NeuVax bc vaccine effective in patients with low Her2 levels

[Hopeful]

http://www.reuters.com/article/healt...31167920080413

Hopeful

I haven't gotten this excited since news of Herceptin. I can't wait till NeuVax becomes available in the market. How long do we have to wait? And would anyone know how this is administered. I heard intradermal -- does that mean injections and not intravenous? What a dream this drug would be if it lives up to its promise.

[mimiflower07]

this is very encouraging except for the part about low her2 expression or do they mean once you have had herceptin then you are considered low her2? just thoughts...still great when we start talking vacc
suzanne

[swimangel72]

Thanks for posting this info Hopeful - it is an exciting development!!

[Hopeful]

from Medscape. You may have to register to view:

http://www.medscape.com/viewarticle/572995

The key finding:

"What was most surprising in this study was that patients with low-HER2/neu-expressing tumors responded so well to the vaccine. In fact, Dr. Benavides pointed out, the patients with low-expressing (0 to 2+ on immunohistochemistry [IHC]) HER2/neu tumors had a better response to the vaccine than women with higher-expressing tumors. They experienced not only a better immune response, but a better clinical one as well, as demonstrated by a decreased rate of breast cancer recurrence and 0% mortality after E75 peptide vaccination."

Hopeful

[dlaxague]

Hi all,

I hope that this does turn out to be something. Vaccines have fascinated me for some time. (I was signed up for one of the Seattle/UW trials when GSK cancelled it). But if you read past the headlines, this study doesn't sound quite as rosy.

For one thing, this was an extremely small study, especially by the time they broke people down into the four groups.

For another thing, the average follow-up was only 3 years. How can they claim a mortality advantage, especially in HER2 negative women, in only 3 years? It does say, in one article of three that I read, that these results were not statistically significant. YES, FIFTY PERCENT REDUCTION, NO DEATHS. But oh, well, yeah, that was not statistically significant.

Plus, what the heck is that about a 38% mortality in the control group. Almost 40% of the HER2negative women DIED by three years!? It would be surprising to see that high a rate of recurrence, let alone death. There's got to be more to this story.

Skeptically, but with hope,

Debbie Laxague

[Cynthia]

Debbie,

I do not believe that any of the participants in the study were Her2 negative. (I believe the article is a bit confusing on this point.) The distinction is among the Her2+++ and Her2+ and Her2++. The surprise here is how effective the vaccine appears to be in the Her2+ and Her2++ population, a group not currently receiving Herceptin.

The control arm was also made up of all Her2 positive patients who received no vaccine.

Given the small size of the trial, we can't draw too many conclusions, though the numbers and trends are large enough to show promise as the vaccicne heads into the Phase III.

By way of disclaimer, I was in this trial as one of the Her2+++ who did receive the vaccine (which was then known as the E75 vaccine).

Best regards,

[dlaxague]

Hi Cynthia,

I've tried to find good information about this study and it's not easy (smile). If it's available on the AACR website, I can't find it.

But one report does say that the "low expressing" cancers had a FISH ratio of <2. By current standards, that's HER2 negative.

>The control arm was also made up of all Her2 positive patients who received no vaccine.

No, I think that the control group had the two ranges of HER2 - "negative" as above, and positive. Just as the vaccine group did. I have an online acquaintance who was also in the trial and received the vaccine and she says she was told that she is HER2 negative.

I wonder what you'd see if you FISH tested all breast cancer. I wonder how many would be more than zero but less that 2. I wonder how many would be zero? Do we know these things? (not a rhetorical question - I am hoping that someone knows the answer).

And again, what's with the report of a 38% mortality rate for the nonvaccinated HER2 negative women? Math is not my strong point so correct me if I'm wrong, but that would be in the neighborhood of 17 deaths of the 44 members of the C-LE (no vaccine low expressor) group, in three years! I must be reading this wrong. Please help me out and correct me.

Debbie, attempting to copy/paste the info from BCN (which I think is the actual abstract rather than a press report of it) below. If that doesn't work I'll try to find a link.

AACR 2008: ABSTRACT #2545: Response to a preventive HER2/neu peptide (E75) vaccine based on HER2/neu status
[American Association for Cancer Research]
Background: HER2/neu is a source of immunogenic peptides and is over-expressed in 30% of early stage breast cancer (BCa) patients. We have conducted clinical trials with the HER2/neu E75-peptide vaccine in node-positive and node-negative BCa patients demonstrating all levels of HER2/neu expression.
Methods: A subset analysis review was performed of 165 BCa patients enrolled in our E75 vaccine trial based on the level of HER2/neu expression. Patients were HLA typed; HLA-A2+/A3+ patients were vaccinated (V); HLA-A2-/A3- patients served as controls (C). HER2/neu over-expressers (OE) were defined as FISH >2.0 and IHC 3+ HER2/neu tumors. Low-expressers (LE) included patients with IHC ranging from 0 to 2+. These 2 groups were assessed by clinicopathologic factors, immunologic response (in vivo DTH reactions and in vitro HLA-A2:IgG dimer assay) to the vaccine, and post-vaccine clinical responses (recurrence and survival).
Results: Of 165 patients assessed; 94 were vaccinated (30 OE = 32%, 64 LE = 68%) and 71 were controls (22 OE = 31%, 49 LE = 69%). HER2/neu over-expressers were similar regarding prognostic and treatment factors, except a statistically larger number of V-OE patients were hormone receptor negative (ER/PR-; p=0.02) and node-negative (p=0.007). Clinicopathologic factors were not significantly different between control and V-LE patients. Immunologic responses were similar as measured by DTH reactions (post DTH V-OE=12.7+1.9 vs. V-LE=15.1+1.8; p=0.6), but V-OE demonstrated a decreased number of E75-specific CD8+ T cells when compared to V-LE post-vaccination (V-OE vs. V-LE Dimer: 0.6+0.06% vs. 0.8+0.07%; p=0.08; V-OE vs. V-LE Max Dimer: 1.5+0.1% 1.9+0.1%; p=0.04). At 30 months median follow-up, disease recurrence rates (RR) were similar between V-OE and C-OE patients (V-OE vs. C-OE RR: 4.3% vs. 5.6%; p=0.7); however there was a 50% reduction in mortality rate (MR) among patients that recurred (V-OE vs. C-OE MR: 25% vs. 50%; p=NS). RR was reduced for vaccinated patients with low HER2/neu expression (V-LE vs. C-LE RR: 6.4% vs. 11.3%; p=0.3). Importantly, MR among those that recurred was 0% vs. 38% (p=0.2) for V-LE and C-LE BCa patients, respectively.
Conclusions: Patients with HER2/neu over-expressing breast cancer (FISH amplified (>2.0) and IHC 3+) respond well to the E75 vaccine immunologically and have a 50% absolute reduction in mortality compared to controls. Unexpectedly, patients with low-expressing (0 - 2+ on IHC) HER2/neu tumors show better response not only immunologically, but clinically with decreased breast cancer recurrence and 0% mortality following E75 peptide vaccination.

And again, these numbers were not significant.

[Cynthia]

The following is an article put out by the drug company that talks a bit more about how patients with different Her2+ levels reacted to the vaccine in the early trials.




Low HER2 Expressing Breast Cancer Patients Respond Preferentially to
Apthera's NeuVax(tm)

Recurrence Data Presented at AACR


Scottsdale, Arizona - April 14, 2008 - Results were announced today from
analysis of a randomized safety and efficacy clinical trial studying
NeuVax (E75) in the adjuvant treatment of early-stage (node-positive and
high risk node-negative), HER2-positive breast cancer. Data presented at
the American Association for Cancer Research (AACR) Annual Meeting in
San Diego showed that patients with low-expressing HER2 tumors
experienced decreased breast cancer recurrence and no mortality to-date
following treatment (Abstract #2545, Monday, April 14, 2008, 3:40 p.m.
PDT).
Dr. Alton Charles Morgan, President and CEO of Apthera stated "These
results are encouraging for HER2 low-expressing breast cancer patients
who have few treatment options in the adjuvant setting and are not
typically eligible for Herceptin(r) therapy."
The Cancer Vaccine Development Program (CVDP) at Brooke Army Medical
Center in San Antonio, Texas conducted a subset analysis review of 163
patients with breast cancer enrolled in the NeuVax trial to determine
whether the level of HER2 expression affected response. Of the patients
assessed, 92 underwent treatment. Within the treatment group, 56 (66
percent) were defined as HER2 low-expressors. The control group included
44 (67 percent) low-expressors.
Low HER2 expressing patients maintained circulating, E75 peptide
reactive T-cells after 1 year whereas patients with HER2 over-expressing
tumors returned to pre-immunization levels. At a median follow-up of 30
months, disease recurrence was substantially reduced for treated
patients with low HER2 expression. Low-expressors by IHC in the
treatment arm of the study experienced 8 percent recurrence, compared
with 21 percent for patients in the control arm. Furthermore, the
mortality rate among low-expressors by IHC with recurrent disease was 0
percent among treated patients, versus 20 percent among controls
(p=0.04).
Taken together these findings may be significant for the greater than 50
percent of breast cancer patients whose tumors fall into the HER2
low-expressing category and who are not typically eligible for Herceptin
treatment.
About Apthera
Apthera, Inc. is developing a pipeline of peptide-based immunotherapies
for cancers that express HER2/neu, a well-validated and established
oncology target. Apthera is privately held with headquarters in
Scottsdale, Arizona. For more information about the Company visit
www.apthera.com <http://www.apthera.com> .
About NeuVax
NeuVax is a HER2/neu peptide-based T-cell immunotherapy aimed at
preventing disease recurrence and prolonging survival in cancer patients
that have tumors expressing the HER2/neu oncoprotein. To date, clinical
study results have demonstrated that NeuVax significantly reduces the
rate of cancer recurrence while showing minimal side effects.


This news release contains forward-looking statements within the meaning
of the Private Securities Litigation Reform Act of 1995. These
statements are not historical facts and are subject to risks and
uncertainties which could cause actual results and the timing of certain
events to differ materially from those set forth in or implied herein
including, without limitation, risks associated with clinical
development, regulatory approvals, product commercialization,
intellectual property claims litigation and other risks associated with
the Company's proposed activities.


Contact Apthera:
Gail Thurston
VP, Corporate and Business Development
(480) 882-8841
gthurston@apthera.com <mailto:gthurston@apthera.com>
www.apthera.com <http://www.apthera.com>

[Cynthia]

Debbie,

Thanks for your response. Rather than guess, I suggest we go to the source. I will contact the PI and his team (I know them) and will try to get some answers to your excellent questions. Stay tuned.

Best,

[Cynthia]

Debbie,

Here is the response I just received from the PI, COL George Peoples, MD:

Valid questions….here’s the scoop…

HER2/neu negative as used in clinical practice today does not mean that HER2/neu isn’t expressed, just not over expressed. The actual distribution of HER2 expression by IHC staining is as follows: 25% - IHC 3+ or over-expressed (the vast majority of these are also FISH >2), 50% - IHC 1-2+ (called negative but actually low-expressors), and approx 25% - IHC 0 (true negatives).

The E75 vaccine trial presented at AACR worked in all patients but best in the low expressors (LE).

The actual rates as reported for the OE (over-expressors – 25% of all breast cancer patients) and LE (low –expressors – 50% of all breast cancer patients):

Recurrence rate OE-controls = 18% at 3 years vs 14% in the OE-vaccinated
<DIR><DIR>LE-controls = 18% at 3 years vs 11% in the LE-vaccinated

</DIR></DIR>Mortality rate OE-controls = 9% at 3 yrs vs 3% in the OE-vaccinated
LE-controls = 7% at 3 yrs vs 0% in the LE-vaccinated

Mortality among patients that recurred
OE-controls = 50% vs 25% in the OE-vaccinated
LE-controls = 38% vs 0% in the LE-vaccinated
<DIR><DIR>


</DIR></DIR>

[dlaxague]

Wow, Cynthia, how handy to have the inside track. Thank you for keeping us all well-informed. And please thank Dr. Peoples for the timely and informative response.

With this information it all makes sense. (I knew I couldn't be getting it correctly) And it sounds more impressive and more intriguing.

Now for larger studies, planned subgroups analyses, and we hope, more of those impressive results.

Debbie

[Hopeful]

Cynthia, I am really impressed by the ability of our Board members (and you, in particular here) to get the definitive information directly from the source. Where else could we go, to get our questions answered timely and accurately. Kudos. Goes to show what a great resource we have here.

Hopeful

[PinkGirl]

Thanks Cynthia - very helpful.