Immune checkpoint inhibitors (ICIs) in combination with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have become a new standard of care in treatment-naïve ...patients with advanced renal cell carcinoma (RCC). The rationale for these combinations relies on the interplay between the immune and angiogenic systems. The angiogenic factors and their receptors can promote an immunosuppressive tumor microenvironment by a direct effect on the innate immune cells and adaptive immune cells, and by an indirect effect through their influence on endothelial cells. Antiangiogenic therapies counteract these immunosuppressive effects by increasing tumor infiltration of mature dendritic cells and effector T cells, and decreasing tumor infiltration of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells. The immunomodulatory properties of antiangiogenic therapies combined with ICIs may provide enhanced activity through various mechanisms of action. Different associations with ICIs such as programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors and antiangiogenic therapies such as VEGFR-TKI or bevacizumab have been tested and led to the approval of pembrolizumab plus axitinib and avelumab plus axitinib in the first-line treatment of patients with advanced RCC. Other VEGFR axis inhibitors and ICI combinations are currently being tested with promising results. More combinations of immune agents, including cancer vaccines and immunostimulatory agents, are also being evaluated in association with VEGFR-TKI. Defining the best combination for each patient as well as the optimal therapeutic sequence will be essential to guide treatment decisions in clinical practice.
The management of advanced-stage renal cell carcinoma (RCC) has been transformed by the development of immune-checkpoint inhibitors (ICIs). Nonetheless, most patients do not derive durable clinical ...benefit from these agents. Importantly, unlike other immunotherapy-responsive solid tumours, most RCCs have only a moderate mutational burden, and paradoxically, high levels of tumour CD8
T cell infiltration are associated with a worse prognosis in patients with this disease. Building on the successes of antibodies targeting the PD-1 and CTLA4 immune checkpoints, multiple innovative immunotherapies are now in clinical development for the treatment of patients with RCC, including ICIs with novel targets, co-stimulatory pathway agonists, modified cytokines, metabolic pathway modulators, cell therapies and therapeutic vaccines. However, the successful development of such novel immune-based treatments and of immunotherapy-based combinations will require a disease-specific framework that incorporates a deep understanding of RCC immunobiology. In this Review, using the structure provided by the well-described cancer-immunity cycle, we outline the key steps required for a successful antitumour immune response in the context of RCC, and describe the development of promising new immunotherapies within the context of this framework. With this approach, we summarize and analyse the most encouraging targets of novel immune-based therapies within the RCC microenvironment, and review the landscape of emerging antigen-directed therapies for this disease.
Immune modulatory treatment regimens, led by immune checkpoint inhibitors, have transformed the treatment of clear-cell renal cell carcinoma. First-in-class, the PD-1 inhibitor nivolumab improved ...overall survival in advanced renal cell carcinoma following prior anti-angiogenic therapy, an important shift in the management of clear-cell renal cell carcinoma. Further improvements of long-term outcomes will be driven by combinations in the first-line setting, including PD-1/PD-L1 associated with antiangiogenic therapies, or PD1/PD-L1 inhibitors with other immune checkpoint inhibitors such as anti-CTLA-4, anti-LAG-3 or TIM-3 targeted therapies. The first two randomized Phase 3 trials assessing these combinations have now challenged sunitinib in first-line setting. First, the CheckMate 214 trial demonstrated an objective response rate and overall survival benefit for the combination of nivolumab plus ipilimumab in the intermediate- and poor-risk patients. Second, the IMMotion 151 study demonstrated a progression-free survival benefit for the atezolizumab plus bevacizumab combination by investigator assessment. Further Phase 3 trials are awaited with tyrosine kinase and immune checkpoint inhibitor combinations. Clinical trials of immune checkpoint inhibitors are also actively investigated in the localized adjuvant or neoadjuvant setting. Nevertheless, the search for biomarkers along with new clinical trial designs will be crucial to better select the patients that may derive the greatest benefit from these advances. The continuing improvement of antitumor immunity comprehension and the emergence of new immune modulatory treatments will deeply change the management of renal cell carcinoma for the years to come.
Long non-coding RNAs (lncRNAs) are regulators of cellular machinery that are commonly dysregulated in genitourinary malignancies. Accordingly, the investigation of lncRNAs is improving our ...understanding of genitourinary cancers, from development to progression and dissemination. lncRNAs are involved in major oncogenic events in genitourinary malignancies, including androgen receptor (AR) signalling in prostate cancer, hypoxia-inducible factor (HIF) pathway activation in renal cell carcinoma and invasiveness in bladder cancer, as well as multiple other proliferation and survival mechanisms. In line with their putative oncogenic roles, new lncRNA-based classifications are emerging as potent predictors of prognosis. In clinical practice, detection of oncogenic lncRNAs in serum or urine might enable early cancer detection, and lncRNAs might also be promising therapeutic targets for patients with genitourinary cancer. Furthermore, as predictors of sensitivity to anticancer treatments, lncRNAs could be integrated into future precision medicine strategies. Overall, lncRNAs are promising new candidates for molecular studies and for discovery of innovative biomarkers and are putative therapeutic targets in genitourinary oncology.
Non-clear cell renal cell carcinomas (RCCs) account for up to 25% of kidney cancers and encompass distinct diseases with distinct pathologic features, different molecular alterations, and various ...patterns of response to systemic therapies. Recent advances in molecular biology and large collaborative efforts helped to better define the oncogenic mechanisms at play in papillary, chromophobe, collecting duct, medullary, translocation, and sarcomatoid RCCs. Papillary RCCs are divided into several subsets of tumors characterized by distinct gene expression profiles, chromatin remodeling genes, cell cycle changes, and alterations of the MET pathway. Chromophobe RCC genomic analysis revealed mostly metabolic pathway alterations with mitochondrial dysfunctions. Translocation RCCs are characterized by MITF fusions and wide genomic reprogramming. Collecting duct carcinomas are distinct entities from upper tract urothelial carcinomas associated with high T-cell infiltration and metabolic alterations. Medullary RCCs present alterations of the INI1 gene and rhabdoid features at pathologic analysis. Finally, sarcomatoid RCCs represent sarcomatoid differentiation for any subsets of RCCs with specific alterations associated with mesenchymal dedifferentiation. From the standpoint of systemic therapy, more than a decade of using VEGF and mTOR inhibitors showed that they generally had limited efficacy in non-clear cell RCCs compared with clear cell RCCs. MET inhibitors are actively being developed for papillary RCC with a specific focus on MET-driven tumors. Other strategies under investigation include CDK4/6 inhibitors in tumors with cell cycle alterations and EZH2 inhibitors in RCCs with INI1 loss. The emergence of immune checkpoint inhibitors and combination strategies enlarges the spectrum of investigational treatments. Better understanding of driver and passenger alterations and better patient stratification along with dedicated clinical networks will be key to improving the management of these rare tumors.
Background
The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype‐specific prospective controlled data lacking, this study retrospectively evaluated doxorubicin plus ...dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone as first‐line treatments for advanced/metastatic leiomyosarcoma treated at European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC‐STBSG) sites.
Methods
The inclusion criteria were a confirmed histological diagnosis, treatment between January 2010 and December 2015, measurable disease (Response Evaluation Criteria in Solid Tumors 1.1), an Eastern Cooperative Oncology Group performance status ≤2, and an age ≥ 18 years. The endpoints were progression‐free survival (PFS), overall survival (OS), and overall response rate (ORR). PFS was analyzed with methods for interval‐censored data. Patients were matched according to their propensity scores, which were estimated with a logistic regression model accounting for histology, grade, age, sex, performance status, tumor site, and tumor extent.
Results
Three hundred three patients from 18 EORTC‐STBSG sites were identified. One hundred seventeen (39%) received doxorubicin plus dacarbazine, 71 (23%) received doxorubicin plus ifosfamide, and 115 (38%) received doxorubicin. In the 2:1:2 propensity score–matched population (205 patients), the estimated median PFS was 9.2 months (95% confidence interval CI, 5.2‐9.7 months), 8.2 months (95% CI, 5.2‐10.1 months), and 4.8 months (95% CI, 2.3‐6.0 months) with ORRs of 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone, respectively. PFS was significantly longer with doxorubicin plus dacarbazine versus doxorubicin (hazard ratio HR, 0.72; 95% CI, 0.52‐0.99). Doxorubicin plus dacarbazine was associated with longer OS (median, 36.8 months; 95% CI, 27.9‐47.2 months) in comparison with both doxorubicin plus ifosfamide (median, 21.9 months; 95% CI, 16.7‐33.4 months; HR, 0.65; 95% CI, 0.40‐1.06) and doxorubicin (median, 30.3 months; 95% CI, 21.0‐36.3 months; HR, 0.66; 95% CI, 0.43‐0.99). Adjusted analyses retained an effect for PFS but not for OS. None of the factors selected for multivariate analysis had a significant interaction with the received treatment for both PFS and OS.
Conclusions
This is the largest retrospective study of first‐line treatment for advanced leiomyosarcoma. In the propensity score–matched population, doxorubicin and dacarbazine showed favorable activity in terms of both ORR and PFS and warrants further evaluation in prospective trials.
In this propensity score‐adjusted, multi‐institutional series, doxorubicin and dacarbazine show better outcomes for the first‐line treatment of advanced leiomyosarcoma and warrant further studies. This series represents a benchmark for the future development of trials for leiomyosarcoma.
Sarcomatoid features in renal cell carcinoma (RCC) have long been associated with dismal prognosis and poor response to therapy, while biological mechanisms underpinning sarcomatoid dedifferentiation ...remained obscure. Several efforts have been conducted to break down the molecular profile of sarcomatoid RCC and investigate different targeted therapeutic approaches. Mutations enriched for in sarcomatoid RCC involve, notably,
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, cell cycle, and chromatin-remodeling genes. The immunological landscape of these tumors is also gradually being uncovered, showing frequent expression of programmed cell death ligand-1 (PD-L1) and high levels of tumor-infiltrating lymphocytes. These features may be major determinants for the activity of immune checkpoint inhibitors in this population, which has been confirmed by retrospective studies and subgroup analyses of large randomized phase 3 trials. Combinations based on PD-1/PD-L1 inhibition have demonstrated response rates and complete responses in >50% and >10% of patients in the first-line metastatic setting, respectively, with median overall survival exceeding two years. This remarkable improvement in outcomes effectively establishes immune checkpoint inhibitor combinations as a new standard of care in patients with sarcomatoid RCC. New research fields, including epigenetic regulations and tumor-microenvironment interactions, may further sharpen understanding of sarcomatoid RCC and advance therapeutic developments.
Until recently, continuing androgen deprivation therapy (ADT) and closely monitoring patients until evolution towards metastatic castration-resistant prostate cancer (CRPC) were recommended in men ...with non-metastatic CRPC (nmCRPC). Because delaying the development of metastases and symptoms in these patients is a major issue, several trials have investigated next-generation androgen receptor (AR) axis inhibitors such as apalutamide, darolutamide, and enzalutamide in this setting. This review summarizes the recent advances in the management of nmCRPC, highlighting the favourable impact of next-generation AR inhibitors on metastases-free survival, overall survival and other clinically meaningful endpoints.
Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to ...define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target.
BackgroundImmune checkpoint inhibitors (ICI) induce a range of immune-related adverse events (irAEs) with various degrees of severity. While clinical experience with ICI retreatment following ...clinically significant irAEs is growing, the safety and efficacy are not yet well characterized.MethodsThis multicenter retrospective study identified patients with metastatic renal cell carcinoma treated with ICI who had >1 week therapy interruption for irAEs. Patients were classified into retreatment and discontinuation cohorts based on whether or not they resumed an ICI. Toxicity and clinical outcomes were assessed descriptively.ResultsOf 499 patients treated with ICIs, 80 developed irAEs warranting treatment interruption; 36 (45%) of whom were restarted on an ICI and 44 (55%) who permanently discontinued. Median time to initial irAE was similar between the retreatment and discontinuation cohorts (2.8 vs 2.7 months, p=0.59). The type and grade of irAEs were balanced across the cohorts; however, fewer retreatment patients required corticosteroids (55.6% vs 84.1%, p=0.007) and hospitalizations (33.3% vs 65.9%, p=0.007) for irAE management compared with discontinuation patients. Median treatment holiday before reinitiation was 0.9 months (0.2–31.6). After retreatment, 50% (n=18/36) experienced subsequent irAEs (12 new, 6 recurrent) with 7 (19%) grade 3 events and 13 drug interruptions. Median time to irAE recurrence after retreatment was 2.8 months (range: 0.3–13.8). Retreatment resulted in 6 (23.1%) additional responses in 26 patients whose disease had not previously responded. From first ICI initiation, median time to next therapy was 14.2 months (95% CI 8.2 to 18.9) and 9.0 months (5.3 to 25.8), and 2-year overall survival was 76% (95%CI 55% to 88%) and 66% (48% to 79%) in the retreatment and discontinuation groups, respectively.ConclusionsDespite a considerable rate of irAE recurrence with retreatment after a prior clinically significant irAE, most irAEs were low grade and controllable. Prospective studies are warranted to confirm that retreatment enhances survival outcomes that justify the safety risks.
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