Real-World Safety and Outcome of First-Line Pembrolizumab Monotherapy for Metastatic NSCLC with PDL-1 Expression ≥ 50%: A National Italian Multicentric Cohort ("PEMBROREAL" Study).

Results from the phase III Keynote-024 clinical trial established pembrolizumab monotherapy as the first-line standard of care for patients with metastatic NSCLC who have PD-L1 expression ≥ 50%, EGFR, and ALK wild-type tumors. However, given the differences between patients treated in routine clinical practice and those treated in a clinical trial, real-world data are needed to confirm the treatment benefit in standard practice. Given the lack of data on large cohorts of patients with long follow-ups, we designed an observational retrospective study of patients with metastatic NSCLC who were treated with pembrolizumab, starting from its reimbursement eligibility until December 2020. The primary endpoints were PFS and OS, determined using the Kaplan-Meier method. Response and safety were also evaluated. We followed 880 patients (median follow-up: 35.1 months) until February 2022. Median PFS and OS were 8.6 months (95% CI: 7.6-10.0) and 25.5 months (95% CI: 21.8-31.6), respectively. We also found that ECOG PS, PD-L1 expression, and habitual smoking were prognostic factors for PFS, while age, sex, ECOG PS, habitual smoking and histology had an impact on OS. Multivariable analysis confirms the prognostic role of PD-L1 for PFS and of ECOG for both PFS and OS. 39.9% of patients reported an adverse event, but only 6.3% of patients discontinued therapy due to toxicity. Our results suggest a long-term benefit of pembrolizumab in the first-line setting, as well as a safety profile consistent with the results of Keynote-024. Many collected variables appear to influence clinical outcome, but results from these exploratory unadjusted analyses should be interpreted with caution.

A real-world retrospective, observational study of first-line pembrolizumab plus chemotherapy for metastatic non-squamous non-small cell lung cancer with PD-L1 tumor proportion score < 50% (PEMBROREAL).

Introduction: The phase III Keynote-189 trial established a first-line treatment combining pembrolizumab with pemetrexed and platinum as a standard treatment for patients with stage IV non-small cell lung cancer (NSCLC) without known EGFR and ALK driver mutations and independent of programmed cell death ligand 1 (PD-L1) expression. However, in Italy, eligibility for the National Health Service payment program is limited to patients with PD-L1 <50%. The PEMBROREAL study assesses the real-world effectiveness and safety of pembrolizumab in patients eligible for the National Health Service payment program. Methods: PEMBROREAL is a retrospective, observational study on patients with NSCLC who started pembrolizumab combined with pemetrexed and platinum within the reimbursability time window, considered as December 2019 to December 2020. The primary endpoints were to assess progression-free survival (PFS) and overall survival (OS; using the Kaplan-Meier method), response to therapy, and tolerability. Results: Until February 2022, 279 patients (median follow-up: 19.7 months) have been observed. The median PFS was 8.0 months (95% confidence interval: 6.5-9.2). OS was not reached, but we can estimate a 12- to 24-month survival rate for the combined treatment: 66.1% and 52.5%, respectively. PD-L1 expression and Eastern Cooperative Group (ECOG) Performance Status were both associated with PFS and OS. Overall, only 44.4% of patients reported an adverse event, whereas toxicity led to a 5.4% discontinuation rate. Conclusion: The results of the PEMBROREAL study have shown that the combined treatment of pembrolizumab with pemetrexed and platinum is effective for metastatic non-squamous NSCLC, even for patients with PD-L1 levels below 50%, despite the differences in patient demographics and pathological features compared to the Keynote-189 study. The adverse events reported during the study were more typical of chemotherapy treatment rather than immunotherapy, and physicians were able to manage them easily.

Improving Drug Safety in Pediatric and Young Adult Patients with Hemato-Oncological Diseases: A Prospective Study of Active Pharmacovigilance.

The acquisition of relevant pediatric clinical safety data is essential to ensure tolerable drug therapies. Comparing the real number of Adverse Drug Reaction (ADR) reports in clinical practice with the literature, the idea of ADR underreporting emerges. An active pharmacovigilance observational prospective study was conducted to assess the safety of oncology pharmacological prescriptions in patients aged 0-24 years at Institute for Maternal and Child Health IRCCS Burlo Garofolo in Trieste and IRCCS CRO National Cancer Institute in Aviano (Italy) between January 2021 and October 2023. Prescriptions and ADRs were evaluated by a multidisciplinary team. A total of 1218 prescriptions for 38 patients were analyzed, and 190 ADRs of grade 3-5 were collected. As compared to historical data, we registered a significant increase (p < 0.001) in the number of ADRs. The risk of ADR was 3.4 times higher in the case of off-label prescriptions compared to on-label ones (OR 3.4; [1.47; 7.89]; p-value = 0.004). The risks of error and near-miss were reported for 6.3% and 18.2% of total prescriptions, respectively. Of the total of 133 interactions, 47 (35.3%) resulted in ADRs. This study shows the importance of pro-active pharmacovigilance to efficiently highlight ADRs, and the fundamental role of multidisciplinary teams (oncologist, pharmacist, pharmacologist, pediatrician, nurse) in improving patients' safety during therapy.

How will the identification and therapeutic intervention of genetic targets in oncology evolve for future therapy?

INTRODUCTION: Mapping of the human genome, together with the broad understanding of new biomolecular pathways involved in cancer development, represents a huge dividing line for advances in cancer treatment. This special article aims to express the next evolution of cancer therapy, while also considering the challenges and uncertainties facing future directions. AREA COVERED: The recent achievements of medical science in the oncology field concern both new diagnostic techniques, such as liquid biopsy, and therapeutic strategies with innovative anticancer drugs. Although several molecular characteristics of tumors are linked to the tissue of origin, some mutations are shared by multiple tumor histologies, thus paving the way for what is called 'precision oncology.' The article highlights the importance of identifying new mutations and biomolecular pathways that can be pursued with new anticancer drugs. EXPERT OPINION: Oncology and medical science have made great progress in understanding new molecular targets; being able to early identify tumor markers that are not confined to a single organ through minimally invasive diagnostic techniques allows us to design new effective therapeutic strategies. Multidisciplinary teams now aim to evaluate the most appropriate and personalized diagnostic/therapeutic approach for the individual patient.

Toxicity Derived from Interaction between Natural Compounds and Cancer Therapeutic Drugs Metabolized by CYP3A4: Lessons Learned from Two Clinical Case Reports.

The use of natural compounds and, in general, the use of Complementary and Alternative Medicine (CAM), is growing steadily worldwide, both due to commercial pressure and the increasing use of self-medication and the desire to manage one's own personal health and well-being. Patients facing a cancer diagnosis are also strongly pressured to use these compounds, which are often added to standard therapeutic regimens, that should instead be based solely on diagnostic and therapeutic care pathways (DTCP) or evidence-based medicine (EBM). This study presents two clinical cases of cancer patients who presented to the pharmaceutical consultation service (PCD-Pharmacy Clinical Desk) established at the CRO Institute in Aviano, Italy. Both patients were using natural products along with prescribed chemotherapy. In the first case, a 55-year-old woman diagnosed with bilateral breast cancer with bone metastases, who was using natural compounds based on diosmin, escin (or aescin) and resveratrol in combination with ribociclib anticancer therapy, a severe ADR (neutropenia) was identified as a consequence of the drug-natural product interaction. In the second case, following a detailed medication review by the PCD, we avoided taking a therapeutic treatment (with natural compounds) that in itself could potentially render chemotherapy ineffective in a 57-year-old woman with multiple infiltrating ductal carcinoma of the left breast; the patient was planning to take a natural product containing St. John's Wort tincture and lemon balm tincture, in combination with paclitaxel and trastuzumab. In addition, we describe the corrective actions taken, thus outlining the main objectives of the activity of the PCD's pharmacy counseling service: first, to identify, report, and manage adverse drug reactions (ADRs), and second, to identify therapeutic combinations that present potential risks of toxicity or ineffectiveness of the drug therapy itself.

Immune checkpoint inhibitors as first line in advanced melanoma: Evaluating progression-free survival based on reconstructed individual patient data.

BACKGROUND: In patients with advanced melanoma, immune-checkpoint inhibitors (ICIs) represent the mainstay for first line treatment. Recently, relatlimab+nivolumab was proposed as a new combination therapy. This review was aimed at summarizing the current data of effectiveness for ICIs. Progression-free survival (PFS) was the endpoint of our analysis. METHODS: After a standard literature search, Phase II/III studies comparing different ICI regimens in previously untreated advanced melanoma patients were analyzed. Patient-level data were reconstructed from Kaplan-Meier curves by application of the IPDfromKM method. These reconstructed datasets were used to perform indirect comparisons between treatments. Standard statistical testing was used, including hazard ratio and medians. A secondary analysis employed the restricted mean survival time. RESULTS: Six trials were included in our analysis. Information on PFS from these trials was pooled according to the following treatments: nivolumab or pembrolizumab as monotherapy, or in combination with ipilimumab, and relatlimab + nivolumab. Pembrolizumab+ipilimumab showed significantly better PFS compared with the other treatments; nivolumab+ipilimumab ranked second; the other treatments showed a similar survival pattern. CONCLUSIONS: The picture of comparative effectiveness resulting from our analysis is complex. The IPDfromKM method is advantageous because it accounts for the length of follow-up but loses the balance between treatment group and controls determined by randomization. Based on indirect comparisons, the combination of pembrolizumab+ipilimumab showed a particularly high efficacy, and so deserves further investigation. While the effect of between-trial differences in inclusion criteria plays an important role, our results do not support the proposal of relatlimab+nivolumab as a new standard of care.

[Application of artificial intelligence for an early comparison of efficacy between new cancer drugs.] / Applicazione dell'intelligenza artificiale per un precoce confronto di efficacia tra nuovi farmaci oncologici.

INTRODUCTION: The clinical choice among recently approved cancer drugs is burdened by the absence of direct comparisons in terms of efficacy across these new agents. In this article we present the IPDfromKM method, an artificial intelligence (AI) application that aims to facilitate the analyses on efficacy based on secondary data. METHODS: Seven therapeutic areas were selected in which at least three new agents were recently approved. Kaplan-Meier curves of related clinical trials were digitized. Then, the IPDfromKM method was employed to reconstruct patient-level survival data. This information allowed us to compare selected agents in each therapeutic area and to rank them in terms of efficacy. RESULTS: We identified the most effective treatment in each of the seven selected therapeutic areas. In two cases, immunotherapies, sharing similar mechanisms of actions, were compared highlighting the most effective one. In the remaining cases, our comparison included also the standard of care, which proved to be superior to new agents in patients with osteosarcoma. DISCUSSION: When randomized clinical trials are not available, indirect comparisons can be a valuable source of information. The experience described herein recommends the use of a new method endowed by two important advantages: remarkable speed of analysis and free access to computational tools. In assessing the place in therapy for newly developed agents, this approach can further promote the application of evidence-based principles.

Genetic Therapy and Molecular Targeted Therapy in Oncology: Safety, Pharmacovigilance, and Perspectives for Research and Clinical Practice.

The impressive advances in the knowledge of biomarkers and molecular targets has enabled significant progress in drug therapy for crucial diseases such as cancer. Specific areas of pharmacology have contributed to these therapeutic outcomes-mainly targeted therapy, immunomodulatory therapy, and gene therapy. This review focuses on the pharmacological profiles of these therapeutic classes and intends, on the one hand, to provide a systematic definition and, on the other, to highlight some aspects related to pharmacovigilance, namely the monitoring of safety and the identification of potential toxicities and adverse drug reactions. Although clinicians often consider pharmacovigilance a non-priority area, it highlights the risk/benefit ratio, an essential factor, especially for these advanced therapies, which represent the most innovative and promising horizon in oncology.

Pharmacovigilance of anti-cancer medicines: opportunities and challenges.

INTRODUCTION: The foundations of pharmacovigilance are the monitoring of drug safety in real-world medicine, and identification of new adverse effects, unknown at the time of market approval. Cancer patients are prone to adverse drug reactions due to the complexity of the neoplastic disease and its treatment. Pharmacovigilance of anti-cancer medicines is further complicated because patients have comorbidities, as for elderly patients. It is even more challenging when complete safety and risk data for a drug are lacking, as may occur for new molecules or when it comes to drugs for children. AREAS COVERED: This article introduces the field of pharmacovigilance of anti-cancer drugs, describing the various layers of complexity that make the recognition of adverse drug events in oncology particularly problematic, including the type of medicines, the phenomenon of underreporting and polypharmacy. Finally, it reviews new digital tools to help pharmacovigilance activities in oncology. EXPERT OPINION: The authors outline some crucial challenges and opportunities that can be useful for pharmacovigilance to keep up with the times and follow the current technological and scientific progress. In addition to the evaluations made by researchers, it will, of course, be necessary to have an equality important concrete response from the institutions and regulatory bodies.

Safety Profiles and Pharmacovigilance Considerations for Recently Patented Anticancer Drugs: Advanced Thyroid Cancer.

BACKGROUND: Thyroid cancer is the most common endocrine neoplasia and represents approximately 1.5% to 2.1% of all cancers diagnosed annually worldwide. Iodine Refractory Differentiated Thyroid Carcinoma (RR-DTC) and advanced/metastatic medullary thyroid carcinoma are relatively uncommon yet prognostically significant thyroid cancers. Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers, including thyroid cancer. Many Multi-Kinase Inhibitors (MKIs) which are now FDA-/EMA approved for thyroid cancer have shown clinical benefit in patients with advanced cancer. Treatment related toxicities occur frequently with these drugs and can be severe or life-threatening. OBJECTIVES: This review summarizes the role of targeted therapy with MKIs in the management of RRDTC and advanced/metastatic MTC patients, focusing on side-effect profiles of these drugs, with a presentation of several recent patents published in this field. METHODS: We review the scientific literature on advanced thyroid cancer and analyze the International Pharmacovigilance database (FAERS, Eudravigilance, and WHO Vigibase) for adverse drug reactions. RESULTS: This systematic analysis highlights the difference in the safety profile of the recent drugs used in the treatment of advanced thyroid cancer and the recent discoveries for diagnosis or treatment of the thyroid cancer. CONCLUSION: It is essential to investigate the safety profile of recent anticancer drugs for advanced thyroid cancer to allow health professionals to make the best choice for each patient by conducting risk/benefit assessment.

Safety Profiles and Pharmacovigilance Considerations for Recently Patented Anticancer Drugs: Cutaneous Melanoma.

BACKGROUND: Malignant melanoma is a skin cancer responsible for 90% of cutaneous cancer- related deaths. In recent years, breakthroughs in treatment strategy have revolutionized the prognosis in both early and advanced melanoma patients. In particular, treatment with monoclonal antibodies targeting co-inhibitory checkpoints or specific molecular pathways leads to a new era of promising options, by prolonging the survival time of these patients. Moreover, unlike the chemotherapy that was used until some time ago, these new drugs have a good and more manageable toxicity profile. However, because of the recent introduction in clinical practice of the new agents, there is a learning curve among physicians regarding early recognition and management of the associated side effects. OBJECTIVES: The analysis of the toxicity profiles of the different agents currently studied for the treatment of early and advanced melanoma, and the description of several relevant recent patents in this field, are the aims of this review. METHODS: This is a systematically conducted review based on current clinical guidelines and on international Pharmacovigilance databases (AERS-Eudravigilance - WHO Vigibase). RESULTS: Our systematic analysis outlines a comprehensive overview of the pharmacology, clinical application and the safety of recent anticancer drugs to treat melanoma, which can be an essential instrument for health professionals and researchers. CONCLUSION: The new oncological therapies against melanoma are based on increasingly specific biological and immunological targets. For this reason, the potential toxicities that are expected from patients would be less relevant than the systemic "classical" chemotherapy. However, the new therapies are not free from the risk of causing adverse reactions, some of which must be managed promptly and appropriately; moreover, the multiplicity of the metabolic pathways exposes the new target therapies to relevant potential interactions. This review can help to understand how important it is not to underestimate potential adverse drug reactions related to new targeted therapies.

Safety Profiles and Pharmacovigilance Considerations for Recently Patented Anticancer Drugs: Lung Cancer.

BACKGROUND: Lung cancer is the most frequent cause of cancer-related death. In the last decades, the introduction of targeted therapies and more recently, of immunotherapy, has led to significant improvements in different outcomes of this malignant neoplasm. OBJECTIVE: The present review provides a balanced overview of most recent targeted therapies and immunotherapies patented for the treatment of lung cancer. METHODS: An extensive scientific literature and patent databases search were performed to identify peerreviewed studies containing information on recently patented drugs for the treatment of lung cancer, with a particular focus on their safety data and recently patented combinations. RESULTS: The development of therapies directed to different pathways involved in the tumor angiogenesis, proliferation, and metastasis has transformed the clinical practice of lung malignancies. Several clinical trials have shown an improvement in terms of progression-free survival and overall survival in patients with advanced/metastatic lung cancer. Safety data, extracted from clinical trials and from the WHO global database of adverse drug reactions (VigiAccessTM database), show that recently patented drugs for the treatment of lung cancer are well-tolerated and most of the adverse events reported are mild to moderate. CONCLUSION: Currently, a consistent number of new drugs and combinations have been introduced for the treatment of patients with advanced-stage lung cancer. Safety data remain essential to better assess the long-term risk/benefit ratio of these valuable emerging therapies. The new patents' development could provide further significant improvements for lung cancer treatment.

An Update of Efficacy and Safety of Cetuximab in Metastatic Colorectal Cancer: A Narrative Review.

Colorectal cancer is the second most common cancer, representing 13% of all diagnosed cancers. Cetuximab is a recombinant chimeric monoclonal IgG1 antibody and epidermal growth factor receptor (EGFR) inhibitor. Cetuximab is approved for the first-line treatment in combination with chemotherapy or as a single agent in patients who have failed or are intolerant to chemotherapy in patients with EGFR-expressing, RAS wild-type metastatic colorectal cancer. Cetuximab efficacy emerged from studies that were conducted to approve the drug. Cetuximab is well tolerated; its toxicities are caused by its mechanism of action and the most common adverse reaction is skin toxicity. The main purpose of this manuscript is to present an update on the evidence-based summary of efficacy and safety and on the cost-effectiveness of cetuximab. Furthermore, it suggests a management of adverse drug reactions to improve the tolerability of the drug.

Pharmacovigilance in oncology.

Background Side effects of cancer therapy are one of the most important issues faced by cancer patients during their illness. Pharmacovigilance, namely the science and activities aimed at monitoring the safety of drugs, is particularly important in oncology, due to the intrinsic biologic toxicity of antineoplastic agents, their narrow therapeutic windows, and the high doses and rigid timing of treatment regimens. Aim of the review To identify the main issues in carrying out an effective pharmacovigilance activity in oncology. Method We searched PubMed for articles about pharmacovigilance in relation to chemotherapy, radiotherapy and targeted therapy for cancer, using MeSH terms and text words. We also searched Embase, CINAHL, Scopus, Micromedex, the Cochrane Library, two pharmacovigilance databases and the gray literature for articles published in 2012-2018. Overall, 137 articles were considered potentially relevant and were critically appraised independently by two authors, leading to the inclusion of 44 relevant studies, guidelines and reviews. Another 10 important research reports were included in the review. Results Eight critical issues of pharmacovigilance in oncology were identified. These issues pertain to: terminology; range of side effects; targeted therapy and immunotherapy; chemoradiotherapy; generic drugs and biosimilars; drug interactions, pharmacogenetics and polypharmacy; special patient categories; and under-reporting of ADRs. Conclusion The importance of pharmacovigilance in oncology must be highlighted with every effort, to improve safety and offer cancer patients every possible help to improve their quality of life during such a critical period of their lives.

Pharmacovigilance workflow in Europe and Italy and pharmacovigilance terminology.

The terminology used in pharmacovigilance can cause confusion, because there are similar terms that describe different phenomena (e.g. adverse reactions, adverse drug reactions, and side effects). Incorrect use of terminology can have negative effects on the reporting of adverse drug reactions and on the interpretation of these reports. To explain the most common terms used in pharmacovigilance, this article first describes the pharmacovigilance workflow process in the European Union and, as an example, in Italy. Then, the article reviews common pharmacovigilance terms.

EU pharmacovigilance regulatory requirements of anticancer biosimilar monoclonal antibodies.

An increasing number of innovative oncology monoclonal antibodies (mAbs) have been introduced into the global market, and biosimilar versions have now also been approved in Europe. Being complex to develop and difficult to manufacture, the biosimilar is a drug similar but not identical in physicochemical characteristics, efficacy, and safety to an original biological drug already approved in the European Union, for which marketing exclusivity rights have expired. Generally, the safety monitoring of biosimilars follows the same requirements that apply to all biologicals, even if specific pharmacovigilance measures exist and some of them are still being debated. The manufacturing process, immunogenicity, traceability, and extrapolation of indication are keywords which may impact on the achievement of additional knowledge about the safety of a biosimilar mAb. In this article, we aim to discuss elements that play a central role in the pharmacovigilance legislation of biosimilar mAbs.

An historical overview over Pharmacovigilance.

Pharmacovigilance started about 170 years ago, although it was not yet named as such at that time. It is structured activity in the professional health field, with important social and commercial implications aimed at monitoring the risk/benefit ratio of drugs, improving patient's safety and the quality of life. In this commentary we report the milestones of pharmacovigilance up to the present day, in order to understand all the steps that have characterized the historical evolution; from the first reports, which were essentially letters or warnings sent by clinicians to publishers of important and famous scientific journals, up to today's modern and ultra-structured electronic registries. The historical phases also help us to understand why pharmacovigilance helped us to achieve such important results for man's health and for pharmacology itself, and to identify the challenges that await Pharmacovigilance in future years.

Amatuximab and novel agents targeting mesothelin for solid tumors.

Mesothelin (MSLN) is considered a promising target for cancer therapy. Originally extracted in 1992 after the immunization of mice with a human ovarian cancer (OC) cell line and cloned in 1996, MSLN seems to be involved in cell adhesion and metastasis. MSLN is prevalent in mesothelia tissues but is expressed in several human cancers, such as OC, pancreatic cancer, mesothelioma, and lung cancer. Amatuximab (MORAb-009) is a mouse-human chimeric monoclonal antibody with a selective affinity for MSLN. The principal mechanism of action comprises inhibition of binding of MSLN with the antigen CA125/MUC16. The highest phase of development is actually a Phase II trial (MORAb-009-201, Europe). In this review, we describe the mechanism of action of amatuximab and other MSLN-targeting novel drugs, along with a discussion about the expected efficacy, safety, and toxicity of this promising group of agents and implications for future research and clinical practice.