FOOD AND DRUG
ADMINISTRATION
Center for Drug
Evaluation and Research
Oncologic Drugs Advisory
Committee Meeting
Questions
to the Committee
NDA
21-649 Genasense (Oblimersen sodium), Genta, Inc.
Indication Genasense in combination with dacarbazine is
indicated for the treatment of patients with advanced melanoma who have not
received prior chemotherapy.
Genta
has submitted a single, international, multi-center, unblinded, active control,
randomized, phase 3 study (GM301) of Genasense plus dacarbazine (DTIC) versus
DTIC alone every three weeks as first-line chemotherapy for metastatic
melanoma, along with a small, supportive, single arm, phase 1/2 study with
various doses and schedules of Genasense plus DTIC. In the phase 3 study, Genasense
was given as a continuous intravenous (IV) infusion over 5 days, requiring
central venous access and an ambulatory pump. DTIC 1000 mg/m2 IV was given over
60 minutes once every three week cycle in each study arm.
The primary endpoint of
the trial was survival. Secondary endpoints were progression-
free survival (PFS),
response rate (RR), response duration, performance status, tumor-related symptoms,
and safety.
The
results from the phase 3 study submitted for efficacy are presented in the
table below.
GM301
results
Endpoint |
Genasense + DTIC (N=386) |
DTIC alone (N=385) |
Hazard Ratio |
p-value |
Survival |
274 days |
238 days |
0.89 |
0.18 |
PFS* |
61 days |
48 days |
0.75 |
0.006 |
Response Rate by
Investigators |
11.7% |
6.8% |
|
0.019 |
Response Rated
Confirmed by Independent Review
Committee |
6.7% |
3.6% |
|
0.056 |
* PFS by censoring on the date of the last
complete evaluation.
Reviewer’s Table
Genta proposes that these study results be considered evidence of
effectiveness. FDA has a number of important concerns. First, the study clearly did not show the
improvement in survival that was the stated endpoint. Second, the PFS endpoint
although nominally improved by Genasense + DTIC has two important problems.
First the effect is very small, well under one month. Second in an open study,
there is concern that critical decisions such as when to obtain radiological
films, could be biased. In this study lesion assessments were done earlier in
the DTIC alone group (p < 0.001). This could lead to earlier documentation of
progression. Thus, it is a concern whether the observed difference is real. Except possibly for response rate, no other secondary
endpoints demonstrated an advantage of Genasense + DTIC over DTIC alone. Furthermore,
it is not clear that the small difference in PFS observed
is clinically meaningful, especially in view of the observed Genasense toxicity.
A recent ODAC consideration of temozolomide
(TMZ) for the treatment of metastatic melanoma (NDA 21-051) appears pertinent. As
in the present application only one phase 3 trial was submitted in support of
the indication. The median survival on the DTIC arm was 6.4 months versus 7.7
months for TMZ, a difference in median survival of 1.3 months. Although 80% of
the events had occurred by the time of the analysis, the difference was not
statistically significant (p=0.2). A
post-hoc analysis suggested an improvement in survival at 6 months (61% for
temozolomide versus 51% for DTIC, p=0.063), but the Committee did not consider
this post-hoc finding to be convincing. Additional secondary endpoints reviewed
were response rate and PFS. The Agency’s analysis showed that median PFS was
1.74 months for TMZ versus 1.38 months for DTIC, a difference of less than a
month, but statistically significant (p=0.002). Additional post-hoc exploratory
analyses included possible prolongation in PFS for some patients in the third
quartile of the survival curve before the curves came together again at 14
months. No symptomatic benefit was identified in association with this
difference. The Agency compared response rates for the 2 arms; the ORR for TMZ
was 12.2% (2.6% CR), versus 9.4% for DTIC (2.7% CR).
During
the Advisory Committee meeting, members considered two questions with regard to
the Temozolomide application. The questions were:
1) Do the results of this
study, particularly the objective tumor response rates and response durations
for the temozolomide versus dacarbazine, and the effect on progression-free
survival, even in the absence of any effect on survival provide substantial
evidence of effectiveness?
2) Does the Committee
recommend approval of temozolomide for the treatment of advanced metastatic
melanoma?
The
vote on the first question was 10 No and one abstention. On the second question
the vote was 10 No and 1 Yes.
TMZ, thus, was not recommended for approval because
the trial did not show superiority in survival to DTIC alone. The small but
statistically significant difference in PFS
(p = 0.002) and slightly higher response rate,
in the absence of any evidence of survival or symptomatic benefit, were not
thought to represent a meaningful benefit.
Page 2.
In the recent case for Genasense, the GM301
study failed to demonstrate an effect on survival, the primary trial
endpoint. No effects were seen on
performance status or tumor-related symptoms, and there was greater toxicity on
the Genasense arm. The PFS improvement was significant but the difference was
very small and there may have been a difference in progression ascertainment
that favored Genasense. Similarly, a small increase in response rate increment
attributed to Genasense is somewhat uncertain because a central reading
(potentially, particularly important in an open study) showed no significant
difference. We would like the panel to comment on whether improvement in PFS
and RR of this magnitude, apart from not being clearly identified planned study
endpoints and any reservations about the validity of the findings, would represent a benefit both on the
persuasiveness of the PFS and RR findings and one that would outweigh the
increase in toxicity seen with the combination. No evidence from this study suggests
that changes of this size represent or are likely to predict clinical benefit,
but that is an issue that bears discussion.
Questions:
1.
Given the concerns noted above, does the committee believe that
the small observed differences in the response rates (< 5%) and in PFS (difference
in median days between arms -13 days, p = 0.006) represent real effects of
Genasense, when added to DTIC?
2.
Do the results of this study, in particular the small difference
in RR (<5%) and / or PFS for the combination of Genasense + DTIC versus DTIC
alone, in the absence of a survival improvement, provide substantial evidence
of effectiveness that outweighs the increased toxicity of administering the
Genasense for the treatment of patients with metastatic melanoma who have not
received prior chemotherapy?
3.
For regular approval of a drug for metastatic melanoma, the FDA
has considered an improvement in survival and/or disease symptoms to constitute clinical benefit. However, in the December ODAC discussion,
considerable interest was expressed in PFS as an endpoint in some settings,
particularly where crossover to other treatment could obscure a potential
survival benefit. In the metastatic melanoma setting, do you believe that a PFS
benefit of some magnitude represents clinical benefit that could support
regular drug approval, even in the absence of an effect on survival?
4.
If yes, please discuss what
magnitude of improvement in this endpoint would be required to demonstrate
clinical benefit and whether this would depend on the toxicity of the treatment?
Page 3.