Latest version of the Phase 3 control arms. Easier to read.

More on the PD-1 stories. The two papers in NEJM are about two different antibodies.
One mAb targets the receptor PD-1, and the other mAb targets its ligand, PD-L1.
In the trial for anti-PD-L1 there were 207 patients. There were 18 with colorectal cancer
and 14 with pancreatic cancer, but no objective responses were seen for these.
They make a point about responses against NSCLC. For the anti-PD-L1 mAb for all doses
tested, nonsquamous type, 36 patients, there was an ORR of 11%. These were all second-line,
or third-line NSCLC cases. In the anti-PD-1 trial (296 patients) there were 56 nonsquamous
NSCLC patients. Again, all heavily pre-treated patients, the ORR was 12%, at all doses.
It seems to me that there is some hype going on here, and that Bavi will be better.

Exactly right.

FF,you might be correct that they will know the MOS of the control arm of the first-line
NSCLC in July, assuming that it is about 10 months or less. If it was 10 months, and the
bavi + CP arm came out to be 13 months then we would have a 30% increase, not bad.
It definitely would help the case for AA for second-line, as you say. Also there is all
the safety data which goes with it.

FF, those tables are for the control arms of the listed trials. So the 13 months is
the control arm MOS. That is also a subset reported for the nonsquamous cases (N = 310).
The trial was comparing albumin-bound paclitaxel (nab-paclitaxel) plus carboplatin to the
usual solvent-based paclitaxel plus carboplatin. The MOS for the nab-paclitaxel plus
carboplatin was 13.1 months for the nonsquamous subset.
The 9.8 month mean in the table is the mean of the MOS from the 12 control arms.

Here is part of the editorial from the NEJM. There is a big difference between Bavi
and this anti-PD-1 antibody. Bavi targets the tumor vasculature through PS.
Macrophages then bind to Bavi and phagocytose (eat) the attached endothelial cells thus
destroying the blood vessels feeding the tumor. There are also a bunch of things Bavi
does to reverse the immunosuppression in the tumor microenvironment. The main
point is Bavi enables the innate immune response (macrophages) to destroy the tumor,
whereas the anti-PD-1 mAb enables T-cells, and hence the adaptive immune response.
Bavi also has the ability to enable T-cells which can lead to long-term immunity.
I think these results for anti-PD-1 are very important in showing that cancer immunotherapy works!

Tumor Immunotherapy Directed at PD-1
Antoni Ribas, M.D., Ph.D.
The treatment of cancer by harnessing immune
responses has long been pursued. Efforts to turn
on the immune system against cancers with inactivated
tumor vaccines or intratumor injections
of bacterial products to induce local inflammation
and recruit an antitumor immune response
have led to anecdotal successes. Increasing knowledge
about how the immune system is activated,
coupled with advances in recombinant DNA technology,
has allowed the clinical testing of immune-
stimulating cytokines such as interferons
and interleukins. These trials have led to a low
frequency of durable tumor responses in selected
cancers such as melanoma and renal-cell carcinoma
at the expense of serious toxic effects. The
finding that dendritic cells play a central role in
orchestrating a T-cell response to cancer has resulted
in multiple clinical trials of dendritic-cell–
based vaccines. These studies again provided evidence
of occasional tumor responses in a minority
of patients.1
A major limitation of the various approaches
to turning on an immune response to cancer is
that the immune system exerts a major effort to
avoid immune overactivation, which could harm
healthy tissues. Cancer takes advantage of this
ability to hide from the immune system by exploiting
a series of immune escape mechanisms
that were developed to avoid autoimmunity.
Among these mechanisms are the hijacking of
immune-cell–intrinsic checkpoints that are induced
on T-cell activation.2
Blockade of one of these checkpoints, cytotoxic
T-lymphocyte–associated antigen 4 (CTLA-4), provided
the first evidence of improvement in overall
survival for the treatment of patients with
metastatic melanoma.3,4 The coinhibitory receptor
CTLA-4 predominantly regulates T cells at the
stage of initial activation by competing with the
CD28+ costimulatory receptor for binding of CD80
(B7-1) and CD86 (B7-2) expressed by antigen-presenting
cells such as dendritic cells (Fig. 1).
CTLA-4 is expressed approximately 48 hours after
T-cell activation and provides dominant negative
signaling. Inhibition of CTLA-4 by blocking
antibodies such as ipilimumab or tremelimumab
results in objective response rates of 10 to 15%
in patients with metastatic melanoma, a response
that is associated with clinically significant inflammatory
or autoimmune toxic effects in 20 to
30% of patients.2
The programmed death 1 (PD-1) receptor is
another inhibitory T-cell receptor that is engaged
by its two known ligands, PD-L1 (also known as
B7-H1 or CD274) and PD-L2 (also known as B7-DC
or CD273), primarily within the tumor microenvironment
(Fig. 1).2,5 The increased selectivity for
immune suppressive signals that are delivered
directly by the cancer, together with the role of
PD-1 in regulating predominantly the effector
phase of T-cell responses, predicts that PD-1 inhibition
will have fewer side effects and greater
antitumor activity than CTLA-4 inhibition.2,6 PD-1
was discovered in 1992 by Honjo and colleagues,
who were studying mechanisms of T-cell death.6
Since then this immune regulatory receptor has
been shown to have a critical role in autoimmunity,
infectious immunity, transplantation immunity,
and allergy, in addition to the demonstration
of its blockade in tumor immunotherapy.7-9 PD-1
activities include the inhibition of T cells during
long-term antigen exposure, as happens in chronic
viral infections10 and cancer.2

This week two articles have appeared in the New England Journal of Medicine, and an editorial.
Two phase 1 trials, both with over 200 patients enrolled, and both funded by Bristol-Myers Squibb.
ASCO presentations on the results. That is how you get recognition.
At least this PD-1 antibody is bringing recognition that immunotherapy can actually work on cancers.
It doesn't look like it would be any better than Bavi, but I'll have to read the articles.

Here is an update including gefitinib (Iressa), which was approved for second-line NSCLC based
on equivalence with docetaxel. The trial is one of the 10 in my table for second-line NSCLC.

Shepherd et al , 2000
Docetaxel vs Best Supportive Care (BSC)
DRUG | ORR | PFS | MOS
Docetaxel | 5.5 % | 2.5 mo | 7.5 mo
Placebo | 0 % | 1.5 mo | 4.6 mo

Hanna et al, 2004
Pemetrexed vs Docetaxel
Docetaxel | 8.8 % | 2.9 mo | 7.9 mo
Pemetrexed | 9.1 % | 2.9 mo | 8.3 mo

Shepherd et al, 2005
Tarceva vs BSC
Tarceva | 8.9 % | 2.2 mo | 6.7 mo
Placebo | 1 < % | 1.8 mo | 4.7 mo

Kim et al, 2008
Gefitinib vs. docetaxel
Gefitinib | 9.1 % | 2.2 mo | 7.6 mo
Docetaxel | 7.6 % | 2.7 mo | 8 mo

Ciuleanu et al, 2012
Tarceva vs either docetaxel or pemetrexed (chemo group)
Tarceva | 7.9 % | 1.5 mo | 5.3 mo
chemo | 6.3 % | 2.0 mo | 5.5 mo

Here is a list from the National Cancer Institute
http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional/Page12#Section_48459

Standard Treatment Options for Recurrent NSCLC
Standard treatment options for recurrent NSCLC include the following:

Radiation therapy (for palliation).[1]
Chemotherapy or kinase inhibitors alone, including the following for patients who have previously received platinum chemotherapy:
Docetaxel.[2,3]
Pemetrexed.[3]
Erlotinib after failure of both platinum-based and docetaxel chemotherapies.[4]
Gefitinib.[5]
Crizotinib for EML4-ALK translocations.[6,7]
Surgical resection of isolated cerebral metastasis (for highly selected patients).[8]
Laser therapy or interstitial radiation therapy (for endobronchial lesions).[9]
Stereotactic radiation surgery (for highly selected patients).[10,11]
Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[12][Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.[13,14] Informed patients with good performance status (PS) and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered.

The evidence for gefitinib:
In a large randomized trial, gefitinib was compared with docetaxel in patients with locally advanced or metastatic NSCLC who had been pretreated with platinum-based chemotherapy.[5] The primary objective was to compare OS between the groups with coprimary analyses to assess noninferiority in the overall population and superiority in patients with high epidermal growth factor receptor (EGFR) gene copy number in the intention-to-treat population. The 1,466 patients were randomly assigned to receive gefitinib (250 mg per day orally; n = 733) or docetaxel (75 mg/m2 intravenously every 3 weeks; n = 733).
Noninferiority of gefitinib compared with docetaxel was confirmed for OS (HR = 1.020; 95% CI, 0.905–1.150). However, superiority of gefitinib in patients with high EGFR gene copy number (85 patients vs. 89 patients) was not proven (HR = 1.09; 95% CI, 0.78–1.51; P = 0.62).
In the gefitinib group, the most common adverse events were rash or acne (49% vs. 10%) and diarrhea (35% vs. 25%). In the docetaxel group, neutropenia (5% vs. 74%), asthenia (25% vs. 47%), and alopecia (3% vs. 36%) were most common.
This trial established noninferior survival of patients treated with gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced NSCLC.

It seems to me that the real problem was because the BLA was based only on ORR. There are a lot of
different combinations used in MBC for second-line treatment. Even if the application was accepted
I doubt it could have been approved only on ORR from a single arm trial. With our second-line NSCLC trial
if the MOS shows a 50% improvement, combined with a 50% increase in PFS and a 100% increase in ORR
I think we could have a chance even if it wasn't statistically significant. However there are now more two-drug
combos out there. Do you have a complete list of all the approved second-line NSCLC treatements?
I have listed the single-agent treatments before, but am not sure about two or three dug combos, if there are any.

Cj,
The FDA turned Genentech down then. The results just announced at ASCO are from the phase III trial.
The phase II trial only had ORR as a primary endpoint, and the PFS, MOS wasn't reported.
At least having the AA turned down wasn't the end of the game. If the MOS for the Bavi + docetaxel
second-line NSCLC are fantastic then I would say we have a chance at AA.
----------------------------------------------------------------------------------
Genentech Provides Update on FDA Application for T-DM1
South San Francisco, Calif. -- August 26, 2010 -- Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced the U.S. Food and Drug Administration (FDA) issued a Refuse to File letter for accelerated approval for the company's trastuzumab-DM1 (T-DM1) Biologics License Application (BLA). As planned, Genentech will continue with its ongoing Phase III registrational T-DM1 trial, EMILIA. Genentech will continue to work with the FDA and expects to submit a new T-DM1 BLA in mid-2012.
The BLA submitted in July 2010 requested accelerated approval for T-DM1 based on the results of a single-arm Phase II study, which showed T-DM1 shrank tumors in one-third of women with advanced HER2-positive breast cancer, who had received on average seven prior medicines, including two HER2-targeted medicines.
Consideration by the FDA for accelerated approval requires recognition of a defined patient population of unmet need (a life-threatening disease with limited treatment choices), for whom a medicine's early safety and efficacy data are reasonably likely to predict clinical benefit. Following the pre-submission meeting with the FDA in March 2010, Genentech concluded it was appropriate to submit a BLA for accelerated approval. In its review of the BLA, the FDA stated the T-DM1 trials did not meet the standard for accelerated approval because all available treatment choices approved for metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population.
"We firmly believe in the potential of T-DM1 as a novel HER2-targeted option and remain fully committed to its ongoing development," said Hal Barron, M.D., executive vice president, Product Development and chief medical officer.
Genentech will submit data from the amended Phase III randomized EMILIA study to the FDA to support a new T-DM1 BLA in mid-2012. The EMILIA study compares T-DM1 to lapatinib in combination with capecitabine in people with advanced HER2-positive breast cancer whose disease has worsened after receiving initial treatment.

More on T-DM1 results from ASCO. PFS increased 50%, MOS for control released, waiting on MOS for treatment arm.
Sounds like our second-line NSCLC trial.
http://www.nytimes.com/2012/06/03/health/research/in-study-drug-delays-worsening-of-breast-cancer-with-fewer-side-effects.html?ref=health

The ASCO news flow starts. Imagine that, a drug that can be used against many cancers. How innovative!
http://www.nytimes.com/2012/06/02/business/drug-helps-immune-system-fight-cancer.html?hp
Our day will come.

Sunstar, my guess is that the results will be close to your "Mean" extrapolation.
If so, then I would expect Bavi + docetaxel will get approved, but I do think Peregrine
will have to do a phase 3 regardless of accelerated approval or not.
Hopefully with a partner and a deal, such as ex-USA/USA.

Don't forget that all those patients with first-line stage 3 or 4 NSCLC either die or go
to become second-line NSCLC patients, except of course those few lucky ones who are cured.

No, I don't think that is valid. It is fun to play around with the numbers though.
Since the MOS < 6 months for the docetaxel arm of our second-line NSCLC trial, and
since we just passed 7.8 months since the last patient was enrolled, I think it is looking
quite good for the bavi + docetaxel arm.

Missing the obvious. In case you missed my post from yesterday (# 80728). The three drugs approved
for second-line NSCLC are below. Both docetaxel and Tarceva were approved because they are
better than nothing, and pemetrexed was approved because it was equivalent to docetaxel but had
fewer side effects. The latest results show that as far as MOS goes they are all equivalent.
If Bavi + docetaxel shows substantive improvement in MOS compared with docetaxel alone then
it gets approved. Minimal added side effects. Nothing has shown an improvement in MOS over docetaxel
since docetaxel was approved in 2000. From what we know now it seems like we are on the way to doing just that.
Of course, I expect that a phase 3 trial will have to be done to confirm this.


Shepherd et al , 2000
Docetaxel vs Best Supportive Care (BSC)
DRUG | ORR | PFS | MOS
Docetaxel | 5.5 % | 2.5 mo | 7.5 mo
Placebo | 0 % | 1.5 mo | 4.6 mo

Hanna et al, 2004
Pemetrexed vs Docetaxel
Docetaxel | 8.8 % | 2.9 mo | 7.9 mo
Pemetrexed | 9.1 % | 2.9 mo | 8.3 mo

Shepherd et al, 2005
Tarceva vs BSC
Tarceva | 8.9 % | 2.2 mo | 6.7 mo
Placebo | 1 < % | 1.8 mo | 4.7 mo

Ciuleanu et al, 2012
Tarceva vs either docetaxel or pemetrexed (chemo group)
Tarceva | 7.9 % | 1.5 mo | 5.3 mo
chemo | 6.3 % | 2.0 mo | 5.5 mo

It seems from the article that the PFS for the T-DM1 arm was 14.2 months and for
the Herceptin/docetaxel arm it was 9.2 months, a 54% increase, for first-line metastatic
breast cancer. Not much different from the Bavi/docetaxel 50% improvement over
docetaxel alone for second-line NSCLC.

Nice piece in the NYT about armed monoclonal antibodies.
http://www.nytimes.com/2012/06/01/business/a-new-class-of-cancer-drugs-may-be-less-toxic.html?pagewanted=1&_r=1&ref=global-home

The wasteland of second-line NSCLC. As far as I can tell there are three drugs that have been approved
as monotherapy in second-line NSCLC. These are

DRUG | ORR | PFS | MOS | STUDY
docetaxel | 5.5 % | 2.5 mo | 7.5 mo | Shepherd et al, 2000
pemetrexed | 9.1 % | 2.9 mo | 8.3 mo | Hanna et al, 2004
Tarceva | 8.9 % | 2.2 mo | 6.7 mo | Shepherd et al, 2005

None of them is superior to any of the others, except that pemetrexed has a better side effects profile.
As far as I can tell nothing else has been approved. A new trial was just published which compared
erlotinib (Tarceva) with chemotherapy (either docetaxel or pemetrexed).
Ciuleanu et al, The Lancet Oncology, March 2012. From the paper:
"Erlotinib was approved for second-line therapy in advanced non-small-cell lung cancer
(NSCLC) after showing a survival benefit compared with best supportive care (based on the
BR.21 study) and docetaxel and pemetrexed were also shown to be efficacious in this setting.
However, head-to-head data for erlotinib versus chemotherapy in second-line NSCLC were absent.
The results of the TITAN trial showed that, in patients not previously treated with erlotinib, erlotinib is
an option as second-line treatment. Since no differences in efficacy (in terms of overall survival,
progression-free survival, and response rate) were noted between erlotinib and second-line
chemotherapy with either pemetrexed or docetaxel, tolerability and patient preference are likely
to play crucial roles in making second-line treatment decisions, given the different toxicity profiles of these
three drugs."
The data from this trial:
DRUG | ORR | PFS | MOS
Tarceva | 7.9 % | 1.5 mo | 5.3 mo
chemo | 6.3 % | 2.0 mo | 5.5 mo

I think these results highlight how good the Bavi + docetaxel data is compared with docetaxel alone.

I found two more first-line NSCLC phase III trials with carboplatin + paclitaxel (CP) control arms
to add to my tables. The statistics were recalculated too. Now a little more noisy.
The latest trial was just published and is the outlier with respect to PFS and MOS. The 6.4 mo PFS
doesn't look so unusual now. I think we are at the mercy of small numbers in our first-line NSCLC
phase II trial. Note the following are the control arm chemotherapies used, all are approved for the indication.
First-line NSCLC: carboplatin + paclitaxel
Second-line NSCLC: docetaxel
Pancreatic: gemcitabine

I have a feeling that the so called "biotech analysts" don't really have much understanding
of the science here. It is not a small molecule, not the same old, same old stuff, they
are used to seeing. Immunotherapy for cancer still is not believed by some people.
So I would say you are correct in that they will wait until it has
been proven without a doubt before going out on a limb. So what are they good for??

Yes, I really would like to see a clinical trial using radiotherapy with Bavi.

WSJ: Vertex Pharmaceuticals Inc. said Tuesday it overstated the efficacy of a cystic-fibrosis therapy earlier this month when it reported better-than-expected clinical trial results that had sent its stock price soaring.

Shares of the Cambridge, Mass., drug maker fell $7.05, or 11%, to $57.80 in 4 p.m. composite trading Tuesday on the Nasdaq Stock Market.

Vertex revised the trial data to a less impressive outcome—erasing a portion of the 55% stock-price gain on May 7, when the company released data from a midstage study that bolstered investor hopes the therapy would have blockbuster sales potential.

Vertex said Tuesday that it misreported ...

Try this calculator for clinical trials
http://hedwig.mgh.harvard.edu/sample_size/size.html

It is assuming something about the distribution and sampling error.

I agree that the ORR is a set of measurements, and not like the time to event data of PFS and OS.
But when you plug the two mean ORR numbers, 7.9% and 17.9% into a calculator to calculate
whether there is a statistical difference between the two means you have to know something
about the variability of the data don't you? So you are assuming something?

Mojojo, I think the noise in the ORR data is too big to worry about if it is statistically
significant or not. Designing a trial with enough power makes much more sense for
PFS and/or MOS. I don't recall reading any statements from Peregrine about whether this
trial is powered to show significance for anything. Have there been?
If it is not designed to show significance then saying that it is not significant is not reasonable.
In any case don't you really need the patient data to compute the significance? What did you do
to calculate this?

For those of you interested in hazard ratios.

Nature Reviews Clinical Oncology 9, 178-183 (March 2012) | doi:10.1038/nrclinonc.2011.217

Hazard ratios in cancer clinical trials—a primer

Krastan B. Blagoev, Julia Wilkerson & Tito Fojo

Abstract
The increase and diversity of clinical trial data has resulted in a greater reliance on statistical analyses to discern value. Assessing differences between two similar survival curves can pose a challenge for those without formal training in statistical interpretation; therefore, there has been an increased reliance on hazard ratios often to the exclusion of more-traditional survival measures. However, because a hazard ratio lacks dimensions it can only inform the reader about the reliability and uniformity of the data. It does not provide practitioners with quantitative values they can use, nor does it provide information they can discuss with patients. Motivated by a non-scientific poll of oncologists in training and those with board certification that suggested only a limited understanding of the derivation of hazard ratios we undertook this presentation of hazard ratios: a measure of treatment efficacy that is increasingly used and often misused.

At this point all I can do is to wait and see the data from the trials. Assuming that the
data is good I expect that until we make a deal with a big pharma company the share price
will stay low.

From the April 18, 2012 JAMA, Zhu et al. Dana Farber Cancer Institute. A retrospective analysis
shows that adding Avastin to CP had no survival advantage for patients >= 65 years old.
Another possible Bavi advantage? Don't know yet.

Context A previous randomized trial demonstrated that adding bevacizumab to carboplatin
and paclitaxel improved survival in advanced non–small cell lung cancer (NSCLC).
However, longer survival was not observed in the subgroup of patients aged 65 years or
older.
Objective To examine whether adding bevacizumab to carboplatin and paclitaxel
chemotherapy is associated with improved survival in older patients with NSCLC.
Design, Setting, and Participants Retrospective cohort study of 4168 Medicare
beneficiaries aged 65 years or older with stage IIIB or stage IV non-squamous cell NSCLC
diagnosed in 2002-2007 in a Surveillance, Epidemiology, and End Results (SEER) region.
Patients were categorized into 3 cohorts based on diagnosis year and type of initial chemotherapy
administered within 4 months of diagnosis: (1) diagnosis in 2006-2007 and
bevacizumab-carboplatin-paclitaxel therapy; (2) diagnosis in 2006-2007 and carboplatinpaclitaxel
therapy; or (3) diagnosis in 2002-2005 and carboplatin-paclitaxel therapy. The
associations between carboplatin-paclitaxel with vs without bevacizumab and overall survival
were compared using Cox proportional hazards models and propensity score analyses
including information about patient characteristics recorded in SEER-Medicare.
Main Outcome Measure Overall survival measured from the first date of chemotherapy
treatment until death or the censoring date of December 31, 2009.
Results The median survival estimates were 9.7 (interquartile range [IQR], 4.4-18.6)
months for bevacizumab-carboplatin-paclitaxel, 8.9 (IQR, 3.5-19.3) months for carboplatin-paclitaxel
in 2006-2007, and 8.0 (IQR, 3.7-17.2) months for carboplatin-paclitaxel in 2002-
2005. One-year survival probabilities were 39.6% (95% CI, 34.6%-45.4%) for bevacizumab-
carboplatin-paclitaxel vs 40.1% (95% CI, 37.4%-43.0%) for carboplatin-paclitaxel
in 2006-2007 and 35.6% (95% CI, 33.8%-37.5%) for carboplatin-paclitaxel
in 2002-2005. Neither multivariable nor propensity score–adjusted Cox models demonstrated
a survival advantage for bevacizumab-carboplatin-paclitaxel compared with carboplatin-
paclitaxel cohorts. In propensity score–stratified models, the hazard ratio for overall
survival for bevacizumab-carboplatin-paclitaxel compared with carboplatin-paclitaxel
in 2006-2007 was 1.01 (95% CI, 0.89-1.16; P=.85) and compared with carboplatin-paclitaxel
in 2002-2005 was 0.93 (95% CI, 0.83-1.06; P=.28). The propensity score–
weighted model and propensity score–matching model similarly failed to demonstrate a
statistically significant superiority for bevacizumab-carboplatin-paclitaxel. Subgroup and
sensitivity analyses for key variables did not change these findings.
Conclusion Adding bevacizumab to carboplatin and paclitaxel chemotherapy was
not associated with better survival among Medicare patients with advanced NSCLC.
JAMA. 2012;307(15):1593-1601 www.jama.com

For second-line MOS I will stick to my previous estimate of Independence Day, but I was off by a week
with my Memorial Day estimate for ORR, PFS, so maybe end of June.

Yes, but this is an estimate. When it will exactly occur? Who knows.

Here are the numbers from the E4599 trial

Paclitaxel–Carboplatin (control group) N = 433
Male: 253 (58%)
Female: 180 (42%)

Median OS (combined): 10.3 months
Male: 8.7 months
Female: 13.1 months

Paclitaxel–Carboplatin–Bevacizumab (Avastin) N = 417
Male: 210 (50%)
Female: 207 (50%)

Median OS (combined): 12.3 months
Male: 11.7 months
Female: 13.3 months

Men had a 34% increase in their MOS, while women had a 1.5% increase!
So let's assume that Bavi + CP does as well for combined men and women, but men and women do equally well.
That is, they both have about a 33% increase in MOS. That to me is a selling point. If you can point to
data showing that Bavi overall works as well as Avastin, with less side effects, and that women can benefit from it too,
then I think you have an advantage.

I'll stick to my guess of Labor Day, which will be almost exactly one year since the last patient was enrolled.

Here is why I think a deal for NSCLC could yield a big payoff. There is plenty of lung cancer around the world.
Making a deal for ex-USA should bring in a lot of money if the second-line NSCLC trial is a complete success.
I still think the MOS for the first-line trial will confirm the previous 12.4 months MOS, which puts first-line into play also.

While we wait for the second-line NSCLC survival I thought I would get back to the first-line NSCLC trial.
It brings up a topic I have mentioned before. Avastin had no survival benefit for women in this trial,
the primary trial used for approval, even though almost half of the patients were women. Lung cancer
is now the biggest cancer killer of women. I think this could be an advantage for Bavi if it can confirm
the 12.4 month MOS reported from the phase IIa trial (equal to Avastin + CP) but work as well for women as for men.

This is from the National Cancer Institute on Avastin in first-line NSCLC http://www.cancer.gov/cancertopics/druginfo/fda-bevacizumab

First-Line Treatment of Non-Small Cell Lung Cancer (NSCLC)
On October 11, 2006, the FDA granted approval for a labeling extension for bevacizumab (Avastin®, Genentech, Inc.), administered in combination with carboplatin and paclitaxel, for the initial systemic treatment of patients with unresectable, locally advanced, recurrent, or metastatic, non-squamous, non-small cell lung cancer. This recommendation is based on the demonstration of a statistically significant improvement in overall survival (OS) in patients receiving bevacizumab with carboplatin and paclitaxel compared to those receiving carboplatin and paclitaxel alone.

The primary trial (E4599) supporting this approval was a randomized, active controlled, open label, multi-center clinical trial evaluating bevacizumab plus carboplatin and paclitaxel (n=434) versus carboplatin and paclitaxel alone (n=444). (See the protocol summary.)

Patients with squamous histology, mixed cell tumors with predominant squamous cell histology, central nervous system metastases, gross hemoptysis (>1/2 tsp red blood), or unstable angina and those receiving therapeutic anticoagulation were excluded from the trial. Patients with squamous cell histology were excluded based on four patients with life-threatening or fatal hemoptysis among 13 patients with squamous cell histology enrolled in a randomized, active-control, phase II study (AVF0757g) who received chemotherapy with bevacizumab.

Among the 878 randomized patients, the median age was 63, 46 percent were female, no patients had received prior chemotherapy, 76 percent had stage IV disease, 12 percent had stage IIIB disease with malignant pleural effusion, 11 percent had recurrent disease, and 40 percent had an ECOG performance status of 0.

OS, the primary endpoint, was significantly longer in patients receiving bevacizumab in combination with paclitaxel and carboplatin as compared to those receiving paclitaxel and carboplatin alone (median OS 12.3 vs 10.3 mos; hazard ratio 0.80, p=0.013 stratified log rank test). Although a consistent effect was observed across most subgroups, in an exploratory analysis, evidence of a survival benefit was not observed in women (HR 0.99; 95 percent CI 0.79, 1.25).

Entdoc, no need to use one of the Fab arms you can just use a linker for the payload.
Also, you can bind the Fab end to something, without the Fc end, but then you are giving
up the Fc-mediated phagocytosis. Then there is the possibility of just using Bavi in
combination with another mAb.

Okay, but that was a subgroup analysis of the original trial which only had 80 patients.
There is nothing here about being statistically significant.
My point is that this is a very small patient population. Only 1% of all thyroid cancer
is the anaplastic type which is the target of this treatment. Why would a big Pharma
be particularly interested in this, instead of say NSCLC?

From the April 2012 press release you referred to:
This subgroup analysis of the FACT trial compared patients with prior cancer-related surgery (thyroidectomy) to patients without prior cancer-related surgery. Key data points from this analysis are as follows.
Patients who had prior surgery and then received ZYBRESTAT tended to live longer than patients who had prior surgery without receiving ZYBRESTAT.
Median survival for patients without surgery was similar for patients on both arms of the study.
The percentage of patients without surgery who survived at one year was greater in the ZYBRESTAT arm (16.7%) than in the control arm (10.0%).
Patients with more extensive surgery (total/near-total thyroidectomy) who received ZYBRESTAT tended to live longer than those who did not have surgery and received ZYBRESTAT, and lived longer than all patients on the control arm of the trial regardless of the extent of surgery.
Median survival for patients with total/near-total thyroidectomy was 10.0 months on the ZYBRESTAT arm and 4.0 months on the control arm.
Survival at one year was 35.0% on the ZYBRESTAT arm and 10.0% on the control arm.
Younger patients (= 60 years) who had cancer-related surgery and received ZYBRESTAT tended to survive longer than younger patients on the control arm (10.9 months vs. 6.8 months) respectively.

I was curious so I looked into the FACT trial results presented at last year's ASCO Annual meeting.
This is a slide from their presentation. Not exactly blowing away SOC is it? Maybe not surprising that
they can't partner given the number of patients with anaplastic thyroid cancer.

Summary and Conclusions
• For CA4P + carboplatin and paclitaxel there is the
suggestion of:
– Improved
• Survival (5.2 vs. 4.0 mos, HR 0.72)
• 1-yr survival with CA4P vs. chemotherapy only (26% vs. 9%)
• Survival in patients with >6 cm tumor size
– AEs related to ATC and disease progression
– Hypertension and myelosuppression increased
• Manageable without stopping therapy
• Results to be confirmed in a larger trial