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Launch of Breakthrough Therapies Will Reshape Renal Cell Carcinoma Market
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
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
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
Key Drug Treatments for Renal Cell Carcinoma in the United States
||RTK inhibitor||Advanced renal cell carcinoma after failure of one prior systemic therapy||2012|
||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|
||mTOR inhibitor||Advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib||2009|
||RTK inhibitor||Advanced renal cell carcinoma after one prior antiangiogenic therapy (in combination with everolimus)||2016|
||TKI||Advanced renal cell carcinoma||2009|
||Kinase inhibitor||Advanced renal cell carcinoma||2005|
||RTK inhibitor||Advanced renal cell carcinoma||2006|
||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.
Promising Drugs in the Renal Cell Carcinoma Pipeline
||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|
||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)
||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|
||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|
||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
- Chittoria N, Rini BI. Renal cell carcinoma. August 2013;Available at: www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/renal-cell-carcinoma. Accessed May 19, 2016.
- Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol 2011;60:615–621.
- Chiu BC, Gapstur SM, Chow WH, et al. Body mass index, physical activity, and risk of renal cell carcinoma. Int J Obes (Lond) 2006;30:940–947.
- Ljungberg B, Bensalah K, Bex A, et al. Guidelines on Renal Cell Carcinoma April 2014;Available at: https://uroweb.org/wp-content/uploads/10-Renal-Cell-Carcinoma_LR.pdf. Accessed May 20, 2016.
- American Cancer Society. Kidney cancer (adult)––renal cell carcinoma February
102016;Available at: www.cancer.org/cancer/kidneycancer/detailedguide/kidney-cancer-adult-key-statistics. Accessed May 20, 2016.
- National Cancer Institute. Renal cell cancer treatment (PDQ)–health professional version April
182016;Available at: www.cancer.gov/types/kidney/hp/kidney-treatment-pdq. Accessed May 20, 2016.
- Beggs J, Bourgognon M, Roberts D. Renal Cell Carcinoma—Global Drug Forecast and Market Analysis to 2023 New York, New York: GlobalData. April 2016;
- Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722–731.
- Escudier B, Porta C, Bono P, et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study. J Clin Oncol 2014;32:1412–1418.
- Eisai Co., Ltd. U.S. FDA approves additional indication for Eisai’s anticancer agent Lenvima in combination with everolimus as treatment for advanced renal cell carcinoma. May
162016;Available at: www.eisai.com/news/enews201633pdf.pdf. Accessed June 29, 2016.
- Food and Drug Administration. FDA approves Lenvima for a type of thyroid cancer. February
132015;Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm434288.htm. Accessed May 25, 2016.
- Exelexis, Inc.. Exelixis announces FDA approval of Cabometyx (cabozantinib) tablets for patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. April
252016;Available at: https://ir.exelixis.com/phoenix.zhtml?c=120923&p=irol-newsArticle_print&ID=2161051. Accessed June 29, 2016.
- McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med 2013;2:662–673.
- ClinicalTrials.gov. A study of atezolizumab in combination with bevacizumab versus sunitinib in participants with untreated advanced renal cell carcinoma. May
42016;Available at: https://clinicaltrials.gov/ct2/show/results/NCT02420821. Accessed May 24, 2016.
- ClinicalTrials.gov. A study of avelumab with axitinib versus sunitinib in advanced renal cell carcinoma (JAVELIN Renal 101). May
22016;Available at: https://clinicaltrials.gov/ct2/show/NCT02684006. Accessed May 24, 2016.
- Food and Drug Administration. FDA approves Opdivo for advanced form of kidney cancer November
232015;Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473971.htm. Accessed May 26, 2016.
- Opdivo (nivolumab injection) prescribing information Princeton, New Jersey: Bristol-Myers Squibb. May 2016;
- ClinicalTrials.gov. Nivolumab combined with ipilimumab versus sunitinib in previously untreated advanced or metastatic renal cell carcinoma (CheckMate 214). May
252016;Available at: https://clinicaltrials.gov/ct2/show/NCT02231749. Accessed May 27, 2016.
- Logan TF, Gardner TA, Amin A, et al. Phase 1/2 study of AGS-003, a personalized immunotherapeutic evaluated in newly diagnosed metastatic renal cell carcinoma subjects. J Clin Oncol 2010;28;(suppl):abstr 379.
- Amin A, Zudek AZ, Logan TF, et al. Survival with AGS-003, an autologous dendritic cell–based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): phase 2 study results. J ImmunoTher Cancer 2015;3:14
- ClinicalTrials.gov. Phase 3 trial of autologous dendritic cell immunotherapy (AGS-003) plus standard treatment of advanced renal cell carcinoma (RCC) (ADAPT). January
212016;Available at: https://clinicaltrials.gov/ct2/show/NCT01582672. Accessed May 27, 2016.
- Aveo Oncology. Aveo announces complete response letter received for tivozanib new drug application in renal cell carcinoma. June
102013;Available at: www.aveooncology.com/wp-content/uploads/2013/06/AVEO-CRL-PDUFA-PR-FINAL-for-61013.pdf. Accessed June 6, 2016.
- ClinicalTrials.gov. A study to compare tivozanib hydrochloride to sorafenib in subjects with refractory advanced RCC. May
182016;Available at: https://clinicaltrials.gov/ct2/show/NCT02627963. Accessed June 6, 2016.