DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ONCOLOGIC DRUGS ADVISORY COMMITTEE
Tuesday, July 27, 2004
ACS Conference Room
5630 Fisher Lane
Otis W. Brawley, M.D., Acting Chair
Johanna M. Clifford, M.S., RN, Executive Secretary
Ronald M. Bukowski, M.D.
Bruce D. Cheson, M.D.
James H. Doroshow, M.D.
Stephen L. George, Ph.D.
Antonio J. Grillo-Lopez, M.D.
Pamela J. Haylock, RN
Maha H.A. Hussain, M.D.
Alexandra M. Levine, M.D.
Joanne E. Mortimer, M.D.
Michael C. Perry, M.D.
Maria Rodriguez, M.D.
Ralph D'Agostino, Ph.D.
PATIENT REPRESENTATIVE (Voting)
Martin Cohen, M.D.
Richard Pazdur, M.D.
Robert Temple, M.D.
Yong-Cheng Wang, Ph.D.
C O N T E N T S
Call to Order and Opening Remarks 5
Introduction of Committee 5
Otis Brawley, M.D.
Conflict of Interest Statement 7
Johanna Clifford, M.D., RN
NDA 21-677, Alimta (pemetrexed)
Eli Lilly & Company
Richard Pazdur, M.D. 10
Introduction and Objectives of the Presentation
Paolo Paoletti, M.D. 21
Background on Non-Small Cell Lung Cancer
Frances Shepherd, M.D. 32
Roy Herbst, M.D., Ph.D. 40
Clinical Efficacy from the Pivotal Study JMEI
Paul Bunn, M.D. 46
Safety Profile from the Pivotal Study JMEI
Richard Gralia, M.D. 64
Paul Bunn, M.D. 78
Martin H. Cohen, M.D. 86
Yong-Cheng Wang, Ph.D. 103
C O N T E N T S (Continued)
Open Public Hearing 112
Questions from the Committee 114
ODAC Discussion 195
P R O C E E D I N G S
Call to Order and Opening Remarks
DR. BRAWLEY: Good morning. I am Otis
Brawley. I am a professor at Winship Cancer
Institute of Emory University. I will be the
Acting Chair of the Oncologic Drugs Advisory
Committee for the day.
I would like to welcome everyone here and
like to start out by coming the meeting to order.
The first order of business will be to
introduce the members of the committee and then we
will have the conflict of interest statement read.
So, if we can start off to my left with
Ms. Sheila Ross, if you would introduce yourself,
and as members introduce themselves, if they could
mention what institution they are from.
Introduction of Committee
MS. ROSS: Thank you. Good morning. My
name is Sheila Ross. I am the Washington
representative for the Alliance for Lung Cancer. I
am here as a patient advocate. I am also a
two-time survivor of non-small cell lung
DR. GRILLO-LOPEZ: My name is Antonio
Grillo-Lopez. I am a hematologist/oncologist with
the Neoplastic and Autoimmune Diseases Research
MS. HAYLOCK: I am Pamela Haylock. I am
an oncology nurse and a doctoral student at the
University of Texas Medical Branch in Galveston,
and I am the consumer representative.
DR. D'AGOSTINO: Ralph D'Agostino from
Boston University, a biostatistician, consultant to
DR. GEORGE: Stephen George, also in
biostatistics, Duke University.
DR. LEVINE: Alexandra Levine,
hematology/oncology at University of Southern
California in L.A.
DR. BUKOWSKI: Ronald Bukowski, medical
oncologist, The Cleveland Clinic.
DR. DOROSHOW: Jim Doroshow, medical
oncology, National Cancer Institute.
DR. RODRIGUEZ: Maria Rodriguez,
hematology/oncology at M.D. Anderson Cancer
MS. CLIFFORD: Johanna Clifford, Executive
Secretary to this committee.
DR. HUSSAIN: Maha Hussain, Professor of
Medicine and Urology, University of Michigan.
DR. PERRY: I am Michael Perry from the
University of MIssouri, Ellis Fischel Cancer Center
in Columbia, Missouri, hematology/oncology.
DR. CHESON: Bruce Cheson,
hematology/oncology, Georgetown University,
Lombardi Comprehensive Cancer Center.
DR. WANG: Yong-Cheng Wang, FDA,
DR. PAZDUR: Richard Pazdur, Division
DR. BRAWLEY: Thank you.
If Ms. Clifford could read the conflict of
Conflict of Interest Statement
MS. CLIFFORD: Thank you. The following
announcement addresses the issue of conflict of
interest and is made a part of the
preclude even the appearance of such at this
Based on the submitted agenda and all
financial interests reported by the committee
participants, it has been determined that all
interests in firms regulated by the Center for Drug
Evaluation and Research present no potential for
appearance of a conflict of interest with the
Dr. Ronald Bukowski has been granted a
208(b)(3) waiver for consulting with a competitor
on an unrelated matter. He receives less than
10,001 a year.
Dr. Maha Hussain has been granted waivers
under 208(b)(3) and 21 USC 505(n) for owning stock
in two competitors. The stocks are valued from
$25,001 to $50,000, and from $50,001 to $100,000.
Sheila Ross has been granted a waiver
under 21 USC 505(n) for owning stock in a
competitor, valued between $5,001 to $25,000.
Because her stock interests falls below the de
minimis exception allowed under 5 CFR
2640.202(b)(2), a waiver under 18 USAC 208 is not
A copy of the waiver statements may be
obtained by submitting a written request to the
agency's Freedom of Information Office, Room 12A-30
of the Parklawn Building.
We would also like to note that Dr.
Antonio Grillo-Lopez is participating as the acting
industry representative, acting on behalf of
regulated industry. Dr. Grillo-Lopez is employed
by the Neoplastic and Autoimmune Disease Research
In the event that the discussions involve
any other products or firms not already on the
agenda for which an FDA participant has a financial
interest, the participants are aware of the need to
exclude themselves from such involvement and their
exclusion will be noted for the record.
With respect to all other participants, we
ask in the interest of fairness that they address
any current or previous financial involvement with
any firm whose products they may wish to
DR. BRAWLEY: Thank you, Ms. Clifford.
The committee is gathered today to discuss
the New Drug Application for Alimta or pemetrexed,
an Eli Lilly compound proposed as a single agent
treatment of patients with locally advanced or
metastatic non-small cell lung cancer after prior
I would now like to introduce Dr. Richard
Pazdur, Director of the Division of Oncology Drug
Products, Center for Drug Evaluation & Research of
the FDA to give us an introduction.
NDA 21-677, Alimta (pemetrexed)
Eli Lilly & Company
Richard Pazdur, M.D.
DR. PAZDUR: Thank you, Otis. It is a
pleasure to be here, and I welcome the
participants, the members of ODAC, as well as the
audience to this most interesting ODAC
I have entitled my comments "Inferiorities
of Non-Inferiority Trials." I will just start off
by saying I was listening to the Democratic
Convention yesterday and Al Gore was talking about
the 2000 election, and he said, "There are winners,
there are losers, and then there is this third
area," and it is kind of this third area, if I
could take some statistical liberties that we are
going to be talking about, and that is this whole
area of non-inferiority, not positive, not
negative, but some assumption of being equal.
I would like to preface today's
presentation with a few comments really to focus
your attention on key issues. This NDA highlights
some unique challenges in developing oncology drugs
regarding non-inferiority trial design and
Survival as an endpoint for regular
approval has been a well-established endpoint for
clinical benefit and regular approval. In oncology
trials, test drugs have generally demonstrated
survival improvements compared to active
Alternatively, an effect on the survival
endpoint may be accomplished by demonstrating a
non-inferior survival effect. Non-inferiority
ensures that a survival advantage, the so-called
"control effect," would not be lost by a new agent.
To determine the control effect, external
historical information from multiple control trials
is generally required.
A certain proportion of the control
effect, known as the margin, should be preserved to
demonstrate non-inferiority. The active control in
a non-inferiority trial should have an effect that
is of substantial magnitude and that can be
precisely estimated with estimates relevant to the
The ICHE9 guidance states that an
acceptable active comparator "could be a widely
used therapy whose efficacy in the relevant
indication has been clearly established and
quantified in well-designed and well-documented
superiority trials"--and I emphasize the plurality
of that word--"and which can be
to have similar efficacy in the contemplated active
The active control, therefore, should be
preferably derived from multiple studies with a
large consistent drug effect suitable for a
convincing meta-analysis to be performed.
Constancy assumptions must be addressed in
designing a non-inferiority trial, ensuring that
the active control effect should be the same as in
the historical controls. These considerations
ensure that the population enrolled in the
historical trials is similar to the population in
the proposed trial with respect to baseline
characteristics, supportive care, additional
available therapies, and observational frequencies.
The primary objective in the present
Alimta trial was not achieved. Neither superiority
nor non-inferiority to docetaxel were adequately
The FDA believed that Alimta's
non-inferiority for overall survival cannot be
demonstrated for two reasons. First, only a single
small historical study exists to estimate the
docetaxel treatment effect. This study randomized
a total of 104 patients, approximately 50 patients
in each arm, to receive either docetaxel or best
A second study was used in the docetaxel
approval consideration. This study compared
docetaxel to either ifosfamide or vinorelbine.
Neither agent had a demonstrated survival effect in
This second trial failed to demonstrate an
overall survival benefit associated with docetaxel,
however, there was an improvement in one-year
survival. Although sufficient data existed to
approve docetaxel in this setting, the FDA believed
that there is not a reliable and reproducible
characterization of the docetaxel effect to use in
a non-inferiority analysis. Constancy assumptions
cannot be verified and interstudy variability is
An additional concern is the existence of
crossover in the present study. Over 30 percent of
patient randomized to receive Alimta subsequently
received docetaxel at disease progression.
Crossover obscures the differences between
treatments, hence, in a superiority trial,
crossover may lead to a false negative conclusion
potentially denying an active drive a marketing
The use of a time to progression endpoint,
an analysis occurring prior to crossover, may be
preferred in settings where significant crossover
In contrast to superiority trials,
crossover in non-inferiority trials may lead to a
false positive conclusion. This crossover
confounds our interpretation of survival since the
observed survival in both arms can theoretically be
attributed to the control drug, in this case
Similarly, data integrity problems, known
as trial sloppiness, either lack of attention to
details in data collection or execution may obscure
the observation of differences leading
positive non-inferiority trials, hence, the agency
has strongly recommended two trials to support a
non-inferiority claim in an attempt to ascertain a
For regular approval of a drug, the
sponsor must demonstrate that the drug is safe and
effective in adequate and well-controlled trials.
The effectiveness must be demonstrated on an
endpoint that the agency believes to represent
clinical benefit, usually survival, disease symptom
amelioration or established surrogates for these.
The sponsor is not obligated to show that
the drug is safer and/or more effective than an
approved drug. Many other therapeutic areas
conduct placebo-controlled trials, drug A versus
placebo, ensuring that superiority can be easily
demonstrated even if a comparator drug is
It is more difficult to demonstrate
superiority in an active control trial, drug A
versus drug B. The test drug must possess the
entire activity of the active control on
endpoint plus an incremental addition effect to
The agency has frequently recommended
add-on trials, A plus B versus B. This design was
used in the approval of Alimta plus cisplatinum in
mesothelioma earlier this year.
In the add-on design, the test drug plus
active control combination is compared to the
active control alone or, alternatively, active
control plus placebo. This design ensures that all
patients receive the active treatment, yet isolates
the test drug's effect.
To demonstrate superiority, the test drug
must only possess an incremental advantage over the
active control on the primary endpoint rather than
the control effect plus an increment.
We will be asking the committee to
consider this application for accelerated approval.
For accelerated approval, an improvement over
available therapy must be demonstrated and may
utilize a surrogate endpoint "reasonably likely to
predict clinical benefit."
A more favorable safety profile could
constitute a "improvement over available therapy."
This decision requires considerable clinical
judgment, and is not merely an exercise in adding
up Grade 3 and 4 toxicities in two columns and
declaring a winner.
The importance of a selected toxicity in
patient management, toxicity duration, and
overlapping toxicity, such as concomitant
neutropenia plus diarrhea, concomitant neutropenia
plus stomatitis may direct your clinical opinion.
With regards to surrogate endpoints for
accelerated approval in this application, the
agency has used response rates of similar magnitude
and duration as demonstrated in this Alimta trial
for past accelerated approvals in similar disease
In making a regulatory decision, we must
consider all available data, a comprehensive drug
evaluation including past approvals and single-arm
studies. As noted, Alimta in combination with
cisplatinum was approved for a
indication earlier this year. An improvement in
overall survival advantage was demonstrated, the
first for a drug in this disease.
In contrast to other accelerated approval
applications that commonly use single-arm trials,
the sponsor has provided a large randomized trial.
Randomized trials always provide greater
We have comparative response rate data, we
have comparative toxicity data, and we have the
ability to examine time to event endpoints although
we believe formal, non-inferiority analysis can
neither be performed on TTP nor survival.
The sponsor is conducting large randomized
trials in early lung cancer that can serve as
confirmatory studies for clinical benefit if
accelerated approval is granted. The statistical
analysis and the design of non-inferiority trials
is an evolving field and represents considerable
Non-inferiority trials are difficulty.
They take considerable resources in
designing, and executing trials and usually require
considerable patient resources.
In conclusion, winning is always better
than tieing. The demonstration of superiority is
always better than that of non-inferiority.
Winning moves the field forward by identifying new
agents and treatments.
However, a win may not only be an efficacy
improvement, but may also be a safety improvement
especially in a field such as oncology where
toxicity concerns may dictate treatment choices or
whether a patient even receives any therapy.
However, as we would like you to discuss
later this morning, this regulatory decision must
be carefully weighed against the clinical relevance
of any potential survival loss.
I hope these comments will focus your
attention and deliberations on the essential issues
presented in this application.
DR. BRAWLEY: Thank you, Dr. Pazdur.
Our sponsor presentation will
and last over the next hour.
If I can introduce Dr. Paolo Paoletti of
Eli Lilly, who will give us the introduction
objectives, and if you would present the presenters
as we move along.
I should add that we are going to hold all
questions until after the open public hearing.
Introduction and Objectives of the Presentation
Paolo Paoletti, M.D.
DR. PAOLETTI: Good morning. My name is
Paolo Paoletti. I am the Vice President for Lilly
Oncology Clinical Research and Oncology Products.
I want to thank the FDA and the members of the
Advisory Board for allowing Lilly to present the
data on Alimta for the treatment of second-line
non-small cell lung cancer.
Here is the agenda for the Lilly
presentation. I will give a short introduction on
the objectives of the presentation, the historical
context, and the rationale for the
design of the
pivotal registration trial.
Dr. Frances Shepherd, Professor of
Medicine at the University of Toronto, and
President of the International Association for the
Study of Lung Cancer, and also principal
investigator for the Phase III pivotal trial,
Alimta versus docetaxel, will give the ground for
the treatment of second-line non-small cell lung
Dr. Roy Herbst, the Chief of Thoracic
Oncology at M.D. Anderson, University of Texas,
will present the development of Alimta after the
pivotal trial JMEI.
Dr. Paul Bunn, Director of the University
of Colorado Cancer Center, past President of ASCO,
and principal investigator for the Phase III trial
Alimta versus docetaxel will present the efficacy
result of the pivotal trial JMEI.
Dr. Richard Gralla, President of the
Multinational Association of Supportive Care, will
report the data on safety profile and patient
reported outcomes for the same trial.
Finally, Dr. Bunn will give the
Additional experts from other
international academic institutions are here today
to answer your questions, and also experts from
In this slide, you can see the specific
expertise are here to answer to your questions.
The objective of the presentation is to
provide evidence that Alimta is effective and safe.
We intend to show that given the superior
safety results, Alimta has a better risk-to-benefit
profile than docetaxel and provides benefit to
patients with non-small cell lung cancer.
This is supported by, first, Alimta is a
novel and effective agent in non-small cell lung
cancer. Alimta has the same efficacy as docetaxel
when looking at the variety of efficacy endpoint
including survival, time to progressive
response rate in the entire population of patients.
In addition, this efficacy is consistently
present when looking at the large number of
subgroups. Alimta is estimated to retain 102
percent of docetaxel benefit over best supportive
Alimta is superior to historical best
supportive care. Alimta has an excellent safety
profile and superior safety results when compared
to docetaxel. Therefore, Alimta offers an
effective and safer second-line treatment option
for patients with non-small cell lung cancer.
We propose the following indication.
Alimta as a single agent is indicated for the
treatment of patients with locally advanced or
metastatic non-small cell lung cancer after prior
chemotherapy, and at the dose of 500 mg/m2 i.v.
with a 10-minute infusion at day 1 of each 21-day
cycle, and to control toxicity, oral folic acid at
the daily dose of 350-1,000 microgram and vitamin
B12 at the dose of 1,000 microgram every
given IM, dexamethasone 4 mg/bid on day minus 1,
day of the treatment, and day plus 1.
In this slide, I summarize the historical
context and the rationale for the statistical
design when the pivotal trial JMEI was initiated.
Alimta showed consistent activity in
non-small cell lung cancer in seven Phase II trials
as a single agent or in combination with platinum
agents both in first- and second-line.
This activity compares well with data from
other commonly used regimens. Folic acid and B12
interventions significantly improve the safety
profile of Alimta, however, the magnitude of this
intervention was not completely known at the time
of the initiation of the Phase III pivotal trial
It was decided to proceed with the Phase
III trial in second-line to offer a better
The trial, as Dr. Pazdur was
presented several design challenges and
limitations, but we decided to run a head-to-head
trial Alimta versus docetaxel.
We wanted to run a global clinical trial
to support global registration. Best supportive
care in second-line treatment of non-small cell
lung cancer was considered not practical because of
the presence of the docetaxel as an approved agent
in second-line treatment and not feasible in the
United States and in many countries in Europe.
Combination chemotherapy was considered
not appropriate especially in this second-line
setting. Docetaxel was approved in second-line
non-small cell lung cancer primarily based on the
result of the trial TAX 317B where superior
survival over best supportive care was demonstrated
in 55 patients treated at the dose of 75 mg/m2.
Survival was selected as the primary
endpoint, however, we acknowledge the presence of
limited historical data on the effect of docetaxel.
Moreover, a pure equivalency trial would require
more than 4,000 patients.
The JMEI is a global registration trial,
and we discussed the statistical design with both
FDA and the European Regulatory Agency. Sample
size of 520 patients allows for testing of
superiority. With the assumption of superiority,
this sample would also allow for testing
non-inferiority. The hazard ratio was the basis to
compare treatment arms for survival.
The protocol specified superiority
testing, as well as testing 10 percent fixed margin
for non-inferiority. This margin was agreed upon
with the European Agency. We always believe this
was a very conservative matching. Indeed, the
magnitude of the effect of folic acid
supplementation on toxicity was not known at the
time. Thus, safety advantages of Alimta were not
considered in the definition of this match.
Before unblinding the data, we included
the percent retention method for non-inferiority in
the statistical analysis plan. The FDA suggested
for the evaluation of Alimta the
retention of the
effect of docetaxel, docetaxel versus best
The FDA used this methodology to approve
docetaxel in breast cancer and capecitabine in
colon cancer. Rothmann and co-authors published
percent retention method in January 2003, and the
details of the percent retention analysis were
included in the statistical analysis plan before
unblinding the data and before any analysis was
This slide shows the Alimta lung cancer
submission timeline. The first patient was
enrolled on March 20, 2001. The last patient was
enrolled on February 6, 2001. The Final
Statistical Analysis Plan was approved on January
Unblinding of the analysis and the data
occurred on January 30, 2003. U.S. fast track
designation for second-line treatment of non-small
cell lung cancer was granted on July 23, 2003.
Non-small cell lung cancer submission
was filed in
November 4, 2003 in the U.S., and in July 2003 for
In June 22nd of this year, the European
CHMP, the regulatory agency, gave a positive
opinion for both second-line non-small cell lung
cancer and mesothelioma.
Alimta has already shown to be an active
agent in cancer. In fact, Alimta, in combination
with cisplatin, was approved on February 4, 2004
for the treatment of mesothelioma in the United
This slide shows the survival curve. You
can see that the combination Alimta plus cisplatin
has a median survival of 12.1 months, while
cisplatin alone has a median survival of 9.3
months. The difference was statistically
significant at P of 0.02.
Based on the evidence of the next
presentation, we believe that Alimta merits the
approval for the treatment of
cell lung cancer for the following reasons.
Seven Alimta Phase II studies in
first-and second-line non-small cell lung cancer
show consistent evidence of activity within the
range of activity of other agents currently
From this large Phase III randomized
clinical trial in second-line non-small cell lung
cancer, Alimta showed consistent similar clinical
efficacy when compared to docetaxel in all primary
and secondary endpoints and in all subgroup
Alimta is better than historical best
supportive care. Moreover, Alimta is significantly
better for clinically relevant toxicity when
compared to docetaxel.
Only docetaxel is approved for second-line
treatment today, and there is a need for more
second-line treatment option.
Alimta is an effective drug for the
treatment of second-line non-small cell
cancer, and it has a better risk-to-benefit profile
when compared to docetaxel.
As you hear the rest of our presentation
and that from the FDA today, please keep into
consideration the following points:
Docetaxel at the dose of 75 mg has shown
activity across several studies in second-line of
non-small cell lung cancer after the pivotal trial
TAX 317B, however, its use is limited by its
toxicity. The results in 288 patients receiving
docetaxel in the JMEI pivotal trial confirms
docetaxel's survival effect.
As I mentioned before, docetaxel was
approved based on limited data, hence, the
imprecision of the effect of docetaxel made
non-inferiority design and related analyses very
This context, together with the lack of
feasibility to conduct placebo-controlled trial
once the drug is approved makes further advancement
in drug development very difficult.
Although post-study treatment,
in the United States, may confound survival result,
the analysis from the pivotal trial JMEI suggest
that such a confounding effect is unlikely.
In conclusion, I respectfully request that
the members of this advisory board evaluate the
data in second-line treatment of non-small cell
lung cancer considering the overall efficacy and
safety that will be presented.
Now, Dr. Frances Shepherd will give the
background for the second-line treatment for
non-small cell lung cancer.
Background on Non-Small Cell
Lung Cancer Second-Line Treatment
Frances A. Shepherd, M.D.
DR. SHEPHERD: Thank you very much,
members and guests.
In 1997, the ASCO Guidelines stated that
"there is no current evidence that either confirms
or refutes that 2nd-line chemotherapy improves
survival in non-small cell lung cancer."
This conclusion was reached
years ago because, at that time, only single-arm,
Phase II trials were available. However, several
trials of the third-generation agent docetaxel
suggested that this agent might be appropriate to
study further in randomized Phase III trials.
In the first trial initiated, the TAX 317
study, patients previously treated with at least
one platinum-based regimen were stratified based on
their ECOG performance status, 0.1 versus 2, and on
their best response to prior chemotherapy.
They were randomized to receive either
docetaxel 100 mg/m2 or best supportive care.
Routine safety monitoring revealed 5 or 10 percent
early toxic deaths in the chemotherapy arm.
Therefore, after discussion with the principal
investigators and the FDA, the docetaxel dose was
reduced to 75 mg/m2 for the second half of the
The sample size was maintained at 200
patients as originally planned due to the
difficulty in accruing patients to this
because of the best supportive care arm.
The overall response rates to docetaxel
100 and 75 mg/m2 were both 6 percent. Time to
progressive disease was 2.8 months for patients
treated with docetaxel 75 mg compared to only 1.6
months for best supportive care. Median survival
was significantly longer for docetaxel 75 mg
treated patients at 7.5 months compared to only 4.6
months for best supportive care. One-year survival
was 3-fold higher for docetaxel patients.
Survival is shown graphically in this
slide for the second half of the trial at docetaxel
75 mg/m2, the FDA approved dose. Survival was
significantly longer for patients treated with
docetaxel with a log-rank p-value of 0.01.
One-year survival was significantly higher with a
chi-square p-value of 0.003.
This is a very important slide to
concentrate on. In this trial, patients
received one platinum-containing regimen, but could
have received more than one regimen before entering
As you can see from this slide, the
numbers of patients unfortunately are small, and
these must be considered exploratory subset
analyses, however, they suggest that patients
treated with docetaxel after two or more regimens
derived absolutely no survival benefit from the
treatment as compared to best supportive care
The entire survival benefit of the trial
came from the administration of docetaxel in the
true or strictly defined second-line setting.
The second large trial was the TAX 320
trial and was performed in the United States where
a best supportive care trial could not be
In this trial, patients were stratified by
their best response to platinum-based therapy and
performance status, and were randomized
docetaxel 100 mg/m2 or docetaxel 75 mg/m2, or a
comparator of vinorelbine or ifosfamide. This was
The overall response rate was 11 percent
for patients treated with docetaxel 100 mg, and 7
percent for patients in the 75 mg group. Both of
these response rates were significantly higher than
the 1 percent response rate noted in the control
group with p-values of 0.001 and 0.036.
There was no difference in median or
overall survival among the three treatment arms,
however, the one-year survival rate of 32 percent
for patients treated with docetaxel 75 mg, the
FDA-approved dose, was significantly better than
the 19 percent one-year survival rate of patients
treated with vinorelbine or ifosfamide. Chi square
p-value for this is 0.05.
This is shown graphically on this slide
where you will see the survival curve separating in
the latter part.
The FDA-approved label for docetaxel 75 mg
reports Grade 3/4 neutropenia of 65.3 percent,
Grade 3/4 infection of 10.2 percent, and using a
very stringent definition, febrile neutropenia rate
of 6.3 percent.
Although Grade 3 and 4 diarrhea and
neurotoxicity are rare at this dose of docetaxel,
lesser grades of both of these toxicities may be
distressing to patients. Similarly, alopecia,
although never life-threatening, may have a major
negative emotional impact on both men and women.
Quality of life and symptom control was
measured in both the TAX 317 and 320 trials. Pain
was significantly better controlled in the 317
trial, and this was not because of increased opioid
use. You can see from this slide that opioid use
was the same at study entry in both arms of the
trial, however, significantly fewer patients
treated with docetaxel required additional opioids
and significantly fewer patients
introduction of new opioids.
Weight loss was measured closely, and you
will see that in the TAX 317B trial, 25 percent of
patients treated with best supportive care had
weight loss greater than 10 percent compared to
only 2 percent of patients treated with docetaxel.
Weight loss greater than 10 percent was seen in
only 5 percent of patients treated with docetaxel
75 mg/m2 in the 320 trial compared to 8 percent for
Treatment was not at the expense of
quality of life or performance status. Indeed,
performance status improved during the study for
patients treated with docetaxel whether measured at
initiation, across the cycles, or at the last
In summary, these landmark trials showed
that second-line chemotherapy prolonged survival in
non-small cell lung cancer. It also improved
symptom control and does not have a negative effect
on quality of life or performance status.
These trials led to the approval of
docetaxel 75 mg/m2 for the second-line treatment of
non-small cell lung cancer in 1999.
In 2003, the revised ASCO evidence-based
guidelines recommended docetaxel for patients with
non-small cell lung cancer who have progressed on
first-line platinum-based therapy.
In summary, the body of evidence shows
that patients derive benefit from second-line
treatment of non-small cell lung cancer with
docetaxel. However, better tolerated or more
effective alternatives are needed.
Finally, docetaxel is being used more
frequently in the first-line setting and no options
are currently available for patients who are
treated first-line with docetaxel-containing
As docetaxel is the only
for the second-line treatment of non-small cell
lung cancer, additional options are required.
Dr. Roy Herbst will now discuss the
development of Alimta.
Roy Herbst, M.D., Ph.D.
DR. HERBST: Good morning, panel members
and guests. My name is Roy Herbst from the M.D.
Anderson Cancer Center. Our group and myself
personally have worked with this drug both in the
front and second-line setting in non-small cell
My purpose this morning is to provide some
background information regarding this novel
antifolate and to share supporting evidence that
Alimta has activity in patients with non-small cell
lung cancer, as well as providing clinical benefit.
First, a word about the structure. As you
can see, Alimta is very similar to folic acid, but
really it is quite a unique and novel
You can see two circles areas on the slide. The
N-10 nitrogen has been replaced by a methylene
group, and most importantly, the pyrrolo-pyrimidine
ring circled makes this structurally different from
other antifolates. That is important because it
gives it some very unique qualities as I will talk
about in the next slide.
Shown here is the mechanism of action of
this drug, which is a multi-targeted antifolate.
As shown in the left, the Alimta enters the cell by
reduced folate carriers. Once inside the cell, it
is polyglutamated. This potentially allows it to
be stored in the cell for higher intracellular
You can then see that it blocks three
different enzymes involved in folate
metabolism - TS, DHFR, and GARFT. There is also the
potential for this drug to be active in MTAP [ph]
efficient cells. This makes it potentially more
active, as well, at any cell that might upregulate
any one of these different enzymes.
Activity has been across a wide spectrum
of tumor models. Today, we will focus on lung
cancer. Here, you can see four non-small cell lung
cancer cell lines with activity in the nanomolar
range. There is also evidence here of a lung
cancer xenograph, and you can see the drug is quite
active, as well.
What about clinical experience? First,
the front-line experience. Shown here are two
studies that looked at Alimta before vitamin
supplementation in patient with non-small cell lung
cancer, compared to several studies with docetaxel
also in the front-line setting.
The important thing to notice here is that
the activity, both based on response rates in the
20 percent range and the median survivals, from 7
to 9 months, is quite consistent with what one
would expect for docetaxel or, in fact, most of the
third-generation chemotherapeutics that we now use
for non-small cell lung cancer.
Activity has also been seen, and quite
favorable toxicity, in combination with platinum,
which, of course, is the way we treat lung cancer
in the front-line setting.
Shown here are four studies, two using
cisplatinum, two using carboplatinum, and again you
can see in these Phase II studies, response rates
that are quite similar to other agents in this
setting, in one case in the 40 percent range,
median survivals between 8 and 10 months, in fact,
13.5 months in our M.D. Anderson study, and one-year
survivals are quite good. This drug clearly
has activity with platinum in the front-line
setting of lung cancer, as well.
Going into the randomized trial that you
are about to hear about, this was the Phase II
experience, the study from Smit and colleagues, 79
patients. This is a refractory group of patients
with non-small cell lung cancer. One hundred
percent of these patients were
three months, and importantly, it's an especially
bad group because 66 percent were refractory within
You can see that this drug demonstrates a
clear response rate of 8.9 percent with a median
survival of 5.7 months, and a one-year survival of
23 percent. There is clearly activity based on
this trial in the second-line setting, and we will
hear more about this, of course, today.
Now, what about safety? As with most
antifolates, the primary toxicity of this drug is
hematologic. Early data showed that high
homocysteine levels, a surrogate for functional
folate or B12 deficiency, correlated with high
levels of toxicity.
So, a decision in development was made
early on to supplement all patients with folic acid
and vitamin B12 when they received this drug. This
resulted in decreased toxicity with no detrimental
effect on efficacy.
I show one slide here. This is basically
showing a group of patients, 246, without vitamin
B12 and folate supplementations, single agent
administration, or 220, who did receive
Shown on the left are all the toxicities
lumped together that I am going to show in this
slide. You can see in the white before, and in the
green after, with a significant improvement.
Then, breaking that up into the top three,
you can see Grade 4 neutropenia is significantly
reduced, Grade 3/4 diarrhea also significantly
reduced, and at least in this Phase II experience,
you can see toxic death rate is zero, and then we
are seeing when the supplementation was given.
So, in summary, Alimta has shown activity
in non-small cell lung cancer as a single agent,
both in the first- and second-line setting, in
combination with platinum agents in the first line.
The safety has been well characterized.
The toxicity is significantly reduced
folic acid and B12, and a very low incidence of
neutropenia, febrile neutropenia, and other
I can personally say, both for my group
and myself, this has been our experience, as well.
Based on these results, a pivotal Phase
III study in the treatment of second-line non-small
cell lung cancer was indicated, and Dr. Paul Bunn
will now present those data.
Clinical Efficacy from the Pivotal Study JMEI
Paul Bunn, M.D.
DR. BUNN: Good morning, Dr. Brawley, ODAC
members, and guests.
As one of the principal investigators, I
will review the results of the pivotal trial JMEI,
which was a head-to-head comparison of Alimta to
docetaxel in the second line treatment of patients
with advanced non-small cell lung cancer.
I will begin this presentation
study design and patient demographics. The results
of the primary endpoint survival will be given with
a detailed discussion of the survival result and
comparison with docetaxel and historical best
supportive care with and without adjustment in a
Following this discussion, I will review
the results of the secondary efficacy endpoints and
a brief discussion of the effect of third line
therapy. Because efficacy cannot be considered in
the absence of toxicity, I will give a brief
overview of toxicity, and then Dr. Gralla will
review the safety results and patient reported
outcomes in detail. Then, I will wrap up with a
few concluding remarks.
After stratification for known prognostic
factors including performance status and stage, as
well as other possible prognostic factors listed,
patient were randomized to Alimta 500 mg/m2 I.V.
day 1 every 21 days or docetaxel 75 mg/m2 day 1
every 21 days.
The 283 patients randomized to Alimta
received B12 and folic acid supplementation and
dexamethasone was given to prevent skin rash.
The 288 patients randomized to receive
docetaxel received dexamethasone according to the
The primary study endpoint was survival.
This survival endpoint is expressed as a hazard
ratio of Alimta to docetaxel with a 95 percent
Secondary endpoints included
progression-free survival, time to tumor
progression, response rate toxicity and patient
reported outcomes as measured by the Lung Cancer
Of course, these endpoints were assessed
in one of two populations, intention to treat and
randomized and treated. The primary endpoint
survival, as well as all other time to event
variables were assessed on an intent to
population. This population included all
randomized patients regardless of therapy.
The toxicity endpoints were evaluated on
randomized and treated population. This group
included randomized patients who received at least
one dose of treatment.
Important inclusion and exclusion criteria
included histologic or cytologic diagnosis of Stage
III or IV non-small cell lung cancer. All patients
had progressed after at least one prior
chemotherapy treatment, but not more than one prior
chemotherapy treatment for metastatic disease.
Prior adjuvant and neoadjuvant therapy was allowed.
Patients had performance status 0 to 2 and
adequate organ function. Active brain metastases,
severe peripheral neuropathy or significant weight
loss were not allowed. Uncontrolled pleural
effusions and prior docetaxel was not allowed.
Prior paclitaxel was allowed and prior platinum was
The most important prognostic variables,
performance status and stage, were well balanced
between the arms. The less important variables,
such as age and gender, there were minor but
nonsignificant differences. Histology and
pre-treatment homocysteine levels were well
There were no differences in the fraction
of patients responding to initial chemotherapy or
the fraction with early relapse after prior
The two groups had no relevant differences
in prior chemotherapy in terms of taxane or
In both groups, dose intensity was well
preserved with a similar number of patients
receiving at least 4 cycles of therapy and a median
of 4 cycles of therapy in both arms. The percent
of the planned dose intensity and dose delays were
There was a significant increase in dose
reductions in the docetaxel arm.
Of course, survival is so important in the
primary endpoint and the unadjusted Kaplan-Meier
survival curves for Alimta and docetaxel were
overlapping and crossed several times. The median
survival times are 8.3 months and 7.9 months,
The one-year survival rates was 29.7
percent in both arms. The unadjusted hazard ratio
was 0.99 in favor of Alimta. The 95 percent
confidence interval was 0.82 to 1.2. This hazard
ratio and confidence interval did not show
superiority, nor rule out a 10 percent margin.
In order to more fully understand the
survival implications of Alimta relative to both
docetaxel and to best supportive care, the data
must be put in the context of this and other
Percent retention analysis is a means of
estimating the amount of benefit of
best supportive care that is retained by Alimta.
This analysis, as you have heard from Dr. Paoletti,
was not in the original protocol, but was
prespecified in the statistical analysis plan prior
to unblinding and prior to data analysis.
The retention analysis was based on the
results of TAX 317B, which was docetaxel 75 mg/m2
versus best supportive care. This analysis takes
into account variability within the studies and
allows for comparison of Alimta to best supportive
An important assumption of the percent
retention analysis is comparability of populations
and results between TAX 317 and JMEI. This allows
for the assumption that if the best supportive care
arm were to be included in JMEI, its survival curve
would have been similar to that seen in TAX 317.
For the most important prognostic factor,
such as performance status and stage, populations
in TAX 317 and JMEI were very similar. There were
less important factors, such as age and
there were minor differences, but overall, the
pre-treatment characteristics make the populations
Looking at the outcome of the 75 mg/m2
docetaxel arms in both TAX 317B and in JMEI, shown
here, shows the results are very similar. The
Kaplan-Meier survival estimate of docetaxel 75
mg/m2 from TAX 317 is shown in green and JMEI in
blue. This outcome confirms the finding of TAX
317B for docetaxel.
Once the populations are shown to be
comparable, then the percent retention analysis
allows for comparison of survival between TAX 317B
Superimposing the Alimta result of JMEI,
which is the yellow curve I just added, it is
evident the result is similar to docetaxel 75 mg/m2
from both 317B, the prior study, and the current
study JMEI. This finding shows that Alimta is
equivalent to docetaxel 75 mg/m2.
Now, adding in the best supportive care
result, in white, strongly suggests the superiority
of Alimta to best supportive care. The hazard
ratio of Alimta to best supportive care is 0.55
with a 95 percent confidence interval that does not
overlap 1, 0.33 to 0.9, the p-value is 0.019.
Another way to understand the survival
results, which are real, and the confidence
interval around these results is to compare hazard
ratio and confidence interval in the trial results.
Shown in yellow are the actual study
results showing an unadjusted 0.99 hazard ratio, a
95 percent confidence interval of 0.82 to 1.2. For
reference, the percent retention of docetaxel's
benefit over best supportive care is shown below
For the actual data, the hazard rate of
0.99 represents retention of 102 percent of
docetaxel's benefit over best supportive care. A
hazard ratio of 0.82 represents 150 percent
retention, and so forth.
If we want to determine whether Alimta has
benefit over best supportive care, we can calculate
the hazard ratio if the percent retention were
zero, indicating that best supportive care and
Alimta were the same. In this case, the hazard
ratio of Alimta to docetaxel would be 1.33.
Since the upper limit of the hazard ratio
was 1.2, we can be quite confident that Alimta is
better than best supportive care.
If we want to determine the hazard ratio
if Alimta retained at least 50 percent of the
benefit of docetaxel, the hazard ratio would need
to be less than 1.21 for 95 percent confidence, and
again this criteria was met.
If the upper limit of the 95 percent
confidence interval was less than 1.11, then,
Alimta would have been within 10 percent of
docetaxel as originally requested by the European
Regulatory Group. As shown, it did not reach this
value. However, after reviewing the totality of
the evidence, the European Authorities have
Alimta would have been declared superior
to docetaxel if the upper limit of the 95 percent
confidence interval had been less than 1. The
result did not reach this threshold of superiority.
Since not receiving therapy can affect
non-inferiority analyses, the ICH Guidelines
recommend that analyses of non-inferiority
performed percent retention calculations on both an
ITT, as well as the randomized and treated RT
This table shows the calculation from both
populations. For the ITT population, Alimta
retained 52 to 150 percent with a p-value for 50
percent retention of 0.047.
For the RT population, Alimta retained 58
to 168 percent with a p-value for 50 percent
retention of 0.036.
These data support retention of docetaxel
survival benefit by Alimta.
As a prespecified secondary
Cox multivariate regression analysis was performed
with these 7 prespecified prognostic factors in the
model. These factors included stage, performance
status, time since last therapy, response to prior
therapy, prior taxane, prior platinum, and number
of prior chemotherapies.
The results from this model showed that
three factors predictive for survival - Performance
Status 2, time since last chemotherapy less than 3
months, and Stage IV, all predictive for a worse
This slide shows the adjusted survival
hazard ratio on a similar number line. The actual
data is represented in yellow. The hazard ratio
was 0.93 with a 95 percent confidence interval of
0.76 to 1.13. The p-value for the 10 percent fixed
margin was p equals 0.051.
The difference between the upper limit of
the confidence interval 1.13, and the prespecified
10 percent fixed margin 1.11, translates
approximately 3.6 days difference.
This slide demonstrates subgroup analyses
unadjusted and adjusted for known or potentially
important prognostic factors for JMEI.
In most instances, relative subgroups,
there were no appreciable treatment effect
differences. For Performance Status 2 patients,
the hazard ratio favored Alimta, but in this case,
the sample was small, and the result was not
For no prior platinum, the apparent
differences in the adjusted hazard disappeared when
imbalances important to other factors were taken
These data provide confidence that the
observed results were consistent across all
subgroups and that the results could not be
explained by a large benefit within any particular
We will now review the
of progression-free survival, time to progression,
tumor response, and toxicity. In addition, I will
provide an exploratory data on possible confounding
effect of post-study chemotherapy.
Shown is the Kaplan-Meier estimate for
progression-free survival in intent to treat
population. It difficult to see that there is two
curves here because they are so overlapping, but
there are two distinct curves with a median
progression-free survival of 2.9 months in both
The hazard ratio was 0.97, slightly
favoring Alimta, with a 95 percent confidence
interval of 0.82 to 1.16.
This is the Kaplan-Meier estimate of the
time to tumor progression for JMEI. Again, the
curves overlap considerably with a median time to
tumor progression of 3.4 and 3.5 months for Alimta
and docetaxel respectively.
The hazard ratio was again
confidence intervals of 0.8 to 1.17.
A review of chemotherapy given after this
study showed that more patients on Alimta received
any chemotherapy. Not surprisingly, docetaxel,
which is the only approved drug, was given more
frequently after progression on Alimta despite the
evidence you have heard that it provides no benefit
in this setting.
Receipt of docetaxel does represent a
crossover of sorts. As expected, patients on
docetaxel received more gemcitabine, more
vinorelbine, and more gefitinib, as well as more
Of course, you will recall that gefitinib
is the only agent for which there is any evidence
for survival effect in third-line non-small cell
To further understand the post-study
treatment effect, an analysis was performed to look
at the type of post-study therapy and
effect on survival. Of course, all of these are
retrospective and are subject to great bias, which
we can discuss later.
Patients who received post-study therapy
lived longer than those who did not, not
surprisingly, regardless of the nature of that
therapy or the study arm.
Patients on Alimta who received
post-therapy docetaxel did numerically worse than
those who received other post-treatment study, such
as gemcitabine or vinorelbine.
Patients on the docetaxel arm who received
post-therapy docetaxel actually had numerically
better survival than those receiving docetaxel
after Alimta. This post hoc analysis does not
suggest any crossover effect or post-study effect
of docetaxel treatment.
In fact, this slide shows the distribution
of survival after progressive disease by treatment
arm, Alimta versus docetaxel. A higher proportion
of patients on the Alimta arm received
and a higher proportion of patients on docetaxel
received other therapies.
The median survival was 4.5 months in both
arm. This comparison suggests there is no
difference between salvage therapies in the two
Assuming that patients with progressive
disease have similar prognoses in the groups, this
comparison implies the crossover to docetaxel in
the Alimta arm did not affect any conclusion
Investigators determined the best response
in the study according to South West Oncology Group
criteria. The response rate between the arms was
virtually identical, 9.1 for Alimta and 8.8 for
Stable disease was seen in about 46
percent of patients on each arm. These data are
consistent with the previously published data using
both docetaxel and Alimta in this setting.
Because all efficacy parameters were
equivalent, much of the clinical benefit of Alimta
relates to toxicity, so the toxicity analysis, of
course, becomes important.
This table provides a brief overview of
significant toxicity differences regardless of
causality. Alimta was associated with significantly
less Grade 3/4 neutropenia, less febrile
neutropenia, less infection with neutropenia, and
There were also significantly less
clinically relevant alopecia of all grades.
Alimta treatment was associated with
significantly more ALT elevations, 2.6 percent
versus 0.4 percent.
In conclusion, the results of JMEI
demonstrate that Alimta afford efficacy benefits
for patients with non-small cell lung cancer
undergoing treatment after progression with prior
The survival result is similar
to that of
docetaxel with a hazard ratio of 0.99. This hazard
ratio translates into 102 percent retention of
docetaxel's benefit over best supportive care.
The results are internally consistent
across subgroups. In JMEI, there is no evidence of
an effective crossover or other post-study
The survival results robustly support
Alimta's superiority to historical best supportive
In addition to the survival endpoint, all
secondary endpoints, including response, time to
progression, progression-free survival affirm
Alimta's activity and benefit to this group of
Finally, the safety profile of Alimta,
which Dr. Gralla will review in detail, is clearly
superior to docetaxel.
Now, I would like to invite Dr. Richard
Gralla to review symptom and safety results from
Safety Profile from the Pivotal
Richard Gralla, M.D.
DR. GRALLA: Thank you, Dr. Bunn, and good
In considering second-line treatment in
any patient with advanced lung cancer, both
physicians and patients also regard the safety or
toxicity of an agent with great concern.
At the same time, all wish to preserve the
efficacy benefits of treatment including symptom
control and to do so with fewer potential risks
Recognizing that significant patient
reported outcome advantages, including pain
control, were seen with the docetaxel when compared
with supportive care, as Dr. Shepherd discussed
with TAX 317 trial, it was important to assess
prospectively this efficacy parameter in the
The study was designed to evaluate the
impact of symptoms as measured by the
symptom burden parameter of the LCSS instrument.
Dr. Bunn outlined briefly the significantly lower
toxicity profile with Alimta, which I will discuss
in greater detail in a few minutes, but it is
crucial to ascertain that the safety advantages
were not achieved at the expense of the decrease in
symptom control as expressed by patients.
PRO, or patient reported outcome
evaluations, are best conducted when using
previously validated instruments. The LCSS has good
published psychometric properties and was selected
for prospective use in this trial for several
It is demonstrated high patient and
observer acceptability, it was designed
specifically for randomized comparative clinical
trials, and was used in the docetaxel TAX 317 and
Patients completed the instrument weekly,
allowing 85 percent of the patients to be included
in the PRO evaluation.
Two major questions are associated with
PRO evaluation. First, are the quality of life
instruments used sensitive enough to reflect
changes that patients experience, and, second, is
there value in receiving second-line chemotherapy
in terms of symptom relief and quality of life
Does the magnitude of response, major
response versus stable disease versus progressive
disease predict the degree of benefit expressed by
This slide shows the patient reported
results displayed by the objective response
category achieved. For this analysis, the results
of both the Alimta and docetaxel arms were
As can be seen, major response was
associated with the greatest patient expressed
benefit, the green bars, while a lesser impact, but
still a positive result, was reported by those
patients in whom stable disease, the
was their best response.
Of note is the fact that over 50 percent
of patients had either a major response or stable
disease in this trial, and that these groups
reported symptomatic benefits as seen on the slide.
In light of the PRO benefits overall in
the trial, and with the significantly lower
toxicity on the Alimta arm, it is important to see
that the response related symptomatic benefits were
preserved with the less toxic Alimta regimen.
This slide shows the evaluations for
patients by randomized treatment arm and examines
the results seen in those patients with major
response or stable disease.
The bar graphs represent the six general
and thoracic symptoms evaluated in the LCSS and the
average symptom burden index, or ASBI. It is clear
that these results show similar symptom
amelioration for each treatment arm in these lung
cancer related symptom areas.
In all new agent evaluation, efficacy and
safety are the main considerations. Given the
similar efficacy endpoints in terms of survival,
response, and patient reported outcomes found with
both agents in this large randomized trial, safety
issues are of marked importance when considering
therapeutic index differences between the agents.
To place the overall safety profiles for
second-line treatment in context, it is useful to
review briefly the safety findings of the currently
available second-line agent docetaxel.
The docetaxel arms at 75 mg/m2 from the
TAX 317 and 320 trials, which Dr. Shepherd outlined
in her presentation, are seen on this slide.
When one concentrates on marked
toxicities, as expressed as a percentage of
patients experiencing Grade 3 or 4 levels of
toxicity, it is clear that neutropenia is the
primary concern occurring in the majority of
patients. In fact, as originally designed, the
amount of docetaxel given in TAX 317 had to
lowered during the study to 75 mg/m2 because of
Nonetheless, even at this dose, nearly
two-thirds of patients still experienced marked or
severe neutropenia. Physicians remain particularly
concerned with the high degree of this potentially
While patients and physicians appreciate
the modest benefits of docetaxel, concerns with
neutropenia and its complications have led to the
frequent need for growth factor injections and
alterations of doses and schedules.
An overall view of the safety in the JMEI
trial is seen in this slide. The table shows the
incidence of the most serious toxicity, death,
serious adverse events or SAEs, and finally, any
adverse event called the treatment emergent adverse
event, or TEAE.
As can be see for any of these parameters,
a higher rate of adverse events was found in this
study with the docetaxel arm.
When one looks at either the serious
adverse events affecting a minority of patients, or
the treatment emergent adverse events affecting
most patients, significant differences favoring the
Alimta arm are found when the results are evaluated
for events that are drug related.
Of course, the toxicity outcome of
greatest concern with any drug is death. As seen
in this slide, while the number of deaths during
the study are relatively similar between the two
treatment arms, fewer deaths are seen in total on
the Alimta arm, and in the important categories of
study drug related deaths and lung cancer related
When examining adverse events, any
toxicity can be relevant, but major toxicity, that
is, Grade 3 and 4, is of greatest concern and
deserves our focus.
Clearly, an approach that lessens toxicity
from the marked Grade 3 and 4 categories
1 and 2 would have the same overall toxicity
percentage, but by lessening the severity would be
a major benefit. All drugs have side effects, the
severity of these side effects is a crucial issue
in patient management and in the assessment of
toxicity in this trial.
This slide is the first of several
summarizing laboratory-based major toxicities from
the current Alimta versus docetaxel randomized
trial as displayed as Grade 3 and 4 level of
As expected, the most commonly occurring
laboratory-measured side effect was neutropenia.
Of note is the finding that there was a markedly
different occurrence of this toxicity depending on
the treatment arm.
Not only was there a highly significantly
different rate of neutropenia, favoring those
patients randomly assigned to Alimta, but the
related life-threatening toxicity of febrile
neutropenia occurred far less often in
Alimta-treated patients affecting fewer than 2
Not surprisingly, documented infection
rates were lower in those patients receiving Alimta
with no occurrences found on this arm of the trial.
Now, stepping away from the statistical
analysis at this point and placing it in a clinical
context, these results mean that 1 of every 8
patients in this study, randomized to docetaxel,
had febrile neutropenia, while this
life-threatening toxicity occurred in less than 1
of every 50 patients on Alimta.
The only laboratory area in which a
significantly higher side effect rate was seen with
the Alimta, was in the hepatic transaminase ALT.
Fortunately, this degree of elevation was uncommon,
occurring in fewer than 3 percent of patients.
In general, rates of non-laboratory side
effects were relatively low in this study.
Nonetheless, the distressing but not
life-threatening side effect alopecia
less often in patients receiving Alimta.
Additionally, a significantly different
rate of serious diarrhea was found again favoring
Thus, when considering both laboratory and
non-laboratory events, threatening overlapping
toxicities, such as neutropenia and diarrhea, were
significantly reduced by the use of Alimta.
When one looks at the occurrence of all
serious laboratory toxicities, that is, Grade 3 and
4, by treatment regimen, it is clear that Grade 3
toxicities occurred in only about half as many
patients randomly assigned to the Alimta arm, and
that Grade 4 toxicities were markedly lower in
patients on that arm.
During the trial, anemia was reported by
about 7 percent of patients on either arm of the
study. This could be related to the chemotherapy
or to anemia associated with the lung cancer
Overall, physicians elected to transfuse
or to give erythropoietin to between 22 percent and
24 percent of patients with no significant
differences between treatment arms.
With markedly lower drug-induced
neutrophil counts on the docetaxel arm, 7 times as
many of these patients were given
granulocyte-stimulating growth factors, again a
highly significant difference.
The advantages in non-laboratory
toxicities are perhaps best illustrated when
looking at serious toxicities of any cause. The
more minor toxicity grades 1 an 2 are similar
between the treatment arms, however, when one
reviews the more serious toxicity grades, important
differences are clear.
Grade 3 toxicity rates approach
statistical significance. In Grade 4, the most
marked toxicity category, a third fewer patients on
the Alimta arm had this rate of serious toxicity a
statistically significant difference between the
It can be useful to review briefly
hospitalization patterns. As seen in this slide,
hospitalizations due to adverse events of all
causes were significantly lower in patients on the
The driving factor behind this rate
involved the significantly fewer hospitalizations
for the life-threatening complication of febrile
neutropenia. Paradoxically, the number of days in
hospital was modestly greater in the Alimta arm.
This imbalance was due entirely to non-drug-related
factors, that is, longer hospitalizations for
social considerations and for management of
complications of the metastatic lung cancer, not
for drug-related issues.
In particular, it is the appropriate
concern with the risk of major toxicity that limits
the willingness of physicians to advise second-line
docetaxel despite demonstrated survival and
symptomatic gains from the TAX 317 study as
outlined by Dr. Shepherd.
Many individuals involved in new agent
investigation have struggled to display clearly
this balance between toxicity and benefit, or at
least ways of showing the overall effect of major
toxicity rates on survival.
This slide demonstrates one attempt to do
this. It is interesting to look at the experiences
of all patients on this large Alimta versus
docetaxel trial with regard to the time of
survival, which was free of serious Grade 4
As is seen in terms of the remaining
period of survival, patients randomized to the
Alimta arm spent two to three times as long without
this degree of serious toxicity when compared with
those on docetaxel.
This analysis helps to demonstrate the
impact of the more favorable toxicity profile of
Alimta when compared with docetaxel.
We conclude that this large
trial demonstrated several major advantages for the
group randomized to Alimta with the real but
limited benefits found in second-line treatment of
non-small cell lung cancer. A decrease in the risk
of treatment is an important advantage for Alimta.
These significant benefits were found in
the key areas of decreased neutropenia and febrile
neutropenia, less risk of alopecia and diarrhea,
and few drug-related deaths and serious adverse
From a safety and patient reported
outcomes perspective, Alimta is a useful and safe
treatment option for patients with non-small cell
lung cancer who are candidates for second-line
The toxicity advantages associated with
Alimta with similar symptomatic and quality of life
benefits are of great value to patients. The PRO
and toxicity evaluations, coupled with the other
major endpoints, help to support the finding that
Alimta treatment is safer without any compromise in
survival response or palliative
I would like now to call on Dr. Bunn to
summarize these results and to put them into the
context of current treatment.
Paul Bunn, M.D.
DR. BUNN: In the past three talks, we
have reviewed the relevant data supporting Alimta
for the treatment of advanced non-small cell lung
cancer after prior chemotherapy. I would like to
take a few minutes to summarize the salient issues
in your review. I also appreciated Dr. Pazdur's
overview of the issues before you and just make a
few comments as I go through my presentation.
Of course, you are here to provide your
advice to the agency. Your advice is largely going
to depend on how much you think about safety and
about efficacy, and your confidence in the safety
and the efficacy relate to survival, they relate to
patient-reported outcomes, and they relate to
safety, and we must consider not only the JMEI
trial, but what is known in the literature, as Dr.
Pazdur alluded to before and how
confident are we
about what best supportive care does and how
confident are we about what docetaxel does and how
many trials are there.
From this presentation, Alimta clearly
provides a new, a safe and clearly an effective
treatment option for patients with advanced
non-small cell lung cancer in the second-line
This is important as advances in
treatment, patients with lung cancer are living
longer and they are living better. As a result,
more of these patients are candidates for
At present, they have only one approved
option, docetaxel. As noted, docetaxel's use is
limited by its significant toxicities and also its
use in the first-line setting.
What about safety? Alimta is clearly
safer than docetaxel with respect to any clinically
relevant toxicity. Its advantage, of course,
most marked in the reduction of febrile
neutropenia, from 12.6 percent to 1.9 percent.
A secondary benefit that results from this
is a concomitant reduction in the use of G and
GM-CSF, fewer visits to the clinic for neutropenia,
fewer hospitalizations for neutropenia.
However, not all the benefit is isolated
to reduction in neutropenia. There was also a
significant reduction in Grade 3/4 diarrhea and a
reduction in alopecia, a side effect particularly
important to patients.
Finally, there was a 3-fold reduction in
hospitalization for drug-related adverse events.
How confident can we be in the safety
profile of Alimta? Shown here are the safety
results of Alimta in JMEI and in the safety
database of all other Phase II monotherapy of
Alimta with vitamins.
Of note is the consistent results of
Alimta in febrile neutropenia, in diarrhea and
alopecia, that were all lower than
On looking at the direct pivotal trial
evidence for survival benefit from JMEI, Alimta has
comparable activity with a hazard ratio of 0.99.
Median survivals are essentially the same.
One-year survival rates were identical and there
was internal consistency across all groups.
When indirectly compared to best
supportive care, Alimta preserved at least 50
percent of docetaxel's benefit over best supportive
With respect to non-inferiority analyses,
the 1.11 fixed margin was not met statistically,
and many p-values can be calculated different
methods, however, we can be confident that Alimta
retains docetaxel survival advantage over best
supportive care, not only from comparison to TAX
317B, but also comparison to other historical best
supportive care trials and the consistency of
Alimta's survival result across all first- and
second-line trials that you have heard.
Reviewing all secondary endpoints, the
following conclusions can be made from a direct
comparison to docetaxel from JMAI.
The time to progression is identical
almost. Progression-free survival was the same,
and the response rate was very similar. Over 50
percent of all patients on each arm showed improved
or stable symptoms.
Indirectly, the response rates of median
time to progression for Alimta are consistent
across all trials and show relevant activity in all
non-small cell lung cancer either in the first line
or second line, and these endpoints are superior to
historical best supportive care. So, this is what
Dr. Pazdur was talking about.
How do clinicians review efficacy of a
compound, and how can we tell if one seems similar
to another? It is helpful if there are multiple
Fortunately, there are five randomized
trials of docetaxel in the second-line
those five randomized trials are shown here.
Obviously, a meta-analysis has not been
done because some of these are recent, but these
are the five randomized trials using docetaxel 75
mg/m2 in one arm. These consistent results with
median survivals of 6 to 8 months in all trials
give us confidence about the effect of docetaxel.
In each of these five studies, docetaxel
75 mg/m2 was numerically superior to the
comparator. Note that two of these trials, the
comparator was docetaxel 100 mg/m2 with the worst
outcome. That is the reason there are not A versus
A + B trials in the second-line setting. Just a
little bit of extra neutropenia made survival worst
in these patients, and it does limit our ability to
develop new agents, because the A + A + B design is
very difficult in this setting.
If one were to review, then, the best
supportive care results from available second-line
randomized trials, once again we see consistent
Median survival in the best supportive
care arms was 4.5 and 5.5 months.
The BR21 slide results that are shown on
this slide is limited to those patients who got
second-line therapy, as that trial also included
some third-line patients.
These survival rates with the best
supportive care are clearly inferior to docetaxel.
Finally, when one reviews the median survival for
Alimta in this context, the similar outcomes of
docetaxel and the superiority to best supportive
care is obvious.
In summary, Alimta merits full approval as
a single agent for the treatment of patients with
locally advanced or metastatic non-small cell lung
cancer after prior chemotherapy.
There are many agents that have received
full approval that you know about, sometimes based
only on response rate. Here, we have data and
efficacy on response rate, progression-free
survival, and survival, as well as patient reported
Alimta has a superior response rate,
progression-free survival, and survival compared to
best supportive care. Alimta has similar response
rate, progression-free survival, and survival
compared to docetaxel.
The safety profile of Alimta is clearly
superior to docetaxel. There are many second-line
lung cancer patients. They deserve to be offered
the safest and most effective treatment that
physicians have available.
Approval of this drug will make a safe and
effective agent available for patients with this
Thank you for your attention.
DR. BRAWLEY: Thank you, Drs. Bunn,
Gralla, Herbst, Shepherd, and Paoletti, and your
support staffs for preparing the presentation.
We would now like to move to the FDA
presentation, the clinical review and the
The clinical review will be given by Dr.
Martin H. Cohen, M.D.
DR. COHEN: Good morning. My name is
Martin Cohen and I am going to present the FDA
clinical review of Alimta, also known as pemetrexed
My review will be followed by the FDA
statistical review by Dr. Wang.
The proposed indication for Alimta is as a
single agent for the treatment of patients with
locally advanced or metastatic non-small cell lung
cancer after prior chemotherapy.
A single study was submitted comparing
treatment with Alimta to treatment with docetaxel.
The stratification factors were performance status,
disease stage, number of prior regimens, response
to the last prior chemotherapy, whether or not the
patient received prior platinum or paclitaxel
therapy, homocysteine levels, and
I would like to comment on the
determination of baseline homocysteine values.
Elevated pre-treatment homocysteine values have
previously been shown to be an excellent predictor
of Alimta treatment toxicity and that reduction of
those elevated homocysteine levels with folic acid
and vitamin B12 was accompanied by a significant
reduction in Alimta toxicity.
Whether vitamin supplementation would also
decrease docetaxel toxicity is unknown. There is
no reason, however, not to expect a toxicity
reduction similar to that observed with Alimta.
Since docetaxel is the comparator in the
Alimta trial, this slide summarizes the clinical
materials that were submitted for approval of
docetaxel as second-line non-small cell lung
The first study listed on this slide, as
previously discussed, was reported by Dr. Shepherd
and colleagues. In this study, patients with
performance status zero to 2, who had failed one or
more platinum-based chemotherapy regimens, were
initially randomized to receive docetaxel 100 mg/m2
or best supportive care.
Because of early toxic deaths, the
protocol was amended to reduce the docetaxel dose
to 75 mg/m2. After this amendment, there were 55
patients who received docetaxel 75 mg/m2 and 49
patients who received best supportive care.
Docetaxel treatment gave a response rate
of 5.5 percent. The median survival was 7.5 months
for docetaxel versus 4.6 months for best supportive
care. The difference in overall survival was
statistically significant at a p-value of 0.01, and
one-year survival was 37 percent versus 12 percent,
and that also was statistically significant.
The second study on the slide was reported
by Fosella and colleagues. This was a randomized
trial comparing docetaxel 100 mg/m2 or docetaxel 75
mg/m2 to a physician's choice of either vinorelbine
The study population had a
of Stage IV patients and more patients who had
received two or more prior chemotherapy regimens
than did the Shepherd study. The docetaxel 100
mg/m2 dose was again associated with early toxic
deaths and will not be discussed further.
The 75 mg/m2 docetaxel-treated patients
had a response rate of 5.7 percent versus 0.8
percent for the physician's choice arm. The median
survivals were 5.7 to 5.6 months, and the one-year
survivals were 30 percent versus 20 percent.
The difference in overall survival between
the two treatment groups was not statistically
significant. The p-value for the one-year survival
difference was 0.025.
Alimta drug administration is shown on
this slide. Alimta 500 mg/m2 was administered
intravenously over 10 minutes on day 1 of a 21-day
Patients receiving Alimta, as mentioned
previously, also received folic acid, vitamin B12,
and dexamethasone at the doses and
on the slide.
Folic acid and vitamin B12 were
administered for the purpose of reducing blood
homocysteine levels so as to ameliorate Alimta
toxicity. Dexamethasone was given to prevent or
decrease the occurrence of skin rash.
Docetaxel drug administration is shown on
this slide. Docetaxel 75 mg/m2 was administered
intravenously over 60 minutes on day 1 of a 21-day
Dexamethasone in the doses scheduled
listed on the slide was given as prophylaxis
against fluid retention and hypersensitivity
There were 135 investigational sites in 23
countries that participated in this study, and
approximately 21 percent of the study population
came from United States institutions.
This slide demonstrates
characteristics. As shown the two treatment groups
were comparable for performance status, prior
chemotherapy regimens, prior platinum and
Approximately 30 percent of patients in
each treatment group had an elevated baseline
This slide shows efficacy endpoints. The
primary endpoint was overall survival, and the FDA
survival analysis will be discussed in the
following FDA presentation.
Secondary efficacy endpoints included
response rate and duration, time to progression,
progression free survival, and lung cancer systems
as measured by the Lung Cancer Symptom Scale.
Because progression free survival results
mirror time to progression, only the former will be
discussed on the subsequent slide. Similarly,
because no differences were identified between the
two patient groups in any of the Lung Cancer
Symptom Scales, symptom burden will also
Alimta treatment resulted in 1 complete
response and 23 partial responses, for an overall
response rate of 9.1 percent. Docetaxel treatment
resulted in no complete responses and 24 partial
responses, for a response rate of 8.8 percent.
The overlapping 95 percent confidence
limits of the two response rates are listed.
Median response durations were 4.6 months for
Alimta and 5.3 months for docetaxel.
This slide shows time to progression for
both the intent to treat, or ITT patient
population, and the randomized treated, or RT
As indicated, time to progression was
similar for Alimta and for docetaxel treatment
groups whether one compares results for either the
ITT or RT population groups. For the ITT
population, there was a slight advantage of median
time to progression favoring Alimta,
the RT population, there was a slight advantage
Now, we get to one of the more
controversial aspects of this review, the issue of
post-study chemotherapy. The patient population
analyzed in this slide is the randomized and
At the time of disease progression,
patients were allowed to receive post-study
chemotherapy. This slide lists the drugs that were
most frequently used. As indicated on this slide,
126 or 48 percent of Alimta-treated patients and
107 or 39 percent of docetaxel-treated patients
received post-study chemotherapy.
Of possible importance to a
non-inferiority survival analysis, 85 or 32 percent
of Alimta-treated patients crossed over to
docetaxel treatment. Patients on the docetaxel arm
were not permitted to cross over to Alimta, and
they received a variety of other drugs including
those listed on this slide.
This slide shows the median survival of
randomized treated populations who received or did
not receive post-study chemotherapy.
139 Alimta patients did not receive
post-study chemotherapy and 169 docetaxel-treated
patients did not receive post-study chemotherapy.
The 30 patient difference between the two treatment
arms might be important, because patients on both
study arms who did not receive post-study
chemotherapy had shorter median survivals, 6.2
months for Alimta patients and 5.0 months for
docetaxel patients than patients who did receive
post-study chemotherapy, as summarized in the last
two lines on this slide.
Because this slide demonstrates that
post-study chemotherapy improved survival, it is
important to look at patients who did not receive
post-study chemotherapy. The presumption might be
made that these patients were too sick to receive
treatment, and that is why they had a
This does not appear to be the case,
however. This slide shows the last recorded
performance status of patients who did not receive
post-study chemotherapy. Again, there were 139
Alimta-treated patients and 169 docetaxel-treated
As is evident from this slide, the large
majority of patients who did not receive post-study
chemotherapy were performance status zero or 1 at
their last study visit, and conceivably, could have
received additional treatment.
In our previous look at this slide, we
were concerned with patient who did not receive
post-study chemotherapy. We are now concerned with
patients who were treated.
While it appears that all treatments,
including post-study docetaxel or post-study other
chemotherapy, gave comparable survival results, it
must be remembered that these are not randomized
patients and that prognostic features of
may be very different.
Thus, post-study chemotherapy treatment
may well have been of more benefit than post-study
docetaxel treatment may well have been more
beneficial than other post-study chemotherapy
Turning now to safety considerations, this
slide shows patient exposure to treatment. The
median number of cycles we see by patients on each
treatment arm was 4, and there was no striking
difference in the percent of planned dose intensity
received by patients on either treatment arm.
This slide summarizes all toxicities
experienced by study patients regardless of
causality based on their CTC grade. As evidence
from this slide, there was no difference between
Alimta and docetaxel for Grade 1 and Grade 2
toxicities. For Grade 3 toxicity, Grade 4
toxicity, and Grade 3 or 4 toxicity, Alimta was
significantly less toxic than docetaxel.
Alimta's safety advantage for Grade 3 or 4
toxicity comes primarily from less neutropenia,
less febrile neutropenia, and less infection
Looking specifically at neutropenia, this
slide shows Grade 3 to 4 neutropenia accompanied
with fever or with infection. Thirty-six or 13
percent of docetaxel-treated patients had febrile
neutropenia versus 5 or 2 percent of Alimta-treated
Also, indicated on this slide, documented
infection in the setting of neutropenia occurred in
5.8 percent versus zero percent of docetaxel and
Alimta-treated patients, respectively.
Therefore, if one now looks at all
toxicities regardless of causality excluding white
blood cell events, such as decreased leukocytes and
lymphocytes, neutrophils, granulocytes, infections,
febrile neutropenia, or other white blood cell
related events, there is no longer a
difference between Alimta and docetaxel treatment.
For Grade 3 or 4 toxicity, for example,
the p-value is 0.781.
CTC Grade 3 or 4 adverse events regardless
of causality are listed on this slide. As
indicated, alopecia and diarrhea occurred
significantly more often with docetaxel treatment
than with Alimta treatment.
Grade 3 to 4 diarrhea occurred at 4
percent of docetaxel-treated patients versus 0.4
percent of Alimta-treated patients.
There was no statistically significant
difference in the occurrence of the other listed
toxicities - fatigue, nausea, vomiting, stomatitis,
pulmonary toxicity, or neurosensory toxicity.
Turning now to treatment emergent adverse
events, of TEAEs, this slide shows all treatment
emergent adverse events regardless of causality for
which there was a statistically significant
difference between treatment groups
based on an
uncorrected p-value of less than 0.001.
As shown, nausea, weight loss, increase in
hepatic enzymes, the alanine and aspartate amino
transferases, and decrease in creatinine clearance
were all more frequent in Alimta-treated patients.
Alopecia was worse in docetaxel-treated patients.
This slide shows all treatment emergent
adverse events regardless of causality for which
there was a statistically significant difference
between treatment groups and an uncorrected p less
than 0.05 value.
Myalgias, arthralgias, neurotoxicity, and
diarrhea were all more common in docetaxel-treated
patients, while constipation, fatigue, and skin
rash were more common in Alimta-treated patients.
Hospitalizations present a mixed picture.
Docetaxel-treated patients had somewhat more
hospital admissions, 364 versus 337, but
Alimta-treated patients spent somewhat more time in
the hospital, 1,722 days versus 1,410
As regards efficacy conclusions, you will
hear the opinion of the FDA statisticians regarding
Whatever your views on the relative merits
of the survival analyses, however, the fact is that
post-study chemotherapy confounds the survival
With regards to post-study chemotherapy,
there are two issues. The first issue is the
crossover of 85 Alimta-treated patients to
docetaxel treatment. While median survival of
these patient is similar to the median survival of
patients receiving other chemotherapy regimens,
such survival analyses do not take into account
possible prognostic differences between the various
The second issue is that patients who did
not receive post-study chemotherapy had a shorter
survival than those who did receive such treatment.
There were 30 more docetaxel-treated
Alimta-treated patients who did not receive
The large majority of untreated patients
had a performance status of zero or 1 at the time
of progression, and could conceivably have received
Alimta did show evidence of activity,
however, in that it produced a response rate of 9.1
The toxicity spectrum of docetaxel clearly
differs from that of Alimta, and this slide
summarizes the differences between the two drugs.
Docetaxel produces more neutropenia and
neutropenic complications, including febrile
neutropenia, infections, and need for
colony-stimulating factors. It also causes more
neurotoxicity, myalgias, alopecia, and diarrhea.
Alimta, on the other hand, produces more
thrombocytopenia, more skin rash, more nausea and
vomiting, more elevations of hepatic enzymes, a
decrease in creatinine clearance, and
loss than does docetaxel treatment.
An important point on this slide is that
folic acid and vitamin B12 supplements presumably
by reducing elevated homocysteine levels have been
shown to ameliorate Alimta toxicity. Whether such
supplements, which were not given to
docetaxel-treated patients, would ameliorate
docetaxel toxicity is not known.
Thank you for your attention.
DR. BRAWLEY: Thank you, Dr. Cohen.
Dr. Yong-Cheng Wang.
Yong-Cheng Wang, Ph.D.
DR. WANG: Thank you, Dr. Cohen.
Good morning. I am Yong-Cheng Wang, the
statistical reviewer for the application being
discussed today. In this presentation, I will
present the results of efficacy analysis of Study
Here is the outline of my presentation.
The results of protocol specified
analyses. Post-hoc 50 percent of retention non-inferiority
analyses, which was submitted in the
The critical issues in Study JMEI. The
results of secondary endpoint analyses. Efficacy
conclusions will be given at the end of this
The protocol specified two study
objectives, superiority hypothesis and fixed margin
In the superiority hypothesis, the goal is
to demonstrate that Alimta is more effective than
In the fixed margin non-inferiority
hypothesis, the goal is to demonstrate that Alimta
is not worse than docetaxel by 11 percent clinical
benefit, or in other words, that non-inferiority
margin is fixed at 1.11.
The fixed margin of 1.11 was specified at
the recommendation of EMEA, and was not based on
any historical trial data. However, from our
calculation, this margin is close to FDA/CBER
Here are the results of primary endpoint
overall survival analysis for the intent to treat
population. For the overall survival, the median
survival is 8.3 months for the Alimta group and 7.9
months for docetaxel group.
The study failed to demonstrate superior
efficacy of Alimta to docetaxel with a log-rank
p-value of 0.93. It also failed to demonstrate
non-inferiority based on the fixed margin
non-inferiority test. The p-value is 0.256.
Based on the Cox regression model, the HR
of Alimta versus docetaxel is 0.99 with 95 percent
confidence interval 0.82 to 1.2. The
non-inferiority margin 1.11 is less than the upper
For the randomized and treated population,
the results are similar to ITT population as
presented in the previous slide.
The sponsor also included a post hoc
non-inferiority hypothesis of 50 percent of
retention of docetaxel effect in the NDA
In this hypothesis, the goal is to
demonstrate that at least 50 percent of docetaxel
effect will be retained by Alimta. In the current
study, we have serious reservation about this
analysis as presented in the next few slides.
There are two major critical issues in
Study JMEI. First, the docetaxel effect is
estimated from only one small historical trial,
therefore, we cannot assure the ability to repeat
Also, we cannot reliably assess the
magnitude of the docetaxel effect.
Second, the survival results are
confounded by crossover of Alimta to docetaxel.
I will now go over the details
critical issues. The historical trial which is
used for the estimation of the docetaxel effect is
TAX 317. As presented here, this is a very small
trial, total of 104 patients were enrolled with 55
patients in the docetaxel arm and 49 patients in
the best supportive care arm.
So, the estimate of the docetaxel effect
is not reliable and not robust. Since this is the
only one historical trial used for the estimation
of docetaxel effect, the constancy assumption that
docetaxel effect in Study JMEI is the same as in
the historical trail cannot be verified.
It should also be noted that these results
are in the ITT population only, and we do not have
results based on the randomized and treated
This slide shows the critical issue of
treatment crossover of Alimta to docetaxel. There
are more than 30 percent patients who crossed over
from Alimta group to docetaxel group. Therefore,
the survival results are confounded.
I will now present the results of
secondary endpoints analysis.
This slide shows the results of survival
rate analysis. For the 6 month, Alimta has a
slightly higher relative risk than docetaxel in the
For the 12, 18, and 24 months, Alimta has
a slightly lower relative risk than docetaxel for
the survival rate.
This slide shows the results of time to
progressive disease. Alimta is not significantly
superior to docetaxel for the time to progressive
disease in the ITT population.
This slide shows the results of
progression-free survival. These results are
similar to the time to progressive disease.
This slide shows the results
rate analysis. Alimta is not significantly
superior to docetaxel with respect to tumor
response. The results of symptom improvement
analysis are not present either, as there was
missing data. Results were based on a subset of
patients in this open label study.
It should be noted that even though
p-values have been presented for all the secondary
endpoint analysis, these values are not
interpretable, and none of them are adjusted for
Efficacy conclusions. Based on the
overall survival analysis, a single, randomized,
open-label, multi-center study JMEI in advanced
non-small cell lung cancer patients treated with
Alimta versus docetaxel failed to demonstrate
superior efficacy of Alimta to docetaxel.
It also failed to demonstrate
non-inferiority compared to docetaxel.
The estimate of docetaxel effect based on
only one small historical trial is not
In the presence of treatment crossover
from Alimta to docetaxel, the survival results are
confounded and non-inferiority analysis is very
difficult to interpret.
Therefore, the result of 50 percent
retention non-inferiority analysis is not
Thank you for your attention.
DR. BRAWLEY: Thank you.
As we move forward, I would like to ask
Dr. Pazdur if he wants the current questions,
Question No. 1 and Question No. 2, and you would
like a vote on Question No. 1 and Question No. 2.
Thank you very much.
At this point, it is 10:31. I would
propose that we go to break until 10:45. I would
ask the members to be back in their seats at 10:45.
I think we can finish a little earlier today than
is currently posted.
DR. BRAWLEY: As we come to order, this is
the section for open public discussion. I
understand there is one discussant. I need to say
Both the Food and Drug Administration and
the public believe in a transparent process for
information gathering and decisionmaking. To
ensure such transparency at the open public hearing
session of the Advisory Committee meeting, FDA
believes that it is important to understand the
context of an individual's presentation.
For this reason, FDA encourages you, the
open public hearing speaker, at the beginning of
your written or oral statement to advise the
committee of any financial relationship that you
may have with the sponsor, its product, and, if
known, its direct competitors.
For example, this financial information
may include the sponsor's payment of your travel,
lodging, or other expenses in connection with your
attendance at the meeting.
Likewise, FDA encourages you at the
beginning of your statement to advise
if you do not have any such financial
relationships. If you choose not to address this
issue of financial relationships at the beginning
of your statement, it will not preclude you from
I am sorry. That is an official sort of
thing that has to be read into the record.
MS. POLLACK: I understand.
Open Public Hearing
DR. BRAWLEY: If you can introduce
yourself and begin your statement.
MS. POLLACK: Certainly. Good morning.
My name is Michelle Pollack and I am the Director
of Marketing and Development for the Wellness
Community, an international non-profit organization
that provides support, education, and hope to
people affected by cancer.
For the record, the Wellness Community
receives unrestricted educational funding from Eli
Lilly, however, we received no funding or
compensation for my presence here today.
The Wellness Community offers
programs including professionally led support
groups, educational seminars, nutritional
workshops, exercise and mind-body programs, among
Our mission is to help people living with
cancer regain a sense of control over their lives,
feel less isolated, and restore their hope for the
future regardless of the stage of their disease.
Last year, we provided support services to
more than 30,000 people with cancer including
people with locally advanced or metastatic
non-small cell lung cancer. Through the virtual
Wellness Community on-line, we were able to reach
even more people.
At the Wellness Community, we have learned
a great deal from those we support and we believe
in the importance and value of an educated and
empowered patient. Since people with cancer often
feel stigmatized, alone, and overwhelmed with
grief, they feel stronger and more hopeful when
they have more treatment options available to them.
With an estimated 174,000 new
lung cancer in 2004 in the United States alone,
with 80 percent of those non-small cell lung
cancer, there is no doubt that we are in need of
improved treatments, more manageable and tolerable
side effects, and greater accessibility to those
We have the opportunity to expand the
chances that these families have for a better life
with new treatment options, and we feel very
strongly about supporting that opportunity.
Today, I ask you to carefully consider the
plight of people with locally advanced or
metastatic non-small cell lung cancer and empathize
with the range of daily physiological and
psychosocial issues that they face.
Please take a leadership role in approving
a broader range of treatments and then encourage
patients to be informed, empowered, and optimistic
about the possibility of longer, healthier lives.
DR. BRAWLEY: Thank you, Ms. Pollack.
I believe there is no other
the open public hearing, am I correct? Hearing
none, then, we are going to move on.
I would like to ask the committee to
address any questions to either the sponsor or the
Questions from the Committee
DR. D'AGOSTINO: If I read correctly the
way the FDA has put the questions to us, the
discussion really gets onto secondary events and
toxicity, and so forth, but there is a couple of
comments in the front statement of the FDA about
the ability with the one small historical study to
actually estimate survival and also the crossovers.
I know they were mentioned in the
discussion of the sponsor, but I think it would be
useful to hear a response from Lilly in terms of
those two questions, so that we discuss them and
put them aside, or discuss them and think they are
DR. PAOLETTI: No crossover is inevitable
in a situation like that especially in
States. I will ask Dr. Frances Shepherd to review
the historical context of third-line treatment in
lung cancer to answer the question in this way.
Then, I will ask Dr. Bunn to respond to the
question in terms of what we have observed in our
data, and, finally, Dr. Scott Emerson from a
statistical point of view to address this issue.
DR. SHEPHERD: Yes, we really do not feel
that there was a significant effect on survival
from crossover. If we could have the first slide
You may be uncomfortable with the survival
that was achieved with docetaxel in the TAX 317 or
the TAX 320 trials. There have been several
studies that have followed after that of docetaxel
75 mg/m2, and as Dr. Bunn showed you, every single
one of those studies had a median survival in a
very tight range that was similar to the TAX 317
So, we now have at least five randomized
trials of docetaxel showing where the median
survival is expected to be in this
With respect to the best supportive care
arm, we have fewer studies, and there has been no
study in the third-line setting of chemotherapy.
Looking at this slide, though, a
retrospective study was done by the M.D. Anderson
and Institute Gustaf Ruce [ph] looking at 700
patients who had had first-line and second-line
chemotherapy. Of those, 43 were treated with
The response rate was a mere 2.3 percent,
and the median survival was less than four months.
When you look on the other side of the slide, this
is the subset analysis from the TAX 317 study.
This is the only randomized data that exist that
compare third-line chemotherapy to best supportive
care. We do not underestimate the small sample
size here. These are exploratory analyses, but
there is nothing in this curve that would suggest
that third-line chemotherapy contributes to
Next slide, please.
I am going to show you the survival curve
from the BR21 trial, No. 568. This is the survival
curve in the BR21 trial, which was a trial of
placebo and best supportive care versus erlotinib
in the second- and third-line setting. Erlotinib
showed a significant survival advantage.
I show this to you for two reasons. One,
to show you that the survival of the untreated
group, the median survival was 4.5 months, almost
identical to the best supportive care group of the
TAX 317 trial.
So, we have a supporting trial that
provides a similar survival advantage or
disadvantage with no treatment. So, it gives us a
little bit more confidence that the best supportive
care group in TAX 317 was exactly what we would
expect to see in larger populations.
Now, in actual fact, if you look
carefully, more patients on the docetaxel arm
received Iressa, a drug very similar to Tarceva, in
the third-line setting. So, in actual fact, the
only treatment that has been shown to
survival in the third-line setting is an EGFR
inhibitor and more patients on the docetaxel arm,
four times as many patients on the docetaxel arm
actually received that kind of treatment.
So, if anything, that would have favored
docetaxel and not Alimta.
DR. BUNN: Not only do we wish that we had
more treatments in the third-line setting to make
people live longer, but when we look at the
analysis, it is not, I don't think, appropriate to
say that the third-line treatment made people live
longer in the study.
People who got chemotherapy in the
third-line did live longer, but that is just a
prognostic group. That is like saying responders
live longer than aggressive disease. That doesn't
mean that the treatment made them live longer.
But we looked very hard to try to sort out
whether there was any evidence that third-line
treatment did anything here to the best of our
So, you see here on the top of
is the overall survival results, and presumably,
the third-line therapy is given after some period
of time, and if it had an effect, the curves might
look different at the end.
I think it is easy to say, in the survival
curve, there is no difference in the beginning,
there is also no difference at the end.
If there had been a difference in
progression, the time of progression, it might have
favored one group, and on the lower left you see
that the time to progressive disease was identical
in the two things.
Finally, if there was an effect post
study, the post-study survival is shown in the
lower right curve, as I showed before, and there
was absolutely no evidence, not even a hint that
there was some survival effect in the post-study
Obviously, post hoc analyses like this are
difficult, and there are many statistical issues.
I am going to ask the statistician to get up, from
a clinical point, no matter how we
looked at this,
we couldn't find any evidence that there was an
effect of post-study treatment that was different
between the groups.
DR. PAOLETTI: Dr. Emerson, please.
DR. EMERSON: Scott Emerson from the
University of Washington. Slide 64, please. This
is a slide, that this is now the fourth time we
have seen this in some version, and as Dr. Bunn
remarked earlier, this is a very biased
presentation, this is not really a very informative
presentation at all, and I would just like to point
out what we can say from this and what we can't say
We certainly can say that those people who
survived long enough to get post-study chemo,
survived longer than those who didn't survive
longer to get post-study chemo.
The grouping is true, that there is longer
survival among those who got post-study chemo, but
that is not quite as strong as what Dr. Cohen said
when he said that the post-study chemo made you
So, to address that, if I could have the
slide 669. We did an analysis that tried to
compare apples more with apples. Let's compare
those people who got post-study chemotherapy at a
certain point in time with other people who had
also survived that long, so we will assign your
group as to whether you got post-study chemo
according to the time that you are on the study.
So, this time-variant covariate analysis
allows us to compare Alimta to docetaxel, keeping
that post-study chemo variable constant across the
groups being compare.
It also allows us to estimate the effect
of post-study chemotherapy. Let me qualify what
that effect is. It allows me to estimate the
difference in survival among those who got post-study
chemotherapy to the survival among those who
I am not going to claim that this is truly
a cause and effect, because, of course, this isn't
randomized. There was a lot of physician
discretion that went into this.
But from this analysis, if I look among
patients who had no post-study chemotherapy at any
time during the study--and again I would have
switched them to another group if they had--the
Alimta to docetaxel hazard ratio is actually 0.84,
it is looking a stronger effect than we saw when we
just did the intention to treat or RT analyses.
If we look at the effect of post-study
chemotherapy, now I am just going to look at among
those patients alive at any given time, on the
docetaxel arm, who are getting post-study
chemotherapy compared to those on the docetaxel arm
that aren't getting post-study chemotherapy at that
same time, the hazard ratio is 1.12. This estimate
suggests there is a 12 percent increased risk of
death if you get post-study chemotherapy.
On the Alimta arm, it is far more
striking. There is a 58 percent higher chance of
death among those subjects on the Alimta arm who
are getting post-study chemotherapy relative to
those who don't.
So, this nonrandomized
comparison, which I
don't really believe is the effect of post-study
chemotherapy, but this analysis would suggest quite
the contrary to what was worried about, was that
the post-study chemotherapy is responsible for the
better survival is actually if we took this at face
value, you would say if we could just write in the
indication that you don't do any post-study
chemotherapy, we are doing better than docetaxel.
I don't believe that, because I truly
believe that physicians are pretty smart.
Can we go back to slide 64 for a moment.
What we see here is that 139 subjects had
no post-study chemotherapy on Alimta and 169
subjects on docetaxel. My personal belief would be
that physicians, faced with a progression or a
patient who is failing on Alimta, would recognize
that docetaxel has been approved for second-line
therapy and those patients should really give that
I think that physicians are pretty able to
recognize when patients are in trouble, that they
are on a path towards worse and worse
and I personally believe that that is the primary
effect that we are seeing with that greater rate.
Patients on docetaxel could not be
switched to another therapy if, in fact, they were
already experiencing a fair amount of toxicity.
You wouldn't want to try them again on that
chemotherapy. We may just be seeing physician
behavior, so again, I am not claiming that that
higher post-study therapy is there, but I am
claiming that we don't have any evidence to suggest
in this data that there is an added benefit of
post-study chemotherapy to improve survival.
Lastly, if I could see slide 20, just to
make a point again that Dr. Shepherd made, and that
is this concept that in this study, the patients
receiving that third-line chemotherapy were not
randomized, but in TAX 317, they were randomized.
It is a subgroup analysis, but when we did
a randomization based on that, we clearly saw no
benefit. That would be presumption, that if we had
done randomization to third-line therapy, that this
would likely have been the case and that
wouldn't have seen that added risk.
DR. PAOLETTI: Dr. D'Agostino, should we
answer your second question, or do you want to
continue on this issue?
DR. D'AGOSTINO: It is up to the Chair.
DR. BRAWLEY: Go ahead with the second
DR. D'AGOSTINO: You don't want to ask
questions on what they just presented?
DR. BRAWLEY: Does anyone have questions
on what was just presented?
DR. D'AGOSTINO: I have a question.
DR. BRAWLEY: Oh, go ahead, I am sorry. I
DR. D'AGOSTINO: What if Alimta was not
effective at all, and it was just the
post-chemotherapy of the crossover that gave these
individuals an increased survival? I don't think
there is an interpretation that they just gave us,
but there is another interpretation that is just as
viable, that the crossover is adding quite a bit to
the--it's not the third line--it's the
The other thing is that I am concerned
with really Dr. Cohen's presentation where he
showed that those who didn't get the added
chemotherapy on the prognosis basis looked pretty
good, and it is hard for to me to understand that
the third line isn't helpful, yet, the ones who
didn't get any added to their line, that some are
crossovers, some aren't doing as well.
I don't really want to make a big
statistic discussion out of it, because I agree 100
percent that we are beyond statistics, it is just
that it does raise a question about how to deal
with this type of data.
DR. EMERSON: Could I address your second
question just slightly. Performance status, we got
identical results essentially in the time variant
covariate, if I adjusted for a time variant
performance status, as well, in this trial.
DR. PAOLETTI: As regards the question
about efficacy, it's a point like progression-free
survival, time to progression of disease
there is no effect of crossover, the results are
identical, as well as response rate.
DR. BUNN: I think if Alimta had no effect
in the early analysis for time to progression, we
would have seen a difference, and we would have
seen a survival difference if it didn't have any
effect. We probably would have seen a response
rate different, and we probably would have seen a
patient reported outcome difference if it didn't
have any effect.
DR. D'AGOSTINO: I mean that was an
extreme statement I made. The point is that it may
be it is not as effective as, and it is the added
boost of the chemotherapy, the second- or the
third-line chemotherapy that makes the difference.
I don't see how you can sort that out from the
DR. BUNN: I would just like to comment
about, you know, giving third-line therapy. You
know, we are oncologists and we generally like to
offer therapy where it might be
effective, and I
think that most of our patients would prefer to get
treatment where it would be effective.
There does come a time when neither the
patient nor the physician is anxious to give
chemotherapy. Usually, that is in people who are
quite ill. Sometimes they are ill and show up as a
performance status, but sometimes they have been
beat up by chemotherapy and they don't have
sufficient blood counts, or they have neuropathy,
or they have many other things that would preclude.
It is hard to imagine, to me, that the
physicians would have a bias in the third-line
setting about treating or not treating patients.
As a doctor, I find that hard to believe.
DR. D'AGOSTINO: I didn't say anything
DR. PAOLETTI: Dr. Shepherd.
DR. SHEPHERD: Just one further point. I
think the point that Dr. Cohen made showing us how
many good performance status patients do not get
chemotherapy underlines the belief of the lung
cancer treating oncologist that
chemotherapy is not beneficial.
When you have no evidence from historical
data to suggest a survival benefit, when you have a
response rate less than 3 percent, the potential
for toxicity is higher than the potential for
benefit, so clinical practice on the whole is not
to offer chemotherapy.
You don't want to make a performance
status zero or 1 patient, performance status 3 or 4
with toxicity, if you don't have a good chance of
DR. NGUYEN: Maybe another clarification
on this point. Binh Nguyen, Eli Lilly, Oncology
I would like to address Dr. D'Agostino's
questions. 471, please. Out of those performance
status that were shown by Dr. Cohen, actually, the
patient who would perform zero and 1 and alive at
one month after discontinuation is only half, so
not all those 139, 169 could receive chemotherapy,
so you have to take that into consideration and
look at the difference between the two
drop now is not 30 patients, it is only 12
So, it is obvious these patients actually
die very quickly, that is why they couldn't receive
post-chemotherapy even thought they had a
performance status of zero and 1. I think these
data are very important.
DR. D'AGOSTINO: I think this is the type
of discussion I was hoping to hear in terms of
responses, why are they looking so good, are they
really dying or not dying. The group actually
again, even though there is this discussion that we
heard, the ones who did not get the second shot out
at the third-line chemotherapy do not do as well,
and it is just not clear to me yet that there is an
obvious reason that one can see on that.
DR. BRAWLEY: Dr. D'Agostino, did you have
a second question?
DR. D'AGOSTINO: I asked a second
question. That was about the sample size.
DR. BRAWLEY: Dr. Mortimer.
DR. PAOLETTI: Actually, you were
referring to the non-inferiority design, et cetera.
Again, we acknowledge that the historical data at
the beginning, when we designed this trial, were
limited to the TAX 317.
However, as Dr. Bunn was showing at the
conclusion of his presentation, additional
historical data, additional data were growing
during all this year, and most importantly, the
results from our trial in 288 patients are
confirming the performance of the TAX 317.
I would like to ask Dr. Don Berry to
answer the question from a statistical point of
DR. BRAWLEY: I think we need to move on.
DR. MORTIMER: I have two sort of
questions. One relates to a comment Dr. Shepherd
just made. I mean is it possible to ferret out the
patients who were on the docetaxel arm who might
have actually refused therapy because of the risk
of hospitalization since they were hospitalized
Secondly, is there a
patterns of relapse in these arms, specifically,
DR. PAOLETTI: Not to my knowledge, but I
will ask--no, actually.
DR. BRAWLEY: Dr. Perry.
DR. PERRY: Thank you. I have a question
for Dr. Pazdur. Did the study proponents run this
proposal through the FDA, was it approved by the
FDA before it was actually set into place?
DR. PAZDUR: I would have to check if it
had a special protocol assessment. Obviously, it
was discussed with the sponsor, the design of the
trial. Whether or not there was a special protocol
assessment, I would have to check on that.
DR. PERRY: The issue to me is there is a
lot of criticism of the protocol design,
particularly about the crossover, and if the