TORISEL Clinical Trial Design and Results¹

TORISEL was studied in a phase 3, multicenter, 3-arm, randomized, open-label study conducted in 626 previously untreated patients with advanced renal cell carcinoma (RCC) with at least 3 of 6 prognostic risk factors.

This study was called the Global Advanced Renal Cell Carcinoma (ARCC) Study. Objectives were to compare the following parameters in patients receiving interferon-alpha (IFN) vs. patients receiving TORISEL or TORISEL plus
IFN:

• Primary end point: overall survival (OS)
• Secondary end points included progression-free survival (PFS) and objective response rate (ORR)
• Safety profile

TORISEL—Studied 1^st line in poor-risk patients with advanced RCC

94% of patients had ≥3 of 6 prognostic risk factors in the phase 3 Global ARCC study at randomization^3*

Treatment with the combination of TORISEL 15 mg and IFN was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival (OS) when compared with IFN alone.¹

Disease Characteristics^2,3

Characteristic	TORISEL 25 mg (n=209)	IFN up to 18 MU 3x weekly (n=207)
Primary cell type     Clear     Other†	81% 19%	82% 18%
Prior nephrectomy     No     Yes	34% 66%	33% 67%

Trial results

• TORISEL demonstrated a statistically significant 49% increase in median overall survival (OS) compared with interferon-alpha (IFN ) (P=0.0078^*)¹
• The O'Brien-Fleming boundary for early success (P<0.0159) was reached at the second planned interim analysis^1,2

Primary End Point: Median Overall Survival¹

Primary end point	TORISEL (n=209)	IFN (n=207)	P-value†	Hazard Ratio (95% CI)‡
Median OS§ Months (95% CI)	10.9 (8.6, 12.7)	7.3 (6.1, 8.8)	0.0078*	0.73 (0.58, 0.92)

Secondary End Points^1-2*

Parameter	TORISEL 25 mg (n=209)	IFN (n=207)	P-value†	Hazard Ratio (95% CI)‡
Median PFS§ by independent review Months (95% CI)	5.5 (3.9-7.0)	3.1 (2.2-3.8)	0.0001	0.66 (0.53-0.81)
ORR|| % (95% CI)	8.6% (4.8-12.4)	4.8% (1.9-7.8)	0.1232¶ (not significant)	NA
Clinical benefit rate (CR, PR, or SD for ≥24 weeks) % (95% CI)#	32.1% (25.7-38.4)	15.5% (10.5-20.4)	<0.0001	NA

Important Safety Information

• TORISEL is contraindicated in patients with bilirubin >1.5 x ULN and should be used with caution when treating patients with mild hepatic impairment (bilirubin >1 - 1.5 x ULN or AST > ULN but bilirubin ≤ ULN). If TORISEL must be given to patients with mild hepatic impairment, reduce the dose of TORISEL to 15 mg/week. In a phase 1 study, the overall frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to progressive disease, was greater in patients with baseline bilirubin > 1.5 x ULN.
• Hypersensitivity/infusion reactions, including flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, may occur very early in the first infusion or with subsequent infusions. Pretreat with an H1 antihistamine. TORISEL infusion should be interrupted in patients with infusion reactions and appropriate therapy given.
• Serum glucose, serum cholesterol, and triglycerides should be tested before and during TORISEL treatment.
• TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.
• TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.
• Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic or had minimal symptoms. Patients should undergo baseline radiography prior to TORISEL therapy and periodically thereafter, even in the absence of clinical respiratory symptoms. Follow patients closely and, if clinically significant respiratory symptoms develop, consider withholding TORISEL until recovery of symptoms and radiographic improvement of pneumonitis findings. Some patients required TORISEL discontinuation and/or treatment with corticosteroids and/or antibiotics.
• Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen.
• Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL.
• Due to abnormal wound healing, use TORISEL with caution in the perioperative period.
• Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL.
• Live vaccinations and close contact with those who received live vaccines should be avoided.
• TORISEL may cause fetal harm. Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped.
• Elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema and pneumonia.
• The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%).
• Most common grades 3/4 adverse events and laboratory abnormalities included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%).
• Pleural effusion, hemodynamically significant pericardial effusions requiring intervention, convulsions, rhabdomyolysis, Stevens-Johnson Syndrome, complex regional pain syndrome and extravasations have been reported during postmarketing use.
• Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.
• Avoid St. John's Wort which may decrease TORISEL plasma concentrations, and grapefruit juice which may increase plasma concentrations of the major metabolite of TORISEL.
• The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization).

Please see the full Prescribing Information for TORISEL.