The FINANCIAL -- Pfizer Inc. on November 16 announced that the U.S. Food and Drug Administration has approved a new indication expanding the use of SUTENT (sunitinib malate) to include the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma (RCC) following nephrectomy (surgical removal of the cancerous kidney).
The approval was based on results from the S-TRAC trial that demonstrated a significant reduction in the risk of a disease-free survival (DFS) event (defined as the interval between randomization and tumor recurrence, or secondary primary cancer or death from any cause) for patients at high risk of RCC recurrence who received SUTENT compared to placebo in the adjuvant setting.
SUTENT has been a standard of care for the treatment of advanced RCC since it was approved more than a decade ago, and is now the first approved adjuvant treatment option for certain patients at high risk of recurrent RCC - the most common type of kidney cancer. The current treatment approach for RCC patients is surgery followed by observation, which is suboptimal for patients at high risk of recurrence, according to Pfizer.
“Today’s approval marks an important step forward for the treatment of adult patients who are at high risk of their renal cell carcinoma returning after surgery,” said Liz Barrett, global president and general manager, Pfizer Oncology. “Pfizer has been dedicated to advancing the science of RCC treatment for over a decade, and we are pleased to see this commitment continue to translate into meaningful options for patients.”
The S-TRAC trial was a multicenter, international, randomized, double-blind, placebo-controlled Phase 3 trial of SUTENT versus placebo in 615 patients with clear cell histology and high risk of recurrent RCC following nephrectomy. The study met its primary endpoint of improving DFS and the results were published by The New England Journal of Medicine in October 2016.
“Some patients who have undergone surgery for locally advanced RCC are at high risk of recurrence and often fear their disease returning,” said Daniel George, MD, study investigator and medical oncologist at Duke University Medical Center. “This adjuvant therapy is the first-of-its-kind and a remarkable clinical development for these patients who before today, have been restricted to a wait and see approach.”
In the S-TRAC trial, the Hazard Ratio (HR) was 0.76 (95% CI: 0.59, 0.98) with a 2-sided p-value=0.03 in favor of SUTENT, representing a statistically significant 24% relative reduction in the risk of a DFS event. The median DFS was 6.8 years (95% CI: 5.8, not reached [NR]) in the SUTENT arm compared with 5.6 years (95% CI: 3.8, 6.6) in the placebo arm. At five years, the DFS rate for patients receiving SUTENT was 59.3% and 51.3% for placebo. This represents a persistent 8% absolute benefit.
No new safety signals were identified in the S-TRAC trial. The most common adverse reactions occurring in ≥20% of patients receiving SUTENT for adjuvant treatment of RCC (all grades) were mucositis/stomatitis (61%), fatigue/asthenia (57%), diarrhea (57%), hand-foot syndrome (50%), hypertension (39%), altered taste (38%), nausea (34%), dyspepsia (27%), abdominal pain (25%), rash (24%), hypothyroidism/TSH increased (24%), bleeding events, all sites (24%), and hair color changes (22%). The prescribing information for SUTENT also includes a boxed warning for hepatotoxicity and notes the following warnings and precautions: cardiovascular events; QT Interval Prolongation and Torsades de Pointes; hypertension; hemorrhagic events and viscus perforation; Tumor Lysis Syndrome (TLS); thrombotic microangiopathy (TMA); proteinuria; dermatologic toxicities; thyroid dysfunction; hypoglycemia; osteonecrosis of the jaw (ONJ); wound healing; and embryo-fetal toxicity. For more information, including Boxed Warning, please see the Important Safety Information for SUTENT below.
SUTENT Important Safety Information
Hepatotoxicity has been observed in clinical trials and postmarketing experience. Hepatotoxicity may be severe, and in some cases fatal. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. Fatal liver failure has been observed. Monitor liver function tests before initiation of treatment, during each cycle of treatment, and as clinically indicated. Interrupt SUTENT for Grade 3 or 4 drug-related hepatic adverse reactions and discontinue if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have signs and symptoms of liver failure.
Cardiovascular events, including myocardial ischemia, myocardial infarction, left ventricular ejection fraction declines to below the lower limit of normal and cardiac failure including death have occurred. Monitor patients for signs and symptoms of congestive heart failure. Discontinue SUTENT for clinical manifestations of congestive heart failure. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered. Baseline and periodic evaluations of left ventricular ejection fraction should also be considered while these patients are receiving SUTENT.
SUTENT can cause QT Prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsades de Pointes, which has been seen in <0.1% of patients. Monitor patients that are at a higher risk for developing QT interval prolongation, including those with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Consider monitoring of electrocardiograms and electrolytes. Concomitant treatment with strong CYP3A4 inhibitors may increase sunitinib plasma concentrations and dose reduction of SUTENT should be considered.
Hypertension may occur. Monitor blood pressure and treat as needed with standard antihypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled.
Hemorrhagic events, including tumor-related hemorrhage, and viscus perforation (both with fatal events) have occurred. These events may occur suddenly, and in the case of pulmonary tumors, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Perform serial complete blood counts (CBCs) and physical examinations.
Cases of tumor lysis syndrome (TLS) (some fatal) have been reported. Patients generally at risk of TLS are those with high tumor burden prior to treatment. Monitor these patients closely and treat as clinically indicated.
Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, has been reported in patients who received SUTENT as monotherapy and in combination with bevacizumab. Discontinue SUTENT in patients developing TMA. Reversal of the effects of TMA has been observed after treatment was discontinued.
Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes. Monitor patients for the development or worsening of proteinuria. Perform baseline and periodic urinalysis during treatment, with follow-up measurement of 24-hour urine protein as clinically indicated. Interrupt treatment for 24-hour urine protein ≥3 grams. Discontinue for repeat episodes of protein ≥3 grams despite dose reductions or nephrotic syndrome.
Dermatologic toxicities: Severe cutaneous reactions have been reported, including cases of necrotizing fasciitis, erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. If signs or symptoms of EM, SJS, or TEN are present, discontinue SUTENT treatment. If a diagnosis of SJS or TEN is suspected, treatment must not be re-started.
Necrotizing fasciitis, including fatal cases, has been reported, including of the perineum and secondary to fistula formation. Discontinue SUTENT in patients who develop necrotizing fasciitis.
Thyroid dysfunction may occur. Monitor thyroid function in patients with signs and/or symptoms suggestive of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, and treat per standard medical practice.
Hypoglycemia may occur. SUTENT can result in symptomatic hypoglycemia, which may lead to a loss of consciousness or require hospitalization. Reductions in blood glucose levels may be worse in patients with diabetes. Check blood glucose levels regularly during and after discontinuation of treatment with SUTENT. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.
Osteonecrosis of the jaw (ONJ) has been reported. Consider preventive dentistry prior to treatment with SUTENT. If possible, avoid invasive dental procedures, particularly in patients receiving intravenous bisphosphonate therapy.
Impaired wound healing has occurred with SUTENT. Temporary interruption of therapy with SUTENT is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume SUTENT therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery.
Embryo fetal toxicity and reproductive potential
Females - SUTENT can cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with SUTENT and for 4 weeks following the final dose
Males - Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with SUTENT and for 7 weeks after the last dose
Male and female infertility - based on findings in animals, male and female fertility may be compromised by treatment with SUTENT
Lactation: Because of the potential for serious adverse reactions in breastfed infants from SUTENT, advise a lactating woman not to breastfeed during treatment with SUTENT and for at least 4 weeks after the last dose.
Venous thromboembolic events: In patients treated with SUTENT (N=7527) for GIST, advanced RCC, adjuvant treatment of RCC and pNET, 3.5% of patients experienced a venous thromboembolic event; 2.2% Grade 3-4.
There have been (<1%) reports, some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness, should be controlled with medical management including control of hypertension. Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating healthcare provider.
Pancreatic function: In a trial of patients receiving adjuvant treatment for RCC, 1 patient (<1%) on SUTENT and none on placebo experienced pancreatitis.
CYP3A4 inhibitors and inducers: Dose adjustments are recommended when SUTENT is administered with CYP3A4 inhibitors or inducers. During treatment with SUTENT, patients should not drink grapefruit juice, eat grapefruit, or take St. John's Wort.
Most common ARs & most common grade 3/4 ARs (adjuvant RCC): The most common ARs reported in ≥20% of patients receiving SUTENT for adjuvant treatment of RCC and more commonly than in patients given placebo (all grades, vs placebo) were mucositis/stomatitis (61% vs 15%), diarrhea (57% vs 22%), fatigue/asthenia (57% vs 34%), hand-foot syndrome (50% vs 10%), hypertension (39% vs 14%), altered taste (38% vs 6%), nausea (34% vs 15%), dyspepsia (27% vs 7%), abdominal pain (25% vs 9%), hypothyroidism/TSH increased (24% vs 4%), rash (24% vs 12%), hair color changes (22% vs 2%). The most common grade 3/4 ARs reported in ≥5% of patients receiving SUTENT for adjuvant treatment of RCC and more commonly than in patients given placebo (vs placebo) were hand-foot syndrome (16% vs <1%), fatigue/asthenia (8% vs 2%), mucositis/stomatitis (6% vs 0%), and hypertension (8% vs 1%).
Most common grade 3/4 lab abnormalities (adjuvant RCC): The most common grade 3/4 lab abnormalities (occurring in ≥ 2% of patients receiving SUTENT) included neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%).
Most common ARs & most common grade 3/4 ARs (advanced RCC): The most common ARs reported in ≥20% of patients receiving SUTENT for treatment-naïve metastatic RCC (all grades, vs IFNα) were diarrhea (66% vs 21%), fatigue (62% vs 56%), nausea (58% vs 41%), anorexia (48% vs 42%), altered taste (47% vs 15%), mucositis/stomatitis (47% vs 5%), pain in extremity/limb discomfort (40% vs 30%), vomiting (39% vs 17%), bleeding, all sites (37% vs 10%), hypertension (34% vs 4%), dyspepsia (34% vs 4%), arthralgia (30% vs 19%), abdominal pain (30% vs 12%), rash (29% vs 11%), hand-foot syndrome (29% vs 1%), back pain (28% vs 14%), cough (27% vs 14%), asthenia (26% vs 22%), dyspnea (26% vs 20%), skin discoloration/yellow skin (25% vs 0%), peripheral edema (24% vs 5%), headache (23% vs 19%), constipation (23% vs 14%), dry skin (23% vs 7%), fever (22% vs 37%), and hair color changes (20% vs <1%). The most common grade 3/4 ARs reported in ≥5% of patients with RCC receiving SUTENT (vs IFNα) were fatigue (15% vs 15%), hypertension (13% vs <1%), asthenia (11% vs 6%), diarrhea (10% vs <1%), hand-foot syndrome (8% vs 0%), dyspnea (6% vs 4%), nausea (6% vs 2%), back pain (5% vs 2%), pain in extremity/limb discomfort (5% vs 2%), vomiting (5% vs 1%), and abdominal pain (5% vs 1%).
Most common grade 3/4 lab abnormalities (advanced RCC): The most common grade 3/4 lab abnormalities (occurring in ≥5% of patients with RCC receiving SUTENT vs IFNα) included lymphocytes (18% vs 26%), lipase (18% vs 8%), neutrophils (17% vs 9%), uric acid (14% vs 8%), platelets (9% vs 1%), hemoglobin (8% vs 5%), sodium decreased (8% vs 4%), leukocytes (8% vs 2%), glucose increased (6% vs 6%), phosphorus (6% vs 6%), and amylase (6% vs 3%).