1.
EXECUTIVE SUMMARY
Erythropoietin
Receptor Agonists (ERAs) are medications that are very similar to human
erythropoietin, both in structure and in biological activities. The first ERA
produced for human use, epoetin alfa, was introduced in the
Other
ERAs, introduced more recently, include epoetin beta (NeoRecormon®,
ex-US) and darbepoetin alfa (Aranesp®, ex-US and available in the
Erythropoietin
receptors are expressed on other cell lines besides erythroid precursor cells.
These include vascular endothelial cells and some tumor cell lines. Whether
these receptors have any functional activity when exposed to clinically
relevant concentrations of ERAs is doubtful, however the theoretical
possibility that ERAs could act as growth factors for tumor cells is reflected in
the labeling of products in this class.
ERAs
have been extensively investigated in clinical trials and are widely used to
provide important benefits in terms of treatment of anemia. The symptoms of
anemia include tiredness, shortness of breath, weakness and fatigue (weariness
from labor or exertion). In addition to
correcting anemia, ERAs have proven benefits in reducing the needs for RBC
transfusions, in their approved indications.
Recent
investigational studies of ERAs have focused on additional potential benefits
for patients with cancer, including benefits on tumor response to radiotherapy
and improved survival. This research was
prompted by observations that cancer patients with anemia may have decreased survival.
Additionally, a trend towards improved survival was noted in two prospective
studies with different ERAs. Those
studies were not designed to test this hypothesis, but were powered for other
end-points. Subsequently studies have been performed to specifically evaluate
potential effects on survival. The design of these studies included treatment
with ERAs beyond the correction of anemia, with the intent of maximizing any
benefit on survival.
Published
findings from two studies evaluating survival, however, have indicated that
there may be increased risks associated with treatment of non-anemic cancer
patients. Treatment beyond the correction of anemia is defined for the purposes
of the Sponsor’s evaluation as: initiation of ERA treatment in cancer patients
who are not anemic, or continued ERA treatment after correction of anemia.
One
of these studies, EPO-INT-76, conducted by the Sponsor, investigated the
effects of prolonged treatment of EPREX (epoetin alfa ex-US product) and
maintenance of non-anemic target hemoglobin levels in patients starting on
chemotherapy for metastatic breast cancer. The other study, conducted by Henke
and colleagues, investigated the effects of treatment with NeoRecormon®
(epoetin beta) to high target hemoglobin levels during radiation therapy for
head and neck cancer.
Both
studies reported adverse survival outcomes associated with ERA treatment. These findings were unexpected and not
representative of the Sponsor’s prior safety experience in clinical trials. These findings occurred in the setting of new
uses of ERAs in studies conducted outside of the US, and did not utilize
US-marketed formulations of ERAs.
However, the findings of these studies are relevant to all ERAs
including PROCRIT, given the close homology of ERAs in structure and mechanism
of action.
The
Sponsor has evaluated the findings of both of these studies as extensively as
possible, has communicated with the FDA regarding the questions raised by these
studies, and has taken appropriate actions based on the information available
to ensure the ongoing safe and effective use of epoetin alfa products in
clinical studies and actual practice.
This included examination of our ongoing oncology clinical research
programs. Study protocols were modified, where necessary, to reduce entry and
target hemoglobin levels to more closely reflect treatment to correct
anemia. Most of the sponsor’s studies of
epoetin alfa in oncology have demonstrated no evidence of safety concerns, and
are continuing. A small number of
studies, with investigational uses beyond the correction of anemia, were
discontinued due to potential safety signals relating to adverse experiences
and/or survival imbalances. The data from these studies are preliminary, and,
as patient enrollment was terminated at an early stage, limited conclusions can
be drawn from these studies except for the potential hazards posed by treating
patients beyond the correction of anemia.
To
address the important question about the appropriate investigational use of
ERAs, and to assess the safety of these products when used for approved
indications, the Sponsor has undertaken an extensive evaluation of data from
prior clinical studies and data from current studies, including
EPO-INT-76. In addition, the Sponsor’s
review of the available data on the study by Henke et al., published in the
literature was considered in this evaluation.
The data for this evaluation are derived from controlled studies to
ensure inclusion of the most reliable information, as follows:
·
12 completed, randomized, double-blind,
placebo-controlled studies that included over 3,000 patients (10 which focused
on treatment of anemia, and 2 that evaluated treatment beyond the correction of
anemia); and
·
2 randomized, double-blind, placebo-controlled
studies, and 11 randomized, open-label, controlled studies, for which only
limited mortality data are available.
The
analyses discussed in this document focus on the 12 completed, randomized,
double-blind, placebo-controlled studies, as these were most rigorous data
available to address these issues. These data were evaluated with respect to
the following key variables; survival, tumor response/tumor progression and
TVEs. A summary of the evaluations from
each section follows.
Clinical
studies involving use of epoetin alfa for the treatment of anemia in patients
with cancer who are receiving chemotherapy (the current approved oncology
indication) have shown no signal of an adverse impact on survival. Data are more limited regarding tumor
response and disease progression, but available data from clinical studies
where these parameters can be evaluated have not revealed any indications of an
adverse effect of epoetin alfa.
Labels
for all ERA products describe the association of TVEs with use of these
products. Experience in clinical trials
of epoetin alfa in treatment of anemia in cancer patients receiving
chemotherapy, and information obtained from post-marketing surveillance, is
consistent with this product labeling.
The
results of the EPO-INT-76 and Henke et al. studies raised concerns regarding
shortened survival, possibly mediated by enhanced disease progression. However, other clinical data have provided
little support for an adverse effect on tumor growth or disease progression.
Similarly, preclinical data regarding tumor proliferative effects of ERAs are
viewed as inconclusive. Alternative explanations for the survival observations
of the EPO-INT-76 and Henke studies must also be considered. In this regard, while ERAs generally have a
limited spectrum of adverse effects, TVEs are described in the labels for all
ERAs, and are potentially more likely to occur when ERA use is extended beyond
the treatment of anemia.
The
evaluation of the Sponsor’s clinical program did not demonstrate that the
survival questions generated from EPO-INT-76 and the study by Henke et al., are
relevant to other studies or clinical settings where ERAs are used to correct
anemia. This
evaluation is supported by the Sponsor’s ongoing post-marketing surveillance
program, which continuously monitors the safety of products in the approved
indications through evaluation and assessment of spontaneous reports. The post-marketing data confirm the
recognized association of epoetin alfa use with TVE occurrence, but do not
suggest any new survival or tumor proliferation signal in the marketed
indications of epoetin alfa. Although
post-marketing surveillance is an imprecise and insensitive tool for detecting
subtle safety signals, and is no substitute for data from randomized studies,
this provided supportive evidence for the more robust clinical trial data
presented in this document.
In addition, the Sponsor’s review of data from EPO-INT-76,
did not support that the survival signal was related to effects of ERA on tumor
response or tumor progression. An excess of TVEs, including fatal TVEs, was
observed on the EPREX arm. These TVEs
account for some of the differences in survival noted, and a blinded chart
review of other deaths in this study support that death due to TVE may
be misdiagnosed as tumor progression and could account for more of the observed
effect on mortality in this study. Patients with cancer have an increased risk
for TVEs, and ERAs are also associated with an increased risk for these events
(as described in the labels for ERAs). Patients should be appropriately managed
to reduce such risk when clinically indicated. Response to ERA therapy should
be closely monitored and dose adjustments made as appropriate to maximize
patient benefit and minimize risk.
In
summary, in some investigational studies, ERA treatment of patients beyond the
correction of anemia has resulted in decreased survival or increased side
effects. These specific investigational
designs should be avoided in future development programs. The available data
also support the conclusion that, when used for approved indications and within
established guidelines for baseline and target hemoglobin concentrations, the
benefits of ERA therapy continue to be supported by a well-defined and
acceptable risk profile.
This
document provides a detailed discussion of the safety of ERAs in patients with
cancer. For this purpose, the document
is divided into the following key sections:
·
an introduction and overview of ERAs including
the clinical benefits, safety and a discussion of the current safety question
raised by the survival findings from a small number of investigations studying
benefits of ERAs beyond the correction of anemia;
·
analyses supporting the safety of the current
labeled indication- treatment of anemia in cancer patients on chemotherapy;
·
a detailed review of the key data from the
investigational studies exploring benefits beyond correction of anemia,
including data on survival, tumor progression/ tumor response and TVEs;
·
an assessment of Benefit-Risk of ERAs in
patients with cancer; and
·
the Sponsor's conclusion about the safe and
effective use of ERAs in patients with cancer.
2.
INTRODUCTION
2.1.
Erythropoietin Receptor Agonists, Overview and
History
Erythropoietin is a glycoprotein hormone
produced primarily by the kidney in response to hypoxia and is the key regulator
of RBC production. It is involved in all phases of erythroid development, and
has its principal effect at the level of erythroid precursors. Erythropoietin
exerts its biological effect by binding to its cell surface receptor, which
results in concomitant tyrosine phosphorylation of the receptor and other
intracellular proteins. After erythropoietin binds to its receptor (the
erythropoietin receptor, EpoR), it activates signal transduction pathways that
interfere with apoptosis and stimulate erythroid cell proliferation. These
pathways are operative in nonhematopoietic as well as hematopoietic cells.
Anemia is a common feature of kidney disease,
when the production of erythropoietin by the kidneys is reduced and levels of
endogenously‑produced erythropoietin are no longer sufficient to maintain
normal levels of erythroid cell production. The development and
commercialization of a recombinant version of erythropoietin (epoetin alfa),
manufactured using recombinant DNA technology to introduce the human erythropoietin
gene into cultured mammalian cells, was completed in the late 1980’s and
provided an important new alternative for the treatment of anemia in patients
with kidney disease. Subsequently, it
has been shown that recombinant erythropoietins have value for treating anemia
associated with cancer chemotherapy and with certain other human illnesses as
well. Additional recombinant
erythropoietins have been developed.
Erythropoietin receptors are known to be
expressed on cells other than erythroid precursor cells, including vascular
endothelial cells and certain tumor cells.
Although the functional role of these receptors on other cells lines is
uncertain, there is a theoretical potential for erythropoietin to act as a
growth factor on cell lines other than erythroid cells. This potential applies to exogenously
administered erythropoietins produced by recombinant techniques as well as to
natural erythropoietin.
The first ERA marketed in the US, epoetin
alfa, was developed by Amgen, and has been marketed as EPOGEN by Amgen for
anemia of kidney disease since 1989.
Under terms of a license agreement with Amgen, epoetin alfa has also
been marketed in the US by Ortho Biotech (an affiliate of the Sponsor) under
the trade name PROCRIT, since April 1993 for use in treatment of anemia in
patients with cancer receiving chemotherapy.
PROCRIT/EPOGEN® solution for injection (recombinant human
erythropoietin, r-HuEPO, epoetin alfa) is a glycoprotein manufactured by
recombinant DNA technology, has an amino acid sequence identical to human
urinary erythropoietin, is indistinguishable from naturally-occurring human
erythropoietin on the basis of biological erythropoietic effects, and has a
molecular weight of 30,400 daltons.
More recently, Amgen has introduced another ERA
in the US, Aranesp (darbepoetin alfa), marketed since 2001 for treatment of
anemia in patients with kidney disease and since 2002 for treatment of anemia
in patients with cancer receiving chemotherapy.
This product is closely homologous with epoetin alfa and differs by 5
amino acids.
ERAs available outside of the US include
Aranesp, marketed by Amgen; EPREX, another formulation of epoetin alfa marketed
by the Sponsor under license from Amgen; and NeoRecormon̉,
an epoetin beta product marketed by Hoffmann – La Roche.
Products in the ERA class of medication share
close structural homology with naturally occurring human erythropoietin, and
differ from each other by minor amino acid substitutions. Epoetin alfa marketed in the U.S (PROCRIT and
EPOGEN) differs from the epoetin alfa marketed ex-U.S (EPREX) in the
preservative that is used.
|
PRODUCTS IN ERA
CLASS |
|||
|
|
Molecule |
Homology
of Amino Acid sequence to human erythropoietin |
Year
Introduced in US for anemia in cancer patients on chemotherapy* |
|
PROCRIT |
Epoetin alfa |
100% |
1993 |
|
EPREX |
Epoetin alfa |
100% |
NA |
|
NeoRecormon̉ |
Epoetin beta |
100% |
NA |
|
Aranesp |
Darbepoetin alfa |
97% |
2002 |
* EPOGEN (epoetin alfa) is the same formulation as
PROCRIT and is marketed by Amgen in the US for the dialysis indication.
2.2.
Clinical Benefits and Safety in Approved
Indications
Over 3 million patients have benefited from
EPREX or PROCRIT therapy in over a decade of clinical experience in multiple
indications. With respect to patients with cancer, EPREX or PROCRIT treatment
of anemic cancer patients receiving cancer chemotherapy has been shown to
significantly ameliorate anemia and to reduce transfusion requirements. This has provided for the effective treatment
of the symptoms of anemia in these patients, including tiredness, shortness of
breath, weakness and fatigue (weariness from labor or exertion). In addition to correcting anemia, ERAs have
proven benefits in reducing the needs for RBC transfusions, while reducing
potential risks that may accompany transfusions of allogeneic RBC products, and
also reducing utilization of the limited supplies of blood products. These
benefits are supported by a well-defined safety profile in currently approved
indications.
Over the years since the initial US marketing
approval of epoetin alfa, numerous additional clinical studies have been
performed by the Sponsor, both to further evaluate the approved uses for
PROCRIT and to explore potential new therapeutic uses. PROCRIT is thus also approved for the
treatment of anemia in zidovudine (azidothymidine, AZT)-treated patients who
are infected with human immunodeficiency virus (HIV), and to reduce allogeneic
blood transfusion requirements in the perisurgical setting.
In addition to providing demonstrated benefits in their
approved indications, by stimulating the
erythropoietin receptor, products in the ERA class also share well
characterized and similar side effect profiles.
Some of the side effects common to this class include hypertension and
thrombotic complications. These ERA
class side effects are reflected in the prescribing information for all
products. Other possible side effects
are also common to products in this class.
Although these side effects have the
potential to result in serious outcomes, they need to be considered in the
context of the important benefits this class of medications provides to
patients with serious and terminal illnesses, and as the only therapeutic
alternatives to blood transfusions.
2.3.
Safety in Investigational Use
ERAs have been extensively investigated in
clinical trials, and safety data from trials investigating ERAs in the
treatment of anemia in patients with cancer receiving chemotherapy supports the
safety and benefits of these products when used for this indication.
More recently, published findings from two
studies evaluating potential new investigational uses for ERAs in patients with
cancer have indicated that there may be increased risks associated with
treatment of non-anemic patients. These
investigational uses were designed to demonstrate benefits from ERA therapy
beyond the reduction in the requirements for transfusion or treatment of
symptoms of anemia. The intent of these studies is described in this briefing
document as treatment beyond the correction of anemia; this is
specifically defined as initiation of ERA treatment in cancer patients who are
not anemic, or continued ERA treatment after correction of anemia, considering
a hemoglobin level of 13 g/dL as a clearly non-anemic value.
One of these studies, EPO-INT-761, investigated the
effects of prolonged treatment of EPREX (epoetin alfa, formulation marketed
ex-US) and maintenance of non-anemic target hemoglobin levels in patients
starting on chemotherapy for metastatic breast cancer. The other study,
conducted by Henke and colleagues2, investigated the effects of
treatment with NeoRecormon (epoetin beta, formulation marketed ex-US) to high
target hemoglobin levels during radiation therapy for head and neck cancer.
These studies, sponsored by different
manufacturers, both independently reported inferior survival associated with
this new investigational use. These
findings were unexpected and did not reflect the Sponsor’s prior safety
experience with established marketed uses.
Although these findings occurred in the setting of new uses of ERAs,
they raised questions as to whether the outcomes observed in those settings
were specific to those investigational settings, and stimulated the need to
examine and confirm the ongoing positive benefit-risk profile of these products
when used to correct anemia associated with chemotherapy in patients with
cancer.
The Sponsor has thus undertaken an extensive
evaluation of all currently available data, including data from these
investigational studies; has communicated with the FDA regarding the issues
raised by these studies; and has taken the following actions deemed appropriate
based on the information available:
·
The Sponsor has undertaken an extensive
evaluation of data from prior clinical studies together with data from current
studies, including EPO-INT-76 and other investigational studies, to assess and
re-affirm the favorable benefit-risk profile of EPREX and PROCRIT when used as
directed in approved indications.
·
The Sponsor took steps to modify or suspend
clinical research studies involving administration of ERAs beyond the
correction of anemia in patients with cancer.
·
The Sponsor has communicated its concerns
regarding such research designs to clinical scientists globally as well as to
regulatory authorities, and has ensured that all of its ongoing clinical
research studies incorporate appropriate patient safeguards, including
avoidance of treatment beyond the correction of anemia, and data monitoring by
independent Data Safety Monitoring Boards
(DSMB)s.
·
While the use of the Sponsor’s epoetin alfa
products in clinical practice (outside of research studies) in patients with
cancer appears to be well-delimited to the approved indication, i.e, the
treatment of anemia, the Sponsor continues to work in cooperation with global
regulatory authorities to ensure that prescribing information provides all
information relevant for making clinical decisions regarding beneficial and
safe use.
·
The
Sponsor also continues to work with global regulatory authorities and clinical
research consultants to identify any additional research that may be needed or
desirable to further define the optimal use of the Sponsor’s ERAs and other
products.
These data are presented in detail in this
document, and form the basis for the Sponsor’s assessment that ERAs continue to
have a favorable benefit-risk profile when used for approved indications. Data from randomized controlled studies form
the primary database that was used for the analyses presented in this document
(detailed study designs are found in Attachment 4). These studies were chosen as they represent
robust, reliable data and have information on the variables of interest
(survival, tumor response/tumor progression and TVE).
3.
SAFETY OF
CURRENT LABELED INDICATION - TREATMENT OF ANEMIA IN CANCER PATIENTS ON
CHEMOTHERAPY
Based on the questions arising from the recently-published
investigational studies of ERAs, the Sponsor has undertaken an examination of
data available from clinical trials and from post-marketing experience. The
Sponsor’s clinical trials database is extensive, and there is a large post‑marketing
experience with epoetin alfa products. The analyses summarized here focus on
all relevant information that has been generated in randomized, controlled
trials, particularly trials that were double-blind. Analyses that are most
useful to the evaluation of the current questions are provided.
3.1.
Adverse Events, Including Thrombotic Vascular
Events
As noted above, ERAs have a long history of use in the
treatment of anemia in patients receiving cancer chemotherapy. Several thousand
patients have been enrolled in PROCRIT controlled clinical studies, and
millions of patients have received PROCRIT for this indication. The adverse events that have been observed in
association with this use are described in product labeling.
Among the adverse events that have been described in
association with ERA use for anemia in cancer patients receiving chemotherapy,
thrombotic events (also described as thrombotic vascular events, or TVEs) are
events that may occur relatively frequently in cancer patients and can be
serious. Examples of serious TVEs may
include such events as deep venous thrombosis with pulmonary embolism, cardiac
ischemia or infarction, or thrombotic stroke.
Other more common but less serious events such as superficial venous
thrombosis may also be considered as TVEs, depending on the definition used to
characterize these events. The list of general TVEs is the Sponsor’s broadest
approach for identifying TVEs, and includes all superficial TVEs, all catheter
related TVEs and events that could, but not necessarily would, be caused by an
underlying thrombovascular event, and where no information was available to
prove the contrary. General TVEs are also subclassified as clinically relevant,
a definition that is still broader than the generally accepted clinically
important TVEs (e.g., DVT, PE, stroke/TIA, and MI).
The Sponsor has performed an analysis of TVEs in 10
double-blind, randomized, placebo-controlled trials of PROCRIT epoetin alfa or
EPREX epoetin alfa that focused on treatment of anemic cancer patients
receiving chemotherapy. All studies were part of regulatory submissions or
filings made by the Sponsor in support of the oncology indication for treatment
of anemia. Many of the studies enrolled
patients with a mix of tumor types, limiting the possibilities to evaluate any
tumor type-specific effects but expected to still have sensitivity to an
adverse event (e.g., TVE) – related effect. Some studies utilized PROCRIT
(epoetin alfa), while others utilized EPREX (a different formulation of epoetin
alfa). A list of the studies is provided in Table 1, below.
|
|
Tumor |
Entry |
Target (initial) |
Dose |
Duration |
|
Type |
Hb (g/dL) |
Hb (g/dL) |
of Therapy |
||
|
Non-Chemo |
Mixed |
£10.5 |
Hct 38%-40% |
100 IU/kg TIW |
8 wks |
|
Noncisplatin |
Mixed |
£10.5 |
Hct 38%-40% |
150 IU/kg TIW |
12 wks |
|
Cisplatin |
Mixed |
£10.5 |
Hct 38%-40% |
150 IU/kg TIW |
12 wks |
|
J89-040 |
CLL |
Hct <32% |
Hct 38%-40% |
150 IU/kg TIW |
12 wks |
|
P-174 |
CLL |
Hct <32% |
Hct 38%-40% |
150 IU/kg TIW |
12 wks |
|
INT-1 |
Ovarian |
<11* |
12.5-14 |
150/300 IU/kg TIW |
1 mo past CTX |
|
INT-2 |
MM |
<11 |
12-14 |
150-300 IU/kg TIW |
12 wks |
|
INT-3 |
Mixed |
<12 |
12-14F, 14-16M |
150-300 IU/kg TIW |
12 wks |
|
INT-10 |
Mixed |
£10.5 |
12-15 |
150-300 IU/kg TIW |
24 wks/6 cycles |
|
PR98-27-008 |
Mixed |
£11.5/10.5** |
13-15 |
40,000 IU QW |
16 wks |
|
*
Patients were also eligible if
they had experienced a Hb decline of ³ 1.5 g/dL (from a
baseline of **
£11.5 g/dL for men; £10.5
g/dL for women |
|||||
Figure 1 illustrates the odds ratios for TVEs in these 10
studies.
Figure 1: Incidence of Clinically Relevant Thrombotic
Vascular Events Odds Ratios
and 95% Confidence Intervals
(10
Double-Blind, Placebo-Controlled, Completed Oncology Studies: Safety Population).
For the pooled analysis, the odds ratio was based on
Mantel-Haenszel estimate stratified by study.
In brief, the odds ratios for TVEs were variable in these
10 studies. The combined analysis of all
10 studies yielded an odds ratio of 1.55 with a 95% CI (0.96, 2.50)
suggesting higher incidence of TVEs with epoetin alfa treatment.
3.2.
Patient Outcomes
3.2.1.
Survival
The Sponsor also has reanalyzed survival data from its
prior clinical studies of PROCRIT and EPREX in anemic patients receiving cancer
chemotherapy. The analyses (including a combined analysis) presented in this
section of this background document are also based on the same
10 completed, randomized, double-blind, and placebo‑controlled
studies identified in Table 1, above. It
should be noted that these studies are generally of relatively shorter double‑blind
duration than the investigational studies that are presented in Section 4,
Investigational Clinical Studies – Treatment Beyond Correction of Anemia, of
this background document. As noted previously, many of the studies enrolled
patients with a mix of tumor types, limiting the possibilities to evaluate any
tumor type‑specific effects but expected to still have sensitivity to
adverse event (e.g., TVE) – related effects. Some studies utilized PROCRIT
(epoetin alfa), while others utilized EPREX (epoetin alfa).
The results of these analyses are presented in Figure 2.
Figure 2: Subject Survival: Hazard
Ratios and 95% Confidence Intervals
(Up to 30 Days After End of Double-Blind Phase)
(10 Double-Blind, Placebo-Controlled, Completed Oncology Studies)
For the pooled analysis, the hazard ratio and its 95% CI
were obtained using Cox’s Regression stratified by study.
Combined analyses of survival from the double-blind phase
plus 30 day follow-up for these 10 double-blind, placebo-controlled oncology
studies were similar for the epoetin alfa and placebo groups.
Finally, an abstract recently presented at the annual
meeting of the American Society of Hematology described an independent
meta-analysis, evaluating survival across a number of studies evaluating
epoetins in the treatment of anemia in patients with cancer. There was no
evidence of an impairment of survival among patients receiving epoetins in
these studies.3
3.2.2.
Tumor Response/Disease Progression
Tumor response to chemotherapy, disease progression, or
both were evaluated in five of the completed, double-blind studies listed in
Table 1, above, at the end of a double-blind phase that ranged from 12 to 24
weeks. Tumor response data were available for studies EPO-INT-1, EPO-INT-2,
EPO-INT-3, EPO-INT-10, and PR98-27-008. Tumor response was assessed after the last
cycle of chemotherapy, and the assessment of response did not require a
complete radiographic assessment. The method for assessing tumor response was
at the investigator's discretion. Of note, a number of caveats commonly applied
to the interpretation of these studies: 1) tumor response was not a primary or
secondary objective of the study; 2) predesignated times and method or
instrument to evaluate tumor response were not specified; 3) baseline data on
the extent of disease was missing in many patients in some studies; 4) time to
tumor progression or progression-free survival was not a primary or secondary
objective of many studies and the methods to evaluate these outcomes varied
from study to study; and 5) by design, many studies were of relatively short
duration and later-occurring outcomes such as tumor progression and death were
not built into the study design. However, when data were available, overall or
clinically objective tumor response rates (complete remission plus partial
remission) were similar for subjects treated with epoetin alfa and those who
received placebo. Thus, results from all five of these completed studies for
which tumor response data are available suggest that treatment with epoetin
alfa had no adverse effect on response to chemotherapy.
Disease progression is another important clinical
observation that may be used to determine a subject’s response to chemotherapy
and any possible role of ERAs on tumor progression. In Studies EPO-INT-1
(ovarian cancer), EPO-INT-2 (multiple myeloma), and EPO-INT-3 (mixed tumor
types), disease progression was similar for subjects in the epoetin alfa and
placebo groups at the end of the double-blind phase of the study. In Study
EPO-INT-10 (mixed tumor types), disease progression was reported in 24% of the
subjects who received epoetin alfa compared with 33% of subjects who received
placebo. These data suggest that disease progression was unlikely to be
affected by treatment with epoetin alfa.
3.2.3.
Post-Marketing Surveillance
Cumulative patient exposure for PROCRIT and EPREX for all
marketed indications is 3.1 million years since their introductions. This
represents a large patient experience, which is continuously monitored.
Although post-marketing surveillance is an imprecise tool for detecting subtle
safety signals, the Sponsor’s ongoing post-marketing surveillance program has
not identified any indications of an adverse effect of PROCRIT or EPREX on
tumor response, disease progression, or survival. Interpretation of these data is constrained
by the known limitations of these reporting systems. TVEs have been reported in
association with PROCRIT and EPREX use.
The frequency and nature of these reports is consistent with the
Sponsor’s prior experience and is adequately reflected in product
labeling.
3.2.4.
Conclusion
Clinical studies involving use of epoetin alfa for the
treatment of anemia in patients with cancer who are receiving chemotherapy (the
current approved oncology indication) have shown no signal of an adverse impact
on survival. Data are more limited
regarding tumor response and disease progression, but available data from
clinical studies where these parameters can be evaluated have not revealed any
indications of an adverse effect of epoetin alfa.
Labeling for all ERA products describes the association of
TVEs with use of these products.
Experience in clinical trials of epoetin alfa in treatment of anemia in
cancer patients receiving chemotherapy, and information obtained from
post-marketing surveillance, is consistent with this product labeling.
4.
INVESTIGATIONAL
CLINICAL STUDIES – TREATMENT BEYOND CORRECTION OF ANEMIA
As noted above, the established, approved use of ERAs in
patients with cancer is to treat anemia in patients receiving chemotherapy.
That is, ERAs are used in the supportive care of patients and are not currently
administered with an expectation of affecting the outcome of anticancer
treatment. However, some preclinical and clinical study findings have suggested
the possibility that ERAs might have a beneficial impact on treatment outcomes
in cancer patients (e.g., a favorable effect on tumor response and/or patient
survival). For example, laboratory and clinical studies have suggested that
tumor hypoxia may reduce the anticancer effectiveness of radiation therapy and
of many chemotherapy drugs; in theory, use of ERAs to increase hemoglobin
levels might enhance tumor oxygenation and thus might enhance the effectiveness
of these treatment modalities.4,5 Also, clinical studies have
frequently suggested that anemic cancer patients do not do as well as
non-anemic patients, raising the question of whether correcting anemia would
have a beneficial impact on patient prognosis.6 Finally, limited survival data from two
earlier studies
(EPO-INT-10 and the study of Vansteenkiste et al.7,8) of ERAs in
anemic cancer patients also suggested the possibility of modestly improved
treatment outcomes for patients receiving ERAs. While these findings and
arguments suggested a possibility of benefit, there was no substantive evidence
and further research was needed.
Several investigational studies have subsequently been
designed to examine whether ERA treatment of patients with cancer could lead to
better treatment outcomes. Given the extensive prior use of these agents, the
perceived high degree of safety of treatment, and the desire to adequately test
the hypothesis that higher hemoglobin levels would be associated with better
patient outcomes, the designs of these investigational studies have commonly
provided for the treatment of patients to higher hemoglobin levels than
described in current prescribing information.
Thus, these studies have involved treatment of cancer patients who were
not anemic, or the use of target hemoglobin levels that were significantly
higher than those recommended for the established use of these agents for
treatment of anemia (i.e., treatment beyond the correction of anemia, as
previously noted). In this regard, these investigational studies differed from
prior clinical studies that had raised the possibility of better treatment outcomes
with ERA treatment; in the prior studies, ERA administration was generally in
accordance with current prescribing information for use of these products in
anemic patients with cancer receiving chemotherapy.
Partial results from two studies evaluating the effects of
ERAs on treatment outcomes in patients with cancer have recently been
published. In the EPO-INT-76 study, patients beginning chemotherapy for
metastatic breast cancer were randomized to receive concomitant EPREX (the
epoetin alfa formulation marketed outside the US) or placebo for one year. In the study performed by Henke et al.,2
patients beginning radiation therapy for head and neck cancer were randomized
to receive concomitant NeoRecormon̉ (epoetin beta) or
placebo prior to and for the duration of their radiation therapy. In brief,
patient survival in these two studies appeared to be worse, not better, with
ERA treatment compared to placebo. The results of these investigational studies
are summarized below. This section also summarizes available data from three
other studies that have examined the impact of ERAs on treatment outcomes in
cancer patients, and provides information from other clinical trials relevant
to the questions raised by the results of the EPO-INT-76 and Henke et al. studies.
4.1.
Study EPO-INT-76 9
4.1.1.
Study Design
EPO-INT-76 was a company-sponsored randomized,
double-blind, placebo-controlled multicenter trial conducted in women with
breast cancer who were receiving first-line chemotherapy for disseminated
disease, and was designed to evaluate the impact on survival and quality of
life of using epoetin alfa to maintain hemoglobin at non-anemic levels for 12
months. The primary efficacy variable was 12-month survival. A total of 939
patients were enrolled, and were randomly assigned to receive either epoetin
alfa (EPREX), 40,000 IU s.c. weekly or placebo in a 1:1 ratio. Study drug was
initiated when the hemoglobin concentration was 13 g/dL or lower and was
to be continued thereafter on a weekly basis, until the end of the 12-month
double‑blind phase of the study; this treatment was intended to continue
regardless of any changes in patients’ anticancer treatments.
Subsequent to the double-blind phase of the study, there
was an optional open-label phase, in which all subjects could receive epoetin
alfa. In both phases, study drug was administered with the goal of maintaining
hemoglobin concentrations in the range of 12 to 14 g/dL. The dose of study drug
could be escalated up to a maximum of 60,000 IU per injection if, after receiving
4 weekly doses, the hemoglobin concentration was less than 10.5 g/dL and
had increased by less than 1 g/dL or the reticulocyte count had increased
by less than 40,000 cells/mL. Treatment was to be interrupted if the rate of rise
in hemoglobin level exceeded 2 g/dL per month or if hemoglobin exceeded 14
g/dL. Randomization was stratified according to 3 categories: disease
restricted to the skeleton, extraskeletal measurable disease, and extraskeletal
nonmeasurable disease. The choice of chemotherapy and hormonal therapy was left
to the discretion of the investigators, except that dose-intense chemotherapy
for bone marrow or stem cell transplantation was not allowed. There were no
detailed requirements for tumor assessment at entry nor during the follow-up period.
Subjects included in the study had a confirmed diagnosis of
metastatic breast carcinoma, including histology of the primary tumor. Subjects were female, at least 18 years of
age, were starting first-line chemotherapy, had an Eastern Cooperative Oncology
Group (ECOG) performance status score of 0, 1, or 2, and were to have an
estimated life expectancy of at least 6 months.
Subjects were excluded if they had brain metastases or leptomeningeal
disease at the time of randomization, if they were receiving dose
intensification chemotherapy for bone marrow or stem cell transplantation, if
they had an active second primary malignancy, if there were causes of anemia
known to be unresponsive to epoetin alfa, or if they had had a prior TVE within
6 months (unlike prior studies of epoetin alfa, which largely excluded patients
with any prior TVE).
4.1.2.
Patient Demographics
Demographic and baseline characteristics for the
intent-to-treat population are summarized by treatment group and overall in
Table 2a; baseline tumor-related characteristics are presented in Table
2b.
|
Table 2a: Demographics and Baseline
Characteristics (Study EPO-INT-76:
Intent-to-Treat Subjects: Metastatic Breast Cancer) |
|||
|
|
Placebo |
Epoetin Alfa |
|
|
|
Characteristic |
(N=470) |
(N=469) |
|
|
|
Age
(years) |
|
|
|
|
|
N |
470 |
469 |
|
|
|
Mean (SD) |
55.1 (10.49) |
55.8 (11.13) |
|
|
|
Median |
55 |
56 |
|
|
|
Range |
30-84 |
24-83 |
|
|
|
Age
categories (years), no. (%) |
|
|
|
|
|
<=35 |
10 (2%) |
14 (3%) |
|
|
|
36-45 |
65 (14%) |
66 (14%) |
|
|
|
46-55 |
149 (32%) |
133 (28%) |
|
|
|
56-65 |
156 (33%) |
145 (31%) |
|
|
|
66-75 |
75 (16%) |
86 (18%) |
|
|
|
>=76 |
15 (3%) |
25 (5%) |
|
|
|
|
|
|
|
|
|
Weight
(kg) |
|
|
|
|
|
N |
470 |
469 |
|
|
|
Mean (SD) |
70.6 (12.88) |
70.6 (14.10) |
|
|
|
Median |
69 |
69 |
|
|
|
Range |
40-120 |
40-138 |
|
|
|
Body
mass index categories (kg/m2), no. (%) |
|
|
||
|
< 18.5 |
9 (2%) |
11 (2%) |
|
|
|
18.5-24.9 |
169 (36%) |
176 ( 38% |
|
|
|
24.9-29.9 |
168 (36%) |
160 (34%) |
|
|
|
>=30.0 |
123 (26%) |
121 (26%) |
|
|
|
Missing |
1 (<1%) |
1 (<1%) |
|
|
|
Reference:
EPO-INT-76 CSR9 |
|
|||
