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First-line treatment

Treatment standards and emerging options for previously untreated advanced NSCLC

Dr West

Talactoferrin Alfa (TLF): Mother’s Milk Becomes Cancer Treatment

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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.

Talactoferrin MOA

(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


Dr West

Thalidomide in Lung Cancer: Answers from Korea

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To many outside of oncology, thalidomide is primarily known for causing severe birth defects in women who received it in the 1960s as a sedative and treatment for morning sickness. These birth defects, in which babies were born with no arms or legs but with hands and feet directly attached to their trunks, was likely related to the anti-angiogenic (blood vessel blocking) effects of thalidomide. Over the last several years, however, its anti-angiogenic activity has been employed as an oral treatment for some cancers, and it is an approved treatment for multiple myeloma and has been studied in several other cancer settings, including lung cancer. Specifically, one of the settings in which thalidomide has been the subject of several studies has been extensive disease small cell lung cancer (ED-SCLC), as small cell is a blood vessel rich tumor that has been suspected to be potentially vulnerable to anti-angiogenic drugs (for instance, I covered some early work with Avastin in SCLC in a prior post). In addition, thalidomide appears to have immunostimulatory activity in lab-based work, and this may also contribute to potential anticancer activity.

A friend of mine, Dr. Afshin Dowlati at Case Western Reserve University in Cleveland, recently published on his group’s experience giving thalidomide to patients as a maintenance therapy after initial chemotherapy (abstract here). They enrolled 30 patients who had received 4-6 cycles of initial chemotherapy, which was not specified, who had achieved either a complete or partial response, or else stable disease. (In other words, they enrolled patients who did not demonstrate progression on chemo, which we don’t expect to see after first-line treatment of ED-SCLC.) After 3-6 weeks off of treatment, a total of 30 patients received thalidomide at 200 mg by mouth every evening, with a primary goal of the study to determine the one-year overall survival and overall tolerability of this treatment. Recall that there is no established benefit for maintenance therapy after initial chemotherapy for ED-SCLC (see my prior post on the topic), but we continue to study it because we know that ED-SCLC is often responsive early and then tends to be much more resistant when it returns. The idea of postponing that recurrence with a manageable oral therapy is very appealing, but we still haven’t seen a significant survival benefit despite the compelling rationale behind it. With only 30 patients enrolled, Dr. Dowlati wasn’t going to establish anything definitive, but he did demonstrate that it was a feasible treatment. Patients stayed on thalidomide for a median of 2.4 months, or 79 days. The median survival was pretty encouraging at 12.8 months, and the one-year survival was 52%. The leading side effects were peripheral neuropathy (numbness and tingling in the longest nerves of the body, affecting the fingers and toes, primarily) in about 30%, and constipation in 16% of patients, despite a bowel regimen that was started on everyone at the time of starting thalidomide. The investigators considered the results encouraging enough to warrant further study. Continue reading


Dr West

Vascular Disrupting Agent AS1404/ ASA404/ DMXAA: A Variant on Anti-Angiogenesis

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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.

Vascular Disrupting Agents mechanisms (Click to enlarge) Continue reading


Dr West

Vorinostat/SAHA: Another Targeted Therapy Being Tested in Lung Cancer

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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, 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.

HDAC mechs 1 (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.

HDAC inhib mechs 2 Continue reading


Dr West

Xyotax: A New Taxane Targeted for Women Only

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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.

Xyotax MOA (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).

STELLAR trial schemas

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.

Women on STELLAR trials Continue reading


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