TIBSOVO® safety profile in acute myeloid leukemia (AML)

TIBSOVO in combination with azacitidine for treatment of newly diagnosed, IC-ineligible mIDH1 AML

Adverse reactions (≥10%) in patients with AML who received TIBSOVO + azacitidine with a difference of ≥2% between arms compared with placebo + azacitidine¹

	TIBSOVO + azacitidine (N=71)		Placebo + azacitidine (N=73)
Body system Adverse reaction	All grades	Grade ≥3	All grades	Grade ≥3
Gastrointestinal disorders
Nausea	42%	3%	38%	4%
Vomiting	41%	0	27%	1%
Investigations
Electrocardiogram QT prolonged	20%	10%	7%	3%
Psychiatric disorders
Insomnia	18%	1%	12%	0
Blood system and lymphatic system disorders
Differentiation syndromea	15%	10%	8%	8%
Leukocytosis	13%	0	1%	0
Vascular disorders
Hematoma	15%	0	4%	0
Hypertension	13%	4%	8%	5%
Musculoskeletal and connective tissue disorders
Arthralgia	30%	4%	8%	1%
Respiratory, thoracic, and mediastinal disorders
Dyspnea	20%	3%	15%	5%
Nervous system disorders
Headache	11%	0	3%	0

	TIBSOVO + azacitidine (N=71)
Body system Adverse reaction	All grades	Grade ≥3
Gastrointestinal disorders
Nausea	42%	3%
Vomiting	41%	0
Investigations
Electrocardiogram QT prolonged	20%	10%
Psychiatric disorders
Insomnia	18%	1%
Blood system and lymphatic system disorders
Differentiation syndromea	15%	10%
Leukocytosis	13%	0
Vascular disorders
Hematoma	15%	0
Hypertension	13%	4%
Musculoskeletal and connective tissue disorders
Arthralgia	30%	4%
Respiratory, thoracic, and mediastinal disorders
Dyspnea	20%	3%
Nervous system disorders
Headache	11%	0

	Placebo + azacitidine (N=73)
Body system Adverse reaction	All grades	Grade ≥3
Gastrointestinal disorders
Nausea	38%	4%
Vomiting	27%	1%
Investigations
Electrocardiogram QT prolonged	7%	3%
Psychiatric disorders
Insomnia	12%	0
Blood system and lymphatic system disorders
Differentiation syndromea	8%	8%
Leukocytosis	1%	0
Vascular disorders
Hematoma	4%	0
Hypertension	8%	5%
Musculoskeletal and connective tissue disorders
Arthralgia	8%	1%
Respiratory, thoracic, and mediastinal disorders
Dyspnea	15%	5%
Nervous system disorders
Headache	3%	0

^aDifferentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased.

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Select laboratory abnormalities (≥10%) that worsened from baseline in patients with newly diagnosed AML who received TIBSOVO + azacitidine^1,b,c

	TIBSOVO + azacitidine (N=71)		Placebo + azacitidine (N=73)
Parameter	All grades	Grade ≥3	All grades	Grade ≥3
Hematology parameters
Leukocytes decreased	65%	55%	64%	58%
Platelets decreased	58%	42%	71%	58%
Hemoglobin decreased	56%	46%	66%	58%
Neutrophils decreased	25%	23%	35%	32%
Lymphocytes increased	24%	1%	10%	1%
Chemistry parameters
Glucose increased	56%	13%	47%	11%
Phosphate decreased	41%	10%	34%	12%
Aspartate aminotransferase increased	37%	0	23%	0
Magnesium decreased	35%	0	26%	0
Alkaline phosphatase increased	32%	0	29%	0
Potassium increased	24%	3%	12%	1%

	TIBSOVO + azacitidine (N=71)
Parameter	All grades	Grade ≥3
Hematology parameters
Leukocytes decreased	65%	55%
Platelets decreased	58%	42%
Hemoglobin decreased	56%	46%
Neutrophils decreased	25%	23%
Lymphocytes increased	24%	1%
Chemistry parameters
Glucose increased	56%	13%
Phosphate decreased	41%	10%
Aspartate aminotransferase increased	37%	0
Magnesium decreased	35%	0
Alkaline phosphatase increased	32%	0
Potassium increased	24%	3%

	Placebo + azacitidine (N=73)
Parameter	All grades	Grade ≥3
Hematology parameters
Leukocytes decreased	64%	58%
Platelets decreased	71%	58%
Hemoglobin decreased	66%	58%
Neutrophils decreased	35%	32%
Lymphocytes increased	10%	1%
Chemistry parameters
Glucose increased	47%	11%
Phosphate decreased	34%	12%
Aspartate aminotransferase increased	23%	0
Magnesium decreased	26%	0
Alkaline phosphatase increased	29%	0
Potassium increased	12%	1%

^bLaboratory abnormality was defined as new or worsened by at least one grade from baseline or if baseline was unknown.

^cThe denominator used to calculate percentages is the number of treated subjects who can be evaluated for Common Terminology Criteria for Adverse Events (CTCAE) for each parameter in each arm.

• TIBSOVO + azacitidine was associated with fewer severe cytopenias compared with azacitidine^1,2
• Median duration of exposure to TIBSOVO was 6 months (range, 0 to 33)¹
• 34 patients (48%) were exposed to TIBSOVO for at least 6 months
• 22 patients (31%) were exposed to TIBSOVO for at least 1 year
• Fatal adverse reactions occurred in 4% of patients due to differentiation syndrome (3%) and one case of cerebral ischemia¹

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TIBSOVO + azacitidine: Dose discontinuations, interruptions, and reductions¹

• The rate of discontinuation due to adverse events in patients treated with TIBSOVO + azacitidine was comparable to that of placebo + azacitidine (26.8% vs 26.0%)³
• Adverse reactions leading to permanent discontinuation of TIBSOVO in ≥2% of patients were differentiation syndrome (3%) and pulmonary embolism (3%)¹
• The most common (>5%) adverse reactions leading to dose interruption of TIBSOVO were neutropenia (25%), electrocardiogram QT prolonged (7%), and thrombocytopenia (7%)¹
• Adverse reactions leading to dose reduction of TIBSOVO included electrocardiogram QT prolonged (8%), neutropenia (8%), and thrombocytopenia (1%)¹

Safety profile: TIBSOVO monotherapy in the newly diagnosed setting

Adverse reactions ≥10% (any grade) or ≥5% (Grade ≥3) reported in newly diagnosed patients who received TIBSOVO¹

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Laboratory abnormalities ≥10% (any grade) or ≥5% (Grade ≥3) reported in newly diagnosed patients who received TIBSOVO^1,e

	TiBSOVO for newly diagnosed AML (N=28)
Parameter	All grades	Grade ≥3
Hemoglobin decreased	54%	43%
Alkaline phosphatase increased	46%	0
Potassium decreased	43%	11%
Sodium decreased	39%	4%
Uric acid increased	29%	4%
Aspartate aminotransferase increased	29%	4%
Creatinine increased	29%	0
Magnesium decreased	25%	0
Calcium decreased	25%	4%
Phosphate decreased	21%	7%
Alanine aminotransferase increased	14%	4%

^eLaboratory abnormality was defined as new or worsened by at least one grade from baseline or if baseline was unknown.

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Dose modifications seen with TIBSOVO¹

• Adverse reactions leading to discontinuation of TIBSOVO were diarrhea (4%) and PRES (4%)
• The most common (≥10%) adverse reactions leading to dose interruption of TIBSOVO were electrocardiogram QT prolonged (14%) and differentiation syndrome (11%)
• Adverse reactions leading to dose reduction of TIBSOVO included electrocardiogram QT prolonged (7%)

Safety profile: TIBSOVO monotherapy in the relapsed or refractory setting

Adverse reactions ≥10% (any grade) or ≥5% (Grade ≥3) reported in R/R patients who received TIBSOVO monotherapy¹

	TIBSOVO for R/R AML (N=179)
Body system Adverse reaction	All grades	Grade ≥3
General disorders and administration site conditions
Fatigue	39%	3%
Edema	32%	1%
Pyrexia	23%	1%
Chest pain	16%	3%
Blood system and lymphatic system disorders
Leukocytosis	38%	8%
Differentiation syndromef	19%	13%
Musculoskeletal and connective tissue disorders
Arthralgia	36%	4%
Myalgia	18%	1%
Gastrointestinal disorders
Diarrhea	34%	2%
Nausea	31%	1%
Mucositis	28%	3%
Constipation	20%	1%
Vomiting	18%	1%
Abdominal pain	16%	1%
Respiratory, thoracic, and mediastinal disorders
Dyspnea	33%	9%
Cough	22%	<1%
Pleural effusion	13%	3%
Investigations
Electrocardiogram QT prolonged	26%	10%
Skin and subcutaneous tissue disorders
Rash	26%	2%
Metabolism and nutrition disorders
Decreased appetite	18%	2%
Tumor lysis syndrome	8%	6%
Nervous system disorders
Headache	16%	0
Neuropathy	12%	1%
Vascular disorders
Hypotension	12%	4%

^fDifferentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased.

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Laboratory abnormalities ≥10% (any grade) or ≥5% (Grade ≥3) reported in R/R patients who received TIBSOVO monotherapy^1,g

	TIBSOVO for R/R AML (N=179)
Parameter	All grades	Grade ≥3
Hemoglobin decreased	60%	46%
Sodium decreased	39%	4%
Magnesium decreased	38%	0
Uric acid increased	32%	6%
Potassium decreased	31%	6%
Alkaline phosphatase increased	27%	1%
Aspartate aminotransferase increased	27%	1%
Phosphate decreased	25%	8%
Creatinine increased	23%	1%
Alanine aminotransferase increased	15%	1%
Bilirubin increased	16%	1%

^gLaboratory abnormality was defined as new or worsened by at least one grade from baseline or if baseline was unknown.¹

• No patient permanently discontinued treatment with TIBSOVO due to the adverse events of differentiation syndrome, QT interval prolongation, or leukocytosis^1,4
• No hepatotoxicity effects were observed with TIBSOVO^1,4
• TIBSOVO does not require monitoring of liver function tests

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Dose modifications seen with TIBSOVO in the R/R setting¹

• Adverse reactions leading to discontinuation of TIBSOVO were Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%)
• The most common adverse reactions leading to dose interruption of TIBSOVO were electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%), and dyspnea (3%)
• Adverse reactions leading to dose reduction of TIBSOVO included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%)

PRES, posterior reversible encephalopathy syndrome; R/R, relapsed/refractory.

Warnings and Precautions

Differentiation Syndrome in AML: In the combination study AG120-C-009, 15% (11/71) of patients with newly diagnosed AML treated with TIBSOVO plus azacitidine experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 11 patients with newly diagnosed AML who experienced differentiation syndrome with TIBSOVO plus azacitidine, 8 (73%) recovered. Differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment.

In the monotherapy clinical trial AG120-C-001, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (eg, anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT₃ receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.