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You are here: Home: BCU 6|2002: Supplement: Joyce O'Shaughnessy,
MD
DR LOVE: When I first talked to you about this
trial, which has generated a lot of interest, one of the obvious
questions, I think, that came up immediately is where is this going
to head in terms of the adjuvant and neoadjuvant setting? What’s
happened since then, and where are you with that?
DR O’SHAUGHNESSY:
A lot has really happened since then. It’s amazing how quickly
this has come about, actually. I guess we all stand up and salute
when there’s a survival advantage in metastatic breast cancer
because we can count on just a couple of fingers any clinical trial
that has given us that. So, I guess that’s why it’s
happened so quickly.
Probably the most important thing is that the NSABP is going to
take this into their next neoadjuvant clinical trial. In the B-27
study that they presented at San Antonio, which was the preoperative
three-arm randomization for operable breast cancer, either clinically
node-negative or node-positive, three way randomization to AC preoperatively
followed by surgery versus AC preoperatively followed by Taxotere,
100 per meter every three weeks for four cycles preoperatively followed
by surgery, or AC preoperatively, surgery, and then Taxotere postoperatively,
what they showed was a doubling of the pathologic CR rate in the
breast when you added the Taxotere preoperatively compared to just
AC alone. So, they don’t have any disease-free or overall
survival data yet, but impressive doubling of pathologic response
rate in both ER-PR-negative and ER-PR-positive, which is a key point
for us, clinicians. So, they are going to make that the standard
arm of their next clinical trial; AC for four, followed by Taxotere
for four, preoperatively, will be their next standard arm. They’ve
decided that the investigational arm will be AC for four, followed
by Taxotere-Xeloda for four. And that’s really cool.
Now, U.S. Oncology is going to do that exact clinical trial design,
except in the adjuvant setting. So, our patient eligibility will
be any node-positive or high-risk node-negative, and they’ll
either receive AC followed by Taxotere or AC followed by Taxotere-Xeloda.
Our doses will be Taxotere, 75 per meter, with Xeloda, 950 per meter
BID, which is 1,900. And that represents a 25-percent dose reduction,
down from the 2,500 milligrams per meter squared. That is okay because
all of our analyses – and there’s been extensive analyses
done now – looking at the effectiveness of either Xeloda alone
or XT combination in the patients who got a 25-percent dose reduction
in Xeloda, it’s interesting. In the XT arm – and I just
saw this analysis – the median delivered dose intensity of
Xeloda on the XT was 75 percent of the intended dose. Interestingly,
that took place by Cycle 2.
So, in fact, that survival advantage really, for all intents and
purposes, took place with a 25-percent dose reduction in the Xeloda
dose. So, the delivered dose intensity – and that was a combination
of dose reduction, as well as some interruptions – was by
Cycle 2. You were down to a delivered dose intensity of 1,900 per
meter, and that maintained. That did not drop during the rest of
the study, it maintained. So, I think that’s very persuasive
evidence that you’re going to still have your effectiveness
with 75 percent of the full dose Xeloda.
DR LOVE: Now, both of these new trials are going
to include both ER-positive and ER-negative patients?
DR O’SHAUGHNESSY:
Yes. Ours for sure is, and I believe the NSABP’s will as well.
DR LOVE: So, you’re not too persuaded by
the subset analyses in terms of ER and taxanes?
DR O’SHAUGHNESSY:Well,
we are all kind of watching that one with interest and trying to
scratch our heads there. As you know, with the AC followed by Taxol,
the subset analysis, both in the B-28 and the CALGB 9344, all show
a very interesting and clinically significant trend towards an improved
hazard ratio for mortality in the ER-PR-negative subset. But it’s
very unimpressive in the ER-PR-positive. It’s virtually nothing
in the ER-PR-positive group. So, here comes the B-27 then, and looks
at pathologic CR rates in the breast. But what’s interesting
is, if you look at the ER-PR-negative subset, the pathologic CR
rate with AC was about 13 percent, and it doubled to 25 percent
with the AC followed by Taxotere. So, it went from 13 to 25 in the
ER-PR-negative. In the ER-PR-positive, I’ve heard two separate
numbers. One was six percent with the AC alone, going to 13 percent,
also a doubling, but much smaller to start off with. The other number
I heard was five percent going to 14 percent. But in that, about
half of the effectiveness in terms of pathologic CR rate in the
breast as your end point, half the effectiveness of chemotherapy
in the ER-PR-positive group compared to the ER-PR-negative group.
DR LOVE: But still a benefit?
DR O’SHAUGHNESSY:Still
a definite benefit and still a doubling. We don’t have disease-free
and overall survival data, so we have to be careful not to make
too much of that, but I personally am taking that as a reason to
use AC followed by Taxotere in the higher-risk patient even if she’s
ER-PR-positive.
DR LOVE: I like the pre-op studies, too, because
you have the tumor right there. You really know exactly what you’re
dealing with, and you know it very quickly. Aman Buzdar has discussed
the work at M.D. Anderson, where they’ve done pre-op Taxol.
He says there’s no difference in what they see in ER-positive
and ER-negative. So, maybe that’s a better testing ground.
I’m sure the NSABP is going to see things way before you will
in the adjuvant setting in terms of response within the tumor.
DR O’SHAUGHNESSY:
Absolutely. Yes.
DR LOVE: So, they’ll be able to report what’s
going on inside the tumor before you start to see or they start
to see the disease-free and overall survival. But it’s great
how these neoadjuvant studies give us a clue that we can just jump
right on.
DR O’SHAUGHNESSY: Yes. It really does. It really does. And
I think it’ll be very neat to see, because I predict that
XT will make an improvement in the pathologic CR rate over Taxotere
alone.
DR LOVE: Unless there’s something not translating
into the neoadjuvant setting, you would expect that to be the case.
DR O’SHAUGHNESSY:
Exactly, because the objective response rate is higher with the
doublet.
DR LOVE: You recently presented an interesting
study on the use of Gemzar and Herceptin. Can you talk a little
bit about that and where you see that combination heading?
DR O’SHAUGHNESSY:
Yes. Yes. That was interesting, as well. We started a Phase II trial
of gemcitabine and Herceptin back in ’99, before we knew that
FISH was critically important in the 2+ overexpressers. It was for
women – they could have been pretreated with other chemotherapies
– they had to have measurable metastatic breast cancer, but
they could not have had prior Gemzar or Herceptin. They had to be
2+ or 3+ overexpressers by immunohistochemistry, done at their local
pathology lab, because we wanted to do a real wide community study.
But all of the blocks and the slides were sent for central review
by a study pathologist, to make sure that they were, in fact, HER2-positive.
64 patients were entered on the study, 61 were eligible, and 59
were actually evaluated for response.
It was interesting, back in 1999-2000 these women had not had prior
Herceptin. The doctors chose to put on patients who had had quite
a bit of chemotherapy because back in those days, we weren’t
using Herceptin routinely for front-line metastatic treatment in
the HER2 overexpressers. I don’t think it was quite so clear
that that’s where your survival advantage was and you didn’t
have as robust a survival advantage if you gave the Herceptin later.
So, it’s interesting, because the patients had a median of
three prior chemotherapy regimens – one in the adjuvant setting
and two for metastatic disease. So, they were really receiving this
as fourth-line therapy, or third-line metastatic therapy.
The Gemzar was 1,200 milligrams per meter squared, day one and
day eight on a 21-day cycle, and the Herceptin was standard Herceptin
weekly. The overall response rate was 37 percent. But if you look
at the subset, most of the women were 3+ overexpressers. About two-thirds
were 3+ overexpressers. The response rate in the 3+ overexpressers
was 45 percent. That’s quite interesting because in Melody
Cobleigh’s big Phase II trial of Herceptin as a single agent,
the patients were receiving that as third-line therapy, second-
or third-line therapy, but most, later line. And that was a 15 percent
response rate with Herceptin. Gemzar as a single agent after anthracyclines
and taxanes – and almost all the women had had prior anthracyclines
and taxanes – very little data on Gemzar in that patient population,
but it ranges from a low of about 12 percent up to a high of about
20 percent in one study.
So, the response rate of 45 percent – now, again, the confidence
intervals are wide, so you’ve got to be careful here. But
at least it would suggest additive effects, putting the Herceptin
together with the Gemzar. It raises the hypothesis that perhaps
there might even be some synergy, with a response rate of 45 percent
in a very heavily pretreated, late-line group of patients where
you might think Gemzar might be a 15-percent drug and Herceptin’s
a 15-percent drug. You might 30 percent. This was 45 percent. Is
something else going on there?
That would be considered strictly hypothesis generating, and I
think what you want to do is you want to move it up. Kevin Fox at
Fox Chase is doing a front-line study of Gemzar and Herceptin for
first-line treatment of metastatic breast cancer to see if you’re
going to come in with these response rates that Navelbine came in
with. Taxotere and weekly Taxol are all coming in around the 70-
or 80-percent response rate in front-line treatment. So, that was
interesting. That was interesting. It was very well tolerated with
no unexpected cardiac effects and no unexpected toxicities.
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