LIBRETTO-431: Is it time to reconsider randomized phase 3 trials for uncommon oncogenic drivers in non-small-cell lung cancer?

The recently published results of LIBRETTO-4311 pave the way for a new standard of care in the first-line setting for RET-fusion-positive NSCLCs, which raises important clinical questions not only in the therapeutic landscape of advanced NSCLC but also in the drug development process in the era of uncommon molecular subtypes.

Therapeutic strategies for HER2-positive breast cancer with central nervous system involvement: a literature review and future perspectives.

Background and Objective: Brain metastases (BMs) are present in approximately 55% of patients with HER2-positive breast cancer (HER2+ BC). The introduction of anti-HER2 agents has radically changed the prognosis of these patients by prolonging overall survival. Methods: In this review, we describe the biology of central nervous system (CNS) spreading in patients with HER2+ BC. We also provide a literature review of current treatment strategies of brain metastatic BC, focusing on HER2+ disease, and future perspectives. Key Content and Findings: Treatment of symptomatic BMs includes traditionally neurosurgery and/or radiotherapy, depending on the number of metastases, performance status and systemic disease control. Local treatments, such as surgical excision of BM and stereotactic radiosurgery (SRS), when feasible, are preferred over whole-brain radiotherapy, because of related cognitive impairment. These treatments can lead to a local control of the disease, however, systemic relapses can affect the prognosis of these patients. Recently, new anti-HER2 agents have demonstrated to be effective on BMs, thereby leading to improved survival outcomes with an acceptable quality of life. Despite the clinical benefit of these approaches, BMs still represent a cause of death and effective therapeutic strategies are needed. Conclusions: Different targeted agents have demonstrated significant efficacy with tolerable safety profiles in HER2+ BC patients with BM, and have already been approved for clinical use in this setting. A better understanding of the molecular mechanisms underlying the onset of BMs could suggest novel targeted approaches in order to prevent CNS localization or delay progression to CNS in HER-2 metastatic patients.

Potential predictive role of gut microbiota to immunotherapy in HCC patients: a brief review.

The recent evolution of immunotherapy has revolutionised the treatment of hepatocellular carcinoma (HCC) and has led to new therapeutic standards. The advances in immunotherapy have been accompanied by the recognition of the role of the gut-liver axis in the progression of HCC but also of the clinical relevance of the gut microbiota, which influences host homeostasis but also cancer development and the response to treatment. Dysbiosis, by altering the tumour microenvironment, favours the activation of intracellular signalling pathways and promotes carcinogenesis. The gut microbiota, through their composition and immunomodulatory role, are thus strong predictors of the response to immune checkpoint inhibitor (ICI) treatment as well as an available target to improve ICI efficacy and reduce drug toxicities. In this review we examine the novel role of the gut microbiota as biomarkers in both the diagnosis of HCC and the clinical response to immunotherapy as well as its potential impact on clinical practice in the future.

Crosstalk between ILC3s and Microbiota: Implications for Colon Cancer Development and Treatment with Immune Check Point Inhibitors.

Type 3 innate lymphoid cells (ILC3s) are primarily tissue-resident cells strategically localized at the intestinal barrier that exhibit the fast-acting responsiveness of classic innate immune cells. Populations of these lymphocytes depend on the transcription factor RAR-related orphan receptor and play a key role in maintaining intestinal homeostasis, keeping host-microbial mutualism in check. Current evidence has indicated a bidirectional relationship between microbiota and ILC3s. While ILC3 function and maintenance in the gut are influenced by commensal microbiota, ILC3s themselves can control immune responses to intestinal microbiota by providing host defense against extracellular bacteria, helping to maintain a diverse microbiota and inducing immune tolerance for commensal bacteria. Thus, ILC3s have been linked to host-microbiota interactions and the loss of their normal activity promotes dysbiosis, chronic inflammation and colon cancer. Furthermore, recent evidence has suggested that a healthy dialog between ILC3s and gut microbes is necessary to support antitumor immunity and response to immune checkpoint inhibitor (ICI) therapy. In this review, we summarize the functional interactions occurring between microbiota and ILC3s in homeostasis, providing an overview of the molecular mechanisms orchestrating these interactions. We focus on how alterations in this interplay promote gut inflammation, colorectal cancer and resistance to therapies with immune check point inhibitors.

Immune Checkpoint Inhibitors and the Kidney: A Focus on Diagnosis and Management for Personalised Medicine.

Immunity plays a crucial role in fighting cancer, but tumours can evade the immune system and proliferate and metastasize. Enhancing immune responses is a new challenge in anticancer therapies. In this context, efficacy data are accumulating on immune checkpoint inhibitors and adjuvant therapies for various types of advanced-stage solid tumours. Unfortunately, immune-related adverse events are common. Although infrequent, renal toxicity may occur via several mechanisms and may require temporary or permanent drug suspension, renal biopsy, and/or immunosuppressive treatment. This short review aims to provide a practical approach to the multidisciplinary management of cancer patients with renal toxicity during treatment with immune checkpoint inhibitors.