6 ADVERSE REACTIONS
- Most common all-causality adverse reactions (≥ 20%) are Constitutional (fatigue), Gastrointestinal (diarrhea, nausea, mucositis/stomatitis, vomiting, constipation, and abdominal pain), Cardiac (hypertension), Dermatology (rash, skin discoloration), Neurology (altered taste, headache), Musculoskeletal (arthralgia, myalgia/limb pain), Metabolism/Nutrition (anorexia, asthenia), Hemorrhage/bleeding (bleeding, all sites).
- Elevated liver function tests, pancreatic enzymes, creatinine, and myelosuppression were more common in GIST patients treated with SUTENT than placebo. Acquired hypothyroidism was noted in 8 patients (4%) on SUTENT versus 1 (1%) on placebo. Common treatment emergent laboratory abnormalities also observed in the MRCC studies included hypophosphatemia, hyperuricemia and increased lipase.
6.1 Overview
One thousand nine hundred twenty-four (1924) patients with solid tumors including 808 patients (42%) with GIST and 816 patients (42%) with MRCC have been treated with SUTENT in 20 completed and ongoing clinical trials. Most patients received SUTENT once daily as a 50-mg oral capsule on Schedule 4/2. One hundred two (102) patients received placebo in the randomized, double-blind, placebo-controlled clinical trial conducted in patients with GIST. Three hundred sixty (360) patients received IFN-α in the randomized clinical trial in patients with treatment-naïve MRCC.
The potentially serious adverse events relating to left ventricular dysfunction, hemorrhage, hypertension, and adrenal function are discussed in Section 5 WARNINGS AND PRECAUTIONS. Other all-causality adverse events occurring in GIST and MRCC studies are described below.
6.2 Adverse Events in GIST Study A
Median duration of blinded study treatment was two cycles for patients on SUTENT (mean 3.0, range 1–9) and one cycle (mean 1.8, range 1–6) for patients on placebo. Dose reductions occurred in 23 patients (11%) on SUTENTand none on placebo. Dose interruptions occurred in 59 patients (29%) on SUTENT and 31 patients (30%) on placebo. The rates of treatment-emergent, non-fatal adverse events resulting in permanent discontinuation were 7% and 6% in the SUTENT and placebo groups, respectively.
Most treatment-emergent adverse events in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse events were reported in 56% vs. 51% of patients on SUTENT versus placebo, respectively. Diarrhea, hypertension, bleeding, mucositis, skin abnormalities, and altered taste were more common in patients receiving SUTENT. Table 1 compares the incidence of common (>10%) treatment-emergent adverse events for patients receiving SUTENT versus those on placebo.
Oral pain other than mucositis/stomatitis occurred in 12 patients (6%) on SUTENT versus 3 (3%) on placebo. Hair color changes occurred in 15 patients (7%) on SUTENT versus 4 (4%) on placebo. Alopecia was observed in 10 patients (5%) on SUTENT versus 2 (2%) on placebo.
Table 1. Treatment-Emergent Adverse Events Reported in at Least 10% of GIST Patients Who Received SUTENT or Placebo in Study ACommon Toxicity Criteria for Adverse Events (CTCAE), Version 3.0 | GIST |
|---|
| SUTENT (n=202) | Placebo (n=102) |
|---|
| Adverse Event, n (%) | All Grades | Grade 3/4Grade 4 AEs in patients on SUTENT included abdominal pain (2%) and bleeding (2%). | All Grades | Grade 3/4Grade 4 AEs in patients on placebo included fatigue (3%), mucositis (1%), vomiting (1%), abdominal pain (3%), back pain (1%), and bone pain (1%). |
|---|
| Any | | 114 (56) | | 52 (51) |
| Constitutional | | | | |
| Fatigue | 84 (42) | 17 (8) | 48 (47) | 8 (8) |
| Fever | 36 (18) | 3 (2) | 17 (17) | 1 (1) |
| Gastrointestinal | | | | |
| Diarrhea | 81 (40) | 9 (4) | 27 (27) | 0 (0) |
| Nausea | 63 (31) | 3 (2) | 33 (32) | 5 (5) |
| Mucositis/stomatitis | 58 (29) | 2 (1) | 18 (18) | 2 (2) |
| Vomiting | 49 (24) | 4 (2) | 24 (24) | 3 (3) |
| Constipation | 41 (20) | 0 (0) | 14 (14) | 2 (2) |
| Abdominal painIncludes abdominal quadrant, gastric, hypochondrial, abdominal, flank, and cancer-related pain | 67 (33) | 22 (11) | 39 (38) | 12 (12) |
| Cardiac | | | | |
| Hypertension | 31 (15) | 9 (4) | 11 (11) | 0 (0) |
| Dermatology | | | | |
| Rash | 28 (14) | 2 (1) | 9 (9) | 0 (0) |
| Skin discoloration | 61 (30) | 0 (0) | 23 (23) | 0 (0) |
| Hand-foot syndrome | 28 (14) | 9 (4) | 10 (10) | 3 (3) |
| Neurology | | | | |
| Altered taste | 42 (21) | 0 (0) | 12 (12) | 0 (0) |
| Headache | 26 (13) | 3 (2) | 23 (23) | 0 (0) |
| Musculoskeletal | | | | |
| Arthralgia | 24 (12) | 2 (1) | 16 (16) | 0 (0) |
| Back pain | 23 (11) | 2 (1) | 16 (16) | 4 (4) |
| Myalgia/limb pain | 28 (14) | 1 (1) | 9 (9) | 1 (1) |
| Respiratory | | | | |
| Dyspnea | 20 (10) | 0 (0) | 19 (19) | 3 (3) |
| Cough | 17 (8) | 0 (0) | 13 (13) | 0 (0) |
| Metabolism/Nutrition | | | | |
| AnorexiaIncludes decreased appetite | 67 (33) | 1 (1) | 30 (29) | 5 (5) |
| Asthenia | 45 (22) | 10 (5) | 11 (11) | 3 (3) |
| Hemorrhage/Bleeding | | | | |
| Bleeding, all sites | 37 (18) | 14 (7) | 17 (17) | 9 (9) |
Table 2 provides common (≥10%) treatment-emergent laboratory abnormalities. Grade 3 or 4 treatment-emergent laboratory abnormalities were observed in 68 (34%) versus 22 (22%) patients on SUTENT and placebo, respectively. Elevated liver function tests, pancreatic enzymes, and creatinine were more common in patients treated with SUTENT than placebo. Decreased LVEF and myelosuppression were also more common with SUTENT treatment. Treatment-emergent electrolyte disturbances of all types were more common in patients on SUTENT than on placebo, including hyperkalemia (6% vs. 4%), hypokalemia (12% vs. 4%), hypernatremia (10% vs. 4%), hyponatremia (6% vs. 1%), and hypophosphatemia (9% vs. 0%). Three SUTENT patients (1.5%) had Grade 3 hypophosphatemia. Acquired hypothyroidism was noted in 8 patients (4%) on SUTENT versus 1 (1%) on placebo.
Table 2. Treatment-Emergent Laboratory Abnormalities (≥10%) from Study ACommon Toxicity Criteria for Adverse Events (CTCAE), Version 3.0 | GIST |
|---|
| Adverse Event, n (%) | SUTENT (n=202) | Placebo (n=102) |
|---|
| All Grades | Grade 3/4Grade 4 AEs in patients on SUTENT included alkaline phosphatase (1%), lipase (2%), creatinine (1%), hypokalemia (1%), neutropenia (2%), anemia (2%), and thrombocytopenia (1%). | All Grades | Grade 3/4Grade 4 AEs in patients on placebo included amylase (1%), lipase (1%), anemia (2%), and thrombocytopenia (1%). |
|---|
| LVEF=Left ventricular ejection fraction |
| Any | | 68 (34) | | 22 (22) |
| Gastrointestinal | | | | |
| AST / ALT | 78 (39) | 3 (2) | 23 (23) | 1 (1) |
| Alkaline phosphatase | 48 (24) | 7 (4) | 21 (21) | 4 (4) |
| Total bilirubin | 32 (16) | 2 (1) | 8 (8) | 0 (0) |
| Indirect bilirubin | 20 (10) | 0 (0) | 4 (4) | 0 (0) |
| Amylase | 35 (17) | 10 (5) | 12 (12) | 3 (3) |
| Lipase | 50 (25) | 20 (10) | 17 (17) | 7 (7) |
| Cardiac | | | | |
| Decreased LVEF | 22 (11) | 2 (1) | 3 (3) | 0 (0) |
| Renal / Metabolic | | | | |
| Creatinine | 25 (12) | 1 (1) | 7 (7) | 0 (0) |
| Hypokalemia | 24 (12) | 1 (1) | 4 (4) | 0 (0) |
| Hypernatremia | 20 (10) | 0 (0) | 4 (4) | 1 (1) |
| Uric acid | 31 (15) | 16 (8) | 16 (16) | 8 (8) |
| Hematology | | | | |
| Neutropenia | 107 (53) | 20 (10) | 4 (4) | 0 (0) |
| Lymphopenia | 76 (38) | 0 (0) | 16 (16) | 0 (0) |
| Anemia | 52 (26) | 6 (3) | 22 (22) | 2 (2) |
| Thrombocytopenia | 76 (38) | 10 (5) | 4 (4) | 0 (0) |
6.3 Adverse Events in MRCC Studies
The as-treated patient population for the interim safety analysis of the treatment-naive MRCC study included 735 patients, 375 randomized to SUTENT and 360 randomized to IFN-α. The median duration of treatment was 5.6 months (range: 0.4–15.6) for SUTENT treatment and 4.1 months (range: 0.1–13.7) on IFN-α treatment. Dose reductions occurred in 121 patients (32%) on SUTENTand 77 patients (21%) on IFN-α. Dose interruptions occurred in 142 patients (38%) on SUTENT and 115 patients (32%) on IFN-α. The rates of treatment-emergent, non-fatal adverse events resulting in permanent discontinuation were 8% and 13% in the SUTENT and IFN-α groups, respectively. Most treatment-emergent adverse events in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse events were reported in 63% versus 48% of patients on SUTENT versus IFN-α, respectively. Diarrhea, mucositis/ stomatitis, dyspepsia, hypertension, bleeding, skin abnormalities, and altered taste were more common in patients receiving SUTENT. Table 3 compares the incidence of common (≥10%) treatment-emergent adverse events for patients receiving SUTENT versus IFN-α.
Data on SUTENT treatment in 169 patients with cytokine-refractory MRCC enrolled in Studies 1 and 2 are also included in Table 3. Dose interruptions occurred in 48 patients (45%) on Study 1 and 45 patients (71%) on Study 2; one or more dose reductions occurred in 23 patients (22%) on Study 1 and 22 patients (35%) on Study 2.
Other significant adverse events occurring in cytokine-refractory MRCC patients receiving SUTENT included peripheral neuropathy (10%), appetite disturbance (9%), blistering of the skin (7%), periorbital edema (7%) and increased lacrimation (6%).
In the treatment-naive MRCC study, 20 (17%) versus 14 patients (10%) experienced treatment-emergent Grade 4 chemistry laboratory abnormalities on SUTENT versus IFN-α, respectively. The most common Grade 4 chemistry abnormalities were hyperuricemia (12% on SUTENT, 8% on IFN-α) and increased lipase (3% on SUTENT, 1% on IFN-α). The most common Grade 3 chemistry abnormalities observed on both arms were increased lipase (13% on SUTENT, 5% on IFN-α) and hypophosphatemia (4% on SUTENT, 6% on IFN-α). Other common Grade 3 laboratory abnormalities on SUTENT were hyponatremia (5%) and increased amylase (4%), and on IFN-α was hyperglycemia (6%).
Common treatment-emergent Grade 3 and 4 chemistry laboratory abnormalities in patients on SUTENT in the cytokine-refractory MRCC studies included increased lipase (16%), increased amylase (5%), hypophosphatemia (10%), and hyperuricemia (10%).
Table 3. Treatment-Emergent Adverse Events Reported in at Least 10% of Patients with MRCC Who Received SUTENT or IFN-αCommon Toxicity Criteria for Adverse Events (CTCAE), Version 3.0 | Treatment-Naïve MRCC | Cytokine-Refractory MRCC |
|---|
| SUTENT
(n=375) | IFN-α
(n=360) | SUTENT
(N=169) |
|---|
| Adverse Event, n (%) | All Grades | Grade 3/4Grade 4 AEs in patients on SUTENT included arthralgia (<1%), asthenia (<1%), back pain (1%), dehydration (<1%), fatigue (<1%), limb pain (<1%) and rash (<1%). | All Grades | Grade 3/4Grade 4 AEs in patients on IFN-α included dyspnea (1%), depression (<1%) and fatigue (1%). | All Grades | Grade 3/4There were no Grade 4 adverse events among the events reported with a ≥10% incidence in the cytokine-refractory MRCC population. |
|---|
| Any | 370 (99) | 235 (63) | 354 (98) | 172 (48) | 169 (100) | 123 (73) |
| Constitutional | | | | | | |
| Fatigue | 215 (57) | 35 (9) | 199 (55) | 47 (13) | 125 (74) | 19 (11) |
| Asthenia | 78 (21) | 26 (7) | 85 (24) | 20 (6) | 16 (9) | 4 (2) |
| Fever | 61 (16) | 3 (1) | 129 (36) | 0 (0) | 26 (15) | 2 (1) |
| Weight decreased | 43 (12) | 0 (0) | 52 (14) | 2 (1) | 19 (11) | 1 (1) |
| Chills | 41 (11) | 3 (1) | 108 (30) | 0 (0) | 18 (11) | 0 (0) |
| Gastrointestinal | | | | | | |
| Diarrhea | 218 (58) | 22 (6) | 71 (20) | 0 (0) | 93 (55) | 8 (5) |
| Nausea | 182 (49) | 14 (4) | 134 (37) | 5 (1) | 92 (54) | 4 (2) |
| Mucositis/stomatitis | 153 (41) | 10 (3) | 13 (4) | 2 (<1) | 90 (53) | 7 (4) |
| Vomiting | 104 (28) | 15 (4) | 49 (14) | 3 (1) | 63 (37) | 7 (4) |
| Dyspepsia | 104 (28) | 3 (1) | 14 (4) | 0 (0) | 77 (46) | 1 (1) |
| Abdominal painIncludes flank pain | 74 (20) | 9 (2) | 39 (11) | 5 (1) | 34 (20) | 5 (3) |
| Constipation | 59 (16) | 0 (0) | 44 (12) | 1 (<1) | 57 (34) | 1 (1) |
| Dry mouth | 44 (12) | 0 (0) | 26 (7) | 1 (<1) | 10 (6) | 0 (0) |
| Flatulence | 36 (10) | 0 (0) | 8 (2) | 0 (0) | 24 (14) | 0 (0) |
| Glossodynia | 37 (10) | 0 (0) | 2 (1) | 0 (0) | 25 (15) | 0 (0) |
| Cardiac | | | | | | |
| Hypertension | 101 (27) | 34 (9) | 13 (4) | 1 (<1) | 48 (28) | 10 (6) |
| Edema, peripheral | 42 (11) | 2 (1) | 15 (4) | 2 (1) | 28 (17) | 1 (1) |
| Dermatology | | | | | | |
| Dry skin | 64 (17) | 1 (<1) | 23 (6) | 0 (0) | 29 (17) | 0 (0) |
| Rash | 85 (23) | 3 (1) | 31 (9) | 2 (1) | 64 (38) | 1 (1) |
| Hair color changes | 54 (14) | 0 (0) | 1 (<1) | 0 (0) | 29 (17) | 0 (0) |
| Hand-foot syndrome | 77 (21) | 19 (5) | 3 (1) | 0 (0) | 21 (12) | 5 (3) |
| Skin discoloration | 60 (16) | 0 (0) | 0 (0) | 0 (0) | 55 (33) | 0 (0) |
| Alopecia | 30 (8) | 0 (0) | 30 (8) | 0 (0) | 20 (12) | 0 (0) |
| Neurology | | | | | | |
| Altered tasteIncludes ageusia, hypogeusia and dysgeusia | 166 (44) | 1 (<1) | 51 (14) | 0 (0) | 73 (43) | 0 (0) |
| Headache | 68 (18) | 3 (1) | 61 (17) | 0 (0) | 43 (25) | 2 (1) |
| Dizziness | 28 (8) | 1 (<1) | 39 (11) | 1 (<1) | 27 (16) | 3 (2) |
| Musculoskeletal | | | | | | |
| Back pain | 68 (18) | 11 (3) | 43 (12) | 6 (2) | 29 (17) | 1 (1) |
| Myalgia/limb pain | 84 (22) | 6 (2) | 91 (25) | 6 (2) | 60 (36) | 2 (2) |
| Arthralgia | 66 (18) | 4 (1) | 60 (17) | 1 (<1) | 48 (28) | 2 (1) |
| Respiratory | | | | | | |
| Cough | 62 (17) | 2 (1) | 43 (12) | 0 (0) | 29 (17) | 1 (1) |
| Dyspnea | 57 (15) | 15 (4) | 64 (18) | 14 (4) | 47 (28) | 8 (5) |
| Metabolism/Nutrition | | | | | | |
| AnorexiaIncludes decreased appetite | 139 (37) | 6 (2) | 145 (40) | 6 (2) | 53 (31) | 1 (1) |
| Dehydration | 30 (8) | 8 (2) | 17 (5) | 2 (1) | 19 (11) | 5 (3) |
| Hemorrhage/Bleeding | | | | | | |
| Bleeding, all sites | 104 (28) | 10 (3)Includes one patient with non-treatment-related Grade 5 gastric hemorrhage | 25 (7) | 2 (1) | 44 (26) | 1 (1) |
| Psychiatric | | | | | | |
| Insomnia | 42 (11) | 1 (<1) | 31 (9) | 0 (0) | 22 (13) | 1 (1) |
| Depression | 28 (8) | 0 (0) | 42 (12) | 4 (1) | 14 (8) | 1 (1) |
Grade 4 hematology laboratory abnormalities in the Phase 3 MRCC study include neutropenia (1% on SUTENT, 0% on IFN-α) and anemia (<1% each arm). Grade 3 hematology laboratory abnormalities included neutropenia (11% on SUTENT, 7% on IFN-α), lymphopenia (12% on SUTENT, 22% on IFN-α), thrombocytopenia (8% on SUTENT, 0% on IFN-α), leukopenia (5% on SUTENT, 2% on IFN-α) and anemia (3% on SUTENT, 4% on IFN-α).
In the SUTENT-treated cytokine-refractory MRCC patients, Grade 4 hematology abnormalities included anemia (2%), neutropenia (1%) and lymphopenia (1%). Grade 3 abnormalities were lymphopenia (20%) neutropenia (12%), leukopenia (7%), anemia (5%) and thrombocytopenia (3%) .
6.4 Cardiovascular Events
See 5 WARNINGS AND PRECAUTIONS for information on left ventricular dysfunction and QTc interval prolongation.
Two patients with cytokine-refractory MRCC experienced Grade 3 myocardial ischemia, one had Grade 2 "cardiovascular toxicity" reported as an adverse event and one patient experienced a fatal myocardial infarction while on treatment.
6.5 Venous Thromboembolic Events
Seven patients (3%) on SUTENT and none on placebo in GIST Study A experienced venous thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT), and two were Grade 1 or 2. Four of these seven GIST patients discontinued treatment following first observation of DVT. Seven (2%) patients receiving SUTENT for treatment-naïve MRCC and four patients (2%) on the two cytokine-refractory MRCC studies had venous thromboembolic events reported. Six of these patients had pulmonary embolism, one was Grade 3 and five were Grade 4, and five patients had DVT, one each with Grade 1 and 4, and three with Grade 3. Dose interruption occurred in one of these cases. In treatment-naïve MRCC patients receiving IFN-α, six (2%) venous thromboembolic events occurred; one patient (<1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolism, one Grade 1 and four with Grade 4.
6.6 Seizures
In clinical studies of SUTENT, seizures have been observed in subjects with radiological evidence of brain metastases. In addition, there have been rare (<1%) reports of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). None of these subjects had a fatal outcome to the event. 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 physician.
6.7 Laboratory Abnormalities/Testing
Hematologic Events
Grade 3 and 4 neutropenia were reported in 19 (9%) and 3 (2%) patients with GIST on SUTENT. Grade 4 neutropenia was reported in 3 (1%) and 1 (1%) patients receiving SUTENT for treatment-naïve and cytokine-refractory MRCC, respectively. Grade 3 neutropenia was reported in 41 (11%) and 21 (12%) patients receiving SUTENT for treatment-naïve and cytokine-refractory MRCC, respectively. Twenty-four (7%) and 0 patients treated with IFN-α for treatment-naïve MRCC had Grade 3 and 4 neutropenia, respectively. In Study A, one GIST patient each in the SUTENT and placebo groups had febrile neutropenia. Grade 3 and 4 thrombocytopenia was reported in 7 (4%) and 1 (1%) patients with GIST on SUTENT and 35 (11%) and 0 patients with MRCC, respectively. No GIST patients receiving placebo experienced either Grade 3 or 4 neutropenia or thrombocytopenia. The rates of dose reductions and delays for hematologic abnormalities were 2% and 4% for neutropenia, 0% and 2% for anemia, and 1% and 1% for thrombocytopenia for GIST and cytokine-refractory MRCC patients, respectively. One cytokine-refractory MRCC patient with an adverse event report of Grade 4 thrombocytopenia discontinued treatment.
Patients receiving SUTENT should be monitored regularly for myelosuppression.
Hypothyroidism
Treatment-emergent acquired hypothyroidism was noted in 8 GIST patients (4%) on SUTENT versus 1 (1%) on placebo. Hypothyroidism was reported as an adverse event in nine patients (2%) on SUTENT in the treatment-naïve MRCC study and one patient (<1%) in the IFN-α arm, and in 7 patients (4%) across the two cytokine-refractory MRCC studies. Additionally, TSH elevations were reported in 4 cytokine-refractory MRCC patients (2%). Overall, 7% of the cytokine-refractory MRCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism.
Patients with symptoms suggestive of hypothyroidism should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.
Gastrointestinal Function
Grade 3 and 4 increases in serum lipase were observed in 23 (14%) and 4 (2%), respectively, of 169 patients receiving SUTENT for cytokine-refractory MRCC and in 49 (13%) and 11 (3%), respectively, of patients receiving SUTENT for treatment-naïve MRCC. Grade 3 and 4 increases in serum amylase were observed in 8 (5%) and 1 (1%) cytokine-refractory MRCC patients, respectively and in 16 (4%) and 3 (1%), respectively, of patients receiving SUTENT for treatment-naïve MRCC. Increases in lipase levels were transient and were generally not accompanied by signs or symptoms of pancreatitis in subjects with either GIST or MRCC. Pancreatitis has been observed rarely (<1%) in patients receiving SUTENT for GIST or MRCC. Hepatic failure was observed in <1% of solid tumor patients treated with SUTENT. If symptoms of pancreatitis or hepatic failure are present, patients should have SUTENT discontinued and be provided with appropriate supportive care.
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