Phd in PHARMACOLOGY AND TOXICOLOGY

Thesis title: Retrospective and observational protocol on the reduction of the time needed for the evaluation of drug interactions and real world evidence in the treatment of Melanoma and Non Small Cell Lung Cancer

The drug-drug interactions (DDIs) are defined as the pharmacological or clinical response to the administration of a drugs combination, other than that provided for the known effects of the two agents when they are administered individually The combined use of two or more drugs triggers pharmacological changes that may result in unexpected effects as side effects, adverse reactions, and even serious toxicity. Furthermore, DDIs-related adverse reactions (ADRs) can increase the rate and the lasting of hospitalizations and decrease the patient compliance. Therefore, these interactions can reduce its effectiveness and lead to therapy failure. As the need for polypharmacy treatments increases, identification of DDIs has become urgent. Over recent years, several “medical tools” or software have been validated in order to detect DDIs, able to include the list of each patient's drug therapy in order to get a pharmacological interactions profile. This study provides for a retrospective observational non-interventional analysis based on anonymous data of the drug associations used in patients affected from different oncological diseases, within our database, from which it the lists of drugs used in each patient will be extracted, without any clinical reference that can be connected to the patient. Data analysis will enable to collect the information on the time required to carry out the therapeutic reconciliation operation manually or with the Drug-Pin platform. Drug-PIN® (Personalized Interactions Network) is a tool able to evaluate the drug interactions. The software provides a DDIs score based on the drugs prescribed at the same time to a single patient, by classifying the degree of interaction as low, medium and high. Aim of my thesis has been to evaluate the pharmacological interactions in treatment of Melanoma and Non Small Cell Lung Cancer (NSCLC). The combination of BRAF and MEK inhibition represents a highly effective strategy for the management of BRAF-mutant melanoma. The objective of this study was to analyse the role of drug–drug interactions (DDIs) on the toxicity profile of anti-BRAF/anti-MEK therapy. In this multicentre, observational, and retrospective study, the assessment of DDIs was carried out utilising the Drug-PIN® software (version 2/23). The relationship between the Drug-PIN continuous score or the Drug-PIN traffic light and the incidence of treatment-related toxicities and oncological outcomes was examined. A total of 177 patients with advanced BRAF-mutated melanoma undergoing BRAF/MEK targeted therapy were included in the study. All grade toxicity was recorded in 79% of patients. Cardiovascular toxicities occurred in 31 patients (17.5%). Furthermore, 94 patients (55.9%) had comorbidities requiring specific pharmacological treatments. The median Drug-PIN score exhibited a marked increase when the target combination was included the patient's home therapy regimen (p-value < 0.0001). A significant association was observed between cardiovascular toxicity and the Drug-PIN score (p-value = 0.048). The Drug-PIN traffic light (p = 0.00821) and the Drug-PIN score (p = 0.0291) were identified as significant predictors of cardiotoxicity. Patients with low-grade interactions exhibited better prognoses with regard to overall survival (OS) (p = 0.0045) and progression-free survival (PFS) (p = 0.012) compared to those with high-grade interactions. The survival analysis of the subgroup of patients with cardiological toxicity demonstrated that patients with low-grade versus high-grade DDIs exhibited superior outcomes compared to OS (p = 0.0012) and they have a trend towards significance in PFS (p = 0.068). Our next focus was on another type of neoplasm, namely no small cell lung cancer (NSCLC). NSCLC represents 80-90% of all lung malignancies. Osimertinib has been shown to exhibit substantial antitumour efficacy in the treatment of advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. However, real-world data of impact of drug-drug interactions on effectiveness and toxicity are limited. The objective of the study was to evaluate the impact of drug-drug interactions on effectiveness and toxicity profile in patients treated with Osimertinib with EGFR mutation positive NSCLC. A retrospective analysis of the medical records of 61 patients treated with Osimertinib during the period between May 2018 and May 2024 was carried out. The outcomes regarded were Drug-Drug interaction (DDI), Best Response (BR), Progression Free Survival (PFS), Overall Survival (OS), Overall response rate (ORR), Disease control rate (DCR) and toxicity. Data treatment, concomitant drugs were recorded in Drug Pin®. The variables considered were age, gender and performance status according to ECOG (Eastern Cooperative Oncology Group). The efficacy was assessed using the Kaplan-Meier method in terms of PFS and OS. Adverse effects were collected and classified in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) scale v5.0. Statistical analyses were performed using R statistical software. A p-value of 0.05 was considered statistically significant. The study included 61 patients; of these, 67% were women. The mean age was 71 years (range 60-78). Most patients (93%) were Caucasian, with only two (3.3%) Asian and two (3.3%) from other ethnic groups. 82% of patients were stage IV at diagnosis and 80% of study subjects showed metastatic disease at baseline, of which 31% (19 patients) had developed brain metastases. The OS was 18 months and PFS was 12 month whereas in the subgroup with brain metastases had OS 20 month and median PFS of 10 months. Besides, the toxicity wasn’t associated to a better PFS (p₌0,35) and OS (p₌0,35). Furthermore, 66% of patients exhibited an ECOG performance status of grade 0, 30% grade 1, 3% grade 2, and 1% grade 3. Of the 61patients, 8% exhibited a complete response, 59 % demonstrated a partial response, 18% displayed stable disease, 7 % exhibited disease progression, and 8 % weren’t evaluable. ORR was 67%. DCR was 85%. The mean value of the drug pin score prior to the administration of osimertinib was 13. Following the initiation of treatment, the mean value increased to 19. This increase wasn’t statistically significant. Adverse effects were observed in 37% of patients (23). The most common adverse effects were diarrhoea (23%), nausea (8%), asthenia (5%), and anaemia (5%). Grade G3-G4 toxicity was observed in 4,9% of patients. One patient with cardiological toxicity has interrupted the treatment. No dose reduction was required. Osimertinib has been demonstrated to be an effective treatment for non-small cell lung cancer in the overall population, with a particularly favourable outcome for females patients compared to males. Furthermore, patients with a lower drug pin score exhibited a more favourable prognosis than those with a higher score. Osimertinib was generally well-tolerated by the majority of patients, although cardiovascular monitoring was deemed necessary. In light of these findings, it can be suggested that this study provides preliminary support for clinicians in avoiding probable DDIs in order to improve clinical practice. DDIs in cancer patients receiving innovative new drugs are still unclear. Clinicians should be aware of the risk of DDIs in patients undergoing poly therapy, which could impact on cancer treatment, toxicity, or drug efficacy. Furthermore, further clinical investigations are required in order to establish the efficacy of the drug pin score as a technical aid in the context of oncological treatments.