Avastin - Erbitux combination - Bond 2 study (long)

J · medicine forum Guru Joined: 29 Apr 2005 Posts: 612

Avastin = (Bevacizumab)
Erbitux = (cetuximab)

http://www.curetoday.com/backissues/v4n1/departments/drugs/index.html
A One-Two Punch Against Advanced Colorectal Cancer

Two weapons against colon cancer include Erbitux™ (cetuximab), which
targets a protein called EGFR that is found on most colon cancer cells,
and Avastin™ (bevacizumab), which helps prevent the formation of new blood
vessels for tumor growth. Oftentimes, researchers will combine two or more
drugs that are proven to work by themselves to see if the combination is
even more powerful.

The BOND 2 study, conducted by Leonard Saltz, MD, and colleagues at
Memorial Sloan-Kettering Cancer Center, combined Erbitux and Avastin in 35
patients with advanced colon cancer whose disease had progressed on
chemotherapy agents like Camptosar® (irinotecan) and Eloxatin®
(oxaliplatin). Twenty-three percent of patients had their tumors shrink by
at least 50 percent using the combination, and the disease stayed in
remission an average of 6.9 months in patients who responded. These
results were significantly better than those seen with Erbitux alone,
which resulted in 50 percent tumor shrinkage in only about 10 percent of
patients.

Thirty-nine patients were given a three-drug combination of Avastin,
Erbitux and Camptosar. With the addition of Camptosar, 38 percent of
patients had their tumors shrink by at least half. The median time to
progression (amount of time before the tumor grows in size) was extended
to 8.5 months compared with 6.9 months with Avastin and Erbitux alone.
Phase III studies are needed to determine if the three-drug combination
can prolong survival. Toxicities included diarrhea, fatigue and rash.

http://www.colorectalcancerupdate.com/edition/2005/3/saltz.htm
BOND-2 study: Cetuximab/bevacizumab plus or minus irinotecan in patients
with metastatic colorectal cancer

Rationale and design

In the BOND-1 trial, patients with irinotecan-refractory metastatic
colorectal cancer were treated with cetuximab alone or in combination with
irinotecan (Cunningham 2003). In the BOND-2 trial, we added bevacizumab to
both arms (Saltz 2005). We wanted to know whether adding bevacizumab
improved efficacy and whether it was safe and tolerable to give both
monoclonal antibodies at the same time.

We had planned to accrue 75 patients in each arm; however, shortly after
opening the study in December 2003, both agents became commercially
available and within a month or so, the rapid rate of accrual slowed
considerably. By the end of 2004, the number of eligible patients —
patients who were bevacizumab naïve — was virtually nil, and we revised
the statistical goals. The current data set is 39 patients who received
irinotecan, cetuximab and bevacizumab and 35 patients who received
cetuximab and bevacizumab. We anticipate that will be close to the final
accrual total.

Efficacy data

The combination of cetuximab, bevacizumab and irinotecan resulted in a
response rate of 38 percent, and the time to progression was 8.5 months.
The historical reference points in two previous trials of cetuximab and
irinotecan without bevacizumab was a response rate of 23 percent and a
time to progression of approximately four months (Saltz 2001, Cunningham
2004; [1.1]).

What I found even more interesting is the response rate with the two
antibodies. In the BOND-2 trial, the response rate was 23 percent, and in
the three historical references for cetuximab alone, the response rates
ranged from nine to 12 percent (Saltz 2002, Cunningham 2004, Lenz 2004).
In the prior studies, the time to tumor progression for single-agent
cetuximab averaged 1.5 months, whereas in the BOND-2 trial the median time
to tumor progression with the two antibodies at this analysis was 6.9
months.

This was a randomized Phase II study, and the comparison of the two arms
was not the primary statistical hypothesis. We have to be very careful
about interpreting a small study with a historical control; however, it’s
intriguing that the three-drug combination seems to show a significant
increase in both response rate and time to tumor progression.

Toxicity data

We saw no clear evidence of synergistic toxicity in the BOND-2 trial. The
toxicities seen were essentially those of single-agent cetuximab or
bevacizumab, such as skin rash and hypertension. We did see some instances
in which it was difficult to discern whether we were seeing side effects
or simply advancing cancer.

The incidence of these events was consistent with what has been reported
in previous trials, so I don’t believe they indicate a synergism of
toxicities. However, we have less than 80 patients, and, as we gain more
experience with the combination, we may begin to see some emerging
toxicities.

Implications of the BOND-2 study in clinical practice and future research

Data from the BOND-2 trial raise some interesting questions: What do we do
with an interesting study that treats a population that no longer exists,
and how do we extrapolate the data to clinical practice today?

This trial doesn’t tells us whether to add bevacizumab to cetuximab-based
therapy in patients who have already received bevacizumab, but our next
study will basically repeat this trial in patients who have failed
bevacizumab.

Until we have that data, I do not advocate routinely adding bevacizumab to
cetuximab in patients who have previously received bevacizumab. However,
if a patient is bevacizumab naïve, I believe these data support adding
bevacizumab to cetuximab in a salvage setting.

While very few circumstances exist where the BOND-2 trial should change
routine practice, it does provide important safety and pilot data for
moving these two antibodies to front-line trials.

In a proposed design for a new Intergroup study, patients will be allowed
to receive either FOLFOX or FOLFIRI at the physician’s discretion. They
will then be randomly assigned to receive bevacizumab, cetuximab or both
in addition to the chemotherapy. In addition, we are considering several
other constructs to evaluate the double-antibody approach as front-line
therapy.

EGFR staining and response to cetuximab

We just published an article in the Journal of Clinical Oncology that
reports activity with cetuximab in colorectal cancer in tumors that do not
express the EGFR by immunohistochemistry (IHC; [Chung 2005]). We reviewed
charts of patients treated for colorectal cancer with cetuximab at
Memorial Sloan-Kettering in a nonprotocol setting and found 16 patients
with documented EGFR-negative tumors.

A reference pathologist confirmed that these tumors were negative, and
then a reference radiologist reviewed the patients’ scans prior to and
during cetuximab treatment. It was confirmed that four patients had major
objective responses and two had minor regressions on cetuximab, so a fair
amount of antitumor activity was confirmed in these EGFR-negative tumors.

These are very compelling data. We all wanted to believe that EGFR would
be an important prognostic indicator, but our technology for assessing
EGFR expression is flawed. We generally use the primary tumor as the basis
for the EGFR status of the metastasis, but that appears to be inaccurate.
Data shows that EGFR degrades over time.

In addition, EGFR staining is very sensitive to the type of fixative used
on the tissue. It appears that EGFR exists in two conformations — tethered
and untethered. The antibodies we use do not discriminate between these
conformations, but only the untethered has biologic activity in terms of
signal transduction, and it represents a very small percentage of the
total.

We know that blocking the EGFR alters regulation of VEGF expression, so
scientific reasons exist to combine bevacizumab and cetuximab. However,
EGFR staining has no prognostic significance, so the BOND-2 study did not
require staining for entry. When we examined the original ImClone and BOND
study, we saw exactly the same activity level regardless of whether the
staining was very weak or very strong.

Putting all this together, I believe EGFR staining should not be permitted
in standard practice. I find it a waste of money, and it’s worrisome that
physicians might rebiopsy a patient just to obtain this material. At this
time, no clinical decision should be made on the basis of EGFR staining.
Specifically, no patient should be excluded from a therapy — cetuximab or
otherwise — simply because their IHC staining for EGFR is negative and,
just as importantly, no patient should be treated with these agents simply
because the tumor is strongly EGFR positive.

This doesn’t mean cetuximab isn’t an EGFR-specific targeted agent — it
almost certainly is. The fact is that cetuximab does bind to the epidermal
growth factor receptor. The question is whether quantitating EGFR by IHC
can give us any handle on cetuximab activity, and the answer is no.

These EGFR-negative data are very fresh and have enormous implications.
They confirm what virtually every GI academic oncologist has known for a
long time, which is that EGFR staining is a sham. It is wrong to use it
for decision-making, and it is unethical to exclude patients from
treatment on the basis of it.

Impact of BOND-2 and ECOG-E3200 data on clinical practice

When Hurwitz presented the data on front-line IFL plus bevacizumab, I
chose a fairly broad interpretation, as did many other oncologists, and
decided it indicated that bevacizumab contributed to the activity of
front-line chemotherapy (Hurwitz 2004). I extrapolated that to second-line
therapy in my practice in bevacizumab naïve patients. Indeed, E3200 data
confirmed that adding bevacizumab to FOLFOX in this patient population was
beneficial (Mitchell 2005). The BOND-2 data builds on that and showed that
adding bevacizumab to cetuximab-based therapy improves activity.

The E3200 study and BOND-2 study both show the utility of adding
bevacizumab to a standard therapy and, at the same time, they’re both
treating a population that no longer exists — bevacizumab naïve patients.
We need to investigate what will happen in patients who have been exposed
to one of the drugs in advance, because one of the major questions
regarding bevacizumab is whether it should be continued forever. Some very
intelligent thought leaders feel that bevacizumab should be continued with
sequential regimens in colorectal cancer. While I believe that’s an
interesting hypothesis, until it’s tested it remains a hypothesis.

I am concerned that physicians will extrapolate the E3200 data to justify
continuing bevacizumab after progression. They may think, “I used
bevacizumab at 5 mg/kg front line, so now I’ll continue it and maybe
double the dose to 10 mg/kg as second-line therapy because that’s what
they did in E3200.” That may be the right thing to do, but we don’t have
the data. Bevacizumab is expensive and while the subjective toxicity is
minimal, it has some very rare but very serious potential toxicities.

Adjuvant therapy for patients with Stage III disease

I’m pretty comfortable with the MOSAIC data (de Gramont 2005), so I
generally use FOLFOX in the adjuvant setting for patients with Stage III
disease. When I have a patient who is particularly dependent on their
fine-motor skills, I discuss with them whether we want to include
oxaliplatin in their treatment because the neurotoxicity might compromise
their quality of life. If I’m concerned about a patient’s ability to
tolerate combination chemotherapy, I might consider using one of several
schedules of 5-FU/leucovorin or capecitabine.

We don’t know the efficacy of FOLFIRI in the adjuvant setting, but if the
PETACC-3 and ACCORD-2 studies are positive, then we would have an
interesting alternative to FOLFOX for combination therapy without
long-term neurotoxicity. We do know that IFL was not effective in the
adjuvant setting, so that’s not an option that should be considered.

Capecitabine as adjuvant therapy: The X-ACT trial

In a reliable patient, capecitabine is a reasonable alternative when we
don’t want to use oxaliplatin, bearing in mind that the capecitabine data
were generated in Europe (Cassidy 2004) and, for reasons that are not
completely clear, European patients tolerate capecitabine better than
American patients.

In the X-ACT trial, the European adjuvant trial comparing capecitabine to
Mayo Clinic 5-FU/leucovorin, the results for patients with Stage III
disease who received capecitabine looked remarkably good. The study was
designed as a non-inferiority study, but in a number of parameters
capecitabine actually appears to be modestly superior.

Dr Saltz is a Professor of Medicine at Weill College of Cornell
University, an Attending Physician and the Colorectal Disease Management
Team Leader at Memorial Sloan-Kettering Cancer Center in New York, New
York.

J · medicine forum Guru Joined: 29 Apr 2005 Posts: 612

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