Two is company, is three a crowd? Triplet therapy, novel molecular targets, and updates on the management of advanced renal cell carcinoma

by Selleckchem | Sep 06 2023

Purpose of review: The purpose of this review is to highlight the most recent changes in the management of advanced renal cell carcinoma, a complicated and ever-changing field of research.

Recent findings: A recent meta-analysis examining combination therapy favors nivolumab plus cabozantinib as the overall survival leader in doublet therapy. Initial results on the first ever trial of triplet therapy have demonstrated improved progression-free survival over current standard of care. The hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan is FDA approved for patients with von Hippel-Lindau disease and is currently being investigated in patients with nonhereditary renal cell carcinoma. The new glutamate synthesis inhibitor, telaglenastat, perhaps confers synergistic benefit when combined with everolimus, but combination with cabozantinib was not so effective. Dual mammalian target of rapamycin (mTOR) inhibition with sapanisertib does not appear to be an effective therapeutic option. New biomarkers and targets are actively being investigated. Four recent trials examining alternative agents to pembrolizumab in the adjuvant setting did not demonstrate an improvement in recurrence-free survival. Cytoreductive nephrectomy in the combination therapy era is supported by retrospective data; clinical trials are recruiting patients.

Summary: The last year ushered in novel approaches of varying success for managing advanced renal cell carcinoma, including triplet therapy, HIF-2α inhibitors, metabolic pathway inhibitors, and dual mTOR inhibitors. Pembrolizumab remains the only modern therapy available in the adjuvant setting, and the waters surrounding cytoreductive nephrectomy are still murky.

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Title: Recent Advances in the Management of Advanced Renal Cell Carcinoma: A Review

Introduction: The management of advanced renal cell carcinoma (RCC) is a complex and rapidly evolving field of research. In this review, we aim to highlight the most recent developments in the management of advanced RCC, including novel treatment approaches, emerging biomarkers, and the role of cytoreductive nephrectomy in the era of combination therapy.

Recent Findings:
1. Combination Therapy: A recent meta-analysis has shown that the combination of nivolumab and cabozantinib leads to improved overall survival compared to other doublet therapies. This combination has emerged as a promising treatment option for advanced RCC.

2. Triplet Therapy: Initial results from the first-ever trial of triplet therapy have demonstrated improved progression-free survival compared to the current standard of care. This novel approach holds promise for further improving outcomes in advanced RCC.

3. HIF-2α Inhibitors: The hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan has received FDA approval for patients with von Hippel-Lindau disease and is being investigated in nonhereditary RCC. This represents a significant advancement in targeted therapy for a specific subgroup of patients.

4. Metabolic Pathway Inhibitors: Telaglenastat, a glutamate synthesis inhibitor, shows potential synergistic benefit when combined with everolimus, although its combination with cabozantinib has shown limited effectiveness. These metabolic pathway inhibitors offer new therapeutic avenues for managing advanced RCC.

5. Dual mTOR Inhibition: The use of sapanisertib, a dual mammalian target of rapamycin (mTOR) inhibitor, does not appear to be an effective therapeutic option in advanced RCC. This finding suggests that alternative strategies need to be explored for targeting the mTOR pathway.

6. Biomarkers and Targets: Ongoing research efforts are actively investigating new biomarkers and therapeutic targets in advanced RCC. These discoveries hold the potential to improve patient stratification and personalize treatment approaches.

7. Adjuvant Therapy: Recent trials exploring alternative agents to pembrolizumab in the adjuvant setting did not demonstrate an improvement in recurrence-free survival. Pembrolizumab remains the only approved therapy in this setting, highlighting the need for further investigation.

8. Cytoreductive Nephrectomy: Retrospective data support the continued use of cytoreductive nephrectomy in the era of combination therapy. However, clinical trials are currently recruiting patients to further evaluate its role in advanced RCC management.

Summary: The past year has witnessed significant advancements in the management of advanced RCC. Combination therapy with nivolumab and cabozantinib has emerged as a favorable option for improving overall survival. Triplet therapy and HIF-2α inhibitors have shown promise in enhancing treatment outcomes. Metabolic pathway inhibitors offer potential benefits, while dual mTOR inhibition appears to be ineffective. Ongoing research aims to identify novel biomarkers and therapeutic targets. Adjuvant therapy options are limited, with pembrolizumab being the only approved agent. The role of cytoreductive nephrectomy in the combination therapy era is still under investigation. These recent developments underline the dynamic nature of the field and emphasize the need for further research to optimize the management of advanced RCC.