# Presentation: 699245

## FDA PresentationNDA  21-661RSR13(efaproxiral sodium)

**Oncology Drug Advisory Committee Meeting**
**May 3, 2004**

## Review Team

- Chemistry
- Josephine Jee, Ph.D.
- Hasmukh Patel, Ph.D.
- Pharmacology
- Anwar  Goheer, Ph.D.
- John Leighton, Ph.D.
- Biopharmaceutics
- Atul Bhattaram, Ph.D.
- Joga Gobburu, Ph.D.
- Atiq Rahman, Ph.D.
- Microbiology
- Vinnie Pawar, Ph.D
- Peter Cooney, Ph.D.

- Statistics
- Rajeshwari Sridhara, Ph.D.
- Kooros Mahjoob, Ph.D.
- Clinical
- Kevin Ridenhour, M.D.
- Ramzi Dagher, M.D.
- Project Manager
- Christy Cottrell

## Outline	

-  **Background**
** ****Description of Clinical Trials**
** ****Results of RT-009**
**Demographics**
**Efficacy**
**Safety**
**Conclusions**

## Proposed Indication

-    **Adjunctive therapy to whole brain radiation for the treatment of brain metastases originating from breast cancer.**

## RT-009: Regulatory History

**June 13, 1995: IND 48,171 submitted to FDA.**
**June 19, 2003: Discussed concerns with the applicant regarding findings in the non-prespecified subgroup of patients with breast cancer.   **
**July 25, 2003: Pharmacology data was submitted as the first component of a rolling NDA.**
**December 4, 2003: Clinical and Statistical components submitted to finalize NDA submission.**

## Description of Clinical Trials

**RT-009****: A randomized, open-label study of standard WBRT/oxygen, with or without RSR13, in patients with brain metastases.**
**Control arm N = 267; RSR13 arm N= 271  **
**RT-008****: A single-arm study of RSR13 administered to patients receiving standard WBRT with oxygen for brain metastases.**
**N = 69**

## RT-009: Treatment Plan

_**RSR13 arm**_
**100 or 75 mg/kg central IV infusion over 30 minutes daily within 30 minutes of WBRT **
**WBRT given as 30 Gy in 10 fractions.**
_**Control arm**_
** ****WBRT given as 30 Gy in 10 fractions.**
**4L/min supplemental oxygen (both arms) **
**35 minutes prior to, during, and for at least 15 minutes after completion of WBRT.**

## RT-009: Endpoints

**Primary: Survival**
**Overall Population (protocol version #1)**
**NSCLC/Breast Subgroup (amendment #2)**
**Secondary Endpoints**
**Time to Radiographic Tumor Progression in the Brain**
**Time to Clinical Tumor Progression in the Brain**
**Response Rate in the Brain**
**Cause of Death**
**Quality of Life**

## RT-009: Eligibility Criteria 

**KPS > or = to 70**
**Radiographic studies consistent with brain metastases**
**Resting / exercise SpO2 > 90% (room air)**
**Concurrent corticosteroid therapy allowed**
**Cytologically confirmed primary malignancy (small cell carcinoma, germ cell and lymphomas were excluded)**

## RT-009: Tumor Histology 

| 

Histology | 
Control
267 patients
N (%) | 
RSR13
271 patients
N (%) |
| --- | --- | --- |
| NSCLC

Breast

Other:
               Melanoma
               Colorectal
               Renal cell | 151 (56)

55 (20)

61 (23)
16 (6)
10 (4)
6 (2) | 148 (55)

60 (22)

63 (23)
22 (8)
9 (3)
10 (4) |

## Post-Randomization Systemic Treatment(RT-009 Overall Population)

| 
Treatment Type | Control
267 patients
N (%) | RSR13
271 patients
N (%) |
| --- | --- | --- |
| Surgical resection | 9 (3) | 8 (3) |
| Radiation therapy | 81 (30) | 89 (33) |
| Chemotherapy | 91 (34) | 105 (39) |
| Hormonal therapy | 14 (5) | 20 (7) |

## Post-Randomization Systemic Therapy(RT-009 Breast Subgroup)

| 
Treatment Type | Control
55 patients
N (%) | RSR13
60 patients
N (%) |
| --- | --- | --- |
| Surgical resection | 4 (7) | 2 (3) |
| Radiation therapy | 13 (24) | 18 (30) |
| Chemotherapy | 25 (45) | 32 (53) |
| Hormonal therapy | 13 (24) | 18 (30) |

## RT-009: Number of Brain Lesions at Baseline (Overall Population)

| 

Number of
Brain
Lesions | 

N | 

Control
261 patients
N (%) | 

RSR13
265 patients
N (%)
 |
| --- | --- | --- | --- |
| 1 | 98 | 53 (26) | 45 (17) |
| 2-3 | 162 | 81 (31) | 81 (31) |
| >3 | 266 | 127 (49) | 139 (52) |

## RT-009: Number of Brain Lesions by Primary Site 

| 
Primary
Site | 
Number of
brain mets | 
Control
 | 
RSR13
 |
| --- | --- | --- | --- |
| Breast
N (%) | 1
2-3
>3 | 7 (13)
9 (16)
40 (71) | 13 (22)
14 (24)
31 (53) |
|  |  |  |  |
| NSCLC
N (%) | 1
2-3
>3 | 35 (23)
51 (34)
64 (43) | 24 (16)
53 (36)
71 (48) |
|  |  |  |  |
| Other
N (%) | 1
2-3
>3 | 11 (20)
21 (38)
23 (42) | 8 (14)
14 (24)
37 (63) |
|  |  |  |  |

## RT-009: Analysis of Survival

**No survival advantage demonstrated in the overall population (p = 0.1688, logrank)**
**No survival advantage in the NSCLC/Breast**
**    ****co-populations (p= 0.1217, logrank) **
**A survival advantage was seen in a non-prespecified breast population considered exploratory at this time (p = 0.0061, logrank)**

## RT-009: Response Rates in the Brain According to Applicant (Overall Population)

| 

Response | Control
267 patients |  | RSR13
271 patients |  |
| --- | --- | --- | --- | --- |
|  | Total
N (%) | “Confirmed”
N (%) | Total
N (%) | “Confirmed”
N (%) |
| CR
 | 16 (6) | 12 (4) | 28 (10) | 17 (6) |
| PR
 | 84 (31) | 31 (12) | 95 (35) | 44 (16) |
| CR + PR
 | 100 (37) | 43 (16) | 123 (45) | 61 (22) |
| 95% confidence interval | (33, 41)  | (12, 21) | (39, 52)  | (18, 28) |

## Cause of Death(RT-009 Overall Population)

| 
Cause of Death | Control
267 patients
N (%) | RSR13
271 patients
N (%) | Total
538 patients
N (%) |
| --- | --- | --- | --- |
| Neurologic | 34 (13) | 36 (13) | 70 (13) |
| Non-neurologic | 128 (48) | 128 (47) | 256 (47) |
| Indistinguishable | 58 (22) | 53 (19) | 111 (20) |
| Alive/NA | 47 (18) | 53 (19) | 100 (18) |
| Unknown | 0 | 1 | 1 |

## RT-009: Steroids Received(Overall Population)

| 
Steroids Administered | Control
267 patients
N (%)
 | RSR13
271 patients
N (%) |
| --- | --- | --- |
| Yes | 257 (96) | 256 (94) |
| No | 10 (4) | 15 (5) |

## RT-009: Response Rate in the Brain According to Applicant

**Given that there is no apparent advantage in response rate in the brain with RSR13, WBRT and oxygen vs. WBRT/oxygen, there does not appear to be a contribution of RSR13 to tumor response.**
**More than 90% of patients in both arms received steroids.**
**Response duration cannot be assessed since confirmatory imaging studies were not required.**
**The designation of CR/PR was given irrespective of the appearance of a new brain parenchymal lesion.**

## RT-009: Other Secondary Endpoints

**No statistically significant difference between the control arm and RSR13 arm in:**
**Time to radiographic tumor progression in the brain.**
**Time to clinical tumor progression in the brain. **
**Quality of life.**

## RT-008

**N = 69:  Lung, breast, melanoma, “other”**
**Median survival 6.4 months**
**Response rate in the brain of 29% **

## RT-009: RSR13 and Radiation Exposure

**RSR13 exposure was similar in the Overall Population and NSCLC/Breast populations**
**Radiation exposure was similar in the Overall Population and NSCLC/Breast populations  **
**The FDA was able to reproduce the applicant’s analyses for RSR13 and radiation exposure **

## Oxygen Exposure for the Overall Population (RT-009)

| 
Exposure
Variable | 
Statistic | 
Control
267 patients | 
RSR13
271 patients |
| --- | --- | --- | --- |
| 
Duration of 
O2 Delivered
(Hours/day) | 
Mean

SD

Min/Max | 
1.1

0.3

0.5 / 5.3 | 
2.2

5.8

0.2 / 207.5 |

## RT-009: All Grade Treatment-Emergent Adverse Events

|  | Control
264 patients
N (%) | RSR13
268 patients
N (%) |
| --- | --- | --- |
| Hypoxemia | 10 (4) | 109 (41) |
| Hypotension | 3 (1) | 36 (13) |
| Vomiting | 45 (17)
80 (30) | 102 (38)
124 (47) |
| Nausea | 
 |  |
| Headache | 86 (33) | 126 (47) |
| Fatigue | 114 (43) | 131 (49) |
| Anemia | 14 (5) | 33 (12) |
| Taste perversion | 11 (4) | 33 (12) |

## RT-009: Grade 3 / 4 Adverse Events

|  | Control
264 patients
N (%)
 | RSR13
268 patients
N (%) |
| --- | --- | --- |
| Hypoxia | 6 (2) | 30 (11) |
| Dyspnea | 19 (7) | 8 (3) |
| Headache | 11 (4) | 18 (7) |
| Pneumonia | 7 (3) | 14 (5) |
| Hypotension | 1 (<1) | 5 (2) |
| Acute renal failure | 1 (<1) | 6 (2) |
| Cerebral edema | 1 (<1) | 4 (1) |

## Conclusions

**No survival advantage demonstrated for the RSR13 arm vs. control arm in RT-009.**
**No advantage demonstrated for RSR13 vs. control in secondary endpoints.**
**Most common all grade treatment adverse events included hypoxia, hypotension, nausea, vomiting, and headache.**
**The exploratory analysis demonstrating a survival advantage in the breast cancer subgroup is being further evaluated in a randomized study. **

## Statistical Review of Efficacy

## Areas of Major Statistical Issues

- Overall Finding (ITT Population)
- Subgroup Findings
- NSCLC/Breast Primary Subgroup
- Breast Primary Subgroup
- Multiplicity

## Overall Finding

- 1. Evidence of Efficacy
- 2. Multiple Survival Analyses
- 3. Internal Consistency

## Evidence of Efficacy in ITT Population

|  | NDA Analysis* | Updated Analysis** |
| --- | --- | --- |
| # of Deaths
WBRT
RSR13 + WBRT | 
221 / 267
220 / 271 | 
247 / 267
249 / 271 |
| Med. Survival
WBRT
RSR13 + WBRT | 
4.5 months
5.3 months | 
4.5 months
5.3 months |
| HR | 0.877 
(0.727, 1.057) | 0.874
(0.732, 1.042) |
| P-value*** | 0.1688 | 0.1333 |

## Evidence of Efficacy in ITT (Contd.)

- *NDA Analysis as of January 31, 2003
- **Updated Analysis as of January, 2004
- ***P-values from comparison of survival distributions using log-rank test.  **Not adjusted for Multiple Looks.**
**	****P-values should not be compared to 0.05**

## Adjusted Analyses

- ICH E-9 Guidelines, Section 5.7:  Subgroups, Interactions and Covariates:
- ‘ When the potential value of an adjustment is in doubt, it is often advisable to nominate the unadjusted analysis as the one for primary attention, the adjusted analysis being supportive.’
- ‘ In most cases, however, subgroup and interaction analyses are exploratory and should be clearly identified as such; they should explore the uniformity of any treatment effects found overall.’

## Applicant’s Description

- The primary analysis was clearly stated to be based on unadjusted log-rank test
- in all protocol amendments (in ITT population)
- and in the final statistical analysis plan
- In SAP under the section on covariates:
- “While designated prospectively, supporting analyses should be considered exploratory in nature, and inferences made based on p-values should be done so with caution.  Primary reasons for exploratory analyses are for estimation rather than hypothesis testing”.

## Protocol / SAP Exploratory Analyses

| Protocol Covariates | SAP Covariates |
| --- | --- |
| RPA class
Site of primary cancer
Primary tumor control
Age
Number of Metastatic lesions 
Presence of extracranial metastases
Baseline KPS
 | RPA class
Site of primary cancer
Primary tumor control
Age
Number of extracranial mets
Number of brain mets
Baseline KPS
Baseline cranial tumor area
Baseline weight (gender*weight)
Presence of liver mets
Usage of subsequent tx
Diagnosis timing
Prior treatment to cranial mets
Site location
Altitude
Baseline hemoglobin
Center size |

## Exploratory Covariate Adjusted Analysis

- Covariates Included (protocol listed):
- 	RPA Class (Class 1 = 0 vs. Class 2 = 1)
- 	Breast primary (No breast = 0 vs. Breast = 1)
- 	NSCLC primary (No NSCLC = 0 vs. NSCLC = 1)
- 	Primary control (No = 0 vs. Yes =1)
- 	Age group (< 65 = 0 vs. 65 or older = 1)
- 	Presence of extracranial mets. (No = 0 vs. Yes = 1)
- 	KPS group (90 or greater = 0 vs. < 90 = 1)
- 	Brain lesions (Single = 0 vs. Multiple = 1)

## Exploratory Covariate Adjusted FDA Analysis – Treatment Effect (Control = 0 vs. RSR13 = 1)

| Data Set | HR (95% C.I.) | P-value* |
| --- | --- | --- |
| NDA
  All  (N = 529)
  Eligible (N = 510) | 
0.842 (0.696, 1.019)
0.854 (0.703, 1.038) | 
0.0631
0.1122 |
| Updated
  All  (N = 529)
  Eligible (N = 510) | 
0.858 (0.717, 1.026)
0.871 (0.725, 1.047) | 
0.0938
0.1417 |

- * By Cox model, Not adjusted for multiple analyses

## Summary of Overall Finding

- The Single, Randomized RT-009 Study conducted in patients with brain metastases does not demonstrate substantial evidence of benefit with respect to Survival in the Overall ITT population

## Subgroup Findings

- NSCLC/Breast Primary Subgroup (Specified as co-primary hypothesis during the study)
- Breast Primary Subgroup

## NSCLC/Breast Primary Subgroup Finding

|  | NDA Analysis* | Updated Analysis** |
| --- | --- | --- |
| # of Deaths
WBRT
RSR13 + WBRT | 
167 / 206
164 /208 | 
189 / 206
188 / 208 |
| Med. Survival
WBRT
RSR13 + WBRT | 
4.5 months
5.9 months | 
4.5 months
5.9 months |
| HR | 0.844 
(0.680, 1.048) | 0.837
(0.684, 1.025) |
| P-value*** | 0.1217 | 0.0837 |

## Summary of NSCLC/Breast Primary Subgroup Finding

- The Single, Randomized RT-009 Study conducted in patients with brain metastases does not demonstrate substantial evidence of benefit with respect to Survival in the Subgroup of Patients with NSCLC/Breast Primary Cancer.
- P-values should not be compared to 0.05

## Breast Primary Subgroup Finding

- 1.  Absence of Overall Survival Benefit
- 2.  Very Small Subgroup
- 3.  Imbalances

## Issue 1:  In the absence of overall survival benefit, any subgroup advantage is questionable

- _ICH E-3 Guidelines: Section 11.4.2.8:  Examination of Subgroups:_
- ‘ These analyses are not intended to "salvage" an otherwise non-supportive study but may suggest hypotheses worth examining in other studies or be helpful in refining labelling information, patient selection, dose selection etc***.’***

## Issue 2:  Small Breast Primary Subgroup

| Number of... | WBRT | RSR13 + WBRT |
| --- | --- | --- |
| Total Patients | 55 | 60 |
| Ineligible Patients | 6 / 55 | 2 / 55 |
| Misclassified Patients | 3 / 55 | 4 / 55 |
| Dead in < 1 month | 2 / 55 | 4 / 55 |
| Received 2 doses or less of RSR13 | NA | 6 / 55 |

## Issue 3: Imbalances within Breast Primary Subgroup– Important Factors

| Characteristic | WBRT | RSR13 + WBRT |
| --- | --- | --- |
| Bidirectional Area of Baseline Brain Lesions (mm2) |  |  |
| Mean (S.D.)
Median (Range) | 882 (695)
699 (17 – 3588) | 762 (706)
579 (16 – 2936) |
| Number of Brain Lesions 3 or more | 74.1% | 56.7% |
| Extracranial Mets. 3 or more | 40% | 31.7% |

- None of these were individually statistically significant;
- P-value for Brain lesions (single vs. multiple) = 0.07)

## Exploratory Breast Primary Subgroup Finding

| Data Set | WBRT
(N = 55) | RSR13 + WBRT
(N = 60) |
| --- | --- | --- |
| NDA Data |  |  |
| Median Survival | 4.6 months | 8.7 months |
| HR (95% CI) | 0.552 (0.359, 0.850) |  |
| P-value* (log-rank) | 0.0061 ? |  |
| Updated Data |  |  |
| Median Survival | 4.6 months | 8.8 months |
| HR (95% CI) | 0.632 (0.422, 0.946) |  |
| P-value* (log-rank) | 0.0243 ? |  |

- *P-value not adjusted for multiplicity

## Breast Primary Subgroup Finding

- Imbalances were observed and true finding can not be isolated
- No robustness to the subgroup finding
- P-values not adjusted for multiplicity
- At best Exploratory and Hypothesis Generating

## Multiplicity

**Multiple Hypotheses** (per protocol Amendment 2, two co-primary hypotheses, alpha adjusted using modified Boneferroni, after accounting for one interim analysis)
**Multiple Analyses** of the same hypothesis (at different times, unadjusted and numerous adjusted analyses)
**Multiple Subgroups** (site of primary, diagnosis timing, etc.)

## Results from Single Study Persuasive?

- Inherent variability may produce a positive trial by chance alone (p =0.05 implies 1/40 studies of ineffective drugs will be positive)
- FDA Guidance: ‘it is critical that the possibility of an incorrect outcome be considered and that all the available data be examined for their potential to either support or undercut reliance on a single multicenter trial’
- Statistically Persuasive? – can only be verified by replication

## Review of Results

- Randomized, Controlled, Open-label, Multicenter, **Single** Trial
- Analysis of Primary Endpoint Overall Survival Not Statistically Significant
- No significant difference in the overall ITT population
- No significant difference in the subgroup of patients with NSCLC/Breast primary
- No significant benefit observed in any of the secondary efficacy endpoints

## Review of Results

- Apparent survival benefit in a subset of patients with breast cancer primary is questionable because of:
- Post-hoc, exploratory analysis
- Very small sample size from a single study
- Imbalances possibly influencing treatment effect