scholarly journals Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3652
Author(s):  
Kevin Zarrabi ◽  
Emily Walzer ◽  
Matthew Zibelman
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Rapid Development ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Renal cell carcinoma (RCC) is a histologically heterogeneous disease with multiple subtypes. Clear cell RCC (ccRCC) represents the most common histology and has thus been easiest to study in clinical trials. Non-clear cell RCC (nccRCC) represents about 25% of RCC tumors, with fewer treatment options available, compared to ccRCC, and with poorer outcomes. Non-clear cell RCC tumors are histologically diverse, with each subtype having distinct molecular and clinical characteristics. Our understanding of nccRCC is evolving, with a gradual shift from treating nccRCC as a single entity to approaching each subtype as its own disease with unique features. Due to the scarcity of patients for study development, trials have predominantly combined all nccRCC subtypes and re-purposed drugs already approved for ccRCC, despite the decreased efficacy. We are now in the early stages of a potential paradigm shift in the treatment of nccRCC, with a rapid development of clinical studies with a focus on this subset of tumors. Investigators have launched trials focused on the molecular drivers of tumorigenesis using targeted therapies. Harboring the immunogenicity of some nccRCC subtypes, and based on promising retrospective studies, clinicians have also devised multiple trials using immune checkpoint inhibitors (ICIs), both alone or in combination with targeted therapies, for nccRCC subtypes. We highlight the promising completed and ongoing studies employing ICIs that will likely continue to improve outcomes in patients with nccRCC and propose future potential immunotherapeutic avenues.

scholarly journals Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 7 (4) ◽  
pp. 17-26
Author(s):  
Alexander T. Toth ◽  
Daniel Cho
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Small Subset ◽  
Front Line ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.

Effectiveness of first-line immune checkpoint inhibitors (ICI) in advanced non-clear cell renal cell carcinoma (ccRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 316-316
Author(s):  
Jeffrey Graham ◽  
Connor Wells ◽  
Shaan Dudani ◽  
Chun Loo Gan ◽  
Frede Donskov ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
First Line ◽  
Cell Renal Cell Carcinoma

316 Background: Immune checkpoint inhibitors (ICI) have demonstrated impressive activity in metastatic clear-cell renal cell carcinoma (ccRCC) and have become standard treatment options in this setting. Data supporting the effectiveness of ICI based therapy in non-clear cell RCC (nccRCC) is more limited. Methods: We performed a retrospective analysis using the International Metastatic RCC Database Consortium (IMDC). Patients with nccRCC were classified into 3 groups based on first-line therapy: ICI based therapy (in monotherapy or in combination), vascular endothelial growth factor targeted therapy (VEGF-TT) monotherapy, or mammalian target of rapamycin (mTOR) inhibitor monotherapy. Primary outcome was overall survival (OS). Secondary outcomes were time to treatment failure (TTF) and objective response rate (ORR). We used Kaplan-Meier method to compare OS and TTF between treatment groups and Cox proportional hazards models to adjust for prognostic covariates. Results: We identified 1181 patients with nccRCC. In first-line, 78.2% received VEGF-TT, 15.8% mTOR inhibitors, and 5.5% ICI based therapy, of which 41.5% in monotherapy, 30.8% doublet-ICIs and 27.7% an ICI combined with VEGF-TT. Median OS in the ICI group was 28.6 months, compared to 19.2 and 12.6 in the VEGF-TT and mTOR groups, respectively. Median TTF was 6.9 months vs. 5.1 and 3.9 and ORR was 25% vs. 17.8% and 5.8% in the ICI, VEGF-TT and mTOR groups, respectively. After adjusting for IMDC risk group, histological subtype, and age, the hazard ratio (HR) for OS was 0.58 (95% CI 0.35-0.94, p=0.03) for ICI vs. VEGF-TT and 0.48 (95% CI 0.29-0.80, p=0.005) for ICI vs. mTOR. Conclusions: In advanced nccRCC, first-line ICI based treatment appears to be associated with improved OS compared to VEGF and mTOR targeted therapy. These results need to be confirmed in prospective randomized trials. [Table: see text]

scholarly journals Molecular Mechanisms of Resistance to Immunotherapy and Antiangiogenic Treatments in Clear Cell Renal Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5981
Author(s):  
Pablo Álvarez Ballesteros ◽  
Jesús Chamorro ◽  
María San Román-Gil ◽  
Javier Pozas ◽  
Victoria Gómez Dos Santos ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.

scholarly journals Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 7 (4) ◽  
pp. 17-26
Author(s):  
Alexander T. Toth ◽  
Daniel C. Cho
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Small Subset ◽  
Front Line ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.

scholarly journals The Role of Epigenetics in the Progression of Clear Cell Renal Cell Carcinoma and the Basis for Future Epigenetic Treatments

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2071
Author(s):  
Javier C. Angulo ◽  
Claudia Manini ◽  
Jose I. López ◽  
Angel Pueyo ◽  
Begoña Colás ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Cell Renal Cell Carcinoma ◽  
Epigenetic Biomarkers ◽  
Therapeutic Decisions

Clear cell renal cell carcinoma (ccRCC) is curable when diagnosed at an early stage, but when disease is non-confined it is the urologic cancer with worst prognosis. Antiangiogenic treatment and immune checkpoint inhibition therapy constitute a very promising combined therapy for advanced and metastatic disease. Many exploratory studies have identified epigenetic markers based on DNA methylation, histone modification, and ncRNA expression that epigenetically regulate gene expression in ccRCC. Additionally, epigenetic modifiers genes have been proposed as promising biomarkers for ccRCC. We review and discuss the current understanding of how epigenetic changes determine the main molecular pathways of ccRCC initiation and progression, and also its clinical implications. Despite the extensive research performed, candidate epigenetic biomarkers are not used in clinical practice for several reasons. However, the accumulated body of evidence of developing epigenetically-based biomarkers will likely allow the identification of ccRCC at a higher risk of progression. That will facilitate the establishment of firmer therapeutic decisions in a changing landscape and also monitor active surveillance in the aging population. What is more, a better knowledge of the activities of chromatin modifiers may serve to develop new therapeutic opportunities. Interesting clinical trials on epigenetic treatments for ccRCC associated with well established antiangiogenic treatments and immune checkpoint inhibitors are revisited.

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