First-Line Treatment for Kidney Cancer with CGP

Avishek Roy

Scientific Liaison Manager
4baseCare

Kidney cancer is mainly of two type i.e., Renal cell carcinoma (RCC) and Renal pelvis carcinoma. RCC is the most common subtype of adult kidney cancer which accounts for 85% of all cases of kidney cancer. It is heterogenic in nature and develops in the proximal renal tubules. Clear cell RCC (ccRCC) is the most common subclass of RCC that accounts for approximately 60% of all RCC and 75%-80% of metastatic RCC. People with metastatic kidney cancer require multiple lines of therapy.

Before the advent of precision oncology, kidney cancer was only treated by chemotherapy, radiotherapy, nephrectomy and cryotherapy. Genomic studies comprised of genome comprehensive profiling (GCP) by next generation sequencing (NGS) techniques, facilitate development of novel targeted therapy and immune checkpoint inhibitors (ICIs) for treatment of advance or metastatic RCC (mRCC). Vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors (TKIs) temper progression of tumor by impeding angiogenesis. ICIs block the immune checkpoint mediated by the interaction between programmed cell death protein 1 (PD-1) on tumor-specific T cells and programmed death ligand 1 (PD-L1) expressed on either tumor cells or myeloid cells.

In the era of precision medicine, there has been significant progress in the treatment outcomes with improved knowledge of biology of kidney cancer with novel targeted agents. Approved and emerging first-line treatment options are available for the treatment of advanced cases of kidney cancer using novel targeted therapies or ICs.

Single drug therapy for first-line treatment in kidney cancer
NCCN guidelines recommend some of novel targeted therapies and ICIs as the first line treatment of patients with relapsed or medically unresectable, predominantly clear cell, stage IV renal carcinoma. The drugs are:

1. Sunitinib is a multikinase inhibitor targeting several receptor tyrosine kinases, including platelet-derived growth factor receptors (PDGFR-α and -β), VEGFR-1, 2 and 3, stem cell factor receptor, FMS-like tyrosine kinase (FLT-3), colony stimulating factor (CSF-1R), and glial cell derived neurotrophic factor receptor (RET).
2. Pazopanib is an oral angiogenesis inhibitor that targets VEGFR (1, 2 and 3), PDGFR (α and β) and c-KIT. It is approved by FDA in 2009 for the treatment of advanced RCC. The safety and effectiveness of pazopanib was evaluated in clinical trial which shown that it prolongs the progression free survival (PFS) significantly. Hepatotoxicity is the main adverse event associated with pazopanib. Hence, liver function must be monitored before and during treatment.
3. Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) protein and was approved for treatment of RCC by the FDA in 2007. Temsirolimus improves overall survival (OS) in untreated patients with advanced RCC. The approval was based on Global Advanced Renal Cell Carcinoma (ARCC) trial.

Combination therapies as first line treatment for advance kidney cancer

Nivolumab + Cabozantinib
The FDA approved nivolumab plus cabozantinib for first-line treatment of advanced RCC. The approval was based on the CheckMate 9ER trial which shows improved PFS, OS and objective response rate (ORR). The NCCN guidelines also have been updated to include this combination as first-line treatment in poor-risk patients.

Lenvatinib + pembrolizumab
Phase 3 clinical trial evaluated lenvatinib plus pembrolizumab compared with sunitinib. It has been shown that a combination of lenvatinib plus pembrolizumab improved PFS, OS and ORR.

Nivolumab + ipilimumab
FDA approved the combination of nivolumab and ipilimumab as first-line treatment for patients with advanced kidney cancer with a poor prognosis. Approval was based on an international phase 3 trial which has demonstrated improvement in OS compared to sunitinib.

Avelumab + Axitinib and Pembrolizumab + Axitinib
FDA approved avelumab plus axitinib and pembrolizumab plus axitinib combinations in 2019 for the first-line treatment in patients with advanced RCC. Approvals of avelumab plus axitinib and pembrolizumab plus axitinib were based on findings of the JAVELIN Renal 101 trial and KEYNOTE-426 trial, respectively.

Bevacizumab + IFN-α
NCCN recommended that bevacizumab in combination with IFN-α can be used for first-line treatment of patients with relapsed or medically unresectable predominantly clear cell stage IV renal carcinoma. The FDA also approved bevacizumab in combination with IFN-α for the treatment of advanced RCC in 2009.

TKIs + interferon
FDA also approved 6 TKIs as first- and second-line treatments for advanced kidney cancer. There are six TKIs (sunitinib, sorafenib, pazopanib, temsirolimus, everolimus, and bevacizumab) with interferon have been approved for the treatment of advanced RCC.