Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

 

BACKGROUND INFORMATION

FOR

 

Oncologic Drugs Advisory Committee Meeting

May 4, 2004

Gaithersburg, MD

 

Safety of Erythropoietin Receptor Agonists (ERAs) in Patients With Cancer

 

 

 

available for public disclosure without redaction

 

 

Issue/Report Date:           30 MARCH 2004

Department:                      Drug Development

Document No.:                  EDMS- USRA-9005967:2.0

 

 

 

 


This Advisory Committee Meeting background package is prepared for the  Oncologic Drugs Advisory Committee (ODAC) meeting, to be held on May 4, 2004.  This document provides a summary of the relevant findings of the Company’s ongoing evaluation of PROCRIT® safety, including evaluation of questions that have arisen from recently published studies of other Erythropoietin Receptor Agonist (ERA) product formulations.  Evaluation of the available data from clinical studies and post-marketing experience continues to support the safety and effectiveness of PROCRIT, when used as directed for the approved indications.


TABLE OF CONTENTS

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS. 5

1.         EXECUTIVE SUMMARY. 7

2.         INTRODUCTION. 12

2.1.      Erythropoietin Receptor Agonists, Overview and History. 12

2.2.      Clinical Benefits and Safety in Approved Indications. 13

2.3.      Safety in Investigational Use. 14

3.         SAFETY OF CURRENT LABELED INDICATION - TREATMENT OF ANEMIA IN CANCER PATIENTS ON CHEMOTHERAPY. 16

3.1.      Adverse Events, Including Thrombotic Vascular Events. 17

3.2.      Patient Outcomes. 19

3.2.1.       Survival 19

3.2.2.       Tumor Response/Disease Progression. 22

3.2.3.       Post-Marketing Surveillance. 22

3.2.4.       Conclusion. 23

4.         INVESTIGATIONAL CLINICAL STUDIES – TREATMENT BEYOND CORRECTION OF ANEMIA. 23

4.1.      Study EPO-INT-76. 25

4.1.1.       Study Design. 25

4.1.2.       Patient Demographics. 26

4.1.3.       Patient Treatment 27

4.1.4.       Early Discontinuation of Study Drug Treatment 29

4.1.5.       Data Sets Analyzed. 30

4.1.6.       Survival – Final Analysis of 12-Month Survival Rate. 30

4.1.7.       Survival – Deaths Within 4 Months After Randomization. 32

4.1.7.1.       Patient Demographics in Patients Who Died Within 4 Months. 32

4.1.7.2.       Causes of Death. 33

4.1.8.       Tumor Response. 35

4.1.8.1.       Optimal Tumor Response to First‑Line Chemotherapy. 35

4.1.8.2.       Tumor Response at the End of First‑Line Chemotherapy. 36

4.1.8.3.       Tumor Response at Individual Subject Study End. 37

4.1.9.       Time to Disease Progression. 38

4.1.10.     Conclusion. 40

4.2.      Study of Henke M, et al. 40

4.2.1.       Study Design. 41

4.2.2.       Reported Study Results. 41

4.3.      Ongoing Study in Follow-Up Phase: Study AGO/NOGGO. 42

4.3.1.       Study Design. 42

4.3.2.       Preliminary Analysis. 43

4.4.      Ongoing Study in Follow-Up Phase: EPO-GBR-7. 44

4.4.1.       Study Design. 45

4.4.2.       Preliminary Analysis. 45

4.4.3.       Demographic and Baseline Characteristics. 46

4.4.4.       Tumor Response. 47

4.4.5.       Disease Progression. 48

4.4.5.1.       Local Tumor Evidence. 48

4.4.6.       Survival 50

4.5.      Study N93‑004. 52

4.5.1.       Tumor Response to Chemotherapy / Disease Progression. 53

4.5.2.       Overall Survival 56

4.6.      Other Relevant Information from Clinical Trials. 58

4.6.1.       Overall Incidence of TVEs in Prior Epoetin Alfa Studies. 58

4.6.2.       Recently Discontinued Studies With Imbalances in Thrombotic Vascular Events and/or Survival 59

4.7.      Conclusion. 62

5.         BENEFIT AND RISK ASSESSMENT OF ERAs IN PATIENTS WITH CANCER. 63

6.         CONCLUSION. 67

7.         REFERENCES. 68

APPENDIX. 70

Attachment 1:        Package Insert 71

Attachment 2:        Lancet Letter to the Editor on EPO-INT-76. 104

Attachment 3:        Henke Lancet Article. 106

Attachment 4:        Overview and Design of PROCRIT and EPREX Clinical Studies in Oncology. 113

Attachment 5:        Preclinical Data on Epoetins and Tumor Proliferation. 122

 


LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

Abbreviations

CAC                      Cvitkovic et Associés Consultants

CI                          confidence interval

CR                         complete remission

CRF                      case report form

DSMB                  Data Safety Monitoring Board

DVT                      deep vein thrombsis

ECOG                   Eastern Cooperative Oncology Group

EpoR                     erythropoietin receptor

ERA                      erythropoietin receptor agonist

FIGO                     International Federation of Gynecology and Obstetrics

HNC                     head and neck cancer

HUVECs              human umbilical vein endothelial cells

IDMC                   Independent Data Monitoring Committee

LRPFS                  locoregional progression‑free survival

MI                         myocardial infarction

PE                         pulmonary embolism

pNi                        peri lymph node metastases

PR                         partial remission

RT                         radiotherapy

RT-PCR                reverse transcriptase polymerase chain reaction

SCLC                    small cell lung cancer

TIA                        transient ischemic attack

TVE                       thrombotic vascular event

Definitions of Terms

Beyond the correction of anemia    initiation of ERA treatment in cancer patients who had a hemoglobin concentration of 13 g/dL or higher, or continued treatment of patients after anemia was corrected

epoetin alfa                                        recombinant human erythropoietin (r-HuEPO)


LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS (CONTINUED)

Definitions of Terms (Continued)

EPREX̉                                             Ex-U.S. trade name of epoetin alfa manufactured by Cilag AG, Division of Johnson and Johnson (Schaffhausen, Switzerland), and distributed in Europe and other countries. The active substance epoetin alfa for EPREX is supplied by Ortho Biologics, L.L.C. (Manati, Puerto Rico).

PROCRIT̉                                         U.S. trade name of epoetin alfa manufactured by Amgen, Inc. (Thousand Oaks, CA) and distributed by Ortho Biotech Products, L.P. (Bridgewater, NJ).

the Sponsor                                        Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Sponsor) and affiliates

 


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 US in 1989, and has an amino acid sequence identical to that of natural human urinary erythropoietin.  Two different epoetin alfa formulations are marketed by the Sponsor including EPREX (ex-US) and PROCRIT (US). These products have provided important benefits to over 3 million patients with anemia due to renal disease or due to cancer chemotherapy. In addition to these indications, extensive ongoing research has led to the identification of additional approved indications for epoetin alfa, including use for anemia related to antiviral therapy (azidothymidine, AZT) for HIV infection, or to reduce the need for transfusions for perisurgical blood loss.  The Sponsor is committed to supporting scientifically appropriate development activities investigating potential additional benefits that ERAs may offer patients in existing and future indications.

Other ERAs, introduced more recently, include epoetin beta (NeoRecormon®, ex-US) and darbepoetin alfa (Aranesp®, ex-US and available in the US since 2001).  These more recent ERAs share a close homology with epoetin alfa and endogenous human erythropoietin.  The products in this class of medications act on the same cellular target (the erythropoietin receptor) on erythroid precursor cells, to produce their benefits by increasing red blood cell (RBC) production.  They also share similar side effect profiles, including thrombotic vascular events (TVEs) and hypertension.  These recognized side effects are described in product labels for all medications in the ERA class. 

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.

Table 1:  Study Characteristics for Double-Blind, Placebo-Controlled Oncology
Studies in Anemic Patients


Study

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
< 14 g/dl), or if they had experienced a Hb decline of ³ 2 g/dL (from a baseline of ³ 14 g/dL).

**     £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

 

 


 

Table 2b: Baseline Tumor-Related Characteristics

(Study EPO-INT-76: Intent-to-Treat Population: Metastatic Breast Cancer)


Characteristic

Placebo
 (N=470)

Epoetin Alfa
 (N=469)

 

 

 

 

 

 

 

Estrogen receptor result, no.(%)

 

 

 

 

 

  Negative

131

( 28)

126

( 27)

 

  Positive

232

( 49)

226

( 48)

 

  Not determined

107

( 23)

117

( 25)

 

ECOG performance status, no.(%)a

 

 

 

 

 

  0

222

( 47)

198

( 42)

 

  1

199

( 42)

216

( 46)

 

  2

49

( 10)

55

( 12)

 

 

a   ECOG performance scores:  0 = able to carry out all normal activity without restriction; 1 = restricted in physically strenuous activity but ambulatory and able to do light work; 2 = ambulatory and capable of all self-care but unable to carry out any work; 3 = capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = completely disabled; cannot carry out any self care; totally confined to bed or chair.

 

Reference: EPO-INT-76 CSR9

 

4.1.3.                       Patient Treatment

Summary statistics regarding exposure to study drug are provided in Table 3 for the intent-to-treat population.

Subjects did not have to be anemic to qualify for study entry; any baseline hemoglobin concentration was acceptable. Following randomization, however, study drug administration was to not to begin until the hemoglobin level was 13.0 g/dL or less. The median time from randomization to study drug start was the same in both treatment groups (4 days). 

Table 3: Time From Randomization to Study Drug Start, Time on
Study and Study Drug, and Number of Doses

(Study EPO-INT-76: Intent-to-Treat Subjects: Metastatic Breast Cancer)

 

Placebo

Epoetin Alfa

 

Exposure Parameters

(N=470)

(N=469)

 

Time from randomization to study drug start (days)

 

 

 

  N

456

448

 

  Mean

12.2

13.0

 

  Median

4

4

 

  Interquartile Range

0-14.0

0-12.5

 

  Range

0-265

0-286

 

Time on study drug (weeks)

 

 

 

  N

456

448

 

  Mean (SD)

36.9 (16.34)

30.4 (17.25)

 

  Median

44.1

32.1

 

  Range

0.1-59.7

0.1-65.4

 

Number doses per subject

 

 

 

  N

456

448

 

  Mean (SD)

35.2 (15.91)

21.4 (13.50)

 

  Median

40

19

 

  Range

1-57

1-58

 

Time on study (weeks)

 

 

 

  N

470

469

 

  Mean (SD)

43.8 (15.18)

41.6 (16.78)

 

  Median

52.0

52.0

 

  Range

0-68

0-66

 

Reference: EPO-INT-76 CSR9

 

During the study, study drug was administered to maintain the subject’s hemoglobin concentration in the range of 12 to 14 g/dL, and doses were to be withheld when the hemoglobin level was increased above 14 g/dL.  Subjects in the epoetin alfa group were on study drug for a shorter length of time and received fewer doses of study drug per subject compared with those assigned to the placebo group (Table 3). In both groups, the majority of subjects in both treatment groups remained in the double-blind study for the specified 12-month duration (median, 52 weeks).

The mean doses of study drug over time in the epoetin alfa and placebo group are shown for the intent-to-treat population in Figure 3.

Figure 3: Mean Weekly Dose Over Time for Patients Receiving Study Drug

(Study PRI/EPO-INT-76: Intent-to-Treat Subjects: Metastatic Breast Cancer)

 

Note: Zero weekly doses were excluded from the summary.

Reference: EPO-INT-769

Patients in the placebo arm tended to receive higher doses of study drug over time, consistent with a lack of pharmacologic effect resulting in dose escalations. Patients in the active treatment arm tended to receive lower doses over time consistent with dose adjustments based on hemoglobin increases or due to adverse events.

4.1.4.                       Early Discontinuation of Study Drug Treatment

In April 2002, the Independent Data Monitoring Committee (IDMC) reviewed available data on the 939 enrolled subjects. The IDMC recommended discontinuation of the study because of an unexpected increase in mortality among subjects in the epoetin alfa‑treated group compared with the placebo group. Although study drug treatment was terminated, study participants were to be followed according to the protocol.  At the time of discontinuation of study drug treatment, all study patients had already been enrolled, 88% of study patients had already completed the study period or had withdrawn from treatment, and the last patients to be enrolled had completed 10 months of the planned 12-month treatment period.

4.1.5.                       Data Sets Analyzed

In general, data and conclusions concerning the analysis of the primary efficacy end point for the efficacy population (defined as patients who received at least one dose of study drug; this included 904 of the 939 patients enrolled) were consistent with those for the intent-to-treat population. Therefore, results for the intent-to-treat population are discussed in the text of this document.

After study drug treatment was discontinued (follow-up continued and is ongoing), and the pre-planned primary analysis was completed, the Sponsor engaged an outside consulting firm (Cvitkovic et Associés Consultants [CAC], Paris, France), staffed by medical oncologists, to review the subjects’ medical charts at all sites. This review was conducted in an attempt to collect further information to better understand the efficacy and safety results. The oncologists who performed the review were blinded to the identity of the study drug previously administered to each subject. Additional information obtained from this medical chart review is utilized in some analyses, and is so identified when used.

4.1.6.                       Survival – Final Analysis of 12-Month Survival Rate

The intent-to-treat population, which included all subjects randomized, consisted of 939 subjects with a mean age of 55.5 years. In general, demographic and baseline characteristics were similar between epoetin alfa- and placebo-treated subjects.  For the intent-to-treat population, survival rates at 12 months after randomization, based on Kaplan-Meier estimates, are presented in Table 4. The 12-month survival rate based on Kaplan-Meier estimates was lower in the epoetin alfa group (70%) compared with the placebo group (76%). The analysis based on Cox’s proportional hazards model stratified by metastatic category showed that the difference between the treatment groups was statistically significant (p=0.012). The Kaplan‑Meier curves for time to death within 12 months after randomization for the intent-to-treat population are presented in Figure 4.

Table 4 also summarizes the 12-month survival results for the efficacy population. For this population, the 12-month survival rate, based on Kaplan-Meier estimates, was also significantly lower in the epoetin alfa group compared with the placebo group (p=0.019). Similar results were seen using the survival data as of the date of treatment discontinuation (hazard ratio=1.33, p=0.024). In this analysis, subjects were censored at the date the study treatment was discontinued or at 12 months, whichever occurred first.

Table 4:  Primary Efficacy Variable:  12‑Month Survival Rate
(Study PRI/EPO-INT-76: Intent-to-Treat and Efficacy Subjects: Metastatic Breast Cancer)

 

Placebo

Epoetin Alfa

Hazard Ratio [95% CI]

p valuea

Intent-to-Treat

(N=470)

(N=469)

 

Diedb

24%

30%

1.37 [ 1.07, 1.74]

Survivedb

76%

70%

0.012

 

 

 

 

Efficacyc

(N=456)

(N=448)

 

Diedb

23%

29%

1.35 [ 1.05, 1.74]

Survivedb

77%

71%

0.019

Key: CI=confidence interval

a    Based on Cox’s model stratified by metastatic category.

b    reported percentages are based on Kaplan-Meier estimates.

c   Efficacy population comprised only of subjects who received study drug.

 

Reference: EPO-INT-76 CSR9

 

Figure 4:  Time to Death Within 12 Months After Randomization
(Study PRI/EPO-INT-76/EPO‑CA‑489: Intent-to-Treat Subjects: Metastatic Breast Cancer)

Note: Survival curves for 365 days (+ 2-week window) post-randomization.

Reference: EPO-INT-76 CSR9

 

4.1.7.                       Survival – Deaths Within 4 Months After Randomization

The Kaplan-Meier survival curves separated early in the study, with nearly the maximum difference in  mortality already evident after the first 4 months of the double-blind study. As the excess deaths occurred largely in the first 4 months, the subset of subjects who died within the first 4 months of randomization was examined further. This was a post-hoc analysis, to better understand the data. For the intent-to-treat population, a total of 57 subjects died within the first 4 months after randomization in the double-blind phase. Of these 57 subjects, 16 were in the placebo group and 41 were in the epoetin alfa group.

4.1.7.1.                 Patient Demographics in Patients Who Died Within 4 Months

No apparent reasons for the observed imbalance in deaths at 4 months were evident from examination of the selected characteristics of patients who died at 4 months, compared to the total population. Table 5 is illustrative of the findings of these comparisons.

 

Table 5:  Selected Baseline Characteristics of
Subjects Who Died Within 4 Months After Randomization
Versus Total Population

(Study EPO-INT-76: Intent-to-Treat Subjects: Metastatic Breast Cancer)

 

 

Placebo

Epoetin Alfa

 

 

Early Deaths

Total

Early Deaths

Total

 

Characteristic

(N=16)

(N=470)

(N=41)

(N=469)

 

Median Age (years)

56.5

55

58

56

 

>65 years of age (%)

31%

19%

41%

24%

Estrogen Receptor Positive (%)

50%

49%

37%

48%

 

Hemoglobin  £ 10.5 g/dL, (%)

6%

11%

29%

14%

 

³3 Indicator lesions at entry (%)

0

21%

37%

23%

 

Reference: EPO-INT-76 CSR9

 

 

 

 

 

There were no notable differences in the prestudy (adjuvant) or on-study chemotherapy received by patients who died in the first 4 months after randomization, compared to the total study population.

4.1.7.2.                 Causes of Death

The causes for all deaths that occurred within 4 months of randomization, and for all deaths that occurred during the 12-month double‑blind phase of Study EPO-INT-76, are summarized in Table 6, for the intent-to-treat population.

As shown in Table 6, a total of 263 (28%) subjects in the intent-to-treat population died during the 12‑month double‑blind phase, including 24% of placebo-treated subjects and 32% of epoetin alfa-treated subjects. During the first 4 months after randomization, 16 placebo-treated subjects died, compared with 41 subjects in the epoetin alfa group. The most common cause of death at 4 months and at 12 months post-randomization was reported as disease progression. During the first 4 months after randomization, deaths attributed by the investigator to disease progression accounted for 13/16 and 28/41 of the deaths in the placebo and epoetin alfa treatment populations, respectively. This pattern was still seen at the 12‑month time point, where a large majority of deaths (91% and 85%) in each of the two treatment groups was attributed to disease progression.

Table 6: Cause of Deaths Among Subjects Who Died Within 4 Months and Within 12 Months of Randomization as Attributed by the Investigator
(Study PRI/EPO-INT-76: Intent‑to‑Treat Subjects: Metastatic Breast Cancer)

 

Placebo

Epoetin Alfa

Difference

 

(N=470)

(N=469)

EPO-PBO

No. (%) died within 4 months

16 (3)

41 (9)

25

 

Cause of death within 4 months as attributed by investigator

Chemotherapy toxicity

1

3

2

Disease progression

13

28

15

Missing

0

1a

1

Otherb

1

4

3

Thrombotic vascular event

1

5

4

 

 

 

 

 No. (%) died during 12 months

115 (24)

 148 (32)

33

 

 

 

 

Cause of death during 12 months as attributed by investigator

Chemotherapy toxicity

1

8

7

Disease progression

105

126

21

Missingc

0

2

2

Otherd

6

6

0

Thrombotic vascular event

3

6

3

a   Cause of death was unknown. Subject 3003 died suddenly on Study Day 36.

b   Other causes include:

    - fatty embolism, ischemic colon perforation, pulmonary edema, unknown

c   Cause of death not listed for 2 subjects in the epoetin alfa treatment group.

d   Other causes of death included
-aspiration of barium – cardiac arrest, cardiomyopathy and disease progression
-cardiomyopathy, circulatory tract insufficiency
-euthanasia, fatty embolism
-heart insufficiency, ischemic colon perforation
-died with traffic accident, pulmonary edema
-renal insufficiency
-respiratory/circulatory insufficiency, serious adverse event: aspiration of barium
-traffic accident, unknown.

 

Reference: EPO-INT-76 CSR9

 

It should be noted that the cause of death given for subjects in Study EPO-INT-76 was based on the assessment of the investigator, and it was not necessary for the study investigator to provide corroborating information when he/she checked off “disease progression” as the cause of death. It is perhaps not surprising that, in this population of subjects with metastatic cancer, most deaths were attributed to “disease progression”. To help determine whether the observed difference in mortality reflected a true difference in tumor treatment response / disease progression, a blinded chart review was undertaken, in which all available information in individual patient charts regarding indicators of disease progression was evaluated, including tumor response, time to disease progression, and progression-free survival. All chart information on the patients who died in the first 4 months was also examined to look for any records regarding associated TVEs.

Based on the information generated in this blinded chart review, among the patients who died in the first 4 months following randomization, 2/16 deaths in the placebo group and 11/41 deaths in the epoetin alfa group were related to TVEs, compared with 1/16 and 5/41 deaths that had been attributed to TVEs according to the original report of the study investigator on the case report form (CRF). Thus, TVEs accounted for some of the increased mortality in the epoetin alfa group in the 4 months following randomization, and this analysis, together with the potential for underdiagnosis of fatal TVEs, suggests that these events may well have accounted for a substantial portion of the observed increased mortality in the epoetin alfa group.

4.1.8.                       Tumor Response

Study EPO-INT-76 was designed as a survival study with limited data collection, and there were no detailed requirements for tumor assessment at entry or during study treatment or follow-up. Further, despite post-hoc efforts to retrospectively collect additional information via chart reviews, 26% of placebo-treated subjects and 29% of epoetin alfa-treated subjects had inadequate tumor assessments before chemotherapy. This substantial level of missing data clearly constrains the interpretation of analyses of response rates and time to progression in this study. However, analyses of tumor response were performed with findings as described below.

4.1.8.1.                 Optimal Tumor Response to First‑Line Chemotherapy

Optimal tumor response rate to first‑line chemotherapy was defined as the best overall response noted at any time during first‑line chemotherapy. Individual investigators made the determination on the basis of tumor measurements obtained during first‑line chemotherapy, and the method of determination was at the investigator's discretion. No detailed requirements were defined for tumor assessment at study entry or during the follow‑up period. As noted above, baseline tumor assessment data were missing in a substantial proportion of patients in each treatment group.

For the intent-to-treat population, the optimal tumor response to chemotherapy was not statistically different between the treatment groups (p=0.93). The proportion of patients who had a complete or partial response to first‑line chemotherapy was similar in the placebo and the epoetin alfa treatment groups (Table 7). The number of patients who developed new lesions, as a manifestation of progressive disease, was also similar in both groups, indicating that epoetin alfa was not associated with a higher incidence of new metastatic lesions.

 

Table 7:  Optimal Tumor Response to First‑Line Chemotherapy
(Study PRI/EPO-INT-76: Intent‑to‑Treat Subjects: Metastatic Breast Cancer)

 

Placebo

Epoetin Alfa

 

 

(N=470)

(N=469)

 

Tumor response, n (%)

 

 

 

   Complete response

  45 (10)

  55 (12)

 

   Partial response

170 (36)

154 (33)

 

   Overall response (CR + PR)

215 (46)

209 (45)

 

   No response (stable disease)

156 (33)

149 (32)

 

   Progressive disease

  84 (18)

  87 (19)

 

        New lesions

56 (12)

43 (9)

 

Unknown

15 (3)

24 (5)

 

p valuea

0.9303

 

 

a    The p‑value was based on a stratified Cochran‑Mantel‑Haenszel test. Response to chemotherapy categories:

    Complete response: complete absence of detectable tumor.

    Partial response: reduction in estimated tumor mass by ³50%; <25% increase in the size of any measurable malignant lesion; <25% increase in the estimated size of any evaluable but non‑measurable malignant lesion; no new lesions.

    No response (stable disease): reduction of tumor mass by <50%; <25% increase in the size of any measurable malignant lesion; <25% increase in the estimated size of any evaluable but non‑measurable malignant lesion; no new lesions.

    Progressive disease: increase in estimated tumor mass by ³25% or appearance of new lesion.


Reference: EPO-INT-76 CSR9

 

4.1.8.2.                 Tumor Response at the End of First‑Line Chemotherapy

For the intent-to-treat population, the tumor response at the end of first‑line chemotherapy was 35% for subjects in the epoetin alfa treatment group and 36% for subjects in the placebo group (Table 8).

 

Table 8:  Tumor Response at the End of First‑Line Chemotherapy
(Study PRI/EPO-INT-76: Intent‑to‑Treat Subjects: Metastatic Breast Cancer)

 

Placebo

Epoetin Alfa

 

 

(N=470)

(N=469)

 

Tumor response, n (%)

 

 

 

   Complete response

41 (9)

49 (10)

 

   Partial response

127 (27)

115 (25)

 

   Overall response (CR + PR)

168 (36)

164 (35)

 

   No response (stable disease)

124 (26)

96 (20)

 

   Progressive disease

123 (26)

125 (27)

 

         New lesions

101 (21)

86 (18)

 

   Unknowna

55 (12)

84 (18)

 

 

a   All information on response to chemotherapy was missing.

    Response to Chemotherapy Categories:

    Complete response: complete absence of detectable tumor.

    Partial response: reduction in estimated tumor mass by ³50%; <25% increase in the size of any measurable malignant lesion; <25% increase in the estimated size of any evaluable but non‑measurable malignant lesion; no new lesions.

    No response (stable disease): reduction of tumor mass by <50%; <25% increase in the size of any measurable malignant lesion; <25% increase in the estimated size of any evaluable but non‑measurable malignant lesion; no new lesions.

    Progressive disease: increase in estimated tumor mass by ³25% or appearance of new lesion.

 

Reference: EPO-INT-76 CSR9

 

4.1.8.3.                 Tumor Response at Individual Subject Study End

For the intent-to-treat population, tumor response at the last assessment for each individual subject during the 12‑month double‑blind phase was similar for the two treatment groups (Table 9). Slightly more subjects who received placebo showed progressive disease than those who received epoetin alfa, with a corresponding finding for the occurrence of new lesions. These data do not indicate any effect of epoetin alfa on tumor response rate. 

 

Table 9:  Tumor Response to First‑Line Chemotherapy at Final Assessment
(Study PRI/EPO-INT-76: Intent‑to‑Treat Subjects: Metastatic Breast Cancer)

 

Placebo

Epoetin Alfa

 

 

(N=470)

(N=469)

 

Tumor response, n (%)

 

 

 

  Complete response

34  (7)

44  (9)

 

  Partial response

66 (14)

45 (10)

 

  Overall response (CR + PR)

100 (21)

89 (19)

 

  No response (stable disease)

88 (19)

102 (22)

 

  Progressive disease

216 (46)

195 (42)

 

         New lesions

177 (38)

140 (30)

 

  Unknowna

66 (14)

83 (18)

 

 

a   All information on response to chemotherapy was missing.

    Response to Chemotherapy Categories:

    Complete response: complete absence of detectable tumor.

    Partial response: reduction in estimated tumor mass by ³50%; <25% increase in the size of any measurable malignant lesion; <25% increase in the estimated size of any evaluable but non‑measurable malignant lesion; no new lesions.

    No response (stable disease): reduction of tumor mass by <50%; <25% increase in the size of any measurable malignant lesion; <25% increase in the estimated size of any evaluable but non‑measurable malignant lesion; no new lesions.

    Progressive disease: increase in estimated tumor mass by ³25% or appearance of new lesion.

 

Reference: EPO-INT-76 CSR9

 

If epoetin alfa were interfering with response to chemotherapy or potentiating tumor growth, a lower objective response rate might have been observed in patients treated with epoetin alfa, and the number of patients in the epoetin alfa group with new lesions or disease progression might have been higher. These findings are not suggestive of an effect of epoetin alfa on tumor response to treatment, and may support consideration of other mechanisms, such thrombotic vascular events (some of which may be occult) and/or other adverse events, to explain the observed survival differences. This also may suggest that disease progression was not the true reason for the difference in deaths in the two treatment groups, despite the attributions assigned in the case records.

4.1.9.                       Time to Disease Progression

 It is again important to note that Study EPO-INT-76 was designed as a survival study with limited data collection, and there were no detailed requirements for tumor assessment at entry or during study treatment or follow-up. Further, despite efforts to retrospectively collect additional information via chart reviews, 26% of placebo-treated subjects and 29% of epoetin alfa-treated subjects had inadequate tumor assessments before chemotherapy. This substantial level of missing data clearly constrains the interpretation of analyses of response rates and time to progression in this study.

For purposes of analysis, the date of disease progression was determined to be the first time the investigator noted disease progression when recording evaluation of optimal tumor response to first‑line chemotherapy, tumor response at the end of first‑line chemotherapy, and tumor response at completion or withdrawal from the study. If a subject did not have disease progression reported on study, time to disease progression was determined by using the following rules:

·       if subject died within 12 months after randomization and death was attributed to disease progression, she was considered as having disease progression with the time to disease progression equivalent to the time to death;

·       if subject died within 12 months after randomization of causes other than disease progression, time to disease progression was censored at the date of death;

·       if death occurred beyond 12 months after randomization, time to disease progression was censored at the date of completion or withdrawal.

Forty subjects (24 in the epoetin alfa group, 16 in the placebo group) were not evaluable for this endpoint, because of early withdrawal from the study before any tumor assessments were conducted.

For the intent-to-treat population, time to disease progression was similar between the 2 treatment groups (p=0.71) (Figure 5). On the basis of Kaplan‑Meier estimates, 43.4% of subjects who received epoetin alfa and 41.1% of those who received placebo had evidence of disease progression by Month 12.

Figure 5:  Time to Disease Progression
(Study PRI/EPO-INT-76: Intent‑to‑Treat Subjects: Metastatic Breast Cancer)

Reference: EPO-INT-76 CSR9

 

4.1.10.                   Conclusion

Study EPO-INT-76 evaluated whether epoetin alfa treatment, administered weekly for one year to maintain hemoglobin levels at 12-14 g/dL in patients starting first-line chemotherapy for metastatic breast cancer, could favorably affect the survival of these patients. Treatment differed from the common uses of ERAs for chemotherapy-associated anemia in that target hemoglobins were relatively high and treatment continued for a year regardless of chemotherapy. The reasons for the observed outcome of EPO-INT-76 are not clear. An effect on tumor treatment response / disease progression cannot be excluded, but it also appears likely that increased adverse effects (TVEs), associated with this use of ERA treatment of patients beyond the correction of anemia, may have played a role.

4.2.           Study of Henke M, et al. 2

It is important to acknowledge that the Sponsor did not have access to the primary data to evaluate the results of this study. This discussion of the results is based on data available in the public domain.

4.2.1.                       Study Design

Henke et al. conducted a multicenter, randomized, double‑blind, placebo‑controlled clinical trial in patients with head and neck cancer, designed to investigate the effects of epoetin beta (NeoRecormonâ) on locoregional progression‑free survival (LRPFS) and overall survival, compared with placebo. The starting dose of epoetin beta was 300 IU/kg t.i.w. for 7 to 9 weeks, beginning 10-14 days before the start of radiation therapy (double the starting dose recommended in product labeling). Study subjects had advanced stage (III/IV) head and neck cancer (HNC) and were to receive postoperative radiation therapy, or radiation therapy alone if their disease was inoperable. The entry level for hemoglobin was <12.0 g/dL for women and <13.0 g/dL for men. The target hemoglobin was ³14.0 g/dL for women and ³15.0 g/dL for men . The study was designed to determine if ERA-induced higher hemoglobin levels can  increase the radiosensitivity of head and neck cancer, and thus improve the outcome of treatment.

The primary end point of the study was LRPFS. Time to locoregional tumor progression and survival were also assessed. A total of 351 subjects were enrolled between March 1997 and April 2001 and were randomly assigned to either the epoetin beta group or the placebo group. Randomization was to three strata, based on complete resection; incompletely resected disease; or not operable (candidates for primary definitive radiotherapy).

4.2.2.                       Reported Study Results

Subjects treated with epoetin beta had a robust increase in hemoglobin concentration that was maintained during treatment, with a reported median hemoglobin at baseline of 11.7 g/dL, rising to reported mean hemoglobin values of 14.8 and 15.4 g/dL after 4 weeks and 9 weeks, respectively. In the intent‑to‑treat population, the median LRPFS was 406 days for subjects in the epoetin beta treatment group and 745 days for those who received placebo. The stage-adjusted and stratum-adjusted relative risk for LRPFS was 1.62 (95% CI, 1.22 to 2.14, p=0.0008). Survival in the intent-to-treat population also favored the placebo group (p=0.02, RR=1.39 [95% CI, 1.05 to 1.84], respectively). Separation of the LRPFS and survival curves began at about 6 months and continued for the duration of follow-up.

A total of 89 (52%) subjects in the placebo arm and 109 (61%) subjects in the epoetin beta arm died. One-third (34%) or 119 subjects in the 2 treatment groups had deaths attributed to cancer. Data on the number of cancer-related deaths by treatment arm are not available in the publication. Interestingly, the majority of the 20 excess deaths in the epoetin beta treatment arm could be accounted for by imbalances in reported deaths from cardiac disorders (5 placebo versus 10 epoetin beta deaths) and “general disorders” (1 placebo versus 9 epoetin beta). There was no difference in the rate of distant metastatic disease in the 2 arms of the study (23% in the placebo group versus 25% in the epoetin beta group,).

Vascular disorders were reported in 5% of placebo patients and 11% of epoetin beta patients, and included hypertension, hemorrhage, venous thrombosis and pulmonary embolism, and cerebrovascular disorders.

These unanticipated results suggested that therapy with epoetin beta in advanced stage HNC treated with radiotherapy might have exerted an adverse effect on LRPFS and survival; and the publication raised concerns that ERAs might be radioprotective or might stimulate tumor cell proliferation, resulting in disease progression and decreased survival. 

4.3.           Ongoing Study in Follow-Up Phase: Study AGO/NOGGO10

The study conducted by a German cooperative group AGO/NOGGO, referred to as Study AGO/NOGGO, is an investigator-sponsored study.  It is important to note that the Sponsor did not have access to the primary data, and results are presented with the author's permission based on a presentation at ASCO in September 2003 together with a draft manuscript.  This study was initiated in 1999 among patients with cervical cancer receiving sequential adjuvant chemoradiotherapy (ifosfamide and carboplatin followed by radiotherapy) and has a primary endpoint of recurrence-free survival after 5 years.  The data presented here are preliminary, as median follow-up for study participants is currently approximately two years.

4.3.1.                       Study Design

The study is a multicenter, randomized, open‑label study conducted primarily to compare relapse-free survival of patients with high-risk cervical cancer receiving adjuvant sequential chemotherapy and radiotherapy with or without epoetin alfa.  Secondary endpoints were change in hemoglobin levels, transfusion requirements, reduction in anemia, changes in ECOG performance status, toxicity, and overall survival. Eligible patients had  International Federation of Gynecology and Obstetrics (FIGO) staging scores of IB, IIA, or IIB, and had undergone radical hysterectomy.  Patients in stages IB or IIA were also required to have one of the following poor prognostic factors: invasion of the tumor into lymph and/or blood vessels, adenocarcinoma, age less than 35 years, grading G3, tumor greater than 4 cm in diameter, and pN1 (pelvic lymph node metastases).  Patients were centrally randomized using three prognostic factors as stratification criteria: lymph node involvement, staging according to FIGO classification system, and quality of tumor resection.  At baseline (after surgery but before chemotherapy or radiotherapy) patients in the epoetin alfa group began treatment with 10,000 IU of epoetin alfa subcutaneously 3 times a week. Administration of epoetin alfa continued until 2 weeks after the end of radiotherapy to a target hemoglobin of 13.0 g/dL.  If hemoglobin at chemotherapy initiation was <10.5 g/dL, epoetin alfa dose was increased to 10,000 IU 6 times weekly.  If hemoglobin rose to >13.0 g/dL, epoetin alfa dose was reduced to 10,000 IU 2 times weekly; epoetin alfa was discontinued if hemoglobin reached >14.0 g/dL. 

Patients in the control group received oral iron (Fe++ 200 mg/day) and blood transfusions for treatment of hemoglobin <9.0 g/dL.  Patients in the epoetin alfa group whose hemoglobin declined to this level also received blood transfusions.

4.3.2.                       Preliminary Analysis

Before the initiation of chemotherapy, 53% of patients who received epoetin alfa and 43% of patients in the control group had hemoglobin levels >12 g/dL.  The respective mean values were 12 g/dL and 11.8 g/dL. Before radiotherapy, mean hemoglobin levels were 12.5 g/dL for the epoetin alfa group and 10.8 g/dL for the control group.  Mean hemoglobin at the end of radiotherapy was 12.9 g/dL for the epoetin alfa group and 12.1 g/dL for the control group. Two weeks after radiotherapy mean hemoglobin levels increased to 13.1 g/dL for the epoetin alfa group and 12.4 g/dL for the control group.

As designed, the study initially had three arms; a chemoradiotherapy (control) arm, a chemoradiotherapy plus epoetin alfa arm, and a radiation therapy alone arm. The third arm accrued very few patients and was closed. Of the 264 patients enrolled, 257 were in the control or epoetin alfa arms. Evaluable patients who had baseline demographics and characteristics for the primary intent-to-treat analysis included 122 epoetin alfa and 125 control patients. The relapse-free survival for the control group and the epoetin alfa group over time is shown in Figure 6. Table 10 summarizes relapse-free survival at a median observation time of 105 weeks (mean 102.6 weeks). The difference between the groups trended towards significance (p = 0.074).

Table 10:  Recurrence of Malignancy at Median of 105 weeks*
(Study AGO/NOGGO: Cervical Cancer)

 

Epoetin alfa group

(n=113)

Control group (n=116)

Total

( n=234)

No recurrence

94 (83%)

87 (75%)