguida.Investigating further, she instead found that the chance of rupture greatly increased as the micronucleus was exposed to more and more toxic forms of oxygen-containing molecules leaking from the mitochondria, called reactive oxygen species (ROS). Through a series of experiments, she pieced together how the membrane unraveling unfolds.Tumors tend to be low on oxygen, which the mitochondria normally need to function; when oxygen is low, nitric oxide binds in its place instead, which produces ROS as a byproduct. ROS are unstable and can steal electrons from other molecules, messing with their forms and functions. Di Bona found that ROS take electrons away from amino acids called cysteines in the protein CHMP7, changing its form so that it abnormally binds to another protein called LEMD2 that sits inside the micronuclear membrane. What’s more, ROS damage also prevents CHMP7 from being kicked out of the cell.“LEMD2 is already in the membrane,” Bakhoum said. “And now imagine a protein that's aggregating inside, right underneath, and pulling it away.” The force of CHMP7 tugging at LEMD2 causes the micronucleus’s membrane to collapse and rupture.Di Bona first looked at CHMP7 because it’s normally a key part of a nuclear membrane repair enzyme called ESCRT-III. But this enzyme is prevented from patching up the rupturing micronucleus due to the actions of another protein called p62.“p62 is a protein that has its own life,” Santaguida said. “It works in the cells by recognizing proteins or organelles that have to be degraded,” targeting them for a process called autophagy.Santaguida’s team found that ROS from mitochondria also alter p62, ramping up its activity to send proteins down the autophagy pathway. This overreactive p62 degrades the repair enzyme ESCRT-III, further dooming the micronuclear membrane to collapse. To connect p62 with cancer prognosis, the team analyzed data from the tumors of 875 gastric cancer patients and found that higher levels of p62 were correlated with shortened survival.“The higher the levels of p62, the higher the likelihood to get a worse prognosis,” Santaguida said. “It's a prognostic marker that can be employed in the clinic tomorrow.” In addition to the prognostic power of p62, the collapse mechanism presents several other potential targets for new drugs. Therapies could target cysteines in CHMP7 and push them away from a pathological path, Bakhoum said. And numerous other molecules play bit parts in the process too, like kinases in the nuclear factor κB pathway—targeting them could reduce the odds of micronuclei rupturing and causing cancer progression.Chromosomes in cancer cells are starting to attract more attention from biotechs. Bakhoum is a co-founder and scientific adviser of Volastra Therapeutics—a biotech focused on chromosomal instability—and also serves on the scientific advisory board of precision oncology company Meliora Therapeutics.“We can't suppress chromosome instability [in cancer] because the cat's out of the bag, but can we at least kneecap it?” Bakhoum said. “Can we intervene in a way that prevents all the bad consequences and sequela of micronuclear rupture?”

Patients with EGFR ex19del or EGFR L858R mutations, the most common EGFR mutations in NSCLC, have until now faced a poor prognosis and limited treatment options after disease progression on an EGFR TKI 1,2,3,4 ​ Amivantamab in combination with chemotherapy is the first treatment regimen to show significant improvement in progression-free survival compared to chemotherapy alone in this patient population 5 BEERSE, Belgium I August 27, 2024 I Janssen-Cilag International NV, a Johnson & Johnson company, today announced that the European Commission (EC) has approved a Type II extension of indication for RYBREVANT ® ▼ (amivantamab) in combination with chemotherapy (carboplatin and pemetrexed), for the treatment of adults with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) Exon 19 deletions (ex19del) or Exon 21 L858R substitution (L858R) mutations, after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI). “While much progress has been made in the lung cancer treatment landscape over the past decade, resistance to existing therapies continues to pose a major challenge for patients with advanced or metastatic non-small cell lung cancer harbouring EGFR mutations, underscoring the critical need for ongoing innovation,” said Antonio Passaro, M.D., Ph.D., Medical Oncologist, Division of Thoracic Oncology at the European Institute of Oncology in Milan, Italy. “The addition of the bispecific antibody amivantamab to chemotherapy offers an important new treatment option for patients with EGFR ex19del or L858R mutations, progressing on or after osimertinib. In this setting, this combination set the new landmark for overall response rate and reduced the risk of disease progression or death by more than half compared to standard chemotherapy alone. It also demonstrated significant improvements in intracranial progression-free survival.” “The approval of amivantamab in combination with chemotherapy addresses a major unmet need for those whose disease has progressed following treatment with an EGFR TKI and who, until now, have faced limited treatment options,” said Henar Hevia, Ph.D., Senior Director, EMEA Therapeutic Area Lead, Oncology, Johnson & Johnson Innovative Medicine. “This milestone further reinforces the critical role of precision medicine in driving enhanced outcomes for patients living with lung cancer.” The expanded indication for amivantamab is based on results from the Phase 3 MARIPOSA-2 study ( NCT04988295 ), evaluating the efficacy and safety profile of amivantamab and chemotherapy in patients with locally-advanced or metastatic EGFR ex19del or L858R substitution NSCLC who had disease progression on or after treatment with osimertinib. 5 The amivantamab plus chemotherapy arm met its primary endpoint, significantly reducing the risk of disease progression or death by 52 percent, compared to chemotherapy alone, with a median progression-free survival (PFS) of 6.3 months, versus 4.2 months (hazard ratio [HR]=0.48; 95 percent confidence interval [CI], 0.36–0.64; P <0.001). 5 Additionally, amivantamab plus chemotherapy showed an objective response rate (ORR) of 64 percent, compared to 36 percent with chemotherapy alone. 5 Data from MARIPOSA-2 study also showed that amivantamab in combination with chemotherapy demonstrates intracranial activity, critical for a disease where nearly 30 percent of patients develop brain metastases. 6,7 Amivantamab plus chemotherapy reduced the risk of intracranial progression or death by 45 percent compared to chemotherapy alone, with a median intracranial progression-free survival of 12.5 versus 8.3 months (HR=0.55; 95 percent CI, 0.38–0.79). 5 The safety profile of amivantamab plus chemotherapy was demonstrated to be consistent with that of its individual components​. 5 Adverse events (AEs) of Grade 3 or higher, mainly due to haematologic toxicities, were reported by 72 percent of patients treated with amivantamab plus chemotherapy, and 48 percent with chemotherapy alone. 5 The most common Grade 3 or higher AEs included neutropenia, thrombocytopenia, anaemia, and leukopenia. 5 Grade 3 or 4 bleeding events were seen in one percent of patients treated with amivantamab plus chemotherapy, and in no patients with chemotherapy. 5 Serious treatment-emergent AEs (TEAEs) were observed in 32 percent of patients treated with amivantamab plus chemotherapy and 20 percent with chemotherapy. 5 Infusion-related reactions in the amivantamab plus chemotherapy arm were 58 percent (all grades). 5 Treatment-related AEs leading to death were infrequent in all arms (2 percent vs. 1 percent) in the amivantamab plus chemotherapy and chemotherapy alone arms respectively. 5 “Today’s approval marks further positive progress in our mission to transform the treatment landscape for people living with lung cancer,” said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumours, Johnson & Johnson Innovative Medicine. “This latest marketing authorisation for amivantamab underscores our commitment to advancing a robust lung cancer portfolio and redefining standards of care through precision medicine approaches.” Results from MARIPOSA-2 were presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) 2023 Congress and simultaneously published in the Annals of Oncology. 5,8 About MARIPOSA-2 MARIPOSA-2 ( NCT04988295 ), which enrolled 657 patients, is a randomised, open-label Phase 3 study evaluating the efficacy and safety of two combination regimens of amivantamab (with and without lazertinib) and chemotherapy. 5 Patients with locally-advanced or metastatic EGFR ex19del or L858R substitution NSCLC who had disease progression on or after treatment with osimertinib were randomised to treatment with amivantamab plus chemotherapy, amivantamab plus chemotherapy with lazertinib, or chemotherapy alone. 5 The dual primary endpoint was used to compare the PFS (using RECIST v1.1 guidelines † ) as assessed by blinded independent central review (BICR) for each experimental arm to chemotherapy alone. 5 Secondary endpoints included objective response as assessed by BICR, overall survival (OS), duration of response (DOR), time to subsequent therapy, PFS2 and intracranial PFS. 5 All study participants underwent serial brain imaging to allow for the robust assessment of intracranial endpoints and to assess the CNS activity of amivantamab and platinum doublet chemotherapy with and without lazertinib. 5 Because brain metastases can lead to significant burden and poor outcomes for patients, this aspect of the study design provides critical information in an area of high unmet need. 7 About 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. 9,10,11,12 The European Commission (EC) has granted marketing authorisation of amivantamab in the following indications: 13 In February 2024, a Type II extension of indication application was submitted 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 ex19del or L858R substitution mutations. 14 In May 2024, an application for the extension of the amivantamab marketing authorisation was submitted seeking 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 NSCLC with EGFR ex19del or L858R mutations, and for the use of SC amivantamab monotherapy in adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations after failure of platinum-based therapy. 15 For 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 . 13 ▼ In line with EMA regulations for new medicines, amivantamab is subject to additional monitoring. About Lazertinib Lazertinib is an oral, third-generation, brain-penetrant EGFR TKI that targets both the T790M mutation and activating EGFR mutations while sparing wild-type EGFR. 16 An analysis of the efficacy and safety of lazertinib from the Phase 3 LASER301 study was published in The Journal of Clinical Oncology in 2023. 16 In 2018, Janssen Biotech, Inc., entered into a license and collaboration agreement with Yuhan Corporation for the development of lazertinib. About Non-Small Cell Lung Cancer In Europe, it is estimated that 484,306 people were diagnosed with lung cancer in 2022. 17 NSCLC accounts for 85 percent of all lung cancer cases. 18 Lung cancer is Europe’s biggest cancer killer, with more deaths than breast cancer and prostate cancer combined. 17 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma. 18 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division. 18,19 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 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations. 24 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. 25 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 Research & Development, LLC, Janssen Pharmaceutica NV, Janssen-Cilag, S.A. and Janssen-Cilag International NV are Johnson & Johnson companies. ‡ RECIST (version 1.1) refers to Response Evaluation Criteria in Solid Tumours, which is a standard way to measure how well solid tumours respond to treatment and is based on whether tumours shrink, stay the same or get bigger. *Dr Passaro has served as a consultant to Janssen-Cilag International NV; they have not been paid for any media work. References 1 Rotow JK, et al. Real-World Genomic Profile of EGFR Second-Site Mutations and Other Osimertinib Resistance Mechanisms and Clinical Landscape of NSCLC Post-Osimertinib. J Thorac Oncol. 2024 Feb;19(2):227-239. 2 Batra U, et al. Differential clinicopathological features, treatments and outcomes in patients with Exon 19 deletion and Exon 21 L858R EGFR mutation-positive adenocarcinoma non-small-cell lung cancer. BMJ Open Respir Res. 2023 Jun;10(1):e001492. 3 Soria JC, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol 2015;16(8):990-998. 4 Araki T, et al. Current treatment strategies for EGFR-mutated non-small cell lung cancer: from first line to beyond osimertinib resistance. Jpn J Clin Oncol. 2023 Jun 29;53(7):547-561. 5 Passaro A, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Annals of Oncology 2024;35(1):77-90. 6 Passaro P, et al. Amivantamab Plus Chemotherapy (With or Without Lazertinib) vs Chemotherapy Alone in EGFR-mutated, Advanced Non-small Cell Lung Cancer (NSCLC) After Progression on Osimertinib: MARIPOSA-2, a Phase 3, Global, Randomized, Controlled Trial. 2023 European Society for Medical Oncology. October 23, 2023. 7 Fuchs J, et al. Resection of isolated brain metastases in non-small cell lung cancer (NSCLC) patients – evaluation of outcome and prognostic factors: A retrospective multicenter study. PLoS ONE 16(6):e0253601. https://doi.org/10.1371/journal.pone.0253601 . 8 Passaro P, et al. Amivantamab Plus Chemotherapy (With or Without Lazertinib) vs Chemotherapy Alone in EGFR-mutated, Advanced Non-small Cell Lung Cancer (NSCLC) After Progression on Osimertinib: MARIPOSA-2, a Phase 3, Global, Randomized, Controlled Trial. 2023 European Society for Medical Oncology. October 23, 2023. 9 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. 10 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. 11 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. 12 Vijayaraghavan S, et al. Amivantamab (JNJ-61186372), an Fc Enhanced EGFR/cMet Bispecific Antibody, Induces Receptor Downmodulation and Antitumor Activity by Monocyte/Macrophage Trogocytosis. Mol Cancer Ther 2020;19(10):2044-2056. 13 European Medicines Agency. Amivantamab Summary of Product Characteristics. January 2023. Available at: Rybrevant, INN-amivantamab (europa.eu). Accessed: August 2024. 14 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. https://www.janssen.com/emea/sites/www_janssen_com_emea/files/amivantamab_mariposa_ema_filing_release_2024_2.pdf . Accessed: August 2024. 15 Janssen EMEA. 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. Available at: https://www.globenewswire.com/news-release/2024/05/31/2891769/0/en/Johnson-Johnson-submits-application-to-the-European-Medicines-Agency-seeking-approval-of-subcutaneous-formulation-of-RYBREVANT-amivantamab-for-the-treatment-of-patients-with-EGFR-m.html . Accessed: August 2024. 16 Cho, BC, et al. Lazertinib versus gefitinib as first-line treatment in patients with EGFR-mutated advanced nonsmall-cell lung cancer: Results From LASER301. J Clin Oncol. 2023;41(26):4208-4217. 17 Global Cancer Observatory. Cancer Today. Available at: https://gco.iarc.who.int/media/globocan/factsheets/populations/908-europe-fact-sheet.pdf. Accessed: August 2024. 18 Zappa C, et al. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res 2016;5(3):288–300. 19 Wee P & Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers 2017;9(12):52. 20 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 2019;37(2):97-104. 21 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 (Singapore); January 29, 2021. 22 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. 23 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. 24 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: August 2024. 25 Lin JJ, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol 2016;11(4):556-65. SOURCE: Johnson & Johnson