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What about the poster for the first-line NSCLC trial? My post # 86358
I think the phase IIa advanced breast cancer study using docetaxel had excellent results. If there are
11% CRs in the second-line NSCLC it will be very noteworthy. I think because it was a single-arm,
open-label trial the results might have not been taken too seriously, but it looks like now they should be.
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Peregrine Reports Promising 20.7 Month Median Overall Survival From Phase II Advanced Breast Cancer Trial
Encouraging Overall Survival Data Show Consistent Trend With Earlier Tumor Response Rate and PFS
Data; Data Further Support Ongoing Randomized Phase II Trial Evaluating Bavituximab With Docetaxel for Lung Cancer
TUSTIN, CA -- (MARKET WIRE) -- 08/24/11 -- Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), a clinical-stage
biopharmaceutical company developing first-in-class monoclonal antibodies for the treatment of cancer and viral infections,
today announced 20.7 month median overall survival (OS) from a prior single-arm Phase II trial evaluating bavituximab in
combination with docetaxel in patients with locally advanced or metastatic breast cancer. In a separate published study(1)
included in the docetaxel package insert, median OS was 11.7 months for metastatic breast cancer patients treated with
docetaxel alone. Currently, Peregrine's bavituximab is being evaluated in randomized Phase II trials in non-small cell lung
cancer (NSCLC), pancreatic cancer, and hepatitis C virus (HCV), as well as in four investigator-sponsored trials (ISTs) in
additional oncology indications, including HER2-negative metastatic breast cancer.
"This newest data point from our prior Phase II signal-seeking trials is encouraging, and shows adding bavituximab to the
standard chemotherapy docetaxel offers meaningful survival benefits to breast cancer patients," said Kerstin B. Menander,
M.D. Ph.D., head of medical oncology at Peregrine Pharmaceuticals. "We are eager to complete patient enrollment in our two
randomized Phase II trials in non-small cell lung cancer to assess further bavituximab's potential in combination with
chemotherapy for advanced cancer patients."
In Peregrine's prior single-arm, multi-center Phase II trial, 46 patients with locally advanced or metastatic breast cancer who
had received one prior chemotherapy regimen were treated with weekly bavituximab and docetaxel. The primary endpoint,
objective response rate (ORR), was 61%, with 11% of the patients achieving a clinical complete response in accordance with
RECIST criteria, compared to ORR of 41% of patients in a separate trial used as a historical control using weekly docetaxel
alone. Neither of these earlier studies selected patients based on hormone receptor status.
For what it is worth, this Late Breaking abstract was assigned to the Plenary Session, while others were
assigned to the Oral Abstract Session. To me that means it has been deemed more significant, but it still is
only for 10 minutes, as they all are.
NHwild, I agree, a lot of noise is being generated. Only another month or so to go.
There is a poster at the Chicago Symposium on the first-line Bavi NSCLC Trial.
Presentation Abstract
Session: PV-Poster Viewing Session
Thursday, Sep 06, 2012, 8:00 AM - 6:00 PM
Presentation: 180 - A Randomized, Open-Label, Phase 2 Trial of Paclitaxel/Carboplatin with or without Bavituximab in Patients with Previously Untreated Locally Advanced or Metastatic Non-Squamous Non-Small-Cell Lung Cancer
Pres. Time: Thursday, Sep 06, 2012, 5:00 PM - 6:30 PM
Category: Metastatic Non-small Cell Lung Cancer
Keywords: bavituximab; lung cancer; angiogenesis
Author(s): K. H. Dragnev1, S. V. Attili2, R. Gagua3, M. M. Jain4, I. Bondarenko5, J. Shan6, 1Dartmouth-Hitchcock Medical Center, Lebanon, NH, 2BiBi General Hospital and Cancer Center, Hyderabad, India, 3National Cancer Centre, Tbilisi, Georgia, 4Ruby Hall Clinic, Pune, India, 5Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine, 6Peregrine Pharmaceuticals, Inc., Tustin, CA
Disclosures: K.H. Dragnev: E. Research Grant; Peregrine to my institution. S.V. Attili: None. R. Gagua: None. M.M. Jain: None. I. Bondarenko: None. J. Shan: A. Employee; Peregrine Pharmaceuticals. K. Stock; Peregrine Pharmaceuticals.
That would be my guess too. Gerber will describe the trial, patient demographics, results
to date and the MOS of the treatment arms will be TBD. The title of the talk does include
"Top-line Results". Then when the MOS actually is triggered a PR will be released.
I think the fact the information will be presented at a major scientific conference
will add weight and call attention to the trial.
Gerber is also giving this poster presentation.
Session: PD1-Poster Discussion Session
Thursday, Sep 06, 2012, 5:30 PM - 6:30 PM
Presentation: 116 - Association Between Baseline Tumor Diameters and Overall Survival in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC)
Pres. Time: Thursday, Sep 06, 2012, 6:10 PM - 6:25 PM
Category: Metastatic Non-small Cell Lung Cancer
Keywords: Advanced NSCLC; Survival; Measurements
Author(s): D. E. Gerber1, S. E. Dahlberg2, A. B. Sandler3, M. C. Perry4, J. H. Schiller1, J. R. Brahmer5, D. H. Johnson1, 1University of Texas Southwestern Medical Center, Dallas, TX, 2Dana Farber Cancer Institute, Boston, MA, 3Oregon Health and Science University, Portland, OR, 4Ellis Fischel Cancer Center, Colubmia, MO, 5Johns Hopkins University, Baltimore, MD
Disclosures: D.E. Gerber: None. S.E. Dahlberg: None. A.B. Sandler: None. M.C. Perry: None. J.H. Schiller: None. J.R. Brahmer: None. D.H. Johnson: None.
Damn, you beat me! I first suggested this meeting on July 12th in post 82904, and have been checking for Peregrine to present.
I think this will be the turning point.
How it all started for me. I read this article online at ScienceDaily in July 2005.
The whole idea just sucked me in, I started reading Thorpe's papers.
http://www.sciencedaily.com/releases/2005/06/050630061607.htm
Bought my first shares of Peregrine on Aug 30, 2005 through my
TD Waterhouse account (now TD Ameritrade), 210 shares @ $1.15 each.
Currently have 20550 shares @ 2.09 each. Green!
Just goes to show you how lifestyle choices can have life or death consequences.
Mojojojo, I looked into this some more and there was an interesting graph from this paper. Something I would
like to see for the Bavi + docetaxel second-line NSCLC trial. It is time to development of new metastatic disease.
Randomized Phase II Study of Erlotinib Plus Tivantinib Versus Erlotinib Plus Placebo in Previously Treated Non–Small-Cell Lung Cancer
Lecia V. Sequist, Joachim von Pawel, Edward G. Garmey, Wallace L. Akerley, Wolfram Brugger, Dora Ferrari,
Yinpu Chen, Daniel B. Costa, David E. Gerber, Sergey Orlov, Rodryg Ramlau, Susan Arthur,
Igor Gorbachevsky, Brian Schwartz, and Joan H. Schiller
Journal of Clinical Oncology, 29(24), 3307-3315, 2011.
Okay, so in phase 3 they are using non-squamous only, just as bavi does, but the graph you posted
shows control arm MOS = 6.8 months, treatment arm = 9.9 months. Respectable, but why would I
think this is one of the drugs that will dominate the NSCLC market in 2020? That was the claim.
We have heard a lot recently about the monoclonal antibody Ipilimumab (anti-CTLA-4), a.k.a Yervoy, a.k.a. MDX-010, which made big news when it was approved for melanoma. The results for the phase 2 trial in first-line NSCLC were published in the June 10, 2012 issue of he Journal of Clinical Oncology.
Ipilimumab in Combination With Paclitaxel and Carboplatin As First-Line Treatment in Stage IIIB/IV Non–Small-Cell Lung Cancer: Results From a Randomized, Double-Blind, Multicenter Phase II Study
Thomas J. Lynch, Igor Bondarenko, Alexander Luft, Piotr Serwatowski, Fabrice Barlesi, Raju Chacko,
Martin Sebastian, Joel Neal, Haolan Lu, Jean-Marie Cuillerot, and Martin Reck
This mAb could be considered as a competitor to Bavi, along with the anti-PD-1 mAb, although they all have totally different MOA.
Here are the trial results, and some text from the above paper. Note that the trial enrolled patients with both squamous and non-squamous histology. There were no complete responses in any arm.
N = 66 in control, N = 68 in Ipilimumab (phased)
CP + I (phased) | CP + P | P
ORR: 32% | 14%
PFS: 5.1 | 4.2 months | 0.02
MOS: 12.2 | 8.3 months | 0.23
INTRODUCTION
Platinum-based chemotherapy combinations are
the standard of first-line care for patients with
advanced non–small-cell lung cancer (NSCLC)
with a median overall survival (OS) that ranges
from 8 to 12 months.1,2 Recent additions to the
standard chemotherapy of biologics, such as bevacizumab
and cetuximab, have made only modest
differences in survival, which necessitated new
therapeutic paradigms.3-6 One anticancer target
of current interest is cytotoxic T-lymphocyte
antigen-4 (CTLA-4), which is a negative regulator
of T-cell activation.7-10
Ipilimumab, which is a fully human monoclonal antibody, specifically
blocks the binding of CTLA-4 to its ligands (CD80/CD86).
This blockade augments T-cell activation and proliferation, which
leads to tumor infiltration by T cells and tumor regression.
....
DISCUSSION
Histology is emerging as a factor in selecting agents for NSCLC
treatment, as suggested by the fact that bevacizumab and pemetrexed
are approved treatments for nonsquamous NSCLC but not for squamous
NSCLC.56,57 In this trial, phased ipilimumab appeared to show
improved efficacy for squamous histology, but there was no apparent
benefit for nonsquamous histology. Although caution is warranted in
interpreting these subset data from a small phase II study, it is notable
that tumor-infiltrating T cells are more abundant in squamous
NSCLC.48,51,58 Additional trials in conjunction with translational research
are needed to confirm our findings in patients with squamous
NSCLC.
....
Note the control arm had 23% squamous carcinoma, the phased Ipilimumab arm had 31%.
Well, I wouldn't be buying their so-called research. I did a little research on Talactoferrin since I
had never heard of it. Not approved yet, in phase 3 trials. So I looked up their phase 2 trials.
A Randomized, Double-Blind, Placebo-Controlled, Phase II
Study of Oral Talactoferrin in Combination with
Carboplatin and Paclitaxel in Previously Untreated Locally
Advanced or Metastatic Non-small Cell Lung Cancer
Journal of Thoracic Oncology • Volume 6, Number 6, June 2011
This is for First-Line NSCLC
N = 100 evaluable patients
TLF | Placebo | P
ORR: 47% | 29% | 0.05
PFS: 7 | 4.2 months | 0.14
MOS: 11.3 | 8.5 months | 0.11
So this is one of the drugs that is going to dominate the lung cancer market in 2020?
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Here is part of the approval announcement from FDA for Xalkori (crizotinib), another on the list:
Aug. 26, 2011
The U.S. Food and Drug Administration today approved Xalkori (crizotinib) to treat certain patients with late-stage (locally advanced or metastatic), non-small cell lung cancers (NSCLC) who express the abnormal anaplastic lymphoma kinase (ALK) gene.
Xalkori is being approved with a companion diagnostic test that will help determine if a patient has the abnormal ALK gene, a first-of-a-kind genetic test called the Vysis ALK Break Apart FISH Probe Kit. It is the second such targeted therapy approved by the FDA this year.
This ALK gene abnormality causes cancer development and growth. About 1 percent to 7 percent of those with NSCLC have the ALK gene abnormality.
Need I say more?
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Then there is ARQ 197 (tivantinib). Also not approved yet, in phase 3 trials now, but with Tarceva. The phase 2 was with Tarceva too.
Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer.
J Clin Oncol. 2011 Aug 20;29(24):3307-15.
So this is for second-line NSCLC (ET = erlotinib plus tivantinib, EP = erlotinib plus placebo)
PURPOSE:
c-MET (MET) receptor activation is associated with poor prognosis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small-cell lung cancer (NSCLC). This global, randomized phase II trial examined erlotinib plus tivantinib (ARQ 197; ArQule, Woburn, MA), a novel MET inhibitor.
RESULTS:
One hundred sixty-seven patients were randomly assigned to ET (n = 84) and to EP (n = 83). Median PFS was 3.8 months for ET and 2.3 months for EP (hazard ratio [HR], 0.81; 95% CI, 0.57 to 1.16; P = .24). Exploratory analysis revealed that the small cohort with KRAS mutations achieved a PFS HR of 0.18 (95% CI, 0.05 to 0.70; interaction P = .006). Objective responses were seen in 10% of patients on ET, 7% of patients on EP, and in two patients who crossed over from EP to ET, including one with EGFR mutation and MET gene copy number greater than 5. There were no significant differences in adverse events between study arms.
......
At the time of OS analysis, median follow-up was 14 months, and 105 patients had died. Median OS was 8.5 months for ET and 6.9 months for EP (HR, 0.87; 95% CI, 0.59 to 1.27; P = .47;
So I ask you, does Bavi have a chance to take over the NSCLC market completely by 2020?
Where did that list come from? Do you have a source? I find the list of drugs that will supposedly be dominant in 2020 to be very dubious.
I am assuming that you mean patients with early stage disease, like stage I-II, rather than patients with
later stage III-IV disease but not yet treated. The current IST for rectal cancer will address this issue.
I think the real difference of using Bavi in early stage disease will be in the reduction of recurrent disease.
Currently chemo, surgery, radiation does a good job in early stage disease but the problem is the recurrence
of the disease.
Thanks for the encouragement, but I have a good job and a girlfriend here in Denver. If that were to change then I will.
Of course you are correct. Almost all trials specify patients have ECOG <= 2, so the very sickest patients are
excluded. It just makes sense that at some point they are beyond help. But I think Bavi can help more of those
marginal patients than thought possible before.
Bavi should work better because it works to normalize the tumor microenvironment so that the adaptive response can function properly. Anti-PD-1/PD-L1 antibodies work with T-cells, part of the adaptive immune response and so are downstream of the innate response where bavi is working. They also are not specific to the tumor environment.
Well, it is unlikely most of the time. Currently we have no data about the whole question of whether resistance develops over time or not. Are there patients who don't respond to bavi + chemo from the beginning? What is going on there? I think there is a spectrum of responsiveness, so what governs it? Lots of research questions. Yes, it seems to work really well as the second-line NSCLC trial is showing, but why doesn't every patient do as well? Since PS is upregulated on the endothelial cells of the tumor vasculature because of the very conditions that exist in the tumor which drive the tumor's diversity, I don't expect the tumor vasculature not to have PS upregulated. Therefore it is the response to that PS which determines the fate of the tumor. If the phagocytosis of the tumor vasculature can be blocked then Bavi will not work. Of course probably some tumor types have more PS on their vasculature than others, and some chemo drugs do a better job of increasing the amount of PS expressed, but what about for the same tumor type? The conventional wisdom used to say that the immune system was too damaged by chemo, and just the poor state of health of patients with stage IV disease, to work well enough for something like Bavi to work. But I think this trial is proving that isn't necessarily correct. I am just full of questions that I would like to know the answers to so we could learn how to make bavi work even better. Sorry, but sometimes I just get carried away. Maybe if I made a few million on this I will volunteer to work in Thorpe's lab!
Bavi is part of the immune system, it is just being added instead of developing naturally.
By adding antibodies, part of the adaptive immune response, you are switching the macrophages
from M2 to M1, also neutrophils from N2 to N1, and enabling the innate immune response
to attack the tumor vasculature. You are also masking the PS and changing the tumor
microenvironment to an anti-tumor state. All this will allow the adaptive immune response
to operate the way it should and develop immunity. So the selection pressure arises from
the destruction of the tumor vasculature, which kills the tumor cells. Eventually
some tumors cells will find a way to block the destruction of the tumor vasculature and
ensure their survival. My guess is some cytokine/chemokine might upregulate CD47,
the don't eat me signal, on the vasculature. So, it is an indirect path to survival for
the tumor cells, and so won't happen very quickly.
Actually there is a pathway in which resistance could develop, but it is much less
likely than what happens in tumors which develop resistance to targeted therapies, or
chemo. It is all about selective pressure. If there is a way then it will happen, it just
might not be very often, and may take some time.
There could be resistance developing to bavi, but as you say it would have probably
already happened. That is why I have said I think some of these patients may have
been cured and developed immunity. If so it would be interesting to look at their blood
for antibodies to the cancer, since you can't inject them with tumor cells to see if they are immune.
Maybe you could implant the tumors in mice and then inject the mice with the antibodies.
Yes, that is what I said, it is the adaptive immune system primed by Bavi.
Here is another paper about the interactions involved. Note the macrophages involved would be of the type M2,
and Bavi would switch them to type M1 breaking the feedback loop with MDSCs.
Seminars in Cancer Biology 22 (2012) 275– 281.
Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic
cells enhances tumor-induced immune suppression
Suzanne Ostrand-Rosenberg*, Pratima Sinha, Daniel W. Beury, Virginia K. Clements
University of Maryland Baltimore County, Dept. Biological Sciences, United States
abstract
The tumor microenvironment is a complex milieu of tumor and host cells. Host cells can include tumor
reactive T cells capable of killing tumor cells. However, more frequently the tumor and host components
interact to generate a highly immune suppressive environment that frustrates T cell cytotoxicity and promotes
tumor progression through a variety of immune and non-immune mechanisms. Myeloid-derived
suppressor cells (MDSC) are a major host component contributing to the immune suppressive environment.
In addition to their inherent immune suppressive function, MDSC amplify the immune suppressive
activity of macrophages and dendritic cells via cross-talk. This article will review the cell–cell interactions
used by MDSC to inhibit anti-tumor immunity and promote progression, and the role of inflammation in
promoting cross-talk between MDSC and other cells in the tumor microenvironment.
Thurly, you have the idea in some respects, but not others. What do you mean by "clearing the system"?
The microenvironment of the tumor is created by cytokines/chemokines that are released by the tumor
or in response to the tumor, like TGF-beta which is immunosuppressive. Feedback loops are
set up between the tumor and immune cells which switch the immune cells to a pro-tumor state.
See the figure in my post # 77572. Bavi binds to the beta2-GPI which is bound to the PS displayed
on the tumor vasculature, apoptotic tumor cells and maybe exosomes. It also will bind directly to the M2
macrophages switching them to M1. When a new tumor appears elsewhere in the body the local
tumor microenvironment is still in a pro-tumor state until treated. We do know that Bavi can lead
to immunity, as was seen in the rat study of glioblastoma when 13% of the surviving rats developed
immunity to rechallenge by the tumor cells. That study used radiation + bavi.
Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels
and induces tumor immunity in a rat model of glioblastoma.
He J, Yin Y, Luster TA, Watkins L, Thorpe PE.
Clin Cancer Res. 2009 Nov 15;15(22):6871-80.
FREE: http://www.ncbi.nlm.nih.gov/pubmed/19887482
There is the possibility that some of the patients still alive in the second-line NSCLC trial have
developed immunity, but the only way to tell is to see if they stay alive and don't have recurrent disease.
Here are two images from these papers on neutrophils
Cancer Cell. 2009 Sep 8;16(3):183-94.
Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN.
Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM.
FREE: http://www.ncbi.nlm.nih.gov/pubmed/19732719
and the Judy et al paper from post # 85862.
Figure 4. Mch1N11 and cis induce apoptosis in tumor endothelial cells. (A) Mice bearing TC1 tumor were treated with C44, mch1N11,
cis, or a combination of mch1N11 and cis. Tumors were harvested, fixed in formalin, sectioned in paraffin, and stained for apoptosis
using TUNEL staining kit. Only the combination therapy group had apoptotic tumor endothelial cells
RRdog, the fact that neutrophils are involved with the response to bavi is indeed new and exciting.
The fact that neutrophils can be polarized to an N1 and N2 phenotype, much as macrophages are
polarized to M1 and M2 phenotypes, has been known for a few years. However, this is the first time
it has been shown that these N1 neutrophils can be induced to attack a tumor, as far as I know. I believe
that what is happening is that bavi is altering the tumor microenvironment by masking PS and by
directly switching macrophages from M2 to M1. When neutrophils are recruited to the tumor they then
remain in the N1 state instead of being switched to the tumorgenic N2 state, as they would be if bavi wasn't used.
The paper is here http://www.ncbi.nlm.nih.gov/pubmed/22577350
Vascular endothelial-targeted therapy combined with cytotoxic chemotherapy induces inflammatory
intratumoral infiltrates and inhibits tumor relapses after surgery.
Judy BF, Aliperti LA, Predina JD, Levine D, Kapoor V, Thorpe PE, Albelda SM, Singhal S.
Discussion
The objective of this study was to determine whether using targeted
vascular therapy after surgery could inhibit local tumor recurrences
without causing the toxicity associated with other vascular-targeting
agents. Our major finding from this study is that combining mch1N11
with cis slows tumor recurrences after surgery. Our data suggest that the
mechanism is that cis, either directly or indirectly (i.e., by killing tumor
cells that then activates their associated vasculature), increases PS expression
of the tumor vasculature. This vascular PS presents a target
for the mch1N11 antibody that binds and induces intense neutrophil
infiltration, leading to vascular disruption and tumor death. This
process seems independent of the adaptive immune system.
....
Note that mch1N11 is the mouse chimeric version of PGN635, and cis is csiplatin. Also,
they show in the paper that macrophages are being switched from M2 to M1, in fact there are
twice as many M1 as M2 macrophages after treatment with bavi, in addition to the neutrophils.
SBRT, bavi, I124-PGN650. One can imagine treating the cancer with SBRT, bavi, then
using the imaging agent I124-PGN650. Since the SBRT will upregulate PS on >90% of
the tumor vasculature, bavi will result in destruction of most of the tumor vasculature,
then you use the imaging agent to look and see what is left and target the next
round of SBRT using that information, and repeat this cycle until all the tumor is gone.
I think with SBRT you could treat each tumor separately so I don't see why you couldn't use it on any stage cancer.
Mojojojo, you are probably correct. But AA could be given very quickly if the survival data is fantastic.
The Gleevec example shows just how fast the FDA can act. It was only 3 months from the time of
application to approval for the FDA to grant AA for Gleevec, without survival data.
http://www.cancer.gov/newscenter/pressreleases/2001/gleevectimeline
2001: February: Novartis submitted the New Drug Application for STI571, now known as Gleevec, to FDA for the treatment of the late phases of CML.
2001: April: Results of a larger study of STI571 in 83 patients were reported in New England Journal of Medicine. In the 54 chronic-phrase CML patients who were treated with doses of 300 milligrams or more, normal blood counts were restored in 53, and in 29 of the 54 patients, the Philadelphia chromosome disappeared. Most side effects were mild.
2001: May: U.S. Food and Drug Administration approved the sale of STI571/Gleevec for CML.
How about this scenario for approvals.
mid-October: second-line reports MOS of 14 months
mid-November: first-line reports MOS of 16 months
May 2013: Peregrine files for accelerated approval for first and
second-line NSCLC at the same time.
See my post #85770 for the picture
What I am getting at is this. The phase 2 second-line NSCLC trial is a randomized, double-blinded, placebo
controlled trial, i.e. "the gold standard". If the survival results are statistically significant then why not go
for regular approval? What more do you need besides that data? There are plenty of other studies with
Bavi providing additional safety data and by the time of application the first-line survival data might also be in hand.
Accelerated approval seems assured if the survival data is not quite significant and needing a larger trial
to show significance.
The case of approval for Gleevec might be relevant here. Sorry for the long post but it seems relevant to me.
From Wikipedia:
"Gleevec received FDA approval in May 2001. On the same month it made the cover of TIME magazine
as the "magic bullet" to cure cancer. Druker, Lydon and Sawyers received the Lasker-DeBakey Clinical
Medical Research Award in 2009 for 'converting a fatal cancer into a manageable chronic condition'.
...
Gleevec also holds the record for the drug with the fastest approval time by the FDA."
The FDA approval of Gleevec was based on data from three phase II open-label, single-arm studies that showed a major cytogenetic response (complete response = 0% Philadelphia chromosome-positive [Ph+] metaphases; partial response = up to 35% Ph+ metaphases) in patients with advanced stages of CML. Patients with chronic-phase CML after failure with interferon therapy achieved an 88% hematologic response (HR) and 49% overall major cytogenetic response—both primary end points of the study.
From the FDA approval report of Gleevec for CML, 2002.
FREE: http://clincancerres.aacrjournals.org/content/8/5/935.long
Regulatory Basis for Approval
The FDA considered two different mechanisms for imatinib
NDA approval, regular approval and accelerated approval. Drugs
approved for marketing in the United States must be safe and
effective. The safety requirement is derived from the Federal Food
Drug and Cosmetic Act of 1938. In 1962, the Act was amended to
require effectiveness to be demonstrated by adequate and well controlled
investigations. For regular NDA approval, drugs must
provide clinical benefit or affect a surrogate end point that is well
established as leading to clinical benefit. In 1992, Subpart H was
added to the NDA regulations (21 CFR 314) to allow accelerated
approval of drugs for diseases that are serious or life-threatening
and for which there is no satisfactory alternative therapy. Accelerated
approval is based on demonstration of an effect of a drug on
a surrogate endpoint that is reasonably likely to predict clinical
benefit. After accelerated approval, the applicant is required to
perform trial(s) to demonstrate that treatment with the drug is
indeed associated with clinical benefit. If the trials fail to demonstrate
clinical benefit or if the sponsor does not show “due diligence”
in performing the trials, a rapid process for removing the
drug from the market may be applied.
As discussed below, the data were deemed sufficient to
support accelerated approval in three CML clinical settings.
CML-BC
In CML-BC, accelerated approval was based on HR. The HR
rate (26%) with imatinib treatment was comparable with results
reported in the literature with cytotoxic drug combinations associated
with significant toxicity (4, 19, 20). Imatinib provided an
advantage over available therapy for CML-BC by achieving at least
a comparable HR rate with less toxicity. Reduction in toxicity is
particularly important in the treatment of blast crisis because survival
is short, and palliation is the goal of therapy.
CML-AP
For CML-AP, accelerated approval was based on the surrogate
endpoints of HR and MCyR. The rates of HR (63%) and
MCyR (21%) with imatinib treatment were at least as good as
results reported in the literature with available treatments and were
achieved with a marked reduction in toxicity. In two studies evaluating
toxic multiagent chemotherapy, the HR rates were 25 and
52%, and the rate of MCyR was 8 and 8.5%. Treatment toxicity
included neutropenia, infection, diarrhea, and mucositis.
CML-CP after Failure of IFN-alpha
Strong evidence of clinical benefit exists for available
treatments for CML-CP. IFN-alpha2a recombinant (Roferon-A) was
approved by the FDA for treatment of early CML-CP, based on
survival benefit demonstrated in a randomized trial conducted
by the Italian Cooperative Study Group on CML (IFN- versus
hydroxyurea or busulfan) and supporting evidence from a Phase
II trial conducted at M. D. Anderson Cancer Center. Continued
IFN-alpha treatment was not a reasonable option for patients entered
in the CML-CP study because patients were intolerant to IFN-alpha
(36%), had CML that progressed during treatment with IFN-alpha
(29%), or had not shown a CHR and/or MCyR after a specified
duration of IFN-alpha treatment (35%). The benefit of additional
IFN-alpha in the last setting has not been studied.
Ordinary drug approval would generally require evidence
of enhanced survival in a controlled study comparing imatinib to
the best available treatment, probably including longer duration
IFN- treatment in patients who did not achieve a satisfactory
response within the protocol specified time interval. Accelerated
approval is based on surrogate endpoints, in this setting, MCyR
and CCyR. The rates of MCyR (49%) and CCyR (30%) with
imatinib treatment were at least as good as results reported with
available therapies (21–26), with less toxicity. The imatinib induced
MCyR rate also appeared higher than those in registration
trials evaluating IFN- for treatment of early CML-CP
(MCyR rates of 10 and 12%).
Phase IV Postmarketing Commitments
The letter advising the manufacturer of the approval for
marketing (approval letter) of imatinib listed several Phase
IV commitments agreed to previously by the NDA applicant.
Two of the commitments are intended to demonstrate that
imatinib treatment provides clinical benefits, e.g., increased
progression-free survival or overall survival (not just an
improvement in surrogate endpoints for clinical benefit). The
applicant committed to conduct and submit a randomized
Phase III study comparing imatinib to IFN- combined with
Cytarabine (1--D-arabinofuranosylcytosine) in patients with
newly diagnosed CML.
If results are really that good, and statistically significant with respect to survival data, then would it be
possible to get regular approval with the data in hand and not have to wait for the phase 3? I think
the AA route was for phase 2 trials showing good results, but needing survival data to be confirmed,
which in this case will not be needed.
In case anyone missed it, from the CPRIT description of the project.
Sunstar, so far SBRT has been used for inoperable early stage cancer, but it seems that the next step
is to use it on operable tumors. From the paper I cite, from 2011, in my post # 85770 we have this,
CONCLUSIONS
Stereotactic ablative radiotherapy, also known as stereotactic
body radiation therapy (SBRT), has emerged as a technique utilizing
innovation within radiation therapy to increase accuracy
and allow for the delivery of oligofractionated, ablative doses
of radiation. Use of SABR for treatment of patients with stage I
NSCLC has been developed as standard treatment option
for medically inoperable patients through careful study in the
prospective, multi-institutional clinical trials described in the
previous sections. Toxicity of this treatment has been well characterized
in the clinical trials, allowing for appropriate selection of candidates for SABR.
Because of the encouraging control rates seen in medically inoperable patients,
study of SABR has now been extended to medically operable patients and is being
compared with surgical resection in ongoing randomized clinical trials.
So maybe some day SBRT with bavi could replace surgery, at least for small tumors. I think for larger
tumors that are operable they would still do surgery first, the new IST is doing that but it doesn't seem
to be using SBRT, but other RT.
Paper by one of the CPRIT grantees about SBRT, and figure showing the region defined as the central lung.
Stereotactic Ablative Radiation Therapy for Primary Lung Tumors
John H. Heinzerling, MD, Brian Kavanagh, MD, and Robert D. Timmerman, MD
The Cancer Journal Volume 17, Number 1, January/February 2011
Abstract: Stereotactic ablative radiotherapy, also known as stereotactic
body radiation therapy, has been developed as an innovative
therapy for stage I non-small cell lung cancer and has now emerged as
a standard treatment option for medically inoperable patients through
careful analysis utilizing prospective, multi-institutional trials. This article
reviews and updates the evidence for use of stereotactic ablative
radiotherapy in medically inoperable patients with stage I lung cancer,
its extension of use to medically operable patients, and the toxicities
associated with this emerging technique
This new grant just goes to show you how much potential there is to bavi. It is quite amazing. SBRT allows
you to use a very highly focused beam of high energy radiation on the tumor. This results in >90% exposure
of PS on the tumor endothelial cells which bavi can then bind to. In the grant description it talks
about patients with central lung cancer. That is patients with tumors deep within the lungs and not out
on the edges. Using too much radiation on these centrally located tumors can destroy the lung tissue.
So even using SBRT, since it will have to pass through lung tissue to irradiate the tumor, the amount of
radiation has to be limited. That is where bavi comes in. You can imagine using this combo of SBRT and bavi
on many other early-stage tumor types too. Talk about depth!