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RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1-2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the 'old' multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events.

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This Viewpoint discusses cancer antigen expression and antibody drug conjugates.

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The clinical development and then the progressive entry in clinical practice of antibody-drug conjugates (ADC) have marked a transformative advancement in the overall cancer treatment. ADCs have been extensively tested for a large number of tumors, reporting heterogeneous clinical efficacy and safety results. In some diseases, the advent of ADCs has yielded significant changes in the prognostic trajectory, portending an improvement of the survival and/or quality of life. ADCs are targeted agents, capable of delivering highly cytotoxic payloads selectively to antigen-expressing cancer cells. As such, they have been intended as perfect "bullets" to enable the promise of precision medicine, toward high-efficacy and limited-toxicity treatment options. However, only some approved ADCs are intended for the use in biomarker-selected patient populations, restricting potentially the opportunity to be more precise. Yet, key characteristics of modern ADCs might allow the activity of ADCs in tumors with heterogeneous or low expression of cancer antigens, resulting in a clinical activity that could sublimate the classic paradigm of a drug-to-target perfect match. In our review, we portrayed the current landscape of approved ADCs, reporting data of activity as related to the expression of the cancer antigens, and elucidating possible determinants of the safety and efficacy, including when used in a therapeutic sequence.

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INTRODUCTION: Drugs available for the treatment of breast cancer are increasing, yielding improved oncological outcomes. The efficacy and safety of anticancer drugs significantly depend on pharmacokinetic profiles, which could be influenced by several factors, such as sex hormones. AREAS COVERED: This article discusses the potential hormone-related pharmacokinetic influences on novel breast cancer pharmacotherapies. EXPERT OPINION: Recently approved drugs for the treatment of breast cancer belong to different classes, each with unique pharmacokinetic profile. The impact of hormones, such as estrogen and progesterone, may occur at different steps of drug metabolism. Key effects of sex hormones ha ve been reported on multidrug-resistant transporters and enzymes involved in the liver metabolism of drugs, such as cytochromes. Nevertheless, no data is currently available to establish hormone-related metabolic interactions that may account for variability in drug scheduling and selection. Whereas we recognize influences may occur, we do not assume hormones alone can yield clinically significant metabolic changes. Rather, we believe that hormonal influences should be considered along with other elements that may affect drugs metabolism, such as concomitant medications, age-related pharmacokinetic changes, and genetic polymorphisms, in order to deliver treatment personalization and ensure better tolerability and safety of anticancer treatments.

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