Pharmacovigilance, drug interactions, pharmacogenetics and therapeutic drug monitoring of anticancer agents: a valuable support for clinical practice

Abstract

Clinical pharmacology is an integral part of oncology, especially in the modern era of precision medicine. The innovations introduced in drug development (conditional accelerated tumor-agnostic approvals through adaptive trials) and clinical practice (liquid biopsy, tumor molecular board) underline the pressing need for clinical pharmacologists, who play a catalyst and translational role in a synchronized multidisciplinary team. This review describes the latest advancements and challenges in actually implementing the precision medicine approach in oncology: pharmacovigilance, drug interactions, pharmacogenetics and therapeutic drug monitoring are often overlooked valuable tools for the understanding, detection, assessment, and prevention of adverse drug reactions, thus supporting safe prescribing in oncology. Introduction We are witnessing a paradigm shift in oncology, both in drug development and clinical practice. On one hand, the identification of new potentially targetable molecular alterations in different types of tumor leads to the development and accelerated approval of the so-called tumor-agnostic treatments, namely pembrolizumab, larotrectinib, and entrectinib (1). On the other hand, the implementation of noninvasive diagnostic tools such as liquid biopsies, and relevant search for predictive biomarkers of clinical response (e.g., circulating tumor DNA, circulating tumor cells, exosomes), are driving the concept of precision medicine in clinical practice within the institutional molecular tumor board (2). The case of immune checkpoint inhibitors (ICIs) is noteworthy. Over the past 6 years, the FDA has approved six ICIs for more than 75 oncological indications (35 through an accelerated pathway), and the term “dangling accelerated approvals” was coined: duplicates or similar indications for which the required confirmatory trials failed to show a clear benefit, and yet their marketing authorization continued [3]. Although the fact that a clinical trial failed to meet its endpoints does not necessarily mean that the drug is ineffective, in this competitive field adaptive trials have been increasingly pursued. Notably, pivotal trials have been also criticized for their “fragile” design, namely non-randomized single-arm trials testing surrogate endpoints (4-8). In this rapidly evolving scenario, real world evidence (RWE), including data from electronic health records, claims, post-marketing safety reports, retrospective medical record reviews, and expanded access studies, has gained increased attention as a complementary source of data to traditional clinical trials (9). Although RWE was conventionally used for post-marketing surveillance, including long-term safety (and detection of rare adverse events) and effectiveness, Regulatory Agencies have demonstrated the willingness to alter the traditional regulatory paradigm and allow the use of RWE to support drug approval, thus expediting access to new therapies. A notable example was palbociclib, expanded to male patients based on data from the IQVIA insurance database, the Flatiron Health Breast Cancer Center database and the Pfizer Global Safety Database (10). This uncertainty surrounding the dynamic risk-benefit profile of anticancer drugs in the modern era supports the proactive role of clinical pharmacology as a translational discipline, bringing together a benchto-bedside approach, including not only laboratory (biomarkers, pharmacokinetics, genetics) and desk skills (design of clinical trials, implementation of guidelines and health technology assessment), but also hand-on clinical support to patient care (consultancy for medication review, drug-drug interactions DDIs) (Figure 1). Ultimately, a clinical pharmacologist, by contributing to the understanding of diseases, plays a key role for public health services by eventually reducing the burden of drug-related hospital admissions, especially in the oncological area (11). The aim of this review is to describe the latest advancements and challenges in actually implementing the precision medicine approach in oncology, focusing on the role of clinical pharmacology as an aid to support safe prescribing. Targeted pharmacovigilance for clinical practice: the ever-changing spectrum of cardio-oncology Pharmacovigilance is becoming a holistic discipline towards safe prescribing. A proactive life-cycle risk management is the hallmark of modern pharmacovigilance, which should not be intended as a desk discipline, but rather as integrated clinical activities dealing with the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related issues. For instance, clinical pharmacologists should implement evidence-based personalized approaches for prevention and treatment of nausea/vomiting, neutropenia-related infections, and cancer-associated thrombosis. In this regard, cardio-oncology is a recognized medical specialty and clinicians are increasingly facing the multifaceted spectrum of cardiovascular toxicities by anticancer agents, including arrhythmias (QT prolongation/Torsade de Pointes, atrial fibrillation), cardiomyopathies, vascular toxicities. The reader may refer to recent reviews for a comprehensive characterization of the cardiovascular phenotypes (12, 13). Overall, the following key messages can be derived: a) various cardiovascular damages may occur in the same patient because different drugs may impair heart function via multiple mechanisms; b) different drugs, especially targeted therapies, can cause multiple cardiovascular effects because of mechanistic overlap in the pathophysiology, whereas only a minority of agents is specifically linked to a unique form of cardiotoxicity; c) although peculiarities may exist within a given pharmacological class, it appears that no anticancer drug is fully devoid of cardiovascular liability. This rapidly evolving spectrum of cardiovascular manifestations with targeted therapy poses new diagnostic and therapeutic challenges for oncologists and cardiologists, who must be aware of clinical pharmacology to target preventive risk minimization/stratification strategies, including medication review and critical assessment of public online tools to predict, among other, DDIs (14, 15). Cardiovascular toxicity with immunotherapy is an emerging clinical and research priority, and the paucity of RWE supports the need for tightening post-marketing surveillance. The case of ICIs, monoclonal antibodies targeting cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1), have boosted the interest in cardio-oncology. They have been especially associated with rare but potentially fatal myocarditis, typically occurring early after ICI initiation (median time of 2 months, with fulminant cases) (16). A recent nationwide Danish study found a higher and long-lasting (after 6 months) absolute risk as compared to previous pharmacovigilance data, thus raising the awareness on a potential underestimated phenomenon (17). The next challenge for onco-cardiologists is represented by cardiac dysfunction with chimeric antigen receptor (CAR)-T cell and bispecific T cell engager (BiTE) therapies, ranging from tachycardia, hypotension, arrhythmia, decreased left ventricular systolic function to cardiogenic shock and death. Notably, cardiac events may overlap with the so-called immune effector cellrelated adverse events, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (18). Pharmacovigilance as a real-world real-time aid to clinical practice: the case of immune checkpoint inhibitors Immunotherapy with ICIs represents a paradigmatic example of how pharmacovigilance data could be exploited to proactively support appropriateness. Because of their rapid uptake and extension in different tumor types and settings, clinicians are increasingly facing off-target toxicities characterized by a unique and distinct spectrum of adverse effects, the so-called immune-related adverse events (irAEs), which can virtually affect any organ or system in the body (19). Regularly updated guidelines offer a compendium of irAEs and discuss both clinical presentation and management. Of note, the pathophysiology of organ-specific irAEs can differ (antibody-mediated bullous pemphigoid vs cytotoxic Tcell–mediated myocarditis), many patients present with multisystem refractory toxicities, and the use of systemic corticosteroids and immunosuppression is challenging (potential detrimental effect on ICI efficacy), thus warranting new skills and a multidisciplinary team comprising clinical pharmacologists (20). Although most common irAEs were identified during preapproval clinical development, their assessment and clinical characterization in terms of spectrum, timing and outcomes were only recently investigated through real-world, large-scale pharmacovigilance analyses (21). Specifically, the Food and Drug Administration Adverse Event Reporting System (FAERS) and the worldwide Vigibase have attracted considerable interest among oncologists. These international spontaneous reporting databases represent an unprecedented opportunity to provide oncologists with major and novel unexpected toxicities, thus informing clinical practice for proactive monitoring (e.g., early assessment of liver function for drugs with similar pharmacodynamics) (22). Of note, these archives can be queried through online tools (e.g., FAERS public dashboard) by individual researchers, or raw data can be accessed/downloaded for customized analyses, namely disproportionality algorithms aimed at detecting higher-than-expected reporting of a given adverse event, also known as a ‘signal’. Of note, the accuracy of these pharmacovigilance analyses is remarkable (i.e., the ability to distinguish between true and false negatives), and a recent study found that risk estimates from metaanalyses and pharmacovigilance analyses were correlate