PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced that Opdivo (nivolumab) 3 mg/kg plus Yervoy (ipilimumab) 1 mg/kg (injections for intravenous use) was approved by the U.S. Food and Drug Administration (FDA) as the first Immuno-Oncology combination therapy for previously untreated patients with intermediate- and poor-risk advanced renal cell carcinoma (RCC).1,2 In the Phase 3 CheckMate -214 clinical trial, the Opdivo + Yervoy combination demonstrated a significant and unprecedented increase in overall survival (OS) in this patient population compared to a current standard of care, sunitinib. An OS benefit was observed regardless of PD-L1 expression level.1,2,3 Opdivo + Yervoy also delivered durable responses, with a higher objective response rate (ORR) compared to sunitinib.1,2 Patients in the CheckMate -214 trial received four cycles of the Opdivo + low-dose Yervoy combination, followed by Opdivo maintenance therapy.1,2 In the combination arm of the trial, 79% of patients received all four doses of Opdivo + Yervoy and went on to the Opdivo monotherapy phase.4 Flexible dosing options are available during the Opdivo maintenance phase (480 mg infused every four weeks or 240 mg infused every two weeks).
“Our goal is to provide cancer patients with medicines that have the potential to extend their lives. As the first treatment option to increase overall survival for subgroups of patients with advanced RCC compared to sunitinib, the Opdivo plus low-dose Yervoy combination helps deliver on that promise,” said Johanna Mercier, head, U.S. Commercial, Bristol-Myers Squibb. “This approval demonstrates our commitment to bringing Immuno-Oncology treatments that may improve outcomes to a broader range of RCC patients.”
Opdivo is associated with the following Warnings and Precautions: immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity. Please see the Important Safety Information section below, including Boxed WARNING for Yervoy regarding immune-mediated adverse reactions.1,2
Results from the CheckMate -214 trial in patients with previously untreated intermediate- and poor-risk advanced RCC include:
- Overall Survival: Opdivo + Yervoy reduced the risk of death by 37% versus sunitinib (hazard ratio [HR] 0.63; 99.8% confidence interval [CI]: 0.44 to 0.89; p<0.0001).1,2 The median OS was not yet reached for Opdivo + Yervoy (95% CI: 28.2 to not estimable [NE]) and was 25.9 months for sunitinib (95% CI: 22.1 to NE).1,2,3
Objective Response Rate: Opdivo + Yervoy was
associated with a 41.6% ORR (95% CI: 36.9 to 46.5; p<0.0001;
n=177/425) versus 26.5% for sunitinib (95% CI: 22.4 to 31.0;
- Complete and Partial Response Rates: The complete response (CR) rate was 9.4% for Opdivo + Yervoy (n=40/425) and 1.2% for sunitinib (n=5/422), and the partial response (PR) rate was 32.2% for Opdivo + Yervoy (n=137/425) and 25.4% for sunitinib (n=107/422).1,2
- Duration of Response: Among patients who responded, median duration of response (durability) for Opdivo + Yervoy was not yet reached (95% CI: 21.8 to NE), compared to 18.2 months for sunitinib (95% CI: 14.8 to NE).1,2
- Progression-Free Survival: Progression-free survival (PFS) was 11.6 months for the Opdivo + Yervoy combination, compared to 8.4 months for sunitinib (HR 0.82; 99.1% CI: 0.64 to 1.05; p=not significant), which did not reach statistical significance.1,2
Among those with advanced RCC, 75% to 80% have one or more risk factors and are considered intermediate- and poor-risk patients according to International Metastatic Renal Cell Carcinoma Database Consortium criteria.5,6 These patients historically had a poor prognosis, and although there have been a number of treatment advances over the past decade, additional options to improve overall survival are still needed.7,8 Currently, only 36% of patients with advanced RCC survive beyond one year, and only 8% will live past five years.7,9
“Physicians treating advanced RCC have had few options to help achieve the goal of improved survival,” said Robert J. Motzer, M.D., medical oncologist, Jack and Dorothy Byrne chair in clinical oncology, Memorial Sloan Kettering Cancer Center. “Data from the CheckMate -214 trial demonstrated superior overall survival with Opdivo + Yervoy, showing the potential for the combination to become a new standard of care for patients with intermediate- and poor-risk advanced RCC. What's more, the combination resulted in fewer overall Grade 3 and 4 adverse reactions compared to sunitinib. Because of these encouraging results, we now have a new treatment option for newly diagnosed advanced RCC patients across PD-L1 expression levels.”
In CheckMate -214, the combination was associated with fewer overall Grade 3 or 4 adverse events than sunitinib (65% versus 76%).1,2 Treatment discontinuation due to adverse events occurred in 31% of patients in the Opdivo + Yervoy arm, compared to 21% in the sunitinib arm. Fifty-four percent (54%) of patients receiving Opdivo + Yervoy and 43% of patients receiving sunitinib had a dose delay for an adverse reaction. In the sunitinib group, 53% of patients required a dose reduction, which was not permitted for patients treated with the Opdivo + Yervoy combination. Serious adverse reactions occurred in 59% of patients receiving Opdivo + Yervoy and in 43% of patients receiving sunitinib.1,2
“Kidney cancer is the deadliest of all urological cancers, and too many patients are faced with this grim diagnosis,” said Dena Battle, president, KCCure. “Today’s approval of Opdivo + Yervoy for advanced RCC has the potential to transform the first-line treatment landscape for kidney cancer. But for patients, it is more than just a new therapy option – it represents hope for a longer life.”
Approval Based on CheckMate -214 Trial: Demonstrating Superior Overall Survival and Objective Response Rate vs. Sunitinib
CheckMate -214 is a Phase 3, randomized, open-label study evaluating the combination of Opdivo + Yervoy versus sunitinib in patients with previously untreated advanced RCC. In the intermediate- and poor-risk study population, 425 patients received Opdivo 3 mg/kg plus Yervoy 1 mg/kg every three weeks for four doses, followed by Opdivo 3 mg/kg every two weeks, and 422 patients received sunitinib 50 mg once daily for four weeks, followed by two weeks off every cycle.1,2 The recommended dosing for the Opdivo + Yervoy combination is Opdivo 3 mg/kg followed by Yervoy 1 mg/kg each infused intravenously over 30 minutes on the same day every three weeks for four doses. After completing four doses of the combination, Opdivo should be administered intravenously 240 mg every two weeks or 480 mg every four weeks over 30 minutes until disease progression or unacceptable toxicity.1,2
The primary efficacy outcome measures of the trial were OS, ORR (CR+PR) and PFS as determined by an independent radiographic review committee (IRRC) in intermediate- and poor-risk patients. Patients were included regardless of their PD-L1 status.1,2 Data from CheckMate -214 were presented at the European Society for Medical Oncology Congress in September 2017 and the Society for Immunotherapy of Cancer Annual Meeting in November 2017 and were published in the New England Journal of Medicine in March 2018.3,10,11
Select Safety Profile for the CheckMate -214 Trial
The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo + Yervoy were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency and colitis. The most common adverse reactions (≥20%) reported in patients receiving Opdivo + Yervoy were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%) and vomiting (20%).1,2
About Renal Cell Carcinoma
Renal cell carcinoma is the most common type of kidney cancer in adults, accounting for nearly 15,000 deaths in the United States each year.12,13 Clear-cell RCC is the most prevalent type of RCC and constitutes 70% to 80% of all patients.14 Renal cell carcinoma is approximately twice as common in men as in women.15 In the United States, the five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 8%.7
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with intermediate or poor-risk, previously untreated advanced renal cell carcinoma (RCC).
OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous use.
IMPORTANT SAFETY INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.
OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients.
OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients.
OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients.
OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients.
Immune-Mediated Skin Adverse Reactions and Dermatitis
OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6% (91/547) of patients.
OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. Encephalitis occurred in one patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure.
Other Immune-Mediated Adverse Reactions
Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.
If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.
OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients.
Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.
It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue breastfeeding during treatment with YERVOY and for 3 months following the final dose.
Serious Adverse Reactions
In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in at least 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea.
Common Adverse Reactions
In Checkmate 214, the most common adverse reactions reported in at least 20% of patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), and decreased appetite (21% vs 29%).
Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research
At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.
We are advancing the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 24 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. Through our leading translational capabilities, we are pioneering immune biology research and identifying a number of potentially predictive biomarkers, including PD-L1, TMB, MSI-H/dMMR and LAG-3, advancing the possibility of precision medicine for more patients with cancer.
We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.
About Bristol-Myers Squibb’s Patient Access Support
Bristol-Myers Squibb remains committed to providing assistance so that cancer patients who need our medicines can access them and expedite time to therapy.
BMS Access Support®, the Bristol-Myers Squibb patient access and reimbursement program, is designed to help appropriate patients initiate and maintain access to BMS medicines during their treatment journey. BMS Access Support offers benefit investigation, prior authorization assistance and co-pay assistance for eligible, commercially insured patients. More information about our access and reimbursement support can be obtained by calling BMS Access Support® at 1-800-861-0048 or by visiting www.bmsaccesssupport.com.
About the Bristol-Myers Squibb and Ono Pharmaceutical Collaboration
In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol-Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube and Facebook.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb’s business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2017 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
1. Opdivo Prescribing Information. Opdivo U.S. Product
Information. Last updated: April 2018. Princeton, NJ: Bristol-Myers
2. Yervoy Prescribing Information. Yervoy U.S. Product Information. Last updated: April 2018. Princeton, NJ: Bristol-Myers Squibb Company.
3. Motzer R, Tannir N, McDermott D, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-1290.
4. Data on file. NIVO 136. Princeton, NJ: Bristol-Myers Squibb.
5. Ko JJ, Xie W, Kroeger N, et al. The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. Lancet Oncol. 2015;16(3):293-300.
6. Heng DYC, Xie W, Regan M, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141-148.
7. American Cancer Society. Survival Rates for Kidney Cancer by Stage. https://www.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.html. Accessed March 27, 2018.
8. Sun M, Thuret R, Abdollah F, et al. Age-adjusted incidence, mortality, and survival rates of stage specific renal cell carcinoma in North America: a trend analysis. Eur Urol. 2011;59(1):135-141.
9. Surveillance, Epidemiology, and End Results Program. Kidney and Renal Pelvis Cancer SEER Survival Rates by Time Since Diagnosis, 2003-2013 By Stage at Diagnosis. National Cancer Institute. https://seer.cancer.gov/explorer/application.php?site=72&data_type=4&graph_type=6&compareBy=stage&chk_sex_1=1&chk_sex_3=3&chk_sex_2=2&chk_race_1=1&chk_age_range_1=1&chk_stage_101=101&chk_stage_106=106&advopt_precision=1&showDataFor=sex_1_and_race_1_and_age_range_1. Published April 14, 2016. Updated December 1, 2018. Accessed March 27, 2018.
10. Escudier B, Tannir N, McDermott D, et al. CheckMate 214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presentation at: European Society of Medical Oncology Annual Meeting; September, 2017; Madrid, Spain.
11. Motzer R, Tannir N, McDermott D, et al. Nivolumab + ipilimumab (N+I) vs sunitinib (S) for treatment‐naïve advanced or metastatic renal cell carcinoma (aRCC): results from CheckMate 214, including overall survival by subgroups. Presentation: Society for Immunotherapy of Cancer Annual Meeting; November, 2017; National Harbor, Maryland.
12. American Cancer Society. Key Statistics About Kidney Cancer. https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html. Accessed January 12, 2018.
13. Cancer.net. Kidney Cancer: Introduction. https://www.cancer.net/cancer-types/kidney-cancer/introduction. Published August 2017. Accessed March 27, 2018.
14. Mehdi A, Riazalhosseini Y. Epigenome aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma. Int J Mol Sci. 2017 Aug 16;18(8)1774.
15. Terris M, Klaassen Z, Kabaria R. Renal Cell Carcinoma: Links and Risks. Int J Nephrol Renovasc Dis. 2016 ;9:45-52.