# Presentation: 672018

## Presented by Yong-Cheng Wangat the27 July 2004meeting of the Oncologic Drugs Advisory Committee

## Efficacy Analyses– Alimta (NDA 21-677) Review

## Outline 

-     Protocol specified primary endpoint analyses
-     Post-hoc non-inferiority analysis of 50% retention
-     Critical issues in Study JMEI
-     Secondary endpoint analyses
-     Efficacy conclusions

## Protocol Specified Study Objectives 

-     **Primary Objective**:
-      Superiority test to determine whether Alimta
-      is more effective than Docetaxel.
- Ha1:  HR(alimta/docetaxel) < 1
-     **Co-Primary Objective**:
-      Fixed margin non-inferiority (NI) test if the
-      superiority test failed.
- Ha2:  HR(alimta/docetaxel) < 1.11

## Protocol Specified Primary Endpoint (OS) Analysis for ITT Population

|  | Survival Analysis for ITT Patients |  |
| --- | --- | --- |
|  | Alimta (N=283) | Docetaxel (N=288) |
| Events | 206 | 203 |
| Overall Survival (month)
    median (95% CI) | 
8.3 (7.0, 9.4) | 
7.9 (6.3, 9.2) |
| Superiority test
    p-value (log-rank) | 
0.930 |  |
| 1.11 Fixed margin NI test
    p-value
    HR (95% CI of HR) | 
0.256
0.99 (0.82, 1.20) |  |

- ITT: All randomized patients

## Protocol Specified Primary Endpoint (OS) Analysis for RT Population

|  | Survival Analysis for ITT Patients |  |
| --- | --- | --- |
|  | Alimta (N=265) | Docetaxel (N=276) |
| Events | 192 | 198 |
| Overall Survival (month)
    median (95% CI) | 
8.4 (7.4, 9.4) | 
8.0 (6.7, 9.2) |
| Superiority test
    p-value (log-rank) | 
0.765 |  |
| 1.11 Fixed margin NI test
    p-value
    HR (95% CI of HR) | 
0.188
0.97 (0.80, 1.18) |  |

- RT: All randomized and treated patients

## Post-hoc NI Hypothesisof 50% Retention

-     **Post-hoc NI Hypothesis of 50% Retention**:
-      To test that Alimta can retain 50% of control
-      (Docetaxel) effect.
- Ha3:  log HR(alimta/docetaxel) <
-          (0.5) log HR(BSC/docetaxel)

## Critical Issues in Study JMEI

- Docetaxel effect can not be estimated from one small historical.
- Can not assure the ability to repeat the results.
- Can not reliably assess the magnitude of the Docetaxel effect.
- Crossover of Alimta to Docetaxel.

## Historical Trial (TAX317) Used for Estimation of Control Effect

|  | Survival Analysis for ITT Patients* |  |
| --- | --- | --- |
|  | Docetaxel (N=55) | BSC (N=49) |
| Overall Survival (month)
    median (95% CI) | 
7.5 (5.5, 12.8) | 
4.6 (3.7, 6.1) |
| Superiority test
    p-value (log-rank)
    HR(Docetaxel/BSC)
    95% CI of HR | 
0.01
0.56
(0.35, 0.88) |  |

- *  Survival data for RT population is not available.

## Crossover of Alimta to Docetaxel

|  | Treatment Crossover for ITT Patients |  |
| --- | --- | --- |
|  | Alimta (N=283) | Docetaxel (N=288) |
| No post-study chemotherapy
    Number of patients (%)
    Median OS (m) (95% CI) | 
151 (53.4)
5.8 (4.5, 7.4) | 
181 (62.8)
4.9 (4.1, 6.2) |
| Post-study Docetaxel therapy
    Number of patients (%)
    Median OS (m) (95% CI) | 
90 (31.8)
9.5 (8.4, 10.2) | 
11 (3.8)
10.1 (7.9, 19.5) |
| Other post-study chemo Rx
    Number of patients (%)
    Median OS (m) (95% CI) | 
42 (14.8)
10.6 (7.8, 14.1) | 
96 (33.3)
11.2 (9.3, 13.9) |

## Exploratory Analyses of Secondary Endpoints

## Survival Rate for ITT Population

| 

Survival at | Alimta
(N=283)
n (%) | Docetaxel
(N=288)
n (%) | 
Relative Risk (95% CI) |
| --- | --- | --- | --- |
| 6 months | 181 (64.0) | 171 (59.4) | 1.08 (0.95, 1.23) |
| 12 months | 99 (35.0) | 107 (37.2) | 0.94 (0.76, 1.17) |
| 18 months | 77 (27.2) | 88 (30.6) | 0.89 (0.69, 1.15) |
| 24 months | 77 (27.2) | 85 (29.5) | 0.92 (0.71, 1.20) |

## Time to Progressive Disease

|  | ITT Population |  |
| --- | --- | --- |
|  | Alimta
(N=283) | Docetaxel
(N=288) |
| Median (month)
Range | 3.4
0.5 – 18.2 | 3.5
0.3 – 19.5 |
| Percent patients with progressive disease
    3 months
    6 months
    9 months | 
47.8
70.6
79.9 | 
45.0
70.9
81.8 |
| Hazard ratio (95% CI)
p-value (Wald) | 0.97 (0.80, 1.17)
0.721 |  |

## Progression-Free Survival

|  | ITT Population |  |
| --- | --- | --- |
|  | Alimta
(N=283) | Docetaxel
(N=288) |
| Median (month)
Range | 2.9
0 – 18.2 | 2.9
0 – 19.5 |
| Percent patients with progressive disease
    3 months
    6 months
    9 months | 
54.7
76.8
87.0 | 
52.7
76.7
87.7 |
| Hazard ratio (95% CI)
p-value (Wald) | 0.97 (0.82, 1.16)
0.759 |  |

## Tumor Response (Investigator-Determined) for Qualified Population

| 
Classification | Alimta
(N=264) | Docetaxel
(N=274) | p-value
(Fisher) |
| --- | --- | --- | --- |
| Response (%)
95% CI for response rate
    CR (%)
    PR (%)
    PRNM (%)
 Stable disease (%) | 24 (9.1)
(5.9, 13.2)
1 (0.4)
20 (7.6)
3 (1.1)
121 (45.8) | 24 (8.8)
(5.7, 12.8)
0
24 (8.8)
0
127 (46.4) | > 0.999

0.491
0.732
0.118
0.931 |

- Relative Risk (95% CI) for response = 1.04 (0.60, 1.78)

## Efficacy Conclusions

- Study JMEI was a single, randomized, open-label, multi-center trial in advanced NSCLC patients treated with Alimta vs. Docetaxel.
- Study JMEI failed to demonstrate superior efficacy of Alimta to Docetaxel.
- Study JMEI also failed to demonstrate NI of Alimta to Docetaxel.

## Efficacy Conclusions

- The estimate of Docetaxel effect based on a single small historical trial is neither reliable nor robust.
- In the presence of crossover from Alimta to Docetaxel, the survival results are confounded and NI analysis is very difficult to interpret.
- The result of 50% retention NI analysis is not  interpretable.