**Food and Drug Administration**

Center for Drug Evaluation and Research

Oncologic Drugs Advisory Committee

*[Questions for Discussion]{.underline}*

[Background]{.underline}

A randomized controlled unblinded trial was conducted in 571 patients
with locally advanced or metastatic non-small cell lung cancer after
prior chemotherapy comparing Alimta with docetaxel. The primary
objectives were 1) to show Alimta\'s superiority to docetaxel for
overall survival and 2) to show Alimta\'s non-inferiority to docetaxel
for overall survival if there was failure to show superiority. The
efficacy results are summarized in the following Table.

+----------------+----------+-------------+-------------+-------------+
|                | ITT^a^   |             | RT^b^       |             |
+----------------+----------+-------------+-------------+-------------+
|                | Alimta   | Docetaxel   | Alimta      | Docetaxel   |
+----------------+----------+-------------+-------------+-------------+
| Resp Rate (%)  |          |             | 9.1         | 8.8         |
|                |          |             |             |             |
| (95% CI)       |          |             | (5.9, 13.2) | (5.7, 12.8) |
+----------------+----------+-------------+-------------+-------------+
| P-val          |          |             | .999        |             |
| (Fisher)^c^    |          |             |             |             |
+----------------+----------+-------------+-------------+-------------+
| Resp Duration  |          |             | 4.6         | 5.3         |
|                |          |             |             |             |
| (median)^d^    |          |             |             |             |
+----------------+----------+-------------+-------------+-------------+
| PFS            | 2.9      | 2.9         | 2.9         | 3.0         |
| (median)^d^    |          |             |             |             |
+----------------+----------+-------------+-------------+-------------+
| HR (95% CI)    | .97      |             | .98         |             |
|                | (.       |             | (.82,1.17)  |             |
| p-val          | 82,1.16) |             |             |             |
| (Wald)^c^      |          |             | .821        |             |
|                | .759     |             |             |             |
+----------------+----------+-------------+-------------+-------------+
| TTP            | 3.4      | 3.5         | 3.1         | 3.5         |
| (median)^d^    |          |             |             |             |
+----------------+----------+-------------+-------------+-------------+
| HR (95% CI)    | .97      |             | 1.  (.83,   |             |
|                | (.80,    |             |     1.22)   |             |
| p-val          | 1,17)    |             |             |             |
| (Wald)^c^      |          |             | .951        |             |
|                | .721     |             |             |             |
+----------------+----------+-------------+-------------+-------------+
| OS (median)^d^ | 8.3      | 7.9         | 8.4         | 8.0         |
+----------------+----------+-------------+-------------+-------------+
| HR (95% CI)    | .99      |             | .97 (.80,   |             |
|                | (.82,    |             | 1.18)       |             |
| p-val          | 1.20)    |             |             |             |
|                |          |             | .765        |             |
| (log rank)^c^  | .930     |             |             |             |
+----------------+----------+-------------+-------------+-------------+

^a^Intent to Treat

^b^Randomized and Treated

^c^All p-values two-sided

^d^Months

The FDA believes Alimta non-inferiority for overall survival can not be
demonstrated for two reasons. First, there is only one small historical
study (total 104 patients) from which to estimate the survival effect of
docetaxel, resulting in inability to estimate the docetaxel effect with
precision, to evaluate interstudy variability and to assess constancy. A
meta-analysis of multiple historical studies is ordinarily required for
a

**Food and Drug Administration**

Center for Drug Evaluation and Research

Oncologic Drugs Advisory Committee

*[Discussion Questions Continued]{.underline}*

non-inferiority analysis. Second, in the Alimta versus docetaxel study
comparison of survival effect is confounded by the 32% crossover rate of

Alimta patients to docetaxel after tumor progression and the greater
number of docetaxel patients who did not receive any post study
chemotherapy.

In the Alimta versus docetaxel study the Alimta 9.1% tumor response rate
provides evidence of some Alimta anticancer activity and the similarity
of Alimta and docetaxel in PFS and TTP provides some support for Alimta
efficacy. If these were taken as surrogate effects reasonably likely to
predict benefit and if Alimta had a documented safety advantage over
docetaxel, accelerated approval could be a possibility.

[Questions]{.underline}

1.  Do you believe Alimta has a more favorable toxicity profile than

> docetaxel?

2.  If the answer is yes, does the more favorable Alimta toxicity
    profile with supporting efficacy data on tumor response and PFS
    outweigh the uncertainty regarding loss of docetaxel survival effect
    by using Alimta?

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3.  Given the potential confounding effects of cross-over,

> and problems in estimating the control effect, is there a
>
> convincing effect on survival to warrant regular approval?

2