A new frontier in precision oncology: the Italian Medicines Agency (AIFA) approved larotrectinib, the first anti-tumor drug with an agnostic indication, i.e. independent of the organ affected by the disease, for the treatment of neoplasms characterized by fusion of NTRK (Neurotrophic Tyrosine Receptor Kinase) genes. The three pivotal studies (so-called ‘basket’ studies) involved adult and pediatric patients with malignancies characterized by NTRK gene fusion and showed a rapid and lasting improvement in tumor response and quality of life, with a high overall response rate, equal to to 75%. Larotrectinib can be considered a “wild card” drug, because it selectively affects certain genetic mutations, regardless of the organ affected by the disease. The significance and scope of this approval for patients in Italy are explored today in a virtual press conference.
“From today, doctors in our country have the opportunity to combine the therapeutic approach based on the tumor histotype with precision oncological therapy guided exclusively by molecular alteration – he says Saverio Cinieri, Director of Medical Oncology and Breast Unit of the ‘Perrino’ Hospital of Brindisi and President-elect AIOM (Italian Association of Medical Oncology) -. Agnostic approval changes the prospects for treatment and is the first step in a ‘cultural’ revolution. The starting point is no longer represented by the location of the tumor, that is, the organ from which the disease originates, according to the histological model. Agnostic approval leads to the affirmation of the mutational model which, while recognizing the value of the morphological and histological data, is based on genomic profiling and on the identification of molecular alterations that are independent of the site of origin of the disease. We are facing the most advanced frontier of precision oncology. To testify the importance of this approach, AIOM has published the ‘Recommendations on Agnostic Drugs’, edited by prof. Antonio Russo, member of the board of the scientific society. Commonly used therapies to treat patients with tumors characterized by NTRK gene fusion, such as chemotherapy or immunotherapy, have not always proved effective. Larotrectinib, first in the class of oral TRK inhibitors, showed rapid responses, with a relevant and long-lasting clinical benefit, regardless of the patient’s age and location of the tumor “.
The EMA (European Medicines Agency), in the annual report “Human Medicine Highlights 2019”, has included larotrectinib (the only cancer therapy selected) in the list of drugs that have made an important contribution to improving public health because it represents progress significant in oncology. “The recognition comes from the important results obtained in the studies, which confirm both the short and long-term clinical advantages of the drug – he explains Carmine Pinto, Director of Medical Oncology Comprehensive Cancer Center AUSL-IRCCS of Reggio Emilia and President of FICOG (Federation of Italian Cooperative Oncology Groups) -. Larotrectinib is a drug that has demonstrated high clinical activity not in relation to a single site or histological type of tumor but in relation to the presence of a specific molecular alteration, the NTRK gene fusion. This is demonstrated by the updated data presented at the last American congress of medical oncology ASCO, coming from three studies on 206 adult and pediatric patients with tumors with NTRK fusion in over 20 different types of cancer. An overall response rate of 75% was observed in these patients, with 22% complete responses. The median duration of tumor responses was over 4 years (49.3 months) and 77% of patients were still alive at 3 years. All this with excellent tolerability. These data have a relevant clinical significance, also because most of the patients presented an advanced state of disease and had already undergone previous therapies “.
Larotrectinib has been investigated in clinical studies in several histologies of solid tumors, including those of the lung, thyroid, melanoma, gastrointestinal stromal tumors, colon cancer, soft tissue sarcomas, salivary gland tumors and childhood fibrosarcoma. . It has shown efficacy in primary central nervous system tumors, as well as in patients with brain metastases, of different age and tumor histologies.
“The results of these studies represent a clear rationale for subjecting cancer patients to a comprehensive genomic test that includes the search for fusions of NTRK genes, to better understand what the tumor ‘driver’ gene is and associate it with the right treatment – they say. Anna Sabino (Director of the Department of Medical Sciences – University of Turin and President of SIAPEC-IAP, Italian Society of Pathological Anatomy and Diagnostic Cytopathology) and Antonio Marchetti (full professor of pathological anatomy at the University of Chieti and Coordinator of the Italian Group of Molecular Pathology and Predictive Medicine SIAPEC-IAP) -. Tumors with NTRK fusion occur when an NTRK gene fuses with another unrelated gene, producing an altered TRK protein, which becomes active or overexpressed, fueling the growth and spread of the tumor, regardless of where it originated. Patients candidates for treatment with agnostic drugs must be selected on the basis of the presence of molecular alterations, through specific diagnostic tests. In this sense, SIAPEC has created a real national network of high-tech laboratories. The scientific society also promoted the ‘Progetto Vita’, a study involving 18 Italian centers with the aim of highlighting rare DNA alterations (including fusions of NTRK genes), using a new technological approach, applied for the first time in Italy, to reduce the time and costs of analyzes “.
“We welcome AIFA’s decision with great satisfaction – he concludes Marius Moscovici, Bayer Head of Medical Affairs Oncology -. The approval of larotrectinib represents a significant step forward in the fight against cancer that is facing a paradigm shift, and as the new era of precision cancer treatment unfolds, we continue our effort to deliver innovative drugs, which can be a great value for patients and doctors. Bayer is committed through its research to developing personalized treatments that help patients live longer and better ”.