FDA Presentation NDA 21-661 RSR13 (efaproxiral sodium)

1
FDA PresentationNDA 21-661RSR13(efaproxiral
sodium)

• Oncology Drug Advisory Committee Meeting
• May 3, 2004

2
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

3
Outline

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

4
Proposed Indication

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

5
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.

6
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

7
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.

8
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

9
RT-009 Eligibility Criteria

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

10
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)
11
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)
12
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)
13
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)
gt3 266 127 (49) 139 (52)
14
RT-009 Number of Brain Lesions by Primary Site
Primary Site Number of brain mets Control RSR13
Breast N () 1 2-3 gt3 7 (13) 9 (16) 40 (71) 13 (22) 14 (24) 31 (53)

NSCLC N () 1 2-3 gt3 35 (23) 51 (34) 64 (43) 24 (16) 53 (36) 71 (48)

Other N () 1 2-3 gt3 11 (20) 21 (38) 23 (42) 8 (14) 14 (24) 37 (63)

15
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)

16
RT-009 Response Rates in the Brain According to
Applicant (Overall Population)
Response Control 267 patients Control 267 patients RSR13 271 patients RSR13 271 patients
Response 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)
17
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
18
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)
19
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.

20
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.

21
RT-008

• N 69 Lung, breast, melanoma, other
• Median survival 6.4 months
• Response rate in the brain of 29

22
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 applicants
  analyses for RSR13 and radiation exposure

23
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
24
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)
25
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 (lt1) 5 (2)
Acute renal failure 1 (lt1) 6 (2)
Cerebral edema 1 (lt1) 4 (1)
26
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.

27
Statistical Review of Efficacy
28
Areas of Major Statistical Issues

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

29
Overall Finding

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

30
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
31
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

32
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.

33
Applicants 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.

34
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 (genderweight) Presence of liver mets Usage of subsequent tx Diagnosis timing Prior treatment to cranial mets Site location Altitude Baseline hemoglobin Center size
35
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 (lt 65 0 vs. 65 or older 1)
• Presence of extracranial mets. (No 0 vs. Yes
  1)
• KPS group (90 or greater 0 vs. lt 90 1)
• Brain lesions (Single 0 vs. Multiple 1)

36
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
37
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

38
Subgroup Findings

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

39
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
40
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

41
Breast Primary Subgroup Finding

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

42
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.

43
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 lt 1 month 2 / 55 4 / 55
Received 2 doses or less of RSR13 NA 6 / 55
44
Issue 3 Imbalances within Breast Primary
Subgroup Important Factors
Characteristic WBRT RSR13 WBRT
Bidirectional Area of Baseline Brain Lesions (mm2) Bidirectional Area of Baseline Brain Lesions (mm2) 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)
45
Exploratory Breast Primary Subgroup Finding
Data Set WBRT (N 55) RSR13 WBRT (N 60)
NDA Data NDA Data NDA Data
Median Survival 4.6 months 8.7 months
HR (95 CI) 0.552 (0.359, 0.850) 0.552 (0.359, 0.850)
P-value (log-rank) 0.0061 ? 0.0061 ?
Updated Data Updated Data Updated Data
Median Survival 4.6 months 8.8 months
HR (95 CI) 0.632 (0.422, 0.946) 0.632 (0.422, 0.946)
P-value (log-rank) 0.0243 ? 0.0243 ?
P-value not adjusted for multiplicity
46
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

47
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.)

48
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

49
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

50
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