We’ve been talking about the potentially relevant molecular markers for EGFR, and the importance of EGFR as a cancer target (see prior post), without really describing what these markers are.   There are three main aspects of EGFR biology that have been studied for their potential predictive value in consideration of EGFR inhibitor therapy, whether the oral tyrosine kinase inhibitors like tarceva (erlotinib) or iressa (gefitinib), or the monoclonal antibodies against EGFR such as erbitux (cetuximab).  What are these markers?

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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:

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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.

Although much of our focus has been on targeted therapies, there are still new conventional chemotherapies that are being introduced and may have a meaningful impact on lung cancer. One that has been tested in late clinical trials, including a phase III randomized study, is vinflunine, which is a novel version of a chemo drug called a microtubule inhibitor, in the same general family as navelbine, one of our more commonly used drugs in NSCLC (and broadly useful in many cancer types). Leading side effects have most typically been decreased blood counts, fatigue, and GI problems like nausea/vomiting, abdominal pain, and constipation. Unlike taxol and taxotere, it doesn’t require any steroid premedication and is given by vein over just 10-20 minutes, typically one day every three weeks.

After the earliest studies, vinflunine was developed in lung cancer, including a second-line trial in 60 patients previously treated with platinum-based chemo (abstract here). There was an 8% response rate and another 50% with stable disease, so overall we can say that there’s proof of activity. But the big test was a randomized phase III trial conducted in Europe, randomizing 551 patients who had received first line chemo, to now receive either taxotere IV every three weeks or vinflunine IV every three weeks (abstract here):

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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. Read the rest of this entry »

Much of the focus on novel agents has been on strategies like inhibition of the epidermal growth factor receptor (EGFR) that can stimulate tumor growth, or anti-angiogenesis, blocking the tumor blood supply. But there are other, novel therapies that are also being tested in lung cancer as well. One of these is proteosome inhibition, with an agent like Velcade (bortezomib), which is approved for treating the plasma cell (blood) cancer multiple myeloma and also has activity in lymphomas.

Sometimes referred to as the “cellular housekeeper”, proteasomes are a set of proteins that are inside the nucleus of the cell and regulate the concentrations of multiple important regulatory proteins, primarily by degrading proteins beyond what are required in the cell. Because proteasomes affect a wide range of regulatory proteins, inhibiting the proteasome can lead to downstream effects that control many cell systems:

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The proteins listed on the slide aren’t ones that are well known to many people, but they have effects on the cell cycle of growth and division, can induce programmed cell death (a normal cell function often lost in cancerous cells), and (of course, in keeping with so many novel agents) can have anti-angiogenic properties. In some preclinical (lab-based) research, velcade can enhance the effects of chemotherapy against many cancer cell lines. In several models, adding velcade can overcome resistance to chemotherapy, although this work has been in the lab and not the clinic, and it has focused on different cancer types than lung cancer (bladder, pancreas, prostate, colon

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.

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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 (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.

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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.

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Historically, chemotherapy has had a relatively minor role in the management of brain metastases. Although there is a rather low response rate in the brain from some standard lung cancer chemo regimens, we generally conclude that most of our chemo can’t be too effective in the brain because of the blood-brain barrier (BBB) that is relatively impermeable to the majority of our commonly used chemo agents (there is some debate about whether the metastases disrupt that barrier and can allow other chemo agents to get into the brain, but that’s still a murky issue). However, some of the drugs that are routinely used to treat primary brain tumors (cancers that start in the brain tissue) can get through the BBB and reach significant concentrations that can effectively fight cancer. One of the agents that has been shown to be valuable in treating primary brain tumors is temozolomide, or Temodar, an oral chemotherapy drug that is given with radiation to the brain and also on its own off of radiation. Because it’s been shown to improve survival for patients with tumors that start in the brain, and is also helpful for patients with metastatic melanomas, it’s also been an agent that has been the focus of research questioning whether it can improve results when added to radiation, or potentially on its own, in patients with brain metastases from solid tumors like lung cancer. Read the rest of this entry »

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).

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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.

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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.

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