12-5-2012: Philip Thorpe & Joe Shan to speak about Bavi at IBC’s Antibody Therapeutics Conf. in San Diego…
Dr. Phil Thorpe is Chair for session, ”Dev. Status of Immunomodulatory Therapeutic Antibodies” - 6 speakers: • Dario Neri (Swiss Federal Inst. of Tech.) - immunocytokines delivering IL-2, TNF-A, IL-12 • Bruce Cree (UCSF) - B cell-depleting mabs that deplete dysregulated Bcells that contribute to MS • Erik Fedyk (Millennium Pharm) – mab vedolizumab [MLN0002] vs. inflammatory bowel disease • Gens Volkmer (Stanford Univ) - CD47-blocking antibodies that inhibit of tumor growth & Mets • Philip Thorpe (UTSW, PPHM SAB) - Bavituximab reactivates innate & adaptive tumor immunity and induces an immune cell-mediated shutdown of tumor vasculature • Joseph Shan (Peregrine’s VP/Clin+RegAffairs) – an update on the perf. of Bavi in cancer clinical trials
Dec5 2012: IBC’s 23rd Annual Intl. Conf – Antibody Eng. & Therapeutics (SDiego) http://tinyurl.com/bv3usce ...11:00am Dr. Philip Thorpe (Chair) “Overcoming Immune Suppression in Tumors with Bavituximab: Preclin. Studies” …11:30am Joe Shan, “Clinical Dev. of Bavituximab, a PS-Targeting Mab”
2012 ANTIBODY THERAPEUTICS SCIENTIFIC ADVISORY BOARD • Rathin C. Das, PhD, CEO, Synergys Biotherapeutics, Inc. • Mark R. Alfenito, PhD, CEO, EnGen Bio, Inc. • Benjamin P. Chen, PhD, Managing Partner, Ignatius Transaction Partners, LLC • Philip E. Thorpe, PhD, Professor of Pharmacology & Serena S. Simmons Distinguished Chair, Univ. of Texas SW • Trudi Veldman, PhD, Director, Biologics Generation, Abbott Laboratories
OVERVIEW http://www.ibclifesciences.com/antibodyeng/overview.xml • Leading Academic Research – MIT, UCSF, Cambridge Univ., Scripps • Innovative Emerging Science – Chugai, Cell-Signal, Zyngenia, Los Alamos Natl Lab • Proven Clinical Results – Seattle-Gen, Pfizer, Amgen, “UTSW examines clinical studies of Bavituximab used to overcome immune suppression in tumors” - - - - - - - - - - - - - - - - Antibody Therapeutics Conference – Wed. Dec. 5, 2012 Track: ”Development Status of Immunomodulatory Therapeutic Antibodies” 12-5-12 8:00am: Chairperson’s Opening Remarks - Philip E. Thorpe, Ph.D., Professor of Pharmacology, Serena S. Simmons Distinguished Chair, Univ. of Texas SW - - - - - - - SESSION CHAIR: Philip E. Thorpe, Univ, of Texas SW Medical Center Session Overview: The development of immunomodulatory antibodies is one of the most significant advances in cancer therapy in the 10 years that IBC’s Antibody Therapeutics Conference has been held. The best known antibodies of this category are anti-CTLA4 (e.g., ipilimumab), anti-PD1, and anti-PD1L mAbs, which have shown meaningful clinical activity in melanoma, renal cell cancer, and non-small cell lung carcinoma (NSCLC). These antibodies act by suppressing the downregulation of activated T cells, thereby maintaining and enhancing immune responses to tumor antigens. This session will focus on new and alternative approaches to creating immunomodulatory antibodies for the treatment of cancer & non-malignant diseases, including rheumatoid arthritis (RA) and multiple sclerosis (MS). SPEAKERS: Dario Neri (Swiss Federal Inst. of Technology) will deliver the keynote presentation in which he will discuss immunocytokines for the treatment of cancer & RA. Immunocytokines are fusions of antibody-binding domains with cytokines that activate or suppress immune activity. The strategy is to create fusion proteins that target fibronectin and tenascin isoforms that are selectively present in the extracellular matrix surrounding angiogenic and remodeling blood vessels. For cancer, the immunocytokines deliver IL-2, TNF-A, or IL-12 to stimulate immune cell attack on the tumor vasculature. For RA, IL-10 is delivered to suppress immune reactivity around inflamed vessels. Bruce Cree (Univ. of California, SanFran) will describe how B cell-depleting monoclonal antibodies can be used to deplete dysregulated B cells that contribute to MS pathogenesis. Clinical studies have shown promising efficacy with > 90% reductions in markers of disease and excellent tolerability; Phase 3 clinical trials are in progress. Erik Fedyk (Millennium Pharm.) will discuss vedolizumab [MLN0002], a humanized monoclonal antibody for treating inflammatory bowel disease. Vedolizumab binds to the gut-tropic A4B7 integrin on vascular endothelium, thereby blocking the homing of MAdCAM-1 positive leukocytes into mucosal & inflamed tissues. Vedolizumab is in Phase 3 trials in patients with moderate to severe Crohn disease. Gens Volkmer (Stanford Univ.) will discuss pre-clinical evidence that CD47, which is overexpressed in numerous tumor types, transmits a “don’t eat me” signal to macrophages and dendritic cells. Treatment with CD47-blocking antibodies enables immune cells to phagocytose tumor cells in vitro. This results in inhibition of tumor growth and prevention of metastases in xenograft tumor models. Philip Thorpe (Univ. of Texas SW Medical Ctr) will give an update on the mechanism of anti-tumor action of bavituximab, an immunostimulatory chimeric monoclonal antibody that is showing promising activity in clinical trials in patients with various types of cancer. Bavituximab targets the immunosuppressive lipid phosphatidylserine (PS) that becomes exposed on tumor blood vessels and tumor cells. Tumors externalize PS and secrete PS-expressing exosomes that impose quiescence on immune cells, thereby creating a tumor microenvironment that supports tumor growth. Bavituximab causes myeloid-derived suppressor cells in tumors to differentiate into tumoricidal M1 macrophages that destroy tumor vasculature and tumor cells by antibody-dependent cell-mediated cytotoxicity. It also causes immature dendritic cells in tumors to mature and present tumor antigens that result in the generation of tumor-specific cytotoxic T cells. Thus, bavituximab reactivates innate & adaptive tumor immunity, and induces an immune cell-mediated shutdown of tumor vasculature. Joseph Shan (Peregrine Pharm.) will then give an update on the performance of bavituximab in clinical trials in patients with cancer. Bavituximab has been shown to be well-tolerated both as a single agent and in combination with approved therapies. Bavituximab has demonstrated promising anti-tumor activity as an adjunct to std. chemotherapy, and is advancing to late stage clinical development in NSCLC. - - - - - - - - - - - - - - - - Session wrapup: “Given that several of the new agents being described in this session have already been established as safe & effective in clinical trials, there is a high likelihood that some will become approved drugs. This is therefore a timely session that will give a glimpse of what is around the corner.” - - - - - - - - - - - - - - - 12-5-12 11:00am Philip E. Thorpe, Ph.D., Professor of Pharmacology, Serena S. Simmons Distinguished Chair, Univ. of Texas SW “Overcoming Immune Suppression in Tumors with Bavituximab: Preclinical Studies” Bavituximab is a monoclonal antibody that is proving safe & effective as a 2nd-Line therapy in advanced lung cancer patients. It targets the immunosuppressive lipid, phosphatidylserine [PS], which becomes exposed on tumor blood vessels & tumor cells. Bavituximab causes MDSCs to differentiate into tumoricidal M1 macrophages that destroy the tumor vasculature and tumor cells by ADCC. It also causes immature dendritic cells in tumors to mature and present tumor antigens, resulting in the generation of tumor-specific cytotoxic T-cells. - - - - - - - 12-5-12 11:30am Joseph Shan, MPH, VP, Clinical & Regulatory Affairs, Peregrine Pharmaceuticals, Inc. “Clinical Development of Bavituximab, a Phosphatidylserine (PS)-Targeting Monoclonal Antibody” Bavituximab, an investigational monoclonal antibody, localizes selectively on tumor vasculature, synergizes with chemotherapy, causes vascular shut down in tumors and reactivates innate and adaptive tumor immunity. In clinical trials to date, bavituximab has been well-tolerated both as a single agent and in combination with approved therapies. Bavituximab has demonstrated promising anti-tumor activity as an adjunct to standard chemotherapy in several solid tumor indications and is advancing to late-stage clinical development in NSCLC.
Dr. Philip Thorpe’s 46min. 5-1-12 NYAS Anti-PS Symposium talk Replay & Slides – see below. He was the last of these 5 speakers at the NYAS “Phosphatidylserine (PS) Asymmetry - Therapeutic Applications in Cancer & Infectious Disease Symposium. If you have the time to listen to all 5 of these talks, you will learn an immense amount about the moa of Peregrine’s PS-targeting antibody therapeutic, Bavituximab.
Dr. Thorpe’s talk is A MUST, but the other 4 are excellent as well.
Of note is PPHM SAB’r Dr. Alan Schroit’s [MDA, adjunct prof. at UTSW/Dallas] talk, “Regulation of PS Asymmetry & Physiologic Consequences of Its Loss” Dr. Schroit is the best in the world with targeting phospholipids and knowledge of cellular membrane expression of altered phospholipids in cancer cells. His work at MDA is critical to Peregrine’s PS-targeting patent estate – see http://tinyurl.com/3cwtdy => 7-9-07: Peregrine Licenses MDA’s “Clipped B2GP1” (inventor: Dr. Schroit)… “Peregrine, Schroit, and MDA will collab. to conduct preclinical studies designed to advance B2GP1 toward human trials.” Dr. Schroit’s MDA bio states this: “Dr. Schroit's lab has concentrated on the chemistry, biology and pathology of phosphatidylserine exposure in the outer leaflet of cells. He is an expert on targeting phospholipids and the knowledge of cellular membrane expression of altered phospholipids in cancer cells. These studies have led to the development of new methods to treat cancer by inducing production of anti-PS antibodies in patients.”
= = = = = = = = = = = = = = May1 2012 1-5pm: “New York Academy of Sciences Symposium”, 7WTC/NYC Symposium Name: “Phosphatidylserine (PS) Asymmetry - Therapeutic Applications in Cancer & Infectious Disease” • Academy Event by the Cancer & Signaling Discussion Group • Sponsors: N.Y. Academy of Sciences & Peregrine Pharmaceuticals ”This symposium will highlight recent developments in the understanding of PS exposure, its biological consequences, and its exploitation to create novel agents for the detection and treatment of cancer & viral diseases” Event: http://www.nyas.org/PSasymmetry NYAS: http://www.nyas.org/WhatWeDo/Default.aspx
SYMPOSIUM DESC: Phosphatidylserine (PS) is a membrane lipid that regulates multiple biological processes. It is normally positioned in the inner leaflet of the plasma membrane but translocates to the outer, extracellular-facing surface to signal clearance of apoptotic cells, to quell unwanted inflammatory reactions and immunity, and to stimulate hemostasis and complement activation at sites of injury. PS exposure can be subverted by cells that become malignant or infected by viruses as a ploy to escape host defenses. This symposium will highlight recent developments in the understanding of PS regulation and its exploitation to create novel therapeutics for cancer & viral diseases.
SPEAKERS: • ALAN SCHROIT (UTSW [PPHM SAB]) will introduce the topic and discuss how PS asymmetry is regulated in resting cells and the physiologic and pathologic consequences of its loss. • DAVID UCKER (Univ. of Illinois at Chicago) will describe how PS exposure suppresses inflammatory and immune responses to cells undergoing apoptosis at the end of their natural lifespan. • ARI HELENIUS (ETH Honggerberg/Switz) will discuss how viruses use macropinocytosis and apoptotic mimcry to enter host cells. • CHRIS REUTELINGSPERGER (Univ. of Maastricht/Netherlands) will discuss the use of annexin A5 to image apoptosis for detecting cardiopulmonary lesions and monitoring tumor responses to therapy. He will also discuss the use of annexin A5 for drug delivery. • PHILIP THORPE (UTSW [PPHM SAB, inventor of Bavituximab]) will discuss clinical trials with bavituximab, an antibody that targets PS-expressing tumor vasculature and reactivates host immunity.
Website: http://www.nyas.org/PSasymmetry Click “E-Briefing” for these tabs: • Meeting Report (textual summaries) • Media (replays, with slides) **See Below for Dr. Thorpe’s 30 Slides** • Resources (speaker pubs) • Speakers (bios) • Sponsors: N.Y. Academy of Sciences & Peregrine Pharmaceuticals
NYAS 5-1-12 Meeting Report - Speaker: Philip Thorpe, UTSW-MC/Dallas HIGHLIGHTS • Bavituximab, an antibody drug in development by Peregrine Pharm., targets PS in tumor blood vessels and can reactivate immunity to cancer cells. • This antibody can serve as both an imaging agent and as an adjuvant treatment with other therapies. • Bavituximab can induce tumor-specific T-cell immunity in some situations.
TARGETING TUMOR VASCULATURE Taking advantage of the externalization of PS on tumor cells could provide new treatment strategies for cancer treatments. Philip Thorpe of UT Southwestern MC (Dallas) described preclinical & clinical studies of bavituximab, an antibody drug developed by Peregrine Pharmaceuticals that targets PS in the vasculature of tumors. As tumors develop, they create a stressful, hypoxic cellular environment that results in the formation of reactive oxygen species and the release of inflammatory cytokines. In this environment, the asymmetry of lipid distribution in the membrane of the endothelial cells that line tumor blood vessels breaks down, leading to the externalization of PS. In addition, PS is often exposed on the surface of tumor cells. As a strategy for targeting PS externalization, Peregrine Pharm. initially developed a mouse monoclonal antibody that targets PS by binding to 2 molecules of B2-glycoprotein-I that in turn bind to PS on the surface of cells. With only a single molecule of the protein, binding to the surface of cells is relatively weak, but the affinity increases by a factor of 30,000 with the addition of a second molecule of B2-glycoprotein-I. The researchers have constructed a series of antibodies that targets the tumor vasculature. Two are mouse antibodies, 3G4 & 2aG4. Bavituximab is a chimeric antibody with mouse PS binding regions fused to human IgG. The fully human antibody is known as PGN635. These antibodies localize specifically to the blood vessels in tumors, which makes them useful as imaging agents. Studies with normal tissues and various tumor types reveal that these antibodies show affinity for a range of tumor types but minimal binding to a variety of normal tissues.
BAVITUXIMAB AS AN ANTI-TUMOR AGENT In rodent studies, antibodies alone inhibit tumor growth by 30%–90%. That variation most likely reflects the differences in PS expression on blood vessels in different tumors. However, combining the antibody treatment with other treatments, including chemotherapy, radiation, or androgen deprivation, improved these results. In studies of prostate tumors in mice, the combination of the mouse antibody 2aG4+docetaxel slowed tumor growth by 98% compared with 90% for docetaxel alone and 80% for antibody alone. The PS-targeting antibody in combination with intense radiation can shrink lung cancer tumors that are resistant to radiation alone. How does the antibody work? As one proposed mechanism of action, these PS-targeting antibodies damage tumor vessels by a process known as Antibody-Dependent Cellular Cytotoxicity (ADCC). As poor blood flow and hypoxia lead cells in the tumor vasculature to expose PS on their surfaces, bavituximab targets those cells and shuts down blood flow, which starves those tumor cells of nutrients. As a 2nd mechanism, bavituximab can overcome the immunosuppressive processes observed with cells that externalize PS. In tumors the expression of PS on cell surfaces keeps macrophages in their M2 state, an activation state that suppresses inflammation and supports angiogenesis. It also prevents myeloid-derived suppressor cells (MDSCs) from differentiating into macrophages and dendritic cells (DCs). In addition, PS inhibits the maturation of DCs, which prevents the presentation of antigens to T cells. Bavituximab repolarizes macrophages to their M1 state, which allows them to kill cells that express PS, including the tumor vascular endothelium. It also leads to differentiation of the MDSCs and prompts DCs to mature and to present tumor antigens to T cells.
TUMOR-SPECIFIC IMMUNITY & CLINICAL TRIALS Bavituximab can also prompt the development of tumor-specific immunity. In experiments with rats with treatment-resistant glioma tumors, 15% of the animals treated both with radiation and with antibody therapies did not die from those tumors. When the researchers reintroduced glioma tumor cells into these surviving rats, the rats were immune to the cancer. The team determined that spleen cells from these animals could kill gliomas, which indicated the antibody treatment had induced T cell immunity. Bavituximab is currently being tested clinically. More than 400 people have been treated with the drug, which is well tolerated and appears not to show combined toxicity when used with chemotherapy, Thorpe said. A variety of single-arm, early Phase II studies have been completed as a 2nd-Line or 1st-Liine treatment in people with advanced breast cancer and as a Frontline treatment for NSCLC. Randomized Phase II studies in NSCLC and pancreatic cancer are also underway. JPG of Dr. Thorpe’s “Report”: Graph only:
= = = = = = = = = = = = = = = = = = = = = = = The 30 Slides (PDF) from Dr. Thorpe’s 5-1-12 NYAS presentation are here: http://www.peregrineinc.com/images/stories/pdfs/nyasweb.pdf . And, I copied them in here: = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = The 30 Slides Dr. Philip Thorpe presented 5-1-2012 at the NYAS PS-Targeting Symposium: …Note that Dr. Thorpe’s describes Bavi’s MOA in several parts: • Mechanism #1: Tumor Vessel Damage by ADCC • Mechanism #2: Blockade of PS-Mediated Immunosuppression in Tumors • Macrophage Polarization M2 to M1 Switch • Generation of Tumor-Specific Cytotoxic T Cells • Proposed Mechanism: PS Blocks MDSC, Macrophage, and DC (Dendritic Cells) Differentiation • Proposed Mechanism: Bavi Reactivates Innate & Adaptive Immunity
= = = = = = = = = = = = = = = 4-26-12 PR: Peregrine's Novel PS-Targeting Technology Platform to Be Highlighted at The New York Academy of Sciences Symposium on May 1, 2012 • Global Experts Convene to Discuss Innovative Science and Applications of Targeting Phosphatidylserine; Philip Thorpe, PhD, to Discuss Peregrine's Lead Drug Candidate, Bavituximab http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=667635 TUSTIN, 4/26/12: Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM) today announced that its phosphatidylserine (PS)-targeting technology platform and its lead drug candidate, bavituximab, will be highlighted at a symposium hosted by The New York Academy of Sciences. The event entitled "Phosphatidylserine Asymmetry and Cell Survival: Therapeutic Applications in Cancer and Infectious Disease" will be held on Tuesday, May 1, 2012 at 1:00pm EDT at The New York Academy of Sciences in New York. The symposium featuring a panel of global scientific experts will examine the role that PS plays in regulating immune response, how cancer and viral diseases exploit PS exposure for their own survival and proliferation in the body, and the latest research and clinical data on therapeutic PS-targeting agents, including Peregrine's bavituximab.
As part of the expert panel, Philip Thorpe, Ph.D., scientific advisor to Peregrine and inventor of the company's PS-targeting antibody technology, will review bavituximab's dual mechanism of action in targeting the vasculature of a tumor, as well as stimulating a lasting immune response in preclinical models of multiple cancers. Peregrine's bavituximab is currently being studied in 7 clinical trials spanning multiple oncology indications. Peregrine anticipates announcing preliminary data from its Phase II clinical trial of 2nd-Line NSCLC patients evaluating bavituximab in combination with docetaxel vs. placebo plus docetaxel in the 2nd quarter…
= = = = = = = = = = = = = = = = = = = = = = = = = By: Freethemice 8-15-12 iHub #87095 http://investorshub.advfn.com/boards/read_msg.aspx?message_id=78580873 I listened to Dr. Thorpe’s 5-1-12 NYAS Anti-PS Symposium talk yet again [ http://tinyurl.com/9qlt6ug ], and came up with this. The minutes 22:30-25:30 tell us about how the MOA has been updated to include exosomes. These very small vesicles are released by the tumor and have PS on their surface. This PS is sensed by the macrophages and dendritic cells which have PS receptors (TIM-3, TIM-4). This then causes an immunosuppresive signal in those immune cells. When bavi is added it binds to the PS on the exosomes and the Fc-gamma receptors on the immune effector cells. This send a immunostimulatory signal to those immune cells. It is then the combination of the two signals which determines what the immune response will be. The immunostimulatory signal over-rides the immunosuppressive signal and the tumor microenvironment is changed to be immunostimulatory. I drew this figure to show what is happening. This was the first time I have heard Thorpe talk about exosomes in such detail. You can replace "exosome" with "tumor cell" also.
The Kaplan-Meier Survival Curve (KM) is not an overly complex thing at all, IMO, once you get over the terminology and its underlying moa. I spent some time here http://cancerguide.org/scurve_km.html , and then just did some thinking on how it MUST Work, and I believe I’ve finally got it right. Repeat, I BELIEVE I’ve finally got it right.
Let’s look at K-M for the Bavi/3mg n=41 arm in the 2nd-Line NSCLC Trial…
PRIMARY PURPOSE OF KM: TO DEAL WITH STAGGERED TRIALS If ALL 41 pts were treated at the same time on Day1, we wouldn’t need KM. MOS would be a snap: just wait for the 21st patient to expire and his Survival Mos. would me MOS.
But, treatment went from Oct’10 to Oct’11 – at any point, you’ve got a mixture of Earliers & Laters and a mixture of Survival Months for indiv. patients. How do you “estimate” MOS on an interim basis while the staggered trial is still ongoing (ie, pts still alive)? KM, enter stage left…
The KM Curve’s purpose is to fairly ESTIMATE MOS on an “interim” basis, and do it only based on FACTS KNOWN at the (latest) point in time when it is being constructed.
Best at this point to look at a simple example of a KM Chart (see Bavi Sept7 KM below, but with this one it’s easier to see the tick marks):
KEYS FOR UNDERSTANDING:
1. The X-axis (horz.) runs from 0 – 3years – that’s from TIME OF TREATMENT (of each indiv. pt), not from start of trial – probably the most important thing to get right in your mind,
2. This KM being “SURVIVAL”, the ONLY thing that triggers a vertical drop segment in the graph is CONFIRMED DEATH. If you count the #downward drops (some may rep. 2 deaths = twice as vertical drop), that’s the # of CONFIRMED DEATHS at that point in time. IMPORTANT/CRITICAL: the 50% point in the KM Curve is based on the #CONFIRMED DEATHS known when KM is done, NOT the Total number of pts Treated in the trial thus far.
3. The “x” tick marks, so-called “Censored” patients represent pts who WERE ALIVE the last time they were followed up and confirmed. The “x” mark is put at the Months spot horizontally representing the #Months they were alive at that point. Too bad they chose the word, “Censored” – misleading – a better word would have been “Pending” or “Last-known-Alive” (there’s nothing subjective or devious about the ‘censoring’ process). So, look at each “X” mark – those rep. pts ALIVE at that point – nothing to do but check them later and see if still Alive. When/if they are later CONFIRMED DEAD, then they will switch from “X” to a vertical drop and officially “enter” the KM Curve, with one more pt in the graph to est. the 50% median MOS point.
****CRITICAL TO GRASP THIS: KM says, ONLY DEATH “Triggers” a vertical drop & expansion of the Curve – until the pts dies they will remain a “censored “X” with a “X” put on the graph at the #Months spot in the Curve when LAST-CONFIRMED Alive.
Said another way, the ONLY thing that affects the “shape” of the Curve is Confirmed Deaths. ALIVE patients are “censored” and “X” marks places on the graph at the #Months Survival point as of their last Confirmation. When a Alive (censored) pt is Confirmed Alive at a later date, their “X” is moved to the right in the graph.
Once you get the technique in your mind, you can move to IMPLICATIONS:
1. The total #pts Treated thus far (at the time the KM graph was created) is the #Vertical Drops + the number of “X” censors. As time marches on, the #Vertical-drops (Confirmed Deaths) increases and the # of X’s (Still Alives) decreases.
2. X’s towards Left End of the graph are pts who as of last Confirmation were Alive the least # of months. Pts treated late in the trial tend to show as censored (still alive) towards the left side, until sufficient survival time elapses to move them over towards the right. If a pt drops out of the trial, or cannot be located for Life/Death confirmation, that “X” just sits there forever (unless later they are found & status confirmed)
3. X’s towards Right End of the graph are pts who as of their last Confirmation were Alive the most # of months. When confirmed Alive at a later date, the new KM Curve will have their “X” moved over further to the right, or if they have Died, then they create a vertical drop in the graph.
4. The purpose of K-M is to fairly Est. MOS based on Confirmed Deaths – as time marches on in an ongoing trial, #DEATHS becomes lager & larger, making the Est. more accurate. While #DEATHS (vert.drops) increases as time-from-1st-treatment increases, the running MOS est. may go UP or DOWN slightly. If the newest Confirmed-Deaths’ indiv. Survival-Months is less than the “running avg./prev.K-M” was, the new K-M MOS Est. will go Down. Conversely, if the newest Confirmed-Deaths’ indiv. Survival-Months is more than the “running avg./prev. K-M” was, the new K-M MOS Est. will go Up. As more & more Deaths are added to the curve, the K-M Est. MOS adjusts to the newer, larger set of deceased Pts. …You’re just adjusting to more actual Survival data being known (ie, confirmed Deaths), until you reach a point where it can’t change anymore.
If this isn’t how K-M works, I’ll be a Monkey’s Uncle, but I’ve been a Monkey’s Uncle before – so, keep that in mind.
= = = = = = = = = = = = = = = = = = = = = = = = = = = FOLLOWUP THOUGHTS: The key to remember is that Only CONFIRMED DEATHS contribute to the overall shape of a K-M Curve, including Peregrine’s 2nd-Line NSCLC K-M Curve presented 9-7-12 by Dr. Gerber.
ALL other (Still Aliveat last followup) pts in the trial are “Censored” with their last-known #Months Survival noted with an “X” tick mark places on the graph. Then those Still-Alive pts are re-confirmed as Alive, their “X” moves to the right to shows the updated #Months since 1st-treatment that they have survived. In a mature trial like our 2nd-Line NSCLC trial is at this point, “X” censors way over to the Left in the graph were probably lost to followup for some reason. “X” censors way over to the Right in the graph can either still be alive or also lost to followup for some reason.
The term “censored” in KM-speak is unfortunate as I see it – they is nothing sinister or subjective about it – it just means “the last time we confirmed them they were Alive” and they are not put into the K-M graph (as vertical drops) since only with Confirmed-Deaths do we know the actual time they survived before death.
A K-M Curve is continually updated in a staggered trial like Bavi’s 2nd-Line NSCLC (enrolled Oct’10 – Oct’11). As more pts are confirmed deceased, their Months-Survival are dropped into the graph – during that period, the “running Est.” of MOS will go up or down based on the new entries. Eventually, when more than ½ of the pts die, and no remaining (later-treated) Alive pt can affect MOS, final MOS is “triggered” and it can no longer change.
All longs should read this post again and again, remember the discrepancy was between SOME patients as to who received which dose of Bavi. That means all this data is true to the fact that Bavi doubles MOS just what dose does it better!
The Ph2/n=120 2Line-NSCLC Trial basically doubled MOS ~6=>~12mos prior to the CMS screwup found in the CTL & 1Mg arms forced Peregrine to combine the 1Mg & CTL arms for comparison with the CMS-untouched 3Mg arm for “Final Data” and FDA approval to proceed with Ph3 SUNRISE. Note that the 9-7-12 interim data (showing stat-sig. doubling of MOS) reported just before CSM Ctl/1mg screwup was found/reported would have been EVEN BETTER had the CTL (DoceOnly) arm not received ~25% of BAVI and the 1Mg arm hadn't received ~25% of DoceOnly...
I. Just Before the CSM CTL<=>1Mg Screwup was found/announced (3mg OK)... ...9-7-12: PPHM PR (& Slides) about Dr. Gerber's plenary at ASTRO/Thoracic/Chicago (INTERIM Ph2 NSCLC Data): http://tinyurl.com/96wrrso …”The interim data showed a statistically significant improvement in OS (Hazard Ratio 0.524, p-value .0154) and a doubling of MOS (12.1/13.1mos. vs. 5.6mos.) in the Bavituximab-containing arms compared to the [Docetaxel] ctl-arm." ......VP Joe Shan's 15min. Webcast & Slideshow recapping Dr. David Gerber's 9-7-12 ASTRO/Chicago Plenary: http://tinyurl.com/96wrrso …9-10-12 Robert Garnick (Head/Reg), QtlyCC ( http://tinyurl.com/8nkwrml ) ……"The Ph2 NSCLC data we announced 9-7-12 has far exceeded our expectations, and I hope that you're as excited as I am with bavituximab's potential. I feel strongly that Peregrine should be recognized for having the corporate courage to conduct the rigorous, randomized placebo-controlled Ph2 trial that provided these robust data and that provide the basis for us to plan for a pivotal Ph3 pgm." - - - - - ->Ph2 Interim B4 CMS CTL/1mg Screwup found: DoceONLY n=38: ECOG0-1-2=25%-62%-13% MOS=5.6mos. Bavi/1mg: n=40 ECOG0-1-2=45%-43%-12% MOS=11.1mos. Bavi/3mg n=39: ECOG0-1-2=20%-56%-24% MOS=13.1mos. ***FOUND OUT LATER: ~25% of CTL had 1mg, and 25% of 1mg had CTL(DoceOnly). Ie, CTL arm was HELPED and 1mg arm was HURT. Ie, Results would have been even better w/o CMS screwup. Also, note 3MG Arm had a hurdle of more ECOG=2 pts (24%).
II. FDA APPROVED SUNRISE AFTER PEREGRINE COMBINED DATA IN CTL & 1MG ARMS DUE TO CSM SCREWUP: 6-3-13/ASCO’13: Final Data Ph.II 2L/NSCLChttp://tinyurl.com/my8qxw7 …60% improvement in MOS: Bavi/3mg=11.7mos. vs. 7.3mos. for CTL-arm(combined Bavi/1mg + DoxyOnly arms), HR=.662, P=.113 =>ECOG=2: Combined-Placebo+1mgBavi: 12.5%, 3mgBavi: 24.4%
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