What our focus is tonight is the goal of targeting multiple therapies.
By targeting both the EGFR with Erlotinib and monoclonal antibodies
with cetuximab, targeting VEGF receptor with bevacizumab, we can
target both of these by adding therapies, monoclonal antibodies,
oral tyrosine kinase inhibitors for EGFR. We can add to that regimen
with an anti-VEGF antibody such as bevacizumab. There are small
molecule VEGFR tyrosine kinase inhibitors in clinical development,
and the ultimate goal then is dual target inhibition.
Ultimately, and I’d like to just introduce this slide because
Dr. Sandler will be going through this slide in more detail, but
this just kind of ties it all together as to the microenvironment
and within the tumor environment, the interaction and the potential
that dual targeting therapies can provide for our patients in
clinical practice.
With that
I would like to go ahead and say thank you very much. We will
take questions at the end but go ahead and fill out your question
cards. Thank you.
Hello
and thanks very much for inviting me to speak. This is my first
ONS meeting so I am just a tad bit nervous here. Anybody from
Nashville, Texas, where I’m from? I thought I saw one. Okay.
I’ll be emphasizing the clinical data on the use of antiangiogenic
agents and antiepidermal growth factor receptor agents, both oral
and antibodies, and also talk about the combination. I have about
25 minutes to do that, so I get to talk fast. I can’t do
that down in Nashville, but I can do that here, I think.
First we will talk about EGFR inhibition or specifically looking
at non-small cell lung cancer and we’ll talk about the chemotherapy
naive patients. Unfortunately, this is the topic where things
haven’t panned out quite as well as we would have thought.
There was preclinical data that suggested putting EGFR inhibitors
with chemotherapy. Preclinical models suggested that there was
at least additivity.
Based on that, there were four very large randomized phase III
studies that were undertaken involving two distinct epidermal
growth factor receptor TK inhibitors. One was gefitinib and another
was erlotinib. Each of those agents were studied in two randomized
studies using two different chemotherapy agents. The basic premise
of this study was chemotherapy for everybody, placebo, or the
oral agent done in a randomized fashion. Each study was over 1000
patients and survival was the principal end point. There was no
crossover.
Unfortunately,
all four of these studies were negative, and so there is no data
to support the use of these oral EGFR-TKI with chemotherapy, at
least in the front-line setting.
The next group of the patients that were studied were looking
at patients who had previously received chemotherapy, but who
had progressed on chemotherapy, and looking at these agents alone
in this patient population.
Let’s look at this somewhat busy slide. If we break it down
and we look at the last two columns here, this is the data of
what you’d expect for patients who are receiving chemotherapy
either in the second or third line setting, and that’s with
docetaxel. This is a randomized study that was done several years
ago comparing docetaxel over supportive care. If you look at the
supportive care, you’d expect about a 4 to 5 month survival
for untreated patients in the second and third line setting. We
know that chemotherapy in the form of docetaxel has shown to improve
survival to the tune of about 7 months. This is sort of the bar
that had been set with chemotherapy.
Now these
EGFR-TK inhibitors had been studied in the same fashion. These
are non-randomized studies. These are just phase II studies where
there is no placebo arm, but at least it gives us a hint that
in fact, these agents have activity, as evidenced by response
rates by about 12% to 20%, and then about another 30% to 40% of
patients who have stable to minimally responsive disease; so really
benefitting about almost half of the patients in some fashion
and looking at the survival data that would appear to be pretty
similar to chemotherapy with obviously a lot less toxicity which
we will talk about later on. Basically, skin NGI toxicity.
In fact,
based on this data, gefitinib actually received initial approval
in the third line setting based on what, at the time, was a non-randomized
study, a non-placebo controlled study and we‘ll talk about
that in a bit.
The first randomized study that looked at an EGFR-TK inhibitor
in a placebo-controlled randomized study was actually with erlotinib.
Based on the initial study of a small phase II study that looked
promising, they conducted a phase III study. Again, this was in
patients who had one or two prior chemotherapy regiments. Interestingly,
if you look at the performance status, it includes zero to three.
In terms of chemotherapy, we sort of considered giving chemotherapy
to PS2s and we would never even think of giving chemotherapy to
a performance status 3 patient. Bear that in mind that it was
a group that, in fact, a third of patients were actually PS2s
and 3s in this study. The randomization, again, are erlotinib,
2/3 of the patients received erlotinib, and 1/3 received placebo.
This is the survival curve. Shown here, statistically significant,
a 28% overall improvement, reduction in death with erlotinib,
median survival of 6.7 versus 4.7 months. But of course, as you
all know, the median survival is not really the best way to look
at a cure. That only shows one point on a curve, where half of
the folks do less well and half of the folks do better.
I think a
better way to look at, particularly for patients from their perspective,
is to take a point farther down on the curve, say the one year
mark, and see how they do. Here you see about a 40% improvement
in those patients alive at one year with erlotinib versus placebo.
This, I think is a bit more easier to understand for a patient.
It gives them the idea, the concept of what chance do they have
of maybe reaching that next anniversary or seeing the birth of
another grandchild, or something of that nature.
Based on
this randomized study, and this randomized study was conducted
by the National Cancer Institute of Canada and did not include
too many patients from the U.S.; they were mostly Canadian and
overseas. Again, based on the results of this study, erlotinib
was approved for use in both the second and third line setting
in the United States.
We all have
heard recently some information regarding mutations in the EGFR.
I’m not going to talk about that very much except to say
that it seems to be that the mutation sort of correlates with
that 10% of patients that have dramatic responses. There were
a lot of questions that were raised saying that maybe the results
of that study only was seen because of the benefits of those patients
with the mutation, which is really only about 10% of the population.
What was done was a subset analysis in this study looking at various
subsets to see whether or not that was actually true. What you
can see, this is called the forest plot where basically this line
is sort of the zero point, in this case it’s called 1, but
if the slash marks are here on the left that’s good, that
means erlotinib was working. If it’s on the right that means
it wasn’t working. You can see that really in all the subgroups
that were looked at, even those patients with squamous cell, because
it looks like the mutations occur predominantly in women, adenocarcinomas,
and never smokers.
If you look
at the groups, men seem to be benefitted by treatment. Squamous
cell seems to be benefitted by treatment. Even the current or
ex-smoker seems to receive benefit from treatment. It’s
pretty convincing evidence that this agent works not only in those
patients with mutations, but works across all subsets of patients.
The next
slide also looks at some other subsets as well. It didn’t
seem to matter whether they received taxane initially or not,
and what their previous treatment response to initial therapy
was. The outlier was those who had no prior platinum therapy.
There were only 50 patients out of 680; unclear whether that’s
actually important or not.
Their suggestion
is that maybe it’s important to be EGFR positive, not the
mutation but just an over expressed EGFR, and that actually occurs
in about 80% of patients with non small cell. People are still
studying that.
Now there’s the ISEL study. Gefitinib, the other TK inhibitor
that was already approved, was to undergo several randomized phase
III studies to sort of prove the results from the phase II. This
is that first study that is a similar design to the erlotinib,
gefitinib versus placebo, performance status 0 to 3, one or two
prior chemotherapies. This was a much larger study, almost 1700
patients. The other study was about 700, and about 800 patients
had adenocarcinoma. This study was designed at the time that people
already had a hint that certain subgroups seemed to do better.
Despite sort of emphasizing the better patient populations, this
study actually proved to be negative. There was no difference
in survival between gefitinib and placebo in terms of overall
survival for the whole group, even though you had just looked
at the adenocarcinomas. There is some question as to what’s
going to happen to gefitinib, as to whether it will be removed
from the market or not, and the FDA is going over that data currently.
Looking at cetuximab, which is an antibody to EGFR receptor, these
are results of phase II studies that were done in the U.S. You
may remember these studies. It’s what got Martha in trouble.
But basically, this is - yes, you do remember. I had a couple
of slides but decided to not put those in.
There is
irinotecan and cetuximab in combination in patients who have already
been treated and progressed on irinotecan, and it looked as if
there was, again, a response rate of 22.5%, suggesting maybe some
sort of synergy between the two. Looking at cetuximab alone in
that patient population with a response rate of about 9%; clearly,
some activity with this antibody to EGFR in colorectal cancer.
This is the fairly landmark study published in the New England
Journal of Medicine last year that looked at the combination of
cetuximab and irinotecan at the same time or giving it in a sequential
fashion, cetuximab followed by irinotecan. For most oncologists,
this is kind of interesting because when someone progresses on
chemotherapy, I typically stop the chemotherapy and move on to
something else. This would suggest, at least, that maybe continuing
the chemotherapy and then adding cetuximab appears to be the way
to go, at least in colorectal cancer patients, as you see improvement
in time to progression and survival as well. Based on this data,
cetuximab was approved for use in patients refractory to CPT-11.
A slide that you’ve essentially seen lots of ways to target
the VEGF pathway, either with antibodies or oral agents to the
tyrosine kinase and we’ll emphasize those two ways of attacking
this particular pathway. This anti-VEGF antibody, of course, is
bevacizumab and there are oral agents that I will talk about,
TK inhibitors of the VEGF receptor as well.
This is a slide that summarizes randomized phase III data looking
at bevacizumab in combination with chemotherapy versus chemotherapy
alone. Actually, in fact, since I’ve made this slide a couple
of weeks ago, there has actually been one additional study that
has been completed and is positive. I’ll tell you about
that. There was, a year or two ago, a negative study that looked
at capecitabine with or without bevacizumab in heavily pretreated
patients with metastatic breast cancer. There has now been a front-line
study looking at Taxol +/- bevacizumab that is a positive study.
There was top-line data that was in the Nurse, I think, this past
week and that will be presented at ASCO in a couple of weeks.
There has
also been a randomized study looking at bevacizumab alone in one
of two doses versus placebo in renal cell patients; a positive
study in terms of time to progression. There’s a front-line
study in colorectal cancer, chemotherapy in terms of IFL with
or without bevacizumab; a positive study. This was about a year
ago, last year’s ASCO. In terms of survival, there was about
a 33% improvement in survival. If you look at oncology, you don’t
see P-values with four zeros before the number very often.
The second
line, this was an ECOG study that will be presented at ASCO this
year, another positive study in terms of median survival. A study
that I was fortunate enough to lead through ECOG looking at Taxol
and carboplatin, alone or with bevacizumab, was just found to
be positive, as well with the additional of bevacizumab versus
chemotherapy, and we’ll present this at ASCO this year.
There’s
a lot of data that suggests that is very interesting that we thought
ahead of time that by blocking angiogenesis it should work across
all tissue types, all types of malignancies.
Because the
concept is not unique to any one, particularly malignancy, and
so this is information that, in fact, that concept is true.
The other
think that’s striking is that I used to think, this is all
bevacizumab, which of course is Genentech’s agent, so I
used to think after I saw this was positive and then this one
was that God merely smiled upon Genentech. Now after this one
and the data that’s already out now with trastuzumab, the
data that’s out with erlotinib, I actually believe that
she’s a stockholder in Genentech. You noticed I said she
right? Okay. The speaker always has to know his or her audience.
A similar type study was performed in metastatic colon cancer,
both in untreated patient populations and previously treated patient
populations with an agent from Novartis. This is an oral agent
that inhibits the VEGF receptor, so it’s an oral TK inhibitor.
That, again, is a chemotherapy alone or chemotherapy with the
oral agent. These results were also made available in the news
a couple of weeks ago and will be presented at ASCO. Unfortunately,
this is a negative result. It’s kind of interesting that
maybe there is something that antibodies seem to be working a
bit better than these oral agents, the small molecules, at least
in certain instances.
This is an ongoing study. The original study that I showed you
in metastatic renal cell was looking at the bevacizumab alone
versus placebo. There is now a study that’s ongoing through
the CALGB, combining it with interferon versus interferon alone
in metastatic renal cell to see if that provides a benefit. The
previous study was in patients who had failed immunotherapy.
Another agent, this is an oral agent that is a multitargeted oral
agent, SU-11248. This is an agent from Pfizer that targets multiple
pathways including C-KIT, that same pathway receptor that Gleevec
blocks, but this one actually also is an oral inhibitor, TK inhibitor,
of VEGF and basically most of its effects seems to be that way.
This is a phase I and II study that was seen previously, treated
renal cell carcinoma and you see that there are responses again
seen in this. In the phase II, again, significant activity that
has been seen roughly about 40%, which is unheard of in metastatic
renal cell carcinoma. Again, a lot of enthusiasm for blocking
angiogenesis across multiple tumor types.
Well good.
Now I get to talk about something that I actually know a little
bit about. We’ll talk about combining targeted agents and
we’ll talk about it in non-small cell lung cancer.
Here is that
slide again that Ms. Woods pointed out earlier. This is a study
that Roy Herbst did at M.D. Anderson and myself at Vanderbilt
and it was a phase I, phase II study combining the oral EGFR-TK
inhibitor erlotinib with the antibody to VEGF bevacizumab. Basically,
the objectives of the study were to look at whether we could put
these two together. No one had ever done that before and to see
if whether were able to do that without causing any untoward toxicity.
Then, of course, once having proven that, the next step was to
see whether there was any enhanced activity. I should tell you
that there’s actually some preclinical data using agents
in this class, not these two specifically, but agents in this
class that showed that there was some additivity preclinically
in mouse models that would suggest that utilizing these two agents
together would be beneficial.
So the rationale is here. This is the slide that Laura showed.
What it does is that it shows -and Roy Herbst has talked about
this before - that you think of cancer as actually an organ because
there are multiple tissue types within a cancer, if you will,
within a tumor. Within the tumor there is the actual malignant
cell itself but there is the structural components with the cell
such as the neovasculature.
Erlotinib
attacks the tumor cell itself. Bevacizumab attacks the blood vessels.
Dig, there is some overlap between the two because the tumor itself
produces pro-angiogenic factors such as bFGF, as well as VEGF.
By inhibiting both of these, you should get additivity if not,
potentially synergy by targeting both pathways.
What we found overall, yes, we were able to complete the phase
1 without any unusual side-effects and that we could combine these
two agents both at their single agent phase to dose so we are
able to use 150 mg daily of erlotinib and then 15 mg/kg every
three weeks of bevacizumab. We saw responses in 8 out of 40 patients,
which is 20% that was pretty exciting. Again, with erlotinib alone
you’d expect about 10%. We also saw stable disease in 65%
of the patients. Basically, there were only 15% of the patients
who actually progressed initially on therapy. We are pretty excited
about that. There were no unusual side effects that were seen.
This is the progression-free survival. The green line is what
you pay attention to. The blue line is just a confidence interval.
Here is the green line here. Median time to progression of seven
months. You’d have expected two to three months in this
patient population. These were all previously treated patients.
Forty-five percent had one prior chemotherapy, 55% of the patients
pro-angiogenic, two or more prior therapies.
This is the overall survival. Again, the green is the curb. The
blue is our confidence intervals, 12.6 months for the median survival;
you would expect in an untreated population about four months;
chemotherapy alone or erlotinib alone about seven months. Again,
enthusiastic about that, but that’s obviously a phase II
study and we need randomized studies to confirm that. Randomized
studies are either ongoing; one looking at the bevacizumab and
erlotinib, compared to docetaxel and bevacizumab or docetaxel
and placebo. Another randomized phase III looking at bevacizumab
and erlotinib versus erlotinib alone is planned.
This combination has been studied in other diseases as well. This
is renal cell and this study actually went on in Nashville, Tennessee
at Vanderbilt as well as the Sara Cannon Group. They saw responses
in 21% and then again those patients were stable or minor responses
in an additional 66%; overall control rate of 87%; again, pretty
much unheard of in renal cell.
Lastly, I think this is the last combination looking at bevacizumab.
This is again, irinotecan refractory colorectal carcinoma with
the concept again being those folks who had measurable metastatic
colorectal cancer previously treated with irinotecan but then
suffering with progression.
The design of the study is to look at cetuximab and bevacizumab,
so a slightly different approach. This is looking at two antibodies:
antibody to EGFR and antibody to VEGF, versus the same combination
with irinotecan, again, with the concept that maybe there’s
some sort of synergy even if someone has progressed on irinotecan
but that there is some synergy that occurs once you add an agent
like bevacizumab to that, so this is that randomized study.
These are some of the results. This is comparing it to historical
data, if you will. This is looking at cetuximab, irinotecan, and
bevacizumab with a time to progression of 8.4 months. When you
compare it to previous studies of cetuximab and irinotecan, four
months, it looks a lot better. It’s kind of actually illegal
to use a P-value here because you’re comparing it to historical
data but just to show that it seems to be fairly significant.
That same thing is looking at cetuximab alone or cetuximab and
bevacizumab. Remember, this was not the study itself where they
randomized patients to either those just looking at historical
data here and what they saw at 6.9 months, time to progression
in the study itself, which again looks very favorable and it’s
something, of course, looks to be worth pursuing.
It’s
time for questions.
Which of
the below are EGFR tyrosine kinase inhibitors:
A) Gefitinib
and panitumumab.
B) Cetuximab and erlotinib
C) Erlotinib and gefitinib
D) Panitumumab and bevacizumab.
For those
of you who get it wrong, we know which buttons you’re pushing,
we know what table you’re at.
The answer
is; you also realize I lose my honorarium if less than 80% of
you get it right.
Well, you
did a lot better teaching than I did. I didn’t even mention
panitumumab. You guys obviously haven’t been taking standarized
tests for a while, have you? Alright, I’m going to give
you one more try.
EGFR inhibitors
and anti-VEGF agents have been combined in clinical trials with
promising results. An example of this combination is:
A) Bevacizumab
and cetuximab.
B) Erlotinib and bevacizumab.
C) Rituximab and gefitinib.
D) Both A and B.
E) All of the above.
Come on.
Well, better. Okay, here is the honorarium. I obviously don’t
know what I’m doing here. Okay. Thanks very much.
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