Dr Rana McKay on First-Line Therapies for Metastatic Renal Cell Carcinoma

Renal cell carcinoma (RCC), or kidney cancer, is among the most common cancers in the United States, affecting men more than women. In this first part of a 2-part series, Rana R. McKay, MD, associate professor of Medicine and Urology, Moores Cancer Center, University of California San Diego, provides an overview of the treatment landscape for advanced RCC.

AJMC®: What are the recommended first-line treatment regimens for advanced RCC?

McKay: The treatment landscape for advanced RCC has really been changing over the last 5 or 6 years. The historic landscape included the treatment of frontline vascular endothelial growth factor (VEGF) inhibition, which was the gold standard for a very long time—over a decade—given as monotherapy. And in 2018 and soon thereafter, there was a series of phase 3 trials that investigated doublet therapy given in the frontline setting, whether that be with 2 immunotherapy combinations given together such as nivolumab and ipilimumab or an immunotherapy given in combination with a VEGF inhibitor. And now the standard of care has evolved in that most patients with advanced metastatic RCC should be receiving doublet immunotherapy-based treatment in the frontline, as opposed to VEGF tyrosine kinase inhibitors (TKI) monotherapy.

AJMC®: Which tyrosine kinase inhibitors have been approved by the FDA for the treatment of advanced RCC, and what are their specific indications?

McKay: There's been a handful of VEGF TKIs that have been approved for the treatment of advanced renal cell carcinoma. There's a laundry list of agents. In the TKI era, the gold standard was largely sunitinib or pazopanib that were utilized in the frontline setting. The treatments have since evolved. The next-generation VEGF targeting agents include cabozantinib, which in addition to targeting VEGF also targets c-MET.

Also, lenvatinib given in combination with everolimus is approved. Lenvatinib targets VEGF in addition to targeting [fibroblast growth receptior] FGFR. Other VEGF TKIs include axitinib, which has been approved in combination with pembrolizumab in combination with avelumab in the frontline setting and also approved in the TKI era in the subsequent line setting or second-line setting.

There are other agents that are out there such as sorafenib, there's also tivozanib, that's probably worthwhile highlighting. Tivozanib was approved based off of the results of the TIVO-3 study and the refractory setting. This is a VEGF TKI that has similar properties to axitinib but a slightly longer half-life and has differential activity at the VEGF receptor.

In totality, there's many VEGF TKIs that are approved for the treatment of advanced renal cell carcinoma. There are 3 VEGF TKIs that are used in combination with checkpoint inhibitors in the frontline setting and that includes axitinib, cabozantinib and lenvatinib and then others that are approved as single agents.

AJMC®: How do TKIs affect tumor growth and spread in advanced RCC?

McKay: Tyrosine kinase inhibitors are used in the treatment of renal cell carcinoma. The tyrosine kinase inhibitors that have been approved to largely target a protein called vascular endothelial growth factor receptor that's found on the tumor cells and can impact angiogenesis and cell proliferation and growth. The VEGF TKIs also have activity at other receptor tyrosine kinases. They can be promiscuous, like I stated—cabozantinib has activity on c-MET, lenvatinib has activity at FGFR. There's activity at the TAM receptors, AXL, KIT, others. So, there can be some non-VEGF effects for the VEGF TKIs.

AJMC®: How are they used in combination with other treatments?

McKay: VGEF TKIs are used in combination with other treatments. In the frontline setting, they're used in combination with immunotherapy. There are several FDA-approved immunotherapy agents given in combination with VEGF TKIs. These include pembrolizumab plus axitinib, nivolumab plus cabozantinib, lenvatinib plus pembrolizumab. And also FDA approved is axitinib plus avelumab, though in clinical practice it’s not largely used given that it has not demonstrated improvements in overall survival. The combination of VEGF TKIs with immunotherapy in the frontline setting results in respectable response rates generally greater than 50%. And also respectable PFS and these therapies have been demonstrated to improve survival for patients with advanced disease.

AJMC®: How has the role of immunotherapy evolved in recent history with the approval of TKIs in the treatment of advanced RCC?

McKay: VEGF TKIs are now largely utilized in combination with frontline immunotherapy options. Following progression on frontline IO, largely single-agent VEGF inhibition is utilized in the salvage setting. In the TKI era, nivolumab was tested post-VEGF progression in a trial comparing nivolumab to everolimus and that was the first approval of a checkpoint inhibitor in renal cell carcinoma. However, that data is largely not relevant in the modern era, because we are largely utilizing IO combinations in the front line.

And we are rarely utilizing IO monotherapy for patients with advanced disease unless they're in select clinical circumstances.

AJMC®: What are some of the challenges associated with TKI treatment in RCC, such as the development of resistance?

McKay: There can be challenges that are associated with any treatment with renal cell carcinoma. Resistance can emerge after immunotherapy, resistance can emerge after VEGF-targeted therapy. Resistance is a problem that I think we as medical oncologists really struggle with. Additionally, side effects of treatment with VEGF TKIs include rash, diarrhea, hand/foot syndrome, hypertension, LFT abnormalities, and these are other issues to contend with for patients that are receiving VEGF TKIs. With the dual-doublet immunotherapy, there can be a tail on the curve, of patients who receive such therapy and can have prolonged long-term durable outcomes.

That's not the majority of patients. But the hope is to try to expand the number of individuals through combination strategies and better selection strategies that are going to have long durable remissions with treatment.