In Italy, oncology is the medical sector in which the largest number of clinical studies are concentrated, about 40% (equal to 268 out of a total of 672 trials active in 2019). But if it is true that our country has a long tradition in participating in the most advanced phase studies, it is equally true that we still lag behind as regards phase 1, the earliest one. “Phase 1, which aims to verify the safety of a therapy tested for the first time in humans – underlines Carmine Pinto, Director of Medical Oncology at the Comprehensive Cancer Center of the AUSL-IRCCS in Reggio Emilia -, represents an important opportunity for patients who can access innovative treatments long before they reach the market “. Not only that: thanks to these experiments, the research centers have the opportunity to receive resources from the world of industry; pharmaceutical companies to publish data in important areas such as pharmacodynamics and molecular mechanisms. “In oncology about 10% of the studies concern phase 1, but there are still critical issues to be addressed because areas of our country lack accredited structures for these trials. It is therefore important to define a single national plan and coordination for clinical research, which must also see the involvement of the Regional Oncological Networks ”, underlines Pinto.
The opportunity to talk about clinical research is given by the arrival of a pharmaceutical company in Italy, Seagen, a world leader in the technology of antibody drug conjugate (ADC), which deliver up to 10 thousand times the power. of standard chemotherapy. There are 20 clinical studies promoted in Italy by the multinational, involving 50 university centers, and at least 5 are in phase 1. “We invest more than 60% of our turnover in research and development – says Alfonso De Rosa, Medical Director Seagen Italia -. Seagen strongly believes in the partnership with the academy and that the Italian centers are able to enroll patients in highly innovative trials “. Like the one about a revolutionary technology based on sugar engineered antibody (SEA), a new frontier in immunotherapy, which the company is beginning to test in pancreatic and blood cancers. “Italy is one of the countries where we want to recruit patients but sometimes the bureaucratic delays prevent Italian centers from competing on an equal footing with those of other nations”, underlines De Rosa. “To participate in phase 1 of the trials it is necessary to have specific research laboratories and platforms, trained personnel and an efficient organization available”, explains Giuseppe Curigliano, Professor of Medical Oncology at the University of Milan and Director of the New Drugs Development Division for Innovative Therapies at the European Institute of Oncology in Milan. “But above all, a system at the national level that is quick and unified”.
In addition to those on molecules in the early stages of study, Seagen is active in Italy with more advanced experiments, for example those on conjugated antibodies. These are drugs that associate with a cytotoxic agent an antibody directed towards a target that is on the tumor cell and which, like ‘guided missiles’, are therefore designed to fight the tumor and release cytotoxic agents that concentrate their activity on the cells. tumors. The first of this family of drugs was brentuximab vedotin, approved ten years ago first in the US and then in Europe for Hodgkin’s lymphoma and diffuse large B cell lymphoma. Developed by Seage, today the molecule, which is managed in Europe by Takeda, it is used first in six forms of lymphomas. Building on that experience, the company developed enfortumab vedotin, which received FDA clearance in 2019 and is operated in Europe by Astellas, the first conjugated antibody in urothelial cancer. A phase 3 study (EV-301) on more than 600 patients, presented at the Genitourinary Cancers Symposium 2021, showed that the conjugated antibody has superior efficacy to chemotherapy in patients with advanced or metastatic urothelial carcinoma already treated with a previous chemotherapy and immunotherapy drugs. “In the study, the median overall survival was 12.8 months with the conjugated antibody versus 8.9 months with chemotherapy,” said Pinto. The FDA also granted accelerated approval in September 2021 to another conjugated monoclonal antibody developed by Seagen, tisotumab vedotin, indicated as monotherapy for the treatment of recurrent or metastatic cervical cancer that has already been treated. Results from a study of approximately 100 patients showed an objective response rate of 24% and the median duration of response was 8.3 months.
The multinational’s research is also active in the development of other types of targeted therapies, which are changing the natural history of advanced breast cancer. In particular in the HER2 positive tumor, which represents 15-20% of cases, a neoplasm that tends to recur and to be more aggressive, so much so that up to 50% of patients develop brain metastases. “In these patients, tucatinib, a tyrosine kinase inhibitor, is able to block the replication of cancer cells very effectively,” explains Curigliano.
The HER2CLIMB study, which led to approval of the molecule in the United States and Europe, evaluated the addition of tucatinib to trastuzumab and chemotherapy in 612 previously treated patients with HER2 positive metastatic breast cancer with and without brain metastases. “HER2CLIMB is the first phase III trial to have also enrolled people with active brain metastases, which were progressing, the most difficult to treat – underlines Curigliano -. Tucatinib showed an improvement in overall survival, with a 34% reduction in the risk of death and a 46% reduction in the risk of tumor progression. These benefits were seen in all subgroups, including those with brain metastases. The regimen with tucatinib therefore helps to live longer ”. A phase 3 study on the new molecule in colorectal cancer will be launched at the beginning of 2022, with the involvement of 15 centers in Italy.