ASH Clinical News ACN_4.13_full issue_Web | Page 63

FEATURE
Just this August and September, NICE
rejected Gilead’s CAR T-cell therapy
axicabtagene ciloleucel for use in the NHS,
calling the therapy too expensive. 9 The
U.K. agency made its decision just one day
after the European Commission approved
this CAR T-cell therapy for the treatment
of patients with non-Hodgkin lymphoma
(NHL) in the European Union, as well as a
second CAR T-cell therapy, tisagenlecleu-
cel for both the NHL indication and for
pediatric patients with acute lymphocytic
leukemia (ALL). 10,11 Then, in September,
Gilead and the NHS reached a deal: Gilead
will provide a confidential discount on
axicabtagene ciloleucel’s £300,000 full list
price, providing partial access of the thera-
py through NHS’s Cancer Drugs Fund. 12
For the U.K., and other countries
including Canada and Australia, the deci-
sion to regulate drug prices centers on
making sure that medical treatments are
Adverse Reactions (All Grades [%], ≥Grade 3 [%]) With ≥10% Incidence a in Patients With
Relapsed or Refractory B-Cell Precursor ALL Who Received SC (N=143 n ) were infection b (76; 54),
thrombocytopenia c (61; 59), neutropenia d (45; 43), anemia e (59; 47), leukopenia f (43; 42), febrile
neutropenia (53; 53), lymphopenia g (27; 26), decreased appetite (13; 2), headache h (27; 1),
hemorrhage i (28; 5), nausea (46; 0), abdominal pain j (23; 1), diarrhea (38; 1), constipation (24;
0), vomiting (24; 0), stomatitis k (26; 3), hyperbilirubinemia (17; 6), fatigue l (25; 3), pyrexia (42;
6), chills (11; 0), transaminases increased m (13; 5), gamma-glutamyltransferase increased (8; 4), and
alkaline phosphatase increased (7; 0).
Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days
after the last dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT).
Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.
Severity grade of adverse reactions were according to NCI CTCAE version 3.0.
Abbreviations: N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
a. Only adverse reactions with ≥10% incidence in the BESPONSA arm are included. b. Infection also includes any reported
preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations. c. Thrombocytopenia also
includes platelet count decreased. d. Neutropenia also includes the following reported preferred terms: neutrophil count
decreased. e. Anemia also includes hemoglobin decreased. f. Leukopenia also includes monocytopenia and white blood cell
count decreased. g. Lymphopenia also includes B-lymphocyte count decreased and lymphocyte count decreased.
h. Headache also includes migraine and sinus headache. i. Hemorrhage also includes terms retrieved in the Standard MedDRA
Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following: Conjunctival hemorrhage,
Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding,
Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous,
Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric
hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural
hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal
hemorrhage, and Vaginal hemorrhage. j. Abdominal pain also includes abdominal pain lower, abdominal pain upper,
abdominal tenderness, esophageal pain, and hepatic pain. k. Stomatitis also includes aphthous ulcer, mucosal inflammation,
mouth ulceration, oral pain, and oropharyngeal pain. l. Fatigue also includes asthenia. m. Transaminases increased
also includes Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and
Hypertransaminasemia. n. 19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment.
Additional adverse reactions (all grades) that were reported in less than 10% of patients treated
with BESPONSA included: lipase increased (9%), abdominal distension (6%), amylase increased
(5%), hyperuricemia (4%), ascites (4%), infusion related reaction (2%; includes the following:
hypersensitivity and infusion related reaction), pancytopenia (2%; includes the following: bone
marrow failure, febrile bone marrow aplasia, and pancytopenia), tumor lysis syndrome (2%),
and electrocardiogram QT prolonged (1%).
Lab abnormalities a (N; All Grades [%]; Grade 3/4 [%]) in patients with relapsed or refractory B-Cell
precursor ALL who received BESPONSA were platelet count decreased (161; 98; 76), hemoglobin
decreased (161; 94; 40), leukocytes decreased (161; 95; 82), neutrophil count decreased (160; 94; 86),
lymphocytes (absolute) decreased (160; 93; 71), GGT increased (148; 67; 18), AST increased (160; 71;
4), ALP increased (158; 57; 1), ALT increased (161; 49; 4), blood bilirubin increased (161; 36; 5), lipase
increased (139; 32; 13), hyperuricemia (158; 16; 3), amylase increased (143; 15; 2).
Lab abnormalities a (N; All Grades [%]; Grade 3/4 [%]) in patients with relapsed or refractory B-Cell
precursor ALL who received SC were platelet count decreased (142; 100; 99), hemoglobin decreased
(142; 100; 70), leukocytes decreased (142; 99; 98), neutrophil count decreased (130; 93; 88),
lymphocytes (absolute) decreased (127; 97; 91), GGT increased (111; 68; 17), AST increased (134; 38;
4), ALP increased (133; 52; 3), ALT increased (137; 46; 4), blood bilirubin increased (138; 35; 6), lipase
increased (90; 20; 2), hyperuricemia (122; 11; 0), amylase increased (102; 9; 1).
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase;
GGT=gamma-glutamyltransferase.
a. Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy.
6.2 Immunogenicity The detection of antibody formation is highly dependent on the sensitivity
and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing
antibody) positivity in an assay may be influenced by several factors including assay methodology,
sample handling, timing of sample collection, concomitant medications, and underlying disease.
For these reasons, comparison of the incidence of antibodies to inotuzumab ozogamicin in the
studies described below with the incidence of antibodies in other studies or to other products
may be misleading. In clinical studies of BESPONSA in patients with relapsed or refractory ALL,
the immunogenicity of BESPONSA was evaluated using an electrochemiluminescence (ECL)-based
immunoassay to test for anti-inotuzumab ozogamicin antibodies. For patients whose sera
tested positive for anti-inotuzumab ozogamicin antibodies, a cell-based luminescence assay
was performed to detect neutralizing antibodies. In clinical studies of BESPONSA in patients with
relapsed or refractory ALL, 7/236 patients (3%) tested positive for anti-inotuzumab ozogamicin
antibodies. No patients tested positive for neutralizing anti-inotuzumab ozogamicin antibodies.
In patients who tested positive for anti-inotuzumab ozogamicin antibodies, the presence of anti-
inotuzumab ozogamicin antibodies did not affect clearance following BESPONSA treatment.
7. DRUG INTERACTIONS
Drugs That Prolong the QT Interval Concomitant use of BESPONSA with drugs known to prolong
the QT interval or induce Torsades de Pointes may increase the risk of a clinically significant QTc
interval prolongation. Discontinue or use alternative concomitant drugs that do not prolong QT/
QTc interval while the patient is using BESPONSA. When it is not feasible to avoid concomitant use
of drugs known to prolong QT/QTc, obtain ECGs and electrolytes prior to the start of treatment, after
initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during
treatment.
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Risk Summary Based on its mechanism of action and findings from animal studies,
BESPONSA can cause embryo-fetal harm when administered to a pregnant woman. There are no
available data on BESPONSA use in pregnant women to inform a drug-associated risk of major
birth defects and miscarriage. In rat embryo-fetal development studies, inotuzumab ozogamicin
caused embryo-fetal toxicity at maternal systemic exposures that were ≥ 0.4 times the exposure in
patients at the maximum recommended dose, based on AUC. If this drug is used during pregnancy,
or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk
to a fetus.
affordable for all citizens of that country,
regardless of income. U.S. approval is
blind to pricing, and while that means
certain high-priced drugs are approved in
the U.S. that aren’t approved in the U.K.
or other countries, some U.S. patients will
still have limited access to these drugs
because of affordability.
The FDA approved axicabtagene cilo-
leucel for the same indication in October
2017. Gilead, the drug’s manufacturer, set
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of
medications. The estimated background risk of major birth defects and miscarriage for the
indicated population is unknown. In the U.S. general population, the estimated background
risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and
15-20%, respectively. Data Animal Data In embryo-fetal development studies in rats, pregnant
animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m 2 during
the period of organogenesis. Embryo-fetal toxicities including increased resorptions and fetal
growth retardation as evidenced by decreased live fetal weights and delayed skeletal ossification
were observed at ≥ 0.11 mg/m 2 (approximately 2 times the exposure in patients at the maximum
recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m 2
(approximately 0.4 times the exposure in patients at the maximum recommended dose, based
on AUC). In an embryo-fetal development study in rabbits, pregnant animals received daily
intravenous doses up to 0.15 mg/m 2 (approximately 3 times the exposure in patients at the
maximum recommended dose, based on AUC) during the period of organogenesis. At a dose of
0.15 mg/m 2 , slight maternal toxicity was observed in the absence of any effects on embryo-fetal
development. 8.2 Lactation Risk Summary There are no data on the presence of inotuzumab
ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects
on milk production. Because of the potential for adverse reactions in breastfed infants, advise
women not to breastfeed during treatment with BESPONSA and for at least 2 months after the
last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on its
mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm
when administered to a pregnant woman. Verify the pregnancy status of females of reproductive
potential prior to initiating BESPONSA. Contraception Females Advise females of reproductive
potential to avoid becoming pregnant while receiving BESPONSA. Advise females of reproductive
potential to use effective contraception during treatment with BESPONSA and for at least 8 months
after the last dose. Males Advise males with female partners of reproductive potential to use
effective contraception during treatment with BESPONSA and for at least 5 months after the last
dose. Infertility Females Based on findings in animals, BESPONSA may impair fertility in females of
reproductive potential. Males Based on findings in animals, BESPONSA may impair fertility in males
of reproductive potential. 8.4 Pediatric Use Safety and effectiveness have not been established in
pediatric patients. 8.5 Geriatric Use In the INO-VATE ALL trial, 30/164 patients (18%) treated with
BESPONSA were ≥65 years of age. No differences in responses were identified between older and
younger patients. Based on a population pharmacokinetic analysis in 765 patients, no adjustment
to the starting dose is required based on age. 8.6 Hepatic Impairment Based on a population
pharmacokinetic analysis, the clearance of inotuzumab ozogamicin in patients with mild hepatic
impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0-1.5 x ULN and AST any
level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST ≤ ULN; n=611).
In patients with moderate (total bilirubin > 1.5-3 x ULN and AST any level; n=3) and severe hepatic
impairment (total bilirubin > 3 x ULN and AST any level; n=1), inotuzumab ozogamicin clearance
did not appear to be reduced. No adjustment to the starting dose is required when administering
BESPONSA to patients with total bilirubin ≤ 1.5 x ULN and AST/ALT ≤ 2.5 x ULN. There is limited
safety information available in patients with total bilirubin > 1.5 x ULN and/or AST/ALT > 2.5 x ULN
prior to dosing. Interrupt dosing until recovery of total bilirubin to ≤ 1.5 x ULN and AST/ALT ≤ to 2.5
x ULN prior to each dose unless due to Gilbert’s syndrome or hemolysis. Permanently discontinue
treatment if total bilirubin does not recover to ≤ 1.5 x ULN or AST/ALT does not recover to ≤ 2.5 x ULN.
17. PATIENT COUNSELING INFORMATION
Hepatotoxicity, Including Hepatic VOD (also known as SOS) Inform patients that liver problems,
including severe, life-threatening, or fatal VOD, and increases in liver tests may develop during
BESPONSA treatment. Inform patients that they should seek immediate medical advice if they
experience symptoms of VOD, which may include elevated bilirubin, rapid weight gain, and
abdominal swelling that may be painful. Inform patients that they should carefully consider
the benefit/risk of BESPONSA treatment if they have a prior history of VOD or serious ongoing
liver disease. Increased Risk of Post-HSCT Non-Relapse Mortality Inform patients that there is
an increased risk of post-HSCT non-relapse mortality after receiving BESPONSA, that the most
common causes of post-HSCT non-relapse mortality included infection and VOD. Advise patients
to report signs and symptoms of infection. Myelosuppression Inform patients that decreased
blood counts, which may be life-threatening, may develop during BESPONSA treatment and that
complications associated with decreased blood counts may include infections, which may be life-
threatening or fatal, and bleeding/hemorrhage events. Inform patients that signs and symptoms
of infection, bleeding/hemorrhage, or other effects of decreased blood counts should be reported
during treatment with BESPONSA. Infusion Related Reactions Advise patients to contact their
health care provider if they experience symptoms such as fever, chills, rash, or breathing problems
during the infusion of BESPONSA. QT Interval Prolongation Inform patients of symptoms that may
be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope.
Advise patients to report these symptoms and the use of all medications to their healthcare
provider. Embryo-Fetal Toxicity Advise males and females of reproductive potential to use effective
contraception during BESPONSA treatment and for at least 5 and 8 months after the last dose,
respectively. Advise females of reproductive potential to avoid becoming pregnant while receiving
BESPONSA. Advise women to contact their healthcare provider if they become pregnant, or if
pregnancy is suspected, during treatment with BESPONSA. Inform the patient of the potential risk
to the fetus. Lactation Advise women against breastfeeding while receiving BESPONSA and for 2
months after the last dose.
This product’s label may have been updated. For current full prescribing information, please visit
www.BESPONSA.com.
This brief summary is based on BESPONSA™ (inotuzumab ozogamicin)
Prescribing Information LAB-0763-1.0
Revised August 2017.
© 2017 Pfizer Inc.
All rights reserved.
August 2017
a list price of $373,000 – not including the
costs of hospitalization, medications to
treat potentially life-threatening compli-
cations that can accompany the therapy,
or supportive care and clinician visits. By
some estimates, these services could drive
the total cost of treatment with axicabta-
gene ciloleucel to more than $1 million
per patient. 13
Following the approval, the Centers for
Medicare and Medicaid Services (CMS)
announced that the agency would
reimburse hospitals the list price plus
6 percent, approximately $400,000 for
the therapy, which is covered under
Medicare Part B. 14 Although out-
patients typically have a 20-percent
copayment for Medicare Part B ser-
vices (approximately $79,000 for this
therapy), CMS said that patient costs
will be capped at $1,340 (the inpatient
deductible for 2018).
Revolutionary Therapies,
Revolutionary Prices
While the U.S. does not have the
health-care watchdog agencies pre-
sent in other developed countries, the
U.S. does have the ICER. The insti-
tute evaluates the cost-effectiveness
and value of new drugs entering the
market but does not have a direct say
in drug prices set by manufacturers.
ICER’s reports also estimate a drug’s
potential long-term value for patients
and its effects on the health-care
system’s budget.
In its final 2018 evaluation of both
tisagenlecleucel (for its approved
NHL and pediatric acute lymphocytic
leukemia [ALL] indications) and
axicabtagene ciloleucel (the other
FDA-approved CAR T-cell therapy for
the treatment of ALL), ICER found
that both therapies, despite their high
prices, were cost-effective. 15
“We noted in our report that, be-
cause of the large number of patients
with NHL, the therapy could create
a substantial short-term financial
impact that would put a strain on
many insurance system budgets,” said
Dr. Pearson. “That strain is something
that needs to be discussed because, if
not managed well, it can lead to real
problems for patients accessing the
drug and possible rapid increases in
insurance premiums.”
Most hospitals are expected to
purchase the CAR T-cell therapy for
a patient, but it is still unclear who
will pay for the accompanying clinical
services. “How we should be paying
for CAR T-cell therapies is still an
open question,” Ms. Kaltenboeck said.
“How can we pay for them in a way
that doesn’t bankrupt patients or put
hospitals and payers at risk?”
Dr. Pearson agreed that the U.S.
needs better cost-management for
therapies like axicabtagene ciloleucel
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