Ipsen and Exelixis Announce Results from Phase 2 CABOSUN Trial of Cabozantinib versus Sunitinib in Previously Untreated Advanced Renal Cell Carcinoma at ESMO 2017
PARIS–(BUSINESS WIRE)– Regulatory News:
Ipsen (Euronext: IPN; ADR: IPSEY) and Exelixis, Inc. (NASDAQ:EXEL) today announced updated results from the CABOSUN randomized phase 2 trial of cabozantinib in patients with previously untreated advanced renal cell carcinoma (RCC) with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Principal investigator Toni K. Choueiri, M.D., will present detailed data from late-breaking CABOSUN abstract [#LBA38_PD] today in the Genitourinary Tumors, Non-Prostate poster discussion session, starting at 2:45 p.m. CEST (local Madrid time) / 8:45 a.m. EDT / 5:45 a.m. PDT at the European Society for Medical Oncology (ESMO) 2017 congress, which is being held September 8-12, 2017 in Madrid, Spain.
CABOSUN is being conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP). The data presented at ESMO 2017 included the analysis from a blinded independent radiology review committee (IRC), which confirmed the primary efficacy endpoint results of investigator-assessed progression-free survival (PFS), as well as an updated investigator-assessed analysis. Per the IRC analysis, cabozantinib demonstrated a clinically meaningful and statistically significant 52 percent reduction in the rate of disease progression or death (HR 0.48, 95% CI 0.31-0.74, two-sided P=0.0008). The median PFS for cabozantinib was 8.6 months versus 5.3 months for sunitinib, corresponding to a 3.3 month (62 percent) improvement favoring cabozantinib over sunitinib.
“These updated analyses from CABOSUN consistently show that cabozantinib provided a statistically significant decrease in the rate of disease progression or death compared to sunitinib, a current standard of care – potentially offering a new treatment option for physicians to treat patients in the first-line advanced renal cell carcinoma setting,” said Toni K. Choueiri, M.D., Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. “The CABOSUN trial included patients with intermediate or poor prognostic factors per the IMDC criteria; in addition, patients had a notable number of other independent adverse prognostic risk factors. These included a high rate of bone metastases, two or more sites of metastatic disease, ECOG 2 performance status, and lack of prior nephrectomy. This patient population fares poorly and is in need of new therapies to better control their disease.”
The following chart outlines data from the CABOSUN trial presented today at ESMO 2017, as compared to the data previously published in the Journal of Clinical Oncology (JCO) in October 2016:
| JCO
Investigator-assessed |
ESMO 2017 Investigator-assessed (Sept 15, 2016 Cut-off) |
ESMO 2017
IRC Review (Sept 15, 2016 Cut-off) |
||||||||||
| Cabozantinib N = 79 |
Sunitinib N = 78 |
Cabozantinib N = 79 |
Sunitinib N = 78 |
Cabozantinib N = 79 |
Sunitinib N = 78 |
|||||||
| Progression-free survival | ||||||||||||
| Median PFS, months | 8.2 | 5.6 | 8.3 | 5.4 | 8.6 | 5.3 | ||||||
| Stratified HR (95% CI) |
0.66 (0.46-0.95) | 0.56 (0.37-0.83) | 0.48 (0.31-0.74) | |||||||||
| P value | 0.012 (1-sided) | 0.0042 (2-sided) | 0.0008 (2-sided) | |||||||||
| Tumor Response | ||||||||||||
| Objective response rate (95% CI),a % | 46 (34-57) | 18 (10-28) | 33 (23-44) | 12 (5-21) | 20 (12-31) | 9 (4-18) | ||||||
| Disease control rate,b % | 78 | 54 | 76 | 49 | 75 | 47 | ||||||
| Progressive disease,c % | 18 | 26 | 18 | 24 | 18 | 29 | ||||||
| Not evaluable or missing, % | 4 | 21 | 6 | 27 | 8 | 23 | ||||||
| Any reduction in target lesions, % | 87 | 44 | 85 | 38 | 80 | 50 | ||||||
a One complete response was observed with cabozantinib for both investigator assessments, and one complete response was observed with sunitinib for the original investigator assessment, all other responses were partial responses; b Complete response + partial response + stable disease; c Progressive disease as best overall response.
The updated 2017 data sets and methods differ from the initial investigator analyses presented in 2016. The comprehensive image collection for IRC review used a later cut-off point (5 months) than the initial investigator analysis and followed a rigorous IRC review process. The analysis of IRC data applied U.S. Food and Drug Administration (FDA) guidance for PFS analyses in oncology studies, including recommended censoring rules (i.e., censoring at the last adequate tumor assessment prior to initiation of subsequent anti-cancer therapy, and censoring for events that occur after two or more missing adequate tumor assessments).1 Both the updated investigator assessment and IRC analysis demonstrated consistent and statistically significant improvement of PFS with cabozantinib as compared to sunitinib.
The updated overall survival (OS) analysis had a data cut-off of July 1, 2017, and showed a favorable trend for patients randomized to cabozantinib compared to sunitinib that was not statistically significant. Median overall survival was 26.6 months for patients receiving cabozantinib versus 21.2 months for those receiving sunitinib (HR= 0.80, 95% CI 0.53-1.21, two-sided P=0.29).
“We are very encouraged by the clinically meaningful and statistically significant efficacy results on the primary endpoint of progression-free survival, which formed the basis of the recent supplemental New Drug Application submitted to the U.S. Food and Drug Administration for cabozantinib in first-line advanced renal cell carcinoma,” said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. “The latest CABOSUN data continue to underscore the value that cabozantinib may offer patients with previously untreated renal cell carcinoma, and we are working tirelessly in our efforts to bring this option to patients and their physicians as quickly as possible.”
David Meek, Chief Executive Officer of Ipsen stated “Following the recent European approval of cabozantinib for second-line treatment of patients with advanced renal cell carcinoma following prior VEGF-targeted therapy, the latest data from the CABOSUN study being presented this year at ESMO extends the clinical benefit of cabozantinib in first-line therapy setting of patients with advanced RCC. With our partner Exelixis, we are committed to strengthening the medical value of cabozantinib and to continuing to bring innovative therapeutic solutions for the treatment of patients with RCC. “
The most common all-causality grade 3 or 4 adverse events in more than 5 percent of patients for cabozantinib (N=78) and sunitinib (N=72), respectively, were diarrhea (10 vs. 11 percent), hypertension (28 vs. 21 percent), fatigue (6 vs. 17 percent), increased alanine aminotransferase (ALT; 5 vs. 0 percent), decreased appetite (5 vs. 1 percent), palmar-plantar erythrodysesthesia syndrome (PPES; 8 vs. 4 percent), decreased platelet count (1 vs. 11 percent) and stomatitis (5 vs. 6 percent). Twenty-one percent of patients in the cabozantinib arm and 22 percent of patients in the sunitinib arm discontinued treatment due to adverse events.
Exelixis filed a supplemental New Drug Application based on the CABOSUN data with the FDA for cabozantinib as a treatment for previously untreated advanced RCC on August 16, 2017. Ipsen also submitted to EMA the regulatory dossier for cabozantinib as a treatment for first-line advanced RCC in the European Union on August 28, 2017; on September 8, 2017, Ipsen announced that the EMA validated the application.
About the CABOSUN Study
On May 23, 2016, Exelixis announced that CABOSUN met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS compared with sunitinib in patients with advanced intermediate- or poor-risk RCC as determined by investigator assessment. The CABOSUN trial is being conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the NCI-CTEP. These results were first presented in a plenary session by Dr. Toni Choueiri at the ESMO 2016 Congress, and published in the JCO.2 In June 2017, a blinded IRC confirmed that cabozantinib provided a clinically meaningful and statistically significant improvement in the primary efficacy endpoint of investigator-assessed PFS.
CABOSUN is a randomized, open-label, active-controlled phase 2 trial that enrolled 157 patients with advanced RCC determined to be intermediate- or poor-risk by the IMDC criteria. Patients were randomized 1:1 to receive cabozantinib (60 mg once daily) or sunitinib (50 mg once daily, 4 weeks on followed by 2 weeks off). The primary endpoint was PFS. Secondary endpoints included OS and objective response rate.
Eligible patients were required to have locally advanced or metastatic clear-cell RCC, ECOG performance status 0-2 and had to be intermediate or poor risk per the IMDC criteria (Heng, JCO, 2009).3 Prior systemic treatment for RCC was not permitted. Baseline characteristics included:
| Characteristic | Cabozantinib (N=79) |
Sunitinib (N=78) |
||
| ECOG performance status, % | ||||
|
0 |
46 | 46 | ||
| 1 | 42 | 41 | ||
| 2 | 13 | 13 | ||
| IMDC risk group, % | ||||
| Intermediate | 81 | 81 | ||
| Poor | 19 | 19 | ||
| Bone metastasis per IxRS,a % | ||||
| Yes | 37 | 36 | ||
| No | 63 | 64 | ||
| Prior nephrectomy, % | ||||
| Yes | 72 | 77 | ||
| No | 28 | 23 | ||
| Number of metastatic sites per investigator, % | ||||
| 1 | 22 | 33 | ||
| 2 | 47 | 26 | ||
| ≥3 | 32 | 41 | ||
a interactive voice/web response system
CABOMETYX is approved in the EU for the treatment of advanced renal cell carcinoma in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy. Please see full EU prescribing information at: https://cabometyx.eu/eu/
Webcast for the Financial Community and Media
Exelixis and its partner Ipsen will jointly host a live webcast later today, Sunday, September 10. The webcast will begin at 18:45 CEST (local Madrid time) / 12:45 p.m. EDT / 9:45 a.m. PDT. During the webcast, Exelixis and Ipsen management and invited guest speakers will review results from the CABOSUN trial, along with the other relevant data sets presented at the conference.
To access the webcast link, log onto www.exelixis.com and proceed to the News & Event Calendar page under the Investors & Media heading. Please connect to the company’s website at least 15 minutes prior to the webcast to ensure adequate time for any software download that may be required to view the program. To listen to an audio-only version of the program by phone, please dial (855) 793-2457 (domestic) or (631) 485-4921 (international/toll dial) and use passcode 68961937. A telephone replay will be available until 11:59 p.m. EDT on September 17, 2017. Access numbers for the telephone replay are: 855-859-2056 (domestic) and 404-537-3406 (international); the passcode is 68961937. A webcast replay will also be available archived on www.exelixis.com for one year.
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2017 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.4 Clear cell RCC is the most common type of kidney cancer in adults.5 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.6 Approximately 30,000 patients in the U.S. and 68,000 globally require treatment, and an estimated 14,000 patients in the U.S. each year are in need of a first-line treatment for advanced kidney cancer.7
The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.8,9 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.10-13 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.8,9
About CABOMETYX® (cabozantinib)
CABOMETYX is the tablet formulation of cabozantinib. Its targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance. CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.
On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy. In February of 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan. This agreement was amended in December of 2016 to include commercialization rights for Ipsen in Canada. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced RCC in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland.
On January 30, 2017, Exelixis and Takeda Pharmaceutical Company Limited announced an exclusive licensing agreement for the commercialization and further clinical development of cabozantinib for all future indications in Japan, including RCC.
CABOMETYX is not indicated for the treatment of previously untreated advanced RCC.
Indications: CABOMETYX® is indicated for the treatment of advanced renal cell carcinoma (RCC) in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy.
Dosage and Administration: The recommended dose of CABOMETYX® is 60 mg once daily. Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of CABOMETYX® therapy. For dose modification, please refer to full SmPC. CABOMETYX® is for oral use. The tablets should be swallowed whole and not crushed. Patients should be instructed to not eat anything for at least 2 hours before through 1 hour after taking CABOMETYX®.
Contraindications: Hypersensitivity to the active substance or to any of the excipients listed in the SmPC.
Special warnings and precautions for use: As most events can occur early in the course of treatment, the physician should evaluate the patient closely during the first eight weeks of treatment to determine if dose modifications are warranted. Events that generally have early onset include hypocalcaemia, hypokalaemia, thrombocytopenia, hypertension, palmarplantar erythrodysaesthesia syndrome (PPES), proteinuria, and gastrointestinal (GI) events (abdominal pain, mucosal inflammation, constipation, diarrhoea, vomiting). Dose reductions and dose interruptions due to an AE occurred in 59.8% and 70%, respectively, of cabozantinib-treated patients in the pivotal clinical trial. Two dose reductions were required in 19.3% of patients. The median time to first dose reduction was 55 days, and to first dose interruption was 38 days.Perforations and fistulas: Serious gastrointestinal perforations and fistulas, sometimes fatal, have been observed with cabozantinib. Patients who have inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, peritonitis, diverticulitis, or appendicitis), have tumour infiltration in the GI tract, or have complications from prior GI surgery (particularly when associated with delayed or incomplete healing) should be carefully evaluated before initiating cabozantinib therapy and subsequently they should be monitored closely for symptoms of perforations and fistulas including abscesses. Persistent or recurring diarrhoea while on treatment may be a risk factor for the development of anal fistula. Cabozantinib should be discontinued in patients who experience a GI perforation or a fistula that cannot be adequately managed.
Thromboembolic events: Events of venous thromboembolism, including pulmonary embolism, and events of arterial thromboembolism have been observed with cabozantinib. Cabozantinib should be used with caution in patients who are at risk for, or who have a history of, these events. Cabozantinib should be discontinued in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.
Haemorrhage: Severe haemorrhage has been observed with cabozantinib. Patients who have a history of severe bleeding prior to treatment initiation should be carefully evaluated before initiating cabozantinib therapy. Cabozantinib should not be administered to patients that have or are at risk for severe haemorrhage.
Wound complications: Wound complications have been observed with cabozantinib. Cabozantinib treatment should be stopped at least 28 days prior to scheduled surgery, including dental surgery, if possible. The decision to resume cabozantinib therapy after surgery should be based on clinical judgment of adequate wound healing. Cabozantinib should be discontinued in patients with wound healing complications requiring medical intervention.
Hypertension: Hypertension has been observed with cabozantinib. Blood pressure should be well-controlled prior to initiating cabozantinib. During treatment with cabozantinib, all patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensives, the cabozantinib dose should be reduced. Cabozantinib should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of cabozantinib. In case of hypertensive crisis, cabozantinib should be discontinued.
Palmar-plantar erythrodysaesthesia syndrome: Palmar-plantar erythrodysaesthesia syndrome (PPES) has been observed with cabozantinib. When PPES is severe, interruption of treatment with cabozantinib should be considered. Cabozantinib should be restarted with a lower dose when PPES has been resolved to grade 1.
Proteinuria: Proteinuria has been observed with cabozantinib. Urine protein should be monitored regularly during cabozantinib treatment. Cabozantinib should be discontinued in patients who develop nephrotic syndrome.
Reversible posterior leukoencephalopathy syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior Reversible Encephalopathy Syndrome (PRES), has been observed with cabozantinib. This syndrome should be considered in any patient presenting with multiple symptoms, including seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued in patients with RPLS.
Prolongation of QT interval
Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using cabozantinib, periodic monitoring with on-treatment ECGs and electrolytes (serum calcium, potassium, and magnesium) should be considered.
Interactions: CYP3A4 inducers and inhibitors: cabozantinib is a CYP3A4 substrate. Concurrent administration of cabozantinib with the strong CYP3A4 inhibitor ketoconazole resulted in an increase in cabozantinib plasma exposure. Caution is required when administering cabozantinib with agents that are strong CYP3A4 inhibitors. Concurrent administration of cabozantinib with the strong CYP3A4 inducer rifampicin resulted in a decrease in cabozantinib plasma exposure. Therefore, chronic administration of agents that are strong CYP3A4 inducers with cabozantinib should be avoided. P-glycoprotein substrates: Cabozantinib was an inhibitor but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate while receiving cabozantinib. MRP2 inhibitors: Administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors should be approached with caution. Bile salt-sequestering agents: Bile salt-sequestering agents may interact with cabozantinib and may impact absorption (or reabsorption) resulting in potentially decreased exposure. The clinical significance of these potential interactions is unknown. Excipient related warnings: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy and lactation: Avoid pregnancy, use effective methods of contraception and discontinue breast-feeding during treatment with cabozantinib, and for at least 4 months after completing therapy.
Drive and use machines: Caution is recommended
Undesirable effects:
The most common serious adverse reactions associated with cabozantinib are abdominal pain (3%), pleural effusion (3%), diarrhoea (2%), and nausea (2%). The most frequent adverse reactions of any grade (experienced by at least 25% of patients) included diarrhoea (74%), fatigue (56%), nausea (50%), decreased appetite (46%), palmar-plantar erythrodysaesthesia syndrome (PPES) (42%), hypertension (37%), vomiting (32%), weight decreased (31%), and constipation (25%). Other very common adverse reactions: anemia, hypophosphataemia, hypoalbuminaemia, hypomagnesaemia, hyponatraemia, hypokalaemia,hyperkalaemia, hypocalcaemia, hyperbilirubinemia, dysgeusia, headache, dizziness, dysphonia, dyspnea, cough, stomatitis, abdominal pain, dyspepsia, rash, dry skin, muscle spasms, arthralgia, proteinuria, mucosal inflammation, serum ALT, AST, and ALP increased, creatinine increased, triglycerides increased, hyperglycaemia, hypoglycaemia, lymphopenia, neutropenia, thrombocytopenia, GGT increased, amylase increased, blood cholesterol increased, lipase increased
For all common and uncommon adverse reactions, please refer to full SmPC. For more information, see the regularly updated registered product information on the European Medicine Agency https://cabometyx.eu/eu/
About Exelixis
Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model genetic systems, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. We discovered our lead compounds, cabozantinib and cobimetinib, and advanced them into clinical development before entering into partnerships with leading biopharmaceutical companies in our efforts to bring them to patients globally. With growing revenues from the three resulting commercialized products – CABOMETYX®, COMETRIQ®, and COTELLIC® – we are reinvesting in our business to maximize the potential of our pipeline, which we intend to supplement with targeted business development activities and internal drug discovery, all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. For more information about Exelixis, please visit www.exelixis.com or follow @ExelixisInc on Twitter.
About Ipsen
Ipsen is a global specialty-driven biopharmaceutical group focused on innovation and specialty care. The group develops and commercializes innovative medicines in three key therapeutic areas – Oncology, Neurosciences and Rare Diseases. Its commitment to oncology is exemplified through its growing portfolio of key therapies for prostate cancer, neuroendocrine tumors, renal cell carcinoma and pancreatic cancer. Ipsen also has a well-established Consumer Healthcare business. With total sales close to €1.6 billion in 2016, Ipsen sells more than 20 drugs in over 115 countries, with a direct commercial presence in more than 30 countries. Ipsen’s R&D is focused on its innovative and differentiated technological platforms located in the heart of the leading biotechnological and life sciences hubs (Paris-Saclay, France; Oxford, UK; Cambridge, US). The Group has about 5,100 employees worldwide. Ipsen is listed in Paris (Euronext: IPN) and in the United States through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information on Ipsen, visit www.ipsen.com.
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References
1. Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. U.S. Department of Health and Human Services Food and Drug Administration; May 2007.
2. Choueiri, T.K., et al. Cabozantinib versus Sunitinib as Initial Targeted Therapy for Patients with Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Am J Clin Oncol. 2016; 35:591-597.
3. Heng D.Y., Xie W., Regan M.M., et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study. Am J Clin Oncol. 2009; 27:5794-5799.
4. American Cancer Society. Cancer Facts & Figures 2017. Atlanta: American Cancer Society; 2017.
5. Jonasch, E., Gao, J., Rathmell, W. Renal cell carcinoma. BMJ. 2014; 349:g4797.
6. Ko, J., Choueiri, T., et al. First-, second- third-line therapy for mRCC: benchmarks for trial design from the IMDC. Br J Cancer. 2014; 110:1917-1922.
7. Decision Resources Report: Renal Cell Carcinoma. October 2014 (internal data on file).
8. Harshman, L., and Choueiri, T. Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J. 2013; 19:316-323.
9. Rankin, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A. 2014; 111:13373-13378.
10. Zhou, L., Liu, X-D., Sun, M., et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016; 35:2687-2697.
11. Koochekpour, et al. The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999; 19:5902–5912.
12. Takahashi, A., Sasaki, H., Kim, S., et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994; 54:4233-4237.
13. Nakagawa, M., Emoto, A., Hanada, T., Nasu, N., Nomura, Y. Tubulogenesis by microvascular endothelial cells is mediated by vascular endothelial growth factor (VEGF) in renal cell carcinoma. Br J Urol. 1997; 79:681-687.
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