Launch of Breakthrough Therapies Will Reshape Renal Cell Carcinoma Market

Abstract

Tyrosine kinase inhibitors (TKIs) are leading systemic therapies for the treatment of renal cell carcinoma. However, programmed death-1 inhibitors, promising new agents in development, may surpass TKIs as the standard of care in the future.

Renal cell carcinoma (RCC) accounts for 90% to 95% of malignant neoplasms involving the kidneys.¹ It is the most common type of kidney cancer in adults,² occurring at an average age of 64 years.³ Key etiologic factors include hypertension, obesity, tobacco use, chronic hepatitis C virus infection, and polycystic kidney disease.^1,4 The initial symptoms of RCC include hematuria, flank pain, cachexia, fever, hypertension, night sweats, and general malaise.^2,5 The American Cancer Society estimates that 62,700 new cases of kidney cancer will occur in the United States in 2016, and that 14,240 people will die from the disease.⁶

Surgical resection is the mainstay of treatment for patients with RCC.³ Surgery is often followed by systemic therapies, including targeted treatments, chemo therapy, and immunotherapy, although these approaches appear to have little effect on survival.^3,6 For renal cancers that cannot be removed surgically, first-line treatment is likely to consist of targeted therapies or cytokine therapy.⁶

Table 1 lists the leading drug treatments for RCC in the United States.⁷ Sunitinib (Sutent, Pfizer), a first-generation small-molecule tyrosine kinase inhibitor (TKI), has been the standard-of-care first-line therapy for treatment-naïve RCC patients since 2013, but it is facing competition from pazopanib (Votrient, GlaxoSmithKline), another TKI.⁷ In 2014, clinical studies showed that sunitinib and pazopanib were noninferior to each other in patients with metastatic RCC.^8,9 Bevacizumab (Avastin, Roche), an anti–vascular endothelial growth factor (VEGF) antibody, is also approved for the first-line treatment of patients with RCC, but it must be administered in combination with interferon-alpha (a cytokine associated with significant toxicity), and it is given intravenously—two barriers to clinical uptake. Sunitinib and pazopanib are oral treatments. Second-line therapy for RCC is currently dominated by everolimus (Afinitor, Novartis), an oral inhibitor of mammalian target of rapamycin, and axitinib (Inlyta, Pfizer), a second-generation small-molecule TKI.⁷

Table 1.

Key Drug Treatments for Renal Cell Carcinoma in the United States⁷,¹⁰,¹²

Drug Name Company	Therapeutic Class	Indication	U.S. Launch
Axitinib (Inlyta) Pfizer	RTK inhibitor	Advanced renal cell carcinoma after failure of one prior systemic therapy	2012
Bevacizumab (Avastin) Roche	VEGF inhibitor	Metastatic renal cell carcinoma (with interferon-alpha)	2009
Cabozantinib (Cabometyx) Exelexis, Inc.	RTK inhibitor	Advanced renal cell carcinoma after prior antiangiogenic therapy	2016
Everolimus (Afinitor) Novartis	mTOR inhibitor	Advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib	2009
Lenvatinib (Lenvima) Eisai	RTK inhibitor	Advanced renal cell carcinoma after one prior antiangiogenic therapy (in combination with everolimus)	2016
Pazopanib (Votrient) GlaxoSmithKline	TKI	Advanced renal cell carcinoma	2009
Sorafenib (Nexavar) Bayer Healthcare	Kinase inhibitor	Advanced renal cell carcinoma	2005
Sunitinib (Sutent) Pfizer	RTK inhibitor	Advanced renal cell carcinoma	2006
Temsirolimus (Torisel) Pfizer	mTOR inhibitor	Advanced renal cell carcinoma	2007

mTOR = mammalian target of rapamycin; RTK = receptor tyrosine kinase; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor.

In January 2016, the Food and Drug Administration approved lenvatinib (Lenvima, Eisai), an oral TKI, in combination with everolimus as second-line treatment for patients with advanced RCC after prior antiangiogenic therapy.¹⁰ Lenvatinib was already indicated for patients with thyroid cancer.¹¹ The product’s main competition is expected to come from cabozantinib (Cabometyx, Exelexis, Inc.) for the same group of patients who are refractory to VEGF receptor inhibitors.⁷

Cabozantinib, a receptor TKI, is the most recently approved medication for the treatment of RCC. It was cleared by the FDA in April 2016 for RCC patients who have received prior antiangiogenic therapy. Cabozantinib’s targets include MET, AXL, and VEGF receptors 1, 2, and 3. In preclinical models, cabozantinib was shown to inhibit the activity of these receptors, which are involved in both normal cellular function and pathological processes, such as tumor angiogenesis, invasiveness, metastasis, and drug resistance.¹²

According to an analysis by consultant GlobalData, programmed death-1 (PD-1) inhibitors—a class of immune checkpoint inhibitors—are poised to displace TKIs as the standard of care in the first-and second-line RCC settings by 2023, with nivolumab (Opdivo, Bristol-Myers Squibb), a PD-1 inhibitor that is already on the market, achieving blockbuster status. In addition, combination regimens will be introduced in the first-line setting, specifically those including PD-1 inhibitors, such as nivolumab plus ipilimumab (Yervoy, Bristol-Myers Squibb), bevacizumab plus atezolizumab (Roche), and axitinib plus avelumab (Pfizer/Merck), in treatment-naïve patients with metastatic RCC. Other new players, such as rocapuldencel-T (AGS-003, Argos Therapeutics) and tivozanib (Aveo Oncology), will also help reshape the RCC market.⁷ Table 2 lists promising late-stage drugs in the RCC pipeline; these treatments are discussed below.

Table 2.

Promising Drugs in the Renal Cell Carcinoma Pipeline⁷

Product Developer(s)	Therapeutic Class	Targeted Indication	Expected Dosing	Expected Pricing Strategy	Anticipated U.S. Launch
Atezolizumab Roche	Immune checkpoint inhibitor	mRCC	1,200 mg IV every three weeks in six-week cycles until disease progression	Branded atezolizumab + bevacizumab (first-line therapy) is expected to be priced at 10% premium to nivolumab + ipilimumab	2021
Avelumab Pfizer/Merck	Immune checkpoint inhibitor	mRCC	10 mg/kg IV every two weeks in combination with oral axitinib 5 mg	Branded avelumab + axitinib is expected to be priced at 10% premium to nivolumab + ipilimumab	2019
Nivolumab (Opdivo) + ipilimumab (Yervoy) Bristol-Myers Squibb	PD-1 inhibitor + PD-1/CTLA-4 inhibitor (immune checkpoint inhibitors)	laRCC or mRCC (first line)	Nivolumab: 3 mg/kg IV every two weeks until disease progression Ipilimumab: 1 mg/kg or 3 mg/kg IV every two weeks until disease progression	Components currently marketed for other indications	2020
Rocapuldencel-T (AGS-003) Argos Therapeutics	Autologous dendritic-cell vaccine	mRCC	Five injections of 1 × 107 cells every three weeks, then every 12 weeks until disease progression	Expected to be priced at 10% premium to nivolumab	2018
Tivozanib Aveo Oncology	TKI (VEGFR inhibitor)	mRCC	1.5 mg/day (oral) for three weeks, followed by one week off	Matched against the price of pazopanib or another TKI	2018

IV = intravenous; laRCC = locally advanced RCC; mRCC = metastatic RCC; PD-1 = programmed death-1; RCC = renal cell carcinoma; TKI = tyrosine kinase inhibitor; VEGFR = vascular endothelial growth factor receptor

Atezolizumab is a monoclonal antibody (mAb) that targets programmed death ligand-1 (PD-L1), the ligand of the PD-1 immune checkpoint receptor. By interfering with interactions between PD-L1 and PD-1, atezolizumab has the potential to restore antitumor T-cell activity.⁷ As a specific PD-L1 inhibitor, atezolizumab is also expected to be less toxic than PD-1 inhibitors.¹³ An ongoing phase 3 trial is comparing atezolizumab plus bevacizumab with the market leader, sunitinib, as first-line therapy in patients with untreated advanced RCC. The study’s tentative completion date is June 2020.¹⁴

Avelumab is another mAb that targets PD-L1. It is being developed as a potential first-line therapy for patients with metastatic RCC.⁷ A pivotal phase 3 trial, JAVELIN Renal 101, is investigating whether avelumab in combination with axitinib can extend progression-free survival compared with sunitinib in patients with advanced RCC. The estimated completion date is June 2018.¹⁵

In November 2015, nivolumab was the first PD-1 inhibitor to be approved for the second- and third-line treatment of patients with advanced (metastatic) RCC.¹⁶ It is also indicated for non–small-cell lung cancer, melanoma, and Hodgkin’s lymphoma in the U.S.¹⁷ The combination of nivolumab and ipilimumab is being developed as a potential first-line treatment for patients with metastatic RCC.⁷ In addition to being a PD-1 inhibitor, ipilimumab inhibits another protein (CTLA-4) involved in the immune checkpoint, and this dual mechanism of action is believed to have an additive effect, when combined with that of nivolumab, in restoring T-cell activity.⁷ A pivotal phase 3 study, CheckMate 214, is comparing the nivolumab/ipilimumab combination with sunitinib in patients with untreated advanced or metastatic RCC. The estimated completion date is September 2019.¹⁸

Rocapuldencel-T is an autologous dendritic-cell vaccine that stimulates cell-mediated immunity.¹⁹ In a phase 2 study, the addition of rocapuldencel-T to sunitinib nearly doubled overall survival (OS) compared with sunitinib alone (30.2 months versus 14.7 months, respectively) in patients with metastatic RCC.²⁰ A phase 3 trial, ADAPT, is investigating the potential for rocapuldencel-T in combination with sunitinib to extend OS compared with sunitinib alone in patients with metastatic RCC. The trial’s estimated completion date is April 2017.²¹

Tivozanib is an oral TKI that inhibits VEGF receptors 1, 2, and 3, thereby interfering with the signaling pathways that induce angiogenesis.⁷ The FDA rejected a new drug application for tivozanib as an RCC treatment in 2013, citing concerns about the design of the pivotal, phase 3 TIVO-1 trial and about the trial’s OS data.²² Aveo plans to submit a new application in 2018, with data from another phase 3 study.^7,23 Without demonstrating a significant OS effect in the first-line treatment of RCC, analysts expect tivozanib to have a hard time competing with standard-of-care therapies.⁷