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This systematic review evaluated treatment patterns and guidelines in advanced/metastatic and adjuvant renal cell carcinoma (RCC) in the Asia-Pacific region.
Embase, PubMed, and congresses were searched for observational studies and guidelines in accordance with PRISMA. Records published during 2016-2021 (2019-2021 for congresses) were included.
Nine studies and three guidelines were identified overall. In advanced/metastatic RCC, the most common treatments were tyrosine kinase inhibitors (TKIs) (notably sunitinib: 33-100%) for first-line, and everolimus (13-85%) or axitinib (2-89%) for second-line therapy. In adjuvant RCC, sunitinib was most used (54%), followed by mammalian target of rapamycin inhibitors (mTORis, 27%) with immunotherapy being less common (16%). The guidelines provided varying recommendations for advanced/metastatic RCC. For first-line in advanced/metastatic clear cell RCC (the most common subtype), guidelines recommended mTORis (everolimus for poor-risk patients) (India, 2016); clinical study enrollment for high-risk patients or TKIs for low- to medium-risk patients (China, 2019); or immunotherapy based on survival benefits over sunitinib; dose adjustment was also recommended to manage TKI toxicities (Hong Kong, 2019). The landscape remained more static in the adjuvant setting, but best practice was uncertain. No clear trends were identified in patient characteristics.

In KEYNOTE-564, adjuvant pembrolizumab, a PD-1 antibody, significantly improved disease-free survival (DFS) in localised clear-cell renal cell carcinoma (ccRCC) with a high risk of relapse. In 2021, the European Association of Urology RCC Guidelines Panel issued a weak recommendation for adjuvant pembrolizumab for high-risk ccRCC as defined by the trial until final overall survival data and results from other trials were available. Meanwhile, the primary DFS endpoints were not met for adjuvant atezolizumab (PD-L1 inhibitor; IMmotion010), adjuvant nivolumab plus ipilimumab (CheckMate 914), or perioperative nivolumab (PROSPER). Owing to heterogeneity, a meta-analysis is not recommended. Pembrolizumab remains the only immune checkpoint inhibitor currently recommended in this setting. Overall survival data are immature and biomarkers to predict outcome are lacking. Uncertainty exists and overtreatment is occurring. Treatment decisions should be made with caution and with the involvement of each patient. PATIENT SUMMARY: New results from three trials of immunotherapy after surgery for kidney cancer to reduce the risk of recurrence showed no improvement with these treatments. These results are in contrast to an earlier study that showed that the antibody pembrolizumab did extend the time before kidney cancer recurrence, even though it is not yet clear if overall survival is longer. Thus, we cautiously recommend pembrolizumab as additional treatment in high-risk kidney cancer after surgery, but patient preference should be carefully considered and the risk of overtreatment should be discussed.

Background: Gastric adenocarcinoma (GAC) is highly heterogeneous and closely related to colorectal cancer (CRC) both molecularly and functionally. GAC is currently subtyped using a system developed by TCGA. However, with the emergence of immunotherapies, this system has failed to identify suitable treatment candidates. Methods: Consensus molecular subtypes (CMSs) developed for CRC were used for molecular subtyping in GAC based on public expression cohorts, including TCGA, ACRG, and a cohort of GAC patients treated with the programmed cell death 1 (PD-1) inhibitor pembrolizumab. All aspects of each subtype, including clinical outcome, molecular characteristics, oncogenic pathway activity, and the response to immunotherapy, were fully explored. Results: CMS classification was efficiently applied to GAC. CMS4, characterized by EMT activation, stromal invasion, angiogenesis, and the worst clinical outcomes (median OS 24.2 months), was the predominant subtype (38.8%~44.3%) and an independent prognostic indicator that outperformed classical TCGA subtyping. CMS1 (20.9%~21.5%) displayed hypermutation, low SCNV, immune activation, and best clinical outcomes (median OS > 120 months). CMS3 (17.95%~25.7%) was characterized by overactive metabolism, KRAS mutation, and intermediate outcomes (median OS 85.6 months). CMS2 (14.6%~16.3%) was enriched for WNT and MYC activation, differentiated epithelial characteristics, APC mutation, lack of ARID1A, and intermediate outcomes (median OS 48.7 months). Notably, CMS1 was strongly correlated with immunotherapy biomarkers and favorable for the anti-PD-1 drug pembrolizumab, whereas CMS4 was poorly responsive but became more sensitive after EMT-based stratification. Conclusions: Our study reveals the practical utility of CMS classification for GAC to improve clinical outcomes and identify candidates who will respond to immunotherapy.

Adjuvant treatment of nonmetastatic high-risk renal cell carcinoma is an unmet medical need. In the past, several tyrosine kinase inhibitor trials have failed to demonstrate an improvement of disease-free survival (DFS) in this setting. Only one trial (S-TRAC) provided evidence for improved DFS with sunitinib but without an overall survival (OS) signal. Keynote-564 is the first trial of an immune checkpoint inhibitor that significantly improved DFS with adjuvant pembrolizumab, a programmed death receptor-1 antibody, in clear cell renal cell carcinoma with a high risk of relapse. The intention-to-treat population, which included a group of patients after metastasectomy and no evidence of disease (M1 NED), had a significant DFS benefit. The OS data are not mature as yet. The Renal Cell Carcinoma Guideline Panel issues a weak recommendation for the adjuvant use of pembrolizumab for high-risk clear cell renal carcinoma, as defined by the trial until final OS data are available. However, the trial reilluminates the discussion on when and in whom metastasectomy should be performed. Here, caution is necessary not to perform metastasectomy in patients with poor prognostic features and rapid progressive disease, which must be excluded by a confirmatory scan of disease status prior to planned metastasectomy. PATIENT SUMMARY: New data from the adjuvant immune checkpoint inhibitor trial with pembrolizumab (a programmed death receptor-1 antibody) for the treatment of high-risk clear cell renal cell carcinoma (ccRCC) after surgery showed that the drug prolonged the period of being cancer free significantly, although whether it prolonged survival remained uncertain. Consequently, pembrolizumab is cautiously recommended as additional (ie, adjuvant) treatment in high-risk ccRCC after kidney cancer surgery.

Cancer is associated with higher morbidity and mortality and is the second leading cause of death in the US. Further, in some nations, cancer has overtaken heart disease as the leading cause of mortality. Identification of molecular mechanisms by which cancerous cells evade T cell-mediated cytotoxic damage has led to the modern era of immunotherapy in cancer treatment. Agents that release these immune brakes have shown activity to recover dysfunctional T cells and regress various cancer. Both cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Death-1 (PD-1) play their role as physiologic brakes on unrestrained cytotoxic T effector function. CTLA-4 (CD 152) is a B7/CD28 family; it mediates immunosuppression by indirectly diminishing signaling through the co-stimulatory receptor CD28. Ipilimumab is the first and only FDA-approved CTLA-4 inhibitor; PD-1 is an inhibitory transmembrane protein expressed on T cells, B cells, Natural Killer cells (NKs), and Myeloid-Derived Suppressor Cells (MDSCs). Programmed Death-Ligand 1 (PD-L1) is expressed on the surface of multiple tissue types, including many tumor cells and hematopoietic cells. PD-L2 is more restricted to hematopoietic cells. Blockade of the PD-1 /PDL-1 pathway can enhance anti-tumor T cell reactivity and promotes immune control over the cancerous cells. Since the FDA approval of ipilimumab (human IgG1 k anti-CTLA-4 monoclonal antibody) in 2011, six more immune checkpoint inhibitors (ICIs) have been approved for cancer therapy. PD-1 inhibitors nivolumab, pembrolizumab, cemiplimab and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab are in the current list of the approved agents in addition to ipilimumab. In this review paper, we discuss the role of each immune checkpoint inhibitor (ICI), the landmark trials which led to their FDA approval, and the strength of the evidence per National Comprehensive Cancer Network (NCCN), which is broadly utilized by medical oncologists and hematologists in their daily practice.

Successful targeting and inhibition of the cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death-1 protein/programmed cell death ligand 1 immune checkpoint pathways has led to a rapidly expanding repertoire of immune checkpoint inhibitors for the treatment of various cancers. The approved agents now include ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab. In addition to antitumor responses, immune checkpoint inhibition can lead to activation of autoreactive T-cells resulting in unique immune-related adverse events (irAEs). Therefore, it is imperative that oncology nurses, and other clinicians involved in the care of cancer patients, are familiar with the management of irAEs which differ significantly from the management of adverse events from cytotoxic chemotherapy. Herein, we review the mechanisms of irAEs and strategies for management of irAEs and highlight similarities as well as differences among clinical guidelines from the National Comprehensive Cancer Network, American Society of Clinical Oncology, Society for Immunotherapy of Cancer, and European Society for Medical Oncology. Understanding these similarities and key differences will facilitate the development and implementation of a practice site-specific plan for the management of irAEs.

Clinical practice guidelines include recommendations intended to optimize patient care. In the last years, the introduction of immune checkpoint inhibitors is rapidly changing lung cancer management and therefore guidelines are essential to assist clinicians in such an evolving field. We reviewed the recommendations about the use of these immune checkpoint inhibitors in clinical practice guidelines issued by three scientific societies [European Society of Medical Oncology (ESMO); American Society of Clinical Oncology (ASCO); Italian Association of Medical Oncology (AIOM)] and one not-for-profit U.S. alliance [National Comprehensive Cancer Network (NCCN)] in order to underline their strengths and limitations. All the examined guidelines include some recommendations about use of immune checkpoint inhibitors in lung cancer patients. ASCO guidelines have a good methodologic background while their major limitation is their slow updating. NCCN guidelines, by contrast, are continuously updated but suffer from weak methodology and poor comparative tools. ESMO guidelines introduce a tool to assess the magnitude of clinical benefit for each recommended intervention that, although with some limitations, may improve clinical decision making. AIOM guidelines apply a robust methodology, but contain recommendations only on drugs reimbursed in Italy, thus limiting their applicability in different contexts. Clinical practice guidelines are useful tools that assist clinicians treating lung cancer patients with immune checkpoint inhibitors. Their use would improve homogeneity and appropriateness, even in this rapidly evolving field.

BACKGROUND: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies.
OBJECTIVE: To review, from an infectious diseases perspective, the safety profile of immune checkpoint inhibitors, LFA-3-targeted agents, cell adhesion inhibitors, sphingosine-1-phosphate receptor modulators and proteasome inhibitors, and to suggest preventive recommendations.
METHODS: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family.
BACKGROUND: T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death (PD)-1/PD-1 ligand 1 (PD-L1)-targeted agents do not appear to intrinsically increase the risk of infection but can induce immune-related adverse effects requiring additional immunosuppression. Although CD4+ T-cell lymphopenia is associated with alefacept, no opportunistic infections have been observed. Progressive multifocal leukoencephalopathy (PML) may occur during therapy with natalizumab (anti-α4-integrin monoclonal antibody (mAb)) and efalizumab (anti-CD11a mAb), but no cases have been reported to date with vedolizumab (anti-α4β7 mAb). In patients at high risk for PML (positive anti-JC polyomavirus serology with serum antibody index >1.5 and duration of therapy ≥48 months), the benefit-risk ratio of continuing natalizumab should be carefully considered. Fingolimod induces profound peripheral blood lymphopenia and increases the risk of varicella zoster virus (VZV) infection. Prophylaxis with (val)acyclovir and VZV vaccination should be considered. Proteasome inhibitors also increase the risk of VZV infection, and antiviral prophylaxis with (val)acyclovir is recommended. Anti-Pneumocystis prophylaxis may be considered in myeloma multiple patients with additional risk factors (i.e. high-dose corticosteroids).
CONCLUSIONS: Clinicians should be aware of the risk of immune-related adverse effects and PML in patients receiving immune checkpoint and cell adhesion inhibitors respectively.

Programmed cell death protein 1 (PD-1) inhibitor therapies are now a standard treatment for advanced melanoma and other tumor types. The immune-related adverse events (irAEs) associated with PD-1 inhibitor therapy are drastically different from the AEs associated with chemotherapy. Because these irAEs reflect immune system activation rather than side effects of therapy, nurses should be cognizant of the range of organ systems potentially affected as well as likely clinical presentations.
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This article presents consensus statements to guide nurses in the recognition and management of irAEs associated with PD-1 inhibitor monotherapy for advanced melanoma.
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Members of the Melanoma Nursing Initiative discussed the current literature and clinical experience regarding nursing interventions related to irAEs associated with PD-1 inhibitor therapy.
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The care step pathways provided for select irAEs represent a proactive, comprehensive nursing care plan to support optimal outcomes for patients receiving PD-1 inhibitor therapy.