How Immunotherapy Has Redefined the Treatment Paradigm of Metastatic or Locally Advanced Muscle-Invasive Urothelial Bladder Carcinoma.

In the past decade, the therapeutic arsenal for metastatic bladder cancer has expanded considerably, with the development of immune checkpoint inhibitors (ICIs), antibody-drug conjugates such as enfortumab vedotin, and anti-fibroblast growth factor receptor agents. Clinical trials evaluating ICIs as neoadjuvants, adjuvants, or first- or second-line treatments have produced conflicting results. However, first-line therapeutic strategies have been redefined by the recent publication of results from two clinical trials: CheckMate-901, which demonstrated the superiority of combined treatment with nivolumab and chemotherapy in extending overall survival, and EV-302, which demonstrated that combined treatment with pembrolizumab and enfortumab vedotin reduced the risk of death by 53%. In this review, we discuss the role of ICIs, alone or in combination, in bladder cancer management in the metastatic and adjuvant settings in 2024, considering the latest published trials. The potential role of ICIs as neoadjuvants is also discussed.

Immunotherapy for head and neck squamous cell carcinoma: current status and perspectives.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several solid cancers, including head and neck squamous cell carcinoma (HNSCC). First approved for second-line settings, ICIs are now used for the first-line treatment of HNSCCs, mainly in combination with standard chemotherapy. This review focuses on the results of the main phase III studies evaluating ICIs in recurrent or metastatic HNSCCs. The efficacy and indications according to the PD-L1 status, the main predictive biomarker, are discussed. The results of trials assessing ICI efficacy for locally advanced disease, including the neoadjuvant setting are also discussed. Finally, therapeutic combinations that are potential treatments for HNSCCs, including ICIs and targeted therapies such as anti-EGFR agents, are presented.

Head and neck (HN) cancer is common and challenging to treat, especially when it relapses locally (recurrence) or in a different organ (metastatic). Immunotherapy, which strengthens the immune system's ability to target tumor cells, has revolutionized the treatment of several cancers, including metastatic HN cancers. Pembrolizumab, an immunotherapy drug, is now combined with chemotherapy as standard treatment for recurrent or metastatic HN cancers; it has a manageable toxicity profile. However, some patients do not respond to treatment, and the disease may relapse after several injections. Efforts are currently underway to improve the efficacies of these immunotherapy treatments by combining them with other therapies, such as anti-EGFR treatment. Current studies seek biomarkers to identify patients likely to benefit from these treatments and those who may require alternative treatments.

Clinical and Biological Differences between Upper Tract Carcinoma and Bladder Urothelial Cancer, Including Implications for Clinical Practice.

Upper tract urothelial carcinoma (UTUC) is a rare disease included, along with the much more frequent urothelial bladder cancer (BUC), in the family of urothelial carcinomas (UCs). However, while UTUCs and BUCs share several features, their epidemiological, clinical, pathological, and biological differences must be considered to establish an optimal therapeutic strategy. This review examines the clinical differences between UTUC and BUC, as well as the main results obtained by molecular screening of the two diseases. The findings of clinical trials, performed in peri-operative and metastatic settings and assessing systemic treatments in UC, are summarised. A comparison of the data obtained for UTUC and BUC suggests improved therapeutic approaches, both in regards to routine practice and future drug development.

Immune checkpoint inhibitor rechallenge in patients who previously experienced immune-related inflammatory arthritis: a multicentre observational study.

OBJECTIVE: Another course of immune checkpoint inhibitors (ICIs) is often considered in patients with cancer progression and previous immune-related adverse events, including inflammatory arthritis (ICI-IA), but there are limited data regarding safety of ICI rechallenge in this setting. We aimed to assess the rate and clinical features associated with ICI-IA flare/recurrence on ICI rechallenge. METHODS: We conducted a multicentre observational study including cancer patients with ICI-IA who started a second course of ICI more than 3 months after ICI discontinuation in four French university hospitals. Primary outcome was the frequency of ICI flare/recurrence after ICI rechallenge. RESULTS: Twenty-three patients were included. At the time of ICI rechallenge, 18 patients reported no symptoms of ICI-IA (78%) and 5 had grade 1 (22%), 11 patients (48%) were not receiving any ICI-IA treatment, 11 (48%) were still on prednisone, 2 (9%) were on conventional synthetic disease-modifying antirheumatic drugs and 1 (4%) on anti-IL-6. ICI-IA flare/recurrence occurred in 12 patients (52%) with a median time of 1 month after ICI rechallenge. ICI-IA phenotype, disease activity and ICI-IA treatment at the time of ICI rechallenge did not differ according to ICI-IA flare/recurrence status. CONCLUSION: In this first observational study of ICI-IA patients rechallenged with ICI, about half of the patients experienced ICI-IA flare/recurrence with a similar phenotype but occurring earlier than the initial ICI-IA, warranting close monitoring during the first month of retreatment. Risk of flare did not differ according to baseline immunosuppressive treatment at the time of rechallenge.

Combinations of Anti-Angiogenic Agents and Immune Checkpoint Inhibitors in Renal Cell Carcinoma: Best Option?

Over the past decade, major advances have been made in the treatment of advanced and metastatic renal cell carcinomas, specifically clear cell carcinomas. For many years the optimal approach was sequential; thus, monotherapies [principally tyrosine kinase inhibitors (TKIs)] targeting angiogenesis until toxicity or progressive disease developed. The rationale was the common mechanisms of action of the targeting agents and avoidance of the risk of overlapping toxicities. Immune checkpoint inhibitors (ICIs) are effective monotherapies, and combinations thereof with anti-angiogenic agents were thus later considered. Synergistic interactions were reported in vitro. Clinical efficacy was evident in three pivotal phase III trials with axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab combinations. Two other combinations showed interesting results but did not improve overall survival. However, the data aided our understanding of the new therapeutic approaches. A combination of the ICIs nivolumab and ipilimumab was the first to evidence better progression-free and overall survival compared to sunitinib in patients with intermediate or unfavourable prognoses as evaluated by the International mRCC Database Consortium (IMDC). Here we focus on the TKI-ICI combinations, emphasising the rationale of their use and the clinical results. To date, no biomarker facilitating the selection of an optimal treatment by disease and patient status has been reported.

Therapeutic Management of Metastatic Clear Cell Renal Cell Carcinoma: A Revolution in Every Decade.

Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010-2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival.

Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies.

BACKGROUND: Tumor-associated macrophages (TAMs) having immunosuppressive properties are one of the most abundant immune cells in the tumor microenvironment (TME). Preclinical studies have highlighted the potential role of TAMs in resistance to immune checkpoint blockers (ICBs). Here, we investigated the predictive value of TAM infiltration in patients with non-small cell lung cancer (NSCLC) treated with ICBs and characterized their transcriptomic profiles. METHODS: Tumor samples were collected from 152 patients with NSCLC before ICB treatment onset. After immunohistochemical staining and image analysis, the correlation between CD163+ cell infiltration and survival was analyzed. Spatial transcriptomic analyses were performed using the NanoString GeoMx Immune Pathways assay to compare the gene expression profile of tumors with high or low levels of CD163+ cell infiltration and to identify determinants of response to ICBs in tumors with high CD163+ infiltration. RESULTS: Low intratumoral CD163+ cell infiltration was associated with longer progression-free survival (PFS; HR 0.61, 95% CI 0.40 to 0.94, p=0.023) and overall survival (OS; HR 0.48, 95% CI 0.28 to 0.80, p=0.004) under ICB treatment. Spatial transcriptomic profiles of 16 tumors revealed the upregulation of ITGAM, CD27, and CCL5 in tumors with high CD163+ cell infiltration. Moreover, in tumors with high macrophage infiltration, the upregulation of genes associated with the interferon-γ signaling pathway and the M1 phenotype was associated with better responses under immunotherapy. Surprisingly, we found also a significantly higher expression of CSF1R in the tumors of responders. Analysis of three independent data sets confirmed that high CSF1R expression was associated with an increased durable clinical benefit rate (47% vs 6%, p=0.004), PFS (median 10.89 months vs 1.67 months, p=0.001), and OS (median 23.11 months vs 2.66 months, p<0.001) under ICB treatment. CONCLUSIONS: Enrichment of TAMs in the TME of NSCLC is associated with resistance to immunotherapy regardless of the programmed death ligand 1 status and is driven by upregulation of CD27, ITGAM, and CCL5 gene expression within the tumor compartment. Our transcriptomic analyses identify new potential targets to alter TAM recruitment/polarization and highlight the complexity of the CSF1R pathway, which may not be a suitable target to improve ICB efficacy.

Combining immune checkpoint inhibitors with chemotherapy in advanced solid tumours: A review.

The use of immune checkpoint inhibitors (ICIs), especially anti-programmed cell death 1 (PD1) and anti-programmed cell death ligand 1 (PD-L1), has changed practices in oncology, becoming a new standard of care in first or subsequent lines for several cancer subtypes. Recent data have highlighted the ability of standard chemotherapy to enhance immunogenicity and/or to break immunoresistance of the tumour and its microenvironment, leading to a rationale for the use of ICIs in combination with the standard chemotherapy regimen to improve efficacy of cancer treatment. Here, we propose to review randomised clinical trials evaluating concomitant administration of ICIs and chemotherapy, to assess clinical efficacy and safety profiles in advanced solid tumours. Association of these two modes of action on treatments has shown improved overall survival and better objective response rates than standard chemotherapy, especially in first-line treatment of non-small cell lung cancer (NSCLC) and for PD1/PD-L1 enriched tumours, highlighting a potential synergistic effect of this treatment combination in certain tumour types. However, improved survival results with the use of anti-PD-L1 avelumab as a maintenance schedule for bladder cancer raises the question of the most appropriate approach between sequential and concomitant administration of chemoimmunotherapy. To date, no trials have compared in a head-to-head protocol the administration of concomitant chemoimmunotherapy with chemotherapy, used for tumour debulking, followed by administration of ICIs. Regarding the tolerance profile, no new safety signals were found with the combination tested to date. Interestingly, recent results have shown an improved Progression Free survival 2 (PFS2) (defined as the progression after the next line of therapy) in head-and-neck cancers or NSCLC after a first-line pembrolizumab-chemotherapy combination, suggesting a potential long-lasting effect of ICIs when used in combination in the first-line setting.

Adjuvant therapy in renal cell carcinoma: Current knowledges and future perspectives.

While many patients with non-metastatic renal cell carcinoma (RCC) can be cured with surgery alone, upward of 40% of patients recur in a short delay, raising the question of additional perioperative treatments. To address this clinical need, multiple trials have investigated the addition of systemic therapy after surgery in localized or locally advanced RCC. However, adjuvant systemic therapies in the past decades have provided disappointing results with only one positive study of antiangiogenic treatments. Debatable clinical benefit of adjuvant antiangiogenic tyrosine kinase inhibitors (TKIs) therapy at cost of high adverse event profiles have paved the way for development of alternative perioperative strategies, such as immune checkpoint inhibitors (ICIs). Further investigation into combination therapies with immunotherapy, neoadjuvant approaches and patient selection will be key to determining optimal adjuvant therapy regimens to improve outcomes and increase cure rates for patients with non-metastatic RCC. In this review, we extensively present the strong and weakness of the five adjuvant antiangiogenic TKI trials, highlight the main differences and discuss about the reasons of failure. We also expose the current ongoing clinical trials in the perioperative setting and provide new insights concerning the evolving landscape of the management of non-metastatic RCC.

New Insights into Adjuvant Therapy in Renal Cell Carcinoma: Is the Chapter of VEGF Inhibitors Definitely Closed?

Adjuvant therapy with antiangiogenic agents in locoregional renal cell carcinoma did not translate into a sufficient benefit and highlight the crucial role of patient selection. Ongoing clinical trials with immune-targeted agents hold great promise for this unmet clinical need.

Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression.

Only a minority of patients derive long-term clinical benefit from anti-PD1/PD-L1 monoclonal antibodies. The presence of tertiary lymphoid structures (TLS) has been associated with improved survival in several tumor types. Here, using a large-scale retrospective analysis of three independent cohorts of cancer patients treated with anti-PD1/PD-L1 antibodies, we showed that the presence of mature TLS was associated with improved objective response rate, progression-free survival, and overall survival independently of PD-L1 expression status and CD8+ T-cell density. These results pave the way for using TLS detection to select patients who are more likely to benefit from immune checkpoint blockade.

Which place for avelumab in the management of urothelial carcinoma?

Introduction: Urothelial carcinoma (UC) has a poor prognosis, with the only standard first-line metastatic treatment being platinum-based chemotherapy. Until 2018, there was no Food and Drug Administration (FDA)-approved drug for second-line setting, and only vinflunine was approved by the European Medicines Agency (EMEA) in Europe. However, targeting the programmed cell-death 1 (PD-1)/PD-ligand 1 (PD-L1) pathway with immune checkpoint inhibitor (ICI) agents has shown encouraging results. Avelumab is a human anti-PD-L1 antibody that is currently being investigated in several trials. Areas covered: In this review article, we summarise preclinical, clinical, and safety data on avelumab for UC, and describeongoing trials that are evaluating avelumab for local or advanced diseases. We also compare its place in the management of UC. Expert opinion: Avelumab has shown clinical efficacy for metastatic and advanced UC in phase I studies after the failure of platinum-based therapy with a well-tolerated safety profile. This anti-PD-L1 targeting agent has the capacity to induce antibody-dependant cellular cytotoxicity (ADCC)-mediated tumor cell lysis compared to other ICI. These results led to FDA approval of avelumab as a second-line treatment for locally advanced and metastatic UC. Avelumab is also investigated in phase II and in a randomized phase III trial as a maintenance therapy in UC as well for combination use with chemotherapy.