|
|
EGFR Inhibitor Combination Tested in Advanced NSCLC
As I’ve described in various posts about targeting the epidermal growth factor receptor (EGFR), one of the main signals that is important in many lung cancers, there are agents like gefitinib (iressa) and erlotinib (tarceva) that target the internal switch that triggers activity inside the cell, and there are agents like cetuximab (erbitux) that work on the external front end receptor to block activity:
(Click on image to enlarge)
I must admit that I’ve always been curious whether combining these two appoaches, giving an oral EGFR tyrosine kinase inhibitor (TKI) with a weekly IV EGFR monoclonal antibody would potentially provide a synergistic inhibition and impressive activity. For the first time, Ramalingam and colleagues have published their limited experience of combining iressa and erbitux in a small trial of patients with advanced NSCLC (abstract here). Unfortunately, the results don’t look particularly impressive.
My friend Dr. Ramalingam has just recently moved from Pittsburgh to head the lung cancer program at Emory University in Atlanta, but while at the University of Pittsburgh he and colleagues there conducted this study to assess the safety and get a sense of the activity of a combination of iressa with erbitux. Iressa, the first EGFR TKI approved for NSCLC, was studied at the previously approved standard dose of 250 mg daily (subsequently found to not be significantly superior to placebo in a large trial of previously treated patients with advanced NSCLC and taken off the market). Erbitux was given at increasing doses, starting at a rather low dose and escalating to a point of maximum safe/tolerable dose for the combination. For these “phase I” trials of safety, small numbers of patients are usually enrolled. This study included 13 patients who had received at least one prior chemo regimen for advanced NSCLC.
Although the numbers were small, there were no responses seen, and only 4 patients (31%) even showed stable disease. Progression was pretty quick, and 3 patients developed severe declines in blood magnesium levels, which is a known side effect of erbitux, but this was a high rate.
The investigators also tried to do some molecular studies from the subset of 10 patients who had some tissue to work with. They didn’t find any EGFR mutations that would be expected to be associated with robust EGFR TKI responses. They also did not detect any RAS mutations that are generally recognized as being very unlikely to show a response on EGFR TKIs.
There are many reasons why this little study is far from the definitive word on the subect. Iressa at the dose tested is not as effective as tarceva, so perhaps the results would have been more favorable with tarceva. Perhaps these results just happen to be particularly disappointing in a small number of patients who happened to not benefit, but a larger study would have shown better results that represent reality better. Or maybe this combination isn’t particularly useful in a general population but could be very impressive in a more selected population, based on EGFR mutations or never-smoker status. I’ve also wondered whether adding erbitux to tarceva in a patient who has now become resistant to tarceva after a prior good response would restore activity. But we don’t have any evidence on any of these questions.
For now, I think all we can say is that a combination of EGFR TKI and monoclonal antibody doesn’t lead to blockbuster activity in NSCLC. But expect to see a lot more trials of targeted agents in coming years.
Recent Results with Talactoferrin: Reason to Move Forward
As I described in part I of this subject (last post here), lactoferrin is an immunostimulatory protein that is found in highest concentrations in breast milk (hence the name), and the recombinant form talactoferrin alfa (TLF) was combined with chemo in a randomized phase II study of front line advanced NSCLC in which the combination was associated with an impressively higher response rate than chemo alone. The rate of side effects was also significantly lower among the patients who had TLF added instead of a placebo. While these results are promising, the agent made relatively little splash in the lung community, generating little attention from the poster presentation of this work in 2006. But this was just a phase II trial with 110 patients, so it’s reasonable to hope for corroborating evidence of benefit before believing these results are more than a fluke. In 2007, another randomized phase II trial of TLF vs. placebo, now as single agents, was reported that supported the findings from the first line trial, this trial with overall survival as the primary endpoint.
The trial presented last year by Parikh and colleagues from several centers in India enrolled 100 advanced NSCLC patients who had previously received either one line (about 3/4 of patients) or two lines (about 1/4 of patients) of prior systemic therapy, who were randomized to receive oral TLF or placebo (ASCO abstract here, subsequent World Conference on Lung Cancer abstract here). Treatment with this oral agent was twice daily for twelve weeks, followed by two weeks off, for a total “cycle” of a rather unconventional 14 weeks. Repeat CT scans were done about 7 weeks into the treatment, with a total of 81 of the original 100 patients getting that follow-up scan and considered evaluable.
So what happened? As shown in the figure below, overall survival was significantly higher in the recipients of TLF, whether you look at the median survival an “intent to treat (IIT)” analysis of everyone enrolled (whether you received enough treatment to be re-scanned seven weeks later), the 81 patients who were evaluable. In addition to median survival, six month survival was significantly greater for TLF recipients by both an IIT analysis and looking at just the evaluable patients:
(Click on image to enlarge) Continue reading
Talactoferrin Alfa (TLF): Mother’s Milk Becomes Cancer Treatment
We’ve covered several novel agents for treating lung cancer, but a new one that has shown promise in early studies and now is the subject of larger phase III trials is a drug called talactoferrin alfa (TLF), from a small company based in Houston called Agennix. I think it’s possible that much of the reason there hasn’t been much buzz behind this treatment, despite the very intriguing results, is that this agent is so different from the mechanisms we know well already, like blocking angiogenesis, inhibiting EGFR, combining these approaches, etc. And the fact that this is a small company far from the big pharma and biotech hubs like New Jersey and the Bay Area probably contribute; in addition, all of the results thus far have been generated out of India, which has many lung cancer patients but few recognized leaders in the field, so there hasn’t been an identifiable spokesperson to introduce the lung cancer world to the novel agent and concept of TLF. But let’s try to remedy this situation, because I’m inclined to keep my eye on it for the next few years.
TLF is an oral protein that is a recombinant product that is structurally identical in all material respects to human lactoferrin, an important immunomodulatory product that is expressed throughout the body in immune cells. As the name implies, it is found in highest concentration in breast milk, and it is important in contributing to the development of an infant’s immune system. The largest component of the immune system is actually the “gut-associated lymphoid tissue” (GALT), where the cells of the immune system interface with vast amounts of new proteins from the outside world (food). TLF is purported to work by getting taken up by the immune cell centers of the gut, called Peyer’s patches, where they induce immature dendritic cells, which are some of the heavy lifters teaching the rest of the immune cells what to focus on and what to ignore, to mature. Although the immune system is very complicated, the end result is that TLF can activate dendritic cells of the immune system and thereby lead to increased immune function against tumor cells.
(Click on image to enlarge) Please don’t worry if you don’t “get” these immune system principle: I show the figure in case people are interested, but it’s not on the quiz. Your immune system is like your television — you don’t need to know how it works to be able to use it. Suffice it to say that there are several lab-based studies with animal models of cancer that support this immunostimulatory role for TLF. But the real issue is what it does in humans. Continue reading
Vascular Disrupting Agent AS1404/ ASA404/ DMXAA: A Variant on Anti-Angiogenesis
First, I want to thank members Jim (dadawg001) and Neil (neilb) for bringing up this topic in the Discussion/Q&A Forum yesterday. Amazingly, yesterday morning I happened to be reviewing slides in my collection on a novel agent and approach that I thought would make a good topic for a post here: the drug DMXAA, which is a “vascular disrupting agent”. Later that same day, Jim raised a question about a new agent, ASA404, which had promising results reported in a press release by its manufacturer, Antisoma, based in London. I noted that I was unfamiliar with the agent, which was only partly true. In fact, it has been known previously as AS1404 and DMXAA, so even though I was thinking about this agent for reasons other than the press release (which I’ll get to), we were all circling around the same drug yesterday. Definitely worthy of a full discusison now. (Antisoma also needs to work on it’s brand identity so that people can actually figure out that ASA404 is AS1404 and also DMXAA.)
Anti-angiogenic drugs like Avastin (bevacizumab) are felt to work largely by causing regression of new blood vessels to tumors as well as inhibition of a new blood supply to a tumor that would otherwise be growing and is now limited by an inability to receive nutrients and oxygen and also to dispose of waste products. In contrast, ASA404 is a vascular disrupting agent that works directly on the endothelial (blood vessel inner wall) cells to cause apoptosis (programmed cell death). In addition, it causes release of the glycoprotein Von Willebrand factor in blood that can lead to clotting of blood vessels (potentially a good feature, also potentially bad) and also a cascade of cytokines, basically proteins with hormonal activities that often contribte to making people with cancer feel terrrible, such as tumor necrosis factor, another focus of cancer treatment modalities. The end result is that this agent can cause the breakdown of existing (not just newly forming) blood vessels and destruction of cancer cells.
(Click to enlarge) Continue reading
DCA Revisited: Is It A Breakthrough Yet?
I’m surprised to find that I’m moving to a topic that may actually be more controversial than a Michael Moore movie, but in fact, I think that’s where I’m headed.
Several months ago, I wrote a post about dichloroacetate, or DCA, which is a chemical used to treat a childhood disease called congenital lactic acidosis, and which has been the study of some more recent study by Dr. Evangelos Michelakis at the University of Alberta in Edmonton, Alberta in Canada. DCA can increase the activity of mitochondria, which produce energe in the cell and can be suppressed in cancer cells; restoring that function can lead the cells to undergo programmed cell death, or apoptosis, that is supposed to occur when a cell recognizes that it has dysfunctional mutations. Recent work by the group in Edmonton (summary here) suggested that DCA was effective in killing tumor cells in test tubes and some animal models, and the authors suggested that DCA should move readily into clinical trials for cancer. One problem is that DCA is a generically available product that no pharmaceutical company stands to profit from, so it does not have a readily available source of funding for the millions of dollars needed to run clinical trials that might lead to a proper demonstration of effectiveness of not. The University of Alberta has established a charitable fund that has thus far raised signficant financial support in order to test DCA in clinical trials despite the absence of a big pharma beneficiary. Trials are reportedly in development.
At the time that this came out, in a real media frenzy, my post covered some of the news and used the occasion to temper some of the extreme enthusiasm about this agent being a likely miracle for the broad treatment of cancer. I described the huge gap between promising preclinical drug that kills cancer cells in test tubes and rodents and the demonstration of clinical benefit in large trials with real patients. The majority of drugs are abandoned along the way for being too toxic or not living up to the early promise of efficacy. We would do well to remember that back in 1998, when emerging work on angiogenesis by Dr. Judah Folkman was hailed as a certain miracle, again based on very promising work in mice. Dr. Folkman was very circumspect and avoided overpromising what his research could accomplish in humans: “if you’re a mouse and you have cancer, we can take good care of you” and, “Going from mice to people is a big jump, with lots of failures” (basically summarizing my first DCA post in one sentence). In contrast, in that same front-page article in the New York Times that featured this reported breakthrough, Dr. James Watson (who along with Francis Crick discovered the molecular structure of DNA and was awarded the 1962 Nobel Prize in Physiology and Medicine) was quoted as saying, “Judah is going to cure cancer in two years”. I cringed when I heard that, fearing that it would feed a media machine and lead to incredible hype, and it did. But nearly ten years later, we have not cured cancer, at least not nearly enough, even though a few antiangiogenic drugs like Avastin (bevacizumab) have recently been shown to improve outcomes for colon, lung, breast, and some other cancers. Continue reading
Vorinostat/SAHA: Another Targeted Therapy Being Tested in Lung Cancer
I’ve got a lot of things on my list of things to cover in the near future…patient sex differences in lung cancer and estrogen, an update I’m trying to generate on DCA (dichloroacetate), the concept of pharmacodynamic separation of chemo and EGFR inhibitors, more on the trials from ASCO that may be changing our practice in treating locally advanced NSCLC, not to mention the discussion I’d like to start on Michael Moore’s new movie Sicko, which I went to see with my wife this past weekend. And then there’s the long list of topics I’ve been meaning to get to for several weeks before ASCO. Yikes. Well, at least we all know we’re not going to run out of things to talk about anytime soon.
Today, since member Spanky3 is starting a trial with the agent vorinostat (you can offer encouragement at the end of this forum thread), I’ll provide some introduction about this new agent. It’s also known as SAHA, which stands for suberoylanilide hydroxamic acid, which is why we always want to call it vorinostat or SAHA or its marketed name, Zolinza. Vorinostat is an oral medication that is approved for treating cutaneuous T-cell lymphoma, or CTCL, and it works as a histone deacytylase (HDAC) inhibitor. A what? Basically, DNA is wrapped up in a form better designed for compact storage rather than use for transcribing genes when it’s not being used, and those histones are what bind DNA into the storage form. Whether they release the DNA for transcription of genes on that DNA into protein depends on whether the histones have an acetyl group (iwhich you don’t need to know — it’s not on the quiz — but if you’re really interested or very bored, info is here) is added or not, so HDAC controls gene expression, and inhibition of this enzyme can inhibit some cancer cells. This is part of a whole new field called epigenetics, which is basically the study of how DNA is modified, in terms of the packaging that leads to more or less use, without changing the underlying instructions.
(Click to enlarge)
If you look at the figure above and a big light bulb doesn’t go on over your head, don’t fret if you still don’t understand it — the scientists are also not sure out it works. In fact, HDAC inhibitors may have other anticancer effects by acetylating proteins other than histones, and they may also interfere with the proteins controlling cell division by acetylating the centromeres, which are important cellular machinery for mitosis.
Axitinib: New Drug with Activity in Lung Cancer
A few new agents emerged from the ASCO 2007 meeting as very real potential players in lung cancer. Probably at the lead of that list, in my opinion, was axitinib (AG-013736, now a Pfizer product). Similar to agents like sunitinib and sorafenib, this is an oral agent that blocks a target called the Platelet-Derived Growth Factor Receptor (PDGFR) and also is a potent, and selective inhibitor of three different receptors in the Vascular Endothelial Growth Factor (VEGF) family: VEGFR-1, VEGFR-2, and VEGFR-3 (scientists are very clever and original with such names, as you can see). As is typical for any complex biological process, there isn’t just one ligand, the protein that fits fits the target, and a single receptor for it, but rather a family of ligands and receptors that act in a coordinated fashion to balance a mechanism like blood vessel and lymphatic channels (the vessels that move lymph, a plasma-based filtering fluid, between lymph nodes). Here’s a basic schema of the VEGF ligands and receptors (VEGFR-2 is the dominant one):
(Click to enlarge)
Axitinib connects to the intracellular, back end portion that has kinase activity, which basically means that it turns on an enzymatic signalling pathway inside the cell with multiple activities, which in this case ultimately promote blood vessel production that can benefit a growing tumor. Like lots of promising drugs, it inhibits cancer cells in test tube and animal models, but more encouragingly, it’s been studied and looks like it has anti-cancer activity human patients with kidney cancers and some other oncology settings. This year, Dr. Joan Schiller, who heads the oncology program at the University of Texas-Southwestern Medical Center and also chairs the ECOG Lung Cancer Committee, presented results of axitinib as a single agent in previously treated patients with advanced NSCLC (abstract here). Continue reading
COX-2/EGFR Inhibitor Therapy: Hope or Hype?
While there have been studies of the COX-2 inhibitor celebrex in combination with chemo for treating NSCLC, the palpable buzz about celebrex in treating lung cancer has been from a trial by my friend Karen Reckamp, formerly at UCLA, now recently moved to City of Hope Cancer Center in nearby Duarte, CA. Several studies have shown that EGFR expression is associated with increased cell growth, increased angiogenesis, increased tissue invasion and metastasis, and a worse survival compared with patients who have tumors that don’t overexpress EGFR. And as I wrote in my introductory post on COX-2 inhibition, high expression of this enzyme can also lead to worse patient outcomes among folks with NSCLC (COX-2 actually hasn’t been shown to be expressed significantly in SCLC). In fact, these two pathways interact to regulate cell proliferation, migration, and invasion (reference article here).
(complex, isn’t it? Click to enlarge — but it won’t help, unless you’ve got a PhD in biochemistry)
Xyotax: A New Taxane Targeted for Women Only
Similar in concept to Abraxane, paclitaxel poliglumex (PPX, or Xyotax) is another novel formulation of paclitaxel in which the taxane is bound to a biodegradeable polymer utilizing a polyglutamate drug delivery system. As with Abraxane, this allows administration without solvents over a recommended infusion time of 10-20 minutes and potentially allowing for improved delivery of the agent to the tumor target with a greater relative sparing of normal tissues. The idea is that the release of the paclitaxel molecule from the polymer backbone by lysosomal proteases (enzymes that cut apart proteins), some of which are overexpressed by tumor cells.
(click to enlarge)
Xyotax has been studied in several phase III randomized trials in the performance status 2 (PS2) patient population . In the STELLAR 3 trial (abstract here), the combination of carboplatin/PPX was compared with carboplatin/paclitaxel q3weeks, while the STELLAR 4 trial compared single-agent PPX to gemcitabine or vinorelbine as a single-agent (abstract here).
Each of these first-line trials demonstrated no significant differences in survival or other efficacy endpoints favoring the Xyotax arm in either trial, but an exploratory analysis of the female patients in both of these trials revealed a markedly superior survival in recipients of PPX.
Nanoparticle Albumin Bound Paclitaxel for Lung Cancer: New, But is it Improved?
Paclitaxel, marketed name Taxol, is among the most commonly used drugs in oncology in general, and definitely also for lung cancer, particularly NSCLC. The combination of carboplatin/taxol is the most frequently prescribed combination for advanced NSCLC in the US and is also employed in many other settings for NSCLC as well. However, there are several potential problems with taxol. It is extremely hard to dissolve and requires a solvent called cremaphor (polyethoxylated castor oil — don’t worry, it’s not on the test!) and special tubing, as well as a three hour infusion time, to administer in its most common schedule. Patients need to take multiple premedications that include steroids, which is a nuisance for lots of patients and a significant problem for some, such as those who have diabetes, because steroids can markedly increase the blood sugar levels of patients. And despite premedications, it’s not uncommon for patients to develop significant hypersensitivity reactions that can be quite serious and, rarely, fatal.
There are several novel formulations of paclitaxel and other chemotherapeutic agents that allow the same paclitaxel molecule to be delivered without the alcohol-based solvent, thereby eliminating the need for steroid premedications and a long “chair time” of patients having to spend most of their day getting chemo because it’s unsafe to give the chemo faster than that. One of these is nanoparticle (tiny little particles) albumin bound (or nab) paclitaxel, which has the scientific name ABI-007 but is commonly known as Abraxane. Not only is this special form of taxol faster to administer and doesn’t require the premedications that solvent-bound taxol does, there is also the possibility that this albumin-bound form may be delivered and picked up by the tumor than standard taxol. In fact, there is some evidence that Abraxane may be superior in some ways to standard paclitaxel in breast cancer, where it has been studied much more than it has been studied in lung cancer thus far. In a large trial with 460 predominantly (86%) chemotherapy pretreated women with breast cancer (abstract here), those who received Abraxane had a significantly higher response rate from Abraxane given every three weeks than standard taxol (21.5% vs. 11.1%), and they also had a significantly longer progression-free survival, but the overall survival was not significantly different. It also had a no hypersensitivity reactions from the Cremaphor solvent, and lower neutropenia rates and severity of neuropathy (although the neuropathy with Abraxane remains a significant side effect challenge). On the basis of this work, Abraxane was approved by the FDA in January, 2005 for recurrent or metastatic advanced breast cancer. Continue reading
| Follow us on... |    |
||
Copyright ©2012 GRACE |
|||