ADMIRAL TRIAL

Help Patients Achieve Remission With XOSPATA^1,2

Higher rate of CR* with XOSPATA vs salvage chemotherapy^1†

14.2^%

CR with XOSPATA (95% CI: 10.1, 19.2; n=35/247)
vs 10.5% CR with salvage chemotherapy
(95% CI: 5.7, 17.3; n=13/124)

*CR was defined as normal marrow differential with <5% blasts, ANC ≥1.0 x 10⁹/L and platelets ≥100 x 10⁹/L, no evidence of extramedullary leukemia, and must have been RBC and platelet transfusion independent.¹

†Only responses prior to HSCT were included in the response rate.¹

MEDIAN DURATION OF COMPLETE REMISSION^1†‡

14.8 months median DOR with XOSPATA
(range: 0.6 to 23.1+ months) 1.8 months median DOR with salvage
chemotherapy (range: <0.1+ to 1.8 months)

14.8 months duration of complete remission (DOR) with XOSPATA. 1.8 months median DOR with salvage chemotherapy.

†Only responses prior to HSCT were included in the response rate.¹

^‡DOR was defined as the time from the date of first remission until the date of a documented relapse.¹

PATIENTS ACHIEVED CR/CRh^§ WITH XOSPATA¹

22.6% CR/CRh rate^|| with XOSPATA (n=55/243)

Median DOR with XOSPATA
(range: <0.1+ to 23.1+ months)

2 months median time to first response
(range: 0.9 to 9.6 months)

In patients who achieved CR/CRh with XOSPATA

§CRh was defined as marrow blasts <5%, partial hematologic recovery, ANC ≥0.5 x10⁹/L and platelets ≥50 x 10⁹/L, no evidence of extramedullary leukemia, and could not have been classified as CR.¹

^||CR/CRh rate was defined as the number of patients who achieved either CR or CRh at any post-baseline visit divided by the number of patients in the analysis population.²

CRc RATE OBSERVED WITH XOSPATA

The following rate and duration of CRc results from the ADMIRAL trial are not contained in the approved product labeling for XOSPATA and were not powered for statistical significance. Therefore, these results should be interpreted with caution and should not be used to make comparisons between treatment arms. CRc is a composite endpoint including CR, CRp, or CRi.² The use of CRi and CRp to demonstrate meaningful treatment benefits in AML clinical trials has not been established.

54.3^%

CRc with XOSPATA (95% CI: 47.8, 60.6; n=134/247)²

21.8^%

CRc with chemotherapy (95% CI: 14.9, 30.1; n=27/124)²

The median duration of CRc was 4.6 months with XOSPATA (95% CI: 3.7, 7.7) and was not estimable with salvage chemotherapy (95% CI: 1.8, NE)²
The rate of CRc was defined as the number of patients who achieved the best response of CRc (CR, CRp, or CRi) divided by the number of patients in the analysis population²
The majority of patients who received salvage chemotherapy finished the study by Cycle 2 of treatment, resulting in a short duration of exposure, limited follow-up response, and high censoring of the duration of CRc²

TRANSFUSION INDEPENDENCE IN THE ADMIRAL TRIAL¹

Among patients in the XOSPATA arm who were transfusion dependent at baseline (n=197),

34.5% became transfusion independent during any 56-day post-baseline period (n=68/197).

Of the 49 patients in the XOSPATA arm who were transfusion independent at baseline, 59.2% remained transfusion independent during any 56-day post-baseline period (n=29/49)¹

¶Transfusion independence was defined as patients who were dependent on RBC and/or platelet transfusions at baseline and became independent of RBC and platelet transfusions during any 56-day post-baseline period.¹

Results Available in Publication

The complete ADMIRAL trial has been peer-reviewed and published in a medical journal. The efficacy and safety evaluated in the ADMIRAL trial contributed to the clinical body of evidence for XOSPATA.

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ANC=absolute neutrophil count; CI=confidence interval; CR=complete remission; CRc=composite complete remission; CRh=complete remission with partial hematologic recovery; CRi=complete remission with incomplete hematologic recovery; CRp=complete remission with incomplete platelet recovery; DOR=duration of remission; HSCT=hematopoietic stem cell transplant; NE=not estimable; RBC=red blood cell.

References: 1. XOSPATA [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Astellas. XOSPATA. Data on File.

Warnings and Precautions

Differentiation Syndrome (See BOXED WARNING) 3% of 319 patients treated with XOSPATA in the clinical trials experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms and other clinical findings of differentiation syndrome in patients treated with XOSPATA included fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as 1 day and up to 82 days after XOSPATA 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. Taper corticosteroids after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt XOSPATA until signs and symptoms are no longer severe.

Posterior Reversible Encephalopathy Syndrome (PRES) 1% of 319 patients treated with XOSPATA in the clinical trials experienced posterior reversible encephalopathy syndrome (PRES) with symptoms including seizure and altered mental status. Symptoms have resolved after discontinuation of XOSPATA. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XOSPATA in patients who develop PRES.

Prolonged QT Interval XOSPATA has been associated with prolonged cardiac ventricular repolarization (QT interval). 1% of the 317 patients with a post-baseline QTc measurement on treatment with XOSPATA in the clinical trial were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with XOSPATA, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration.

Pancreatitis 4% of 319 patients treated with XOSPATA in the clinical trials experienced pancreatitis. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of XOSPATA in patients who develop pancreatitis.

Embryo-Fetal Toxicity XOSPATA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with XOSPATA and for 6 months after the last dose of XOSPATA. Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for 4 months after the last dose of XOSPATA. Pregnant women, patients becoming pregnant while receiving XOSPATA or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

Adverse Reactions

Fatal adverse reactions occurred in 2% of patients receiving XOSPATA. These were cardiac arrest (1%) and one case each of differentiation syndrome and pancreatitis. The most frequent (≥5%) nonhematological serious adverse reactions reported in patients were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%).

7% discontinued XOSPATA treatment permanently due to an adverse reaction. The most common (>1%) adverse reactions leading to discontinuation were aspartate aminotransferase increased (2%) and alanine aminotransferase increased (2%).

The most frequent (≥5%) grade ≥3 nonhematological adverse reactions reported in patients were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/malaise (6%).

Other clinically significant adverse reactions occurring in ≤10% of patients included: electrocardiogram QT prolonged (9%), hypersensitivity (8%), pancreatitis (5%), cardiac failure (4%), pericardial effusion (4%), acute febrile neutrophilic dermatosis (3%), differentiation syndrome (3%), pericarditis/myocarditis (2%), large intestine perforation (1%), and posterior reversible encephalopathy syndrome (1%).

Lab Abnormalities Shifts to grades 3-4 nonhematologic laboratory abnormalities in XOSPATA treated patients included phosphate decreased (14%), alanine aminotransferase increased (13%), sodium decreased (12%), aspartate aminotransferase increased (10%), calcium decreased (6%), creatine kinase increased (6%), triglycerides increased (6%), creatinine increased (3%), and alkaline phosphatase increased (2%).

Drug Interactions

Combined P-gp and Strong CYP3A Inducers Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases XOSPATA exposure which may decrease XOSPATA efficacy. Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers.

Strong CYP3A inhibitors Concomitant use of XOSPATA with a strong CYP3A inhibitor increases XOSPATA exposure. Consider alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for XOSPATA adverse reactions. Interrupt and reduce XOSPATA dosage in patients with serious or life-threatening toxicity.

Drugs that Target 5HT2B Receptor or Sigma Nonspecific Receptor Concomitant use of XOSPATA may reduce the effects of drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these drugs with XOSPATA unless their use is considered essential for the care of the patient.

P-gp, BCRP, and OCT1 Substrates Based on in vitro data, gilteritinib is a P-gp, breast cancer resistant protein (BCRP), and organic cation transporter 1 (OCT1) inhibitor. Coadministration of gilteritinib may increase the exposure of P-gp, BCRP, and OCT1 substrates, which may increase the incidence and severity of adverse reactions of these substrates. For P-gp, BCRP, or OCT1 substrates where small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of such substrate and monitor for adverse reactions as recommended in the respective prescribing information.

ADMIRAL TRIAL

Help Patients Achieve Remission With XOSPATA1,2

Higher rate of CR* with XOSPATA vs salvage chemotherapy1†

MEDIAN DURATION OF COMPLETE REMISSION1†‡

PATIENTS ACHIEVED CR/CRh§ WITH XOSPATA1