# Presentation: 669111

##  Update on the Safety of Erythropoietin Products in Patients With Cancer

***Peter Bowers, MD***
***Senior Director******Clinical Team Leader***
***Johnson & Johnson******Pharmaceutical Research & Development***

## Today’s Agenda

**Evaluation of Studies ****	****Dr. Peter Bowers**
**Supportive Anemia Care**
**Beyond Correction of Anemia**
**Future Clinical Data ****	****Dr. Martine George**
**Conclusions****	****Dr. Martine George**

## Supportive Anemia Care StudiesAnalysis 

**Combined analysis from all completed, randomized, double-blind trials of anemic patients (n = 1,976; 10 trials) **
**Mortality hazard ratios**
**Tumor response and disease progression where data available (5 of 10 studies)**
**Thrombotic vascular event (TVE) frequency**
**Considerations for this analysis**
**Variations in design and patient heterogeneity**
**Studies primarily evaluated transfusion reduction over 12 to 24 weeks**

## Supportive Anemia Care StudiesNo Survival Effect Seen in Combined Analysis

| Tumor type/study | Hazardratio |
| --- | --- |
| Mixed (non-chemo) | 0.89 |
| Mixed (non-cisplatin) | 1.08 |
| Mixed (cisplatin) | 0.86 |
| CLL (J89-040) | 1.68 |
| CLL (P-174) | 0.42 |
| Ovarian (EPO-INT-1) | 1.58 |
| MM (EPO-INT-2) | 0.15 |
| Mixed (EPO-INT-3) | 1.56 |
| Mixed (EPO-INT-10) | 0.81 |
| Mixed (PR98-27-008) | 1.17 |
| OVERALL | 0.99 |

| Mortality, n/N (%) |  |
| --- | --- |
| Placebo | Epoetin alfa |
|   13/59 (22.0) |   13/65 (20) |
|     9/76 (12) |   10/81 (12) |
|     9/65 (14) |     8/67 (12) |
|     6/79 (8) | 16/142 (11) |
|     1/12 (8) |     1/33 (3) |
|     2/80 (3) |   6/164 (4) |
|     7/76 (9) |     1/69 (1) |
|     3/65 (5) |   9/135 (7) |
| 22/124 (18) | 41/251 (16) |
| 26/165 (16) | 31/168 (19) |
|  |  |

**(0.76, 1.28)**

**0.1**

**1**

**10**

**Favors ****Epoetin alfa**

**Favors****placebo**

**HR (95% CI) log scale**

**Test for heterogeneity, *****P***** = .66**

## Supportive Anemia Care Studies—Similar Tumor Response/Disease Progression

|  |  | ResponseDisease progression | Patients, % |  |
| --- | --- | --- | --- | --- |
| Tumor type/study | N |  | Placebo | Epoetin alfa |
| Ovarian (EPO-INT-1) | 246 | CR/PR | 72 | 68 |
|  |  | Disease progression | 15 | 16 |
| MM (EPO-INT-2) | 145 | CR/PR | 26 | 29 |
|  |  | Disease progression | 21 | 22 |
| Mixed (EPO-INT-3) | 201 | CR/PR | 54 | 48 |
|  |  | Disease progression | 20 | 20 |
| Mixed (EPO-INT-10) | 375 | CR/PR | 32 | 45 |
|  |  | Disease progression | 33 | 24 |
| Mixed (PR98-27-008) | 344 | CR/PR | 19 | 16 |
|  |  | Disease progression | — | — |

## Supportive Anemia Care Studies Conclusion: Favorable Benefit/Risk Profile

**Established benefits include transfusion reduction and reduction in debilitating symptoms of anemia**
**No adverse survival signal or indication of adverse impact on tumor response or****disease progression**

## Today’s Agenda

**Evaluation of Studies ****	****Dr. Peter Bowers**
**Supportive Anemia Care**
**Beyond Correction of Anemia**
**Preclinical Background**
**EPO-INT-76**
**Other Studies**
**Future Clinical Data ****	****Dr. Martine George**
**Conclusions**

## Studies Beyond the Correction of Anemia— Preclinical Experience and Rationale  

**Tumor cell lines (> 25) did not proliferate in presence of EPO including lines EPO-R+ **
**Systemic administration did not increase tumor volume in several *****in vivo***** models**
**Erythropoietin products with chemotherapy or radiotherapy delay tumor growth *****in vivo***
**Despite extensive investigations, inconsistent reports of proliferation seen with EPO concentrations 5- to 100-fold greater than achieved clinically**

**16**

## Studies Beyond Correction of Anemia EPO-INT-76 (Metastatic Breast Cancer)

**Key design elements—large trial, simple design**
**EPREX****®**** QW or placebo continued for 12 mo regardless of chemotherapy changes or disease progression**
**Initiate at ≤ 13 g/dL, target hemoglobin 12 to 14 g/dL**
**Primary endpoint 12-mo survival**
**Design limitations**
**Objective measures of tumor response and disease progression not specified (timing/method) **
**Study drug treatment discontinued at recommendation of DSMB, 88% completed or withdrawn**

## Summary of Survival Over TimeEPO-INT-76

| 470 | 453 | 419 | 348 | 168 | 79 | 33 | 7 | 0 | 0 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 469 | 426 | 390 | 320 | 154 | 74 | 39 | 11 | 3 | 0 |

| At-risk pts |
| --- |
| Placebo |
| Epoetin |

**Time, mo**

**25**

**Vertical line represents end of double-blind phase at 12 mo.  **
**†****Based on Kaplan-Meier estimate.**

**	****    ****	****12-mo mortality**
**	**** ****N ****	****n (%)****†****	**** Censored ****	*****P *****value**
**Placebo****	****470****	****115 (24)****	****92****	****.012**
**Epoetin alfa****	****469****	****148 (30)****	****81****	**

**12-mo****hazard ratio (95% CI)**
**1.37 (1.07, 1.74)**

## Studies Beyond Correction of Anemia Factors Considered in Analyses EPO-INT-76

**Extensive analysis to understand differences**
**Additional data collection from source documents**
**Retrospective blinded chart review**
**Some imbalances noted but did not explain difference**
**Analyses provide hypotheses that might explain survival difference**

## Studies Beyond Correction of Anemia Investigator-attributed Causes of DeathsEPO-INT-76

|  | Patients, n |  |  |
| --- | --- | --- | --- |
|  | Placebon = 470 | Epoetin alfan = 469 | DifferenceEPO-placebo |
| Died within 4 mo, n (%) | 16 (3) | 41 (9) | 25 |
| Investigator attributed |  |  |  |
| 	Disease progression | 13 | 28 | 15 |
| 	Thrombotic vascular event |   1 |   5 |   4 |
| 	Chemotherapy toxicity |   1 |   3 |   2 |
| 	Missing/other |   1 |   5 |   4 |
| Retrospective chart review |  |  |  |
| 	Disease progression | 10 | 21 | 11 |
| 	Thrombotic vascular event |   2 | 11 |   9 |
| 	Chemotherapy toxicity |   1 |   2 |   1 |
| 	Missing/other |   3 |   7 |   4 |

**Table 6 BD**

**Intent-to-treat population.**

## Studies Beyond Correction of Anemia Time to Disease Progression EPO-INT-76

| 454 | 445 | 425 | 400 | 368 | 338 | 314 | 297 | 284 | 274 | 261 | 247 | 194 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 445 | 437 | 411 | 386 | 361 | 332 | 311 | 288 | 269 | 248 | 239 | 227 | 188 |

| At-risk pts |
| --- |
| Placebo |
| Epoetin |

**Time, mo**

**25**

**	****   ****N ****	****  CR/PR, %****	****Hazard ratio (95% CI)**
**Placebo****	****    454****	****46****	**** 0.97 (.82, 1.14)**
**Epoetin alfa****	****   445****	****45**

**Intent-to-treat population**

***P***** = .71**

## Studies Beyond Correction of Anemia ConclusionsEPO-INT-76

**Survival disadvantage observed in ****treatment group**
**Reasons for outcome not well understood, despite extensive investigation and analysis of data**
**Investigators attributed a greater number of deaths to disease progression in the ****epoetin alfa arm, yet, reported TTP and ****CR/PR are similar**
**Other possible explanations for outcome merit consideration**
**Excess mortality due to TVEs**

## Today’s Agenda

**Evaluation of Studies ****	****Dr. Peter Bowers**
**Supportive Anemia Care**
**Beyond Correction of Anemia**
**Preclinical Background**
**EPO-INT-76**
**Other Studies**
**Future Clinical Data ****	****Dr. Martine George**
**Conclusions****	****Dr. Martine George**

## Studies Beyond Correction of Anemia—  Summary of Design Features

|  | Cancertherapy | Hemoglobin, g/dL |  |
| --- | --- | --- | --- |
| Tumor type (study) |  | Initiate | Target |
| Completed or in follow-up |  |  |  |
|    MBC (EPO-INT-76) | CT | 13 | 12 - 14 |
|    SCLC (N93-004) | CT |    14.5 | 14 - 16 |
|    H&N (EPO-GBR-7) | RT | 15 | 12.5 - 15 |
|    Cervical (AGO/NOGGO) | CT+RT | 14 | 12.5 - 13.5 |
| Discontinued |  |  |  |
|    SCLC (EPO-CAN-15) | CT+RT | 14 |   14 - 16 † |
|    NSCLC (EPO-CAN-20) | ±CT | 12 | 12 - 14 |
|    H&N (RTOG-99-03) | RT (+CT) |    13.5 | 12 - 16 |
|    Cervical (GOG-0191) | CT+RT | 12 |  13 |
|    Gastric, rectal (PR00-03-006) | CT+RT | 15 |  14 - 15 |

**†****Pre-amendment.**

## Studies Beyond Correction of Anemia—Analysis of Mortality Outcomes

|  | Mortality, n/N (%) |  |
| --- | --- | --- |
| Tumor type (study) | Control | Epoetin alfa |
| Completed or in follow-up |  |  |
| MBC (EPO-INT-76) | 115/470   (24)    | 148/469   (30)† |
| SCLC (N93-004) | 101/115   (88) | 100/109   (92) |
| H&N (EPO-GBR-7) |   50/149   (34) |   52/151   (34) |
| Cervical (AGO/NOGGO) |   23/116   (20) |   16/113   (14) |
| Discontinued |  |  |
| SCLC (EPO-CAN-15) |     10/53   (19) |     21/53   (40) |
| NSCLC (EPO-CAN-20) |     20/31   (65) |     25/31   (81) |
| H&N (RTOG-99-03) |     12/68   (18)     |     17/67   (25)   |
| Cervical (GOG-0191) |       9/55   (16)         |       8/58   (14) |
| Gastric, rectal (PR00-03-006) |       1/31     (3) |       0/28     (0) |

**†****Based on Kaplan-Meier estimates.**

## Studies Beyond Correction of Anemia No Evidence of Tumor Proliferation/Response

| Tumor type (study) | N | Endpoint | Control vs EPO |
| --- | --- | --- | --- |
| Completed or in follow-up |  |  |  |
|    MBC (EPO-INT-76) | 939 | CR+PR, % | 46 vs 45 |
|    SCLC (N93-004) | 224 | CR+PR, % | 67 vs 72 |
|    H&N (EPO-GBR-7) | 109 | 2-yr local DFS, % | 85 vs 93 |
|    Cervical (AGO/NOGGO) | 229 | DFS (126 wk), % | 73 vs 83 |
| Discontinued |  |  |  |
|    SCLC (EPO-CAN-15) | 106 | Median TTP (days) | 419 vs 467 |
|    NSCLC (EPO-CAN-20) | 62 | — | — |
|    H&N (RTOG-99-03) | 117 | 1-yr local PFS, % | 65 vs 60 |
|    Cervical (GOG-0191) | 113 | Progression free, % | 82 vs 83  |
|    Gastric, rectal (PR00-03-006) | 60 | — | — |

## Studies Beyond the Correction of AnemiaClinically Relevant TVEs

|  | Patients with TVEs, n/N (%) |  | Difference, %EPO-control |
| --- | --- | --- | --- |
| Tumor type (study) | Control | Epoetin alfa |  |
| SCLC (EPO-CAN-15) |     2/52 (4) |   16/52 (31) | 27 |
| Gastric, rectal (PR00-03-006) |     2/31 (6) |     6/28 (21) | 15 |
| Cervical (GOG-0191) |     5/55 (9) |   10/58 (17) |   8 |
| SCLC (N93-004) | 11/115 (10) | 12/109 (11) |   1 |
| MBC (EPO-INT-76) | 25/456 (5) | 36/448 (8) |   3 |
| H&N (EPO-GBR-7) |   2/149 (1) |   4/133 (3) |   2 |
| NSCLC (EPO-CAN-20) | 2/31 (6) |     1/31 (3) | –3 |
| Cervical (AGO/NOGGO) |   3/122 (2) |   2/119 (2) | 0 |
| H&N (RTOG-99-03) |     0/68 (0) |     1/67 (1) |   1 |

## Supportive Anemia Care - Clinically Relevant TVEs Consistent With Known Risks

**Overall odds ratio (95% CI): 1.55 (0.96, 2.50)**

|  | Patients with TVEs, n/N (%) |  | Difference, %
EPO-placebo |
| --- | --- | --- | --- |
| Tumor type (study) | Placebo | Epoetin alfa |  |
| Mixed (cisplatin) |   8/65 (12) |     6/67 (9) | –3 |
| MM (EPO-INT-2) |   1/76 (1) |     5/69 (7) |   6 |
| CLL (J89-040) |   2/79 (3) |   9/142 (6) |   3 |
| Mixed (EPO-INT-3) |   1/65 (2) |   8/135 (6) |   4 |
| Mixed (EPO-INT-10) | 5/124 (4) | 14/251 (6) |   2 |
| Mixed (PR98-27-008) | 6/165 (4) |   9/168 (5) |   1 |
| Mixed (non-cisplatin) |   3/76 (4) |     2/81 (2) | –2 |
| Ovarian (EPO-INT-1) |   1/80 (1) |   3/164 (2) |   1 |
| Mixed (non-chemo) |   0/59 (0) |     1/65 (2) |   2 |
| CLL (P-174) |   0/12 (0) |     0/33 (0) |   0 |

## Evaluation of Safety Conclusions

**In supportive anemia care, data and extensive clinical experience support favorable benefit/risk profile**
**No signal of tumor proliferation**
**In investigational studies beyond correction of anemia, adverse outcomes have been seen**
**Signal in overall survival in some studies**
**Lack of clear signal regarding tumor proliferation**
**Increased incidence of TVEs in studies of ****epoetin alfa beyond correction of anemia**
**Additional data being collected, new trial under discussion**