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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   The topic of what is EGFR is one that really deserves to have been covered here from the beginning, but somehow I skipped to the drugs and what they do in cancer patients. It’s time to take a step back and discuss EGFR and why it’s been an important target in cancer.

EGFR stands for Epidermal Growth Factor Receptor, and it can be targeted from the outside of the cell by intravenous monoclonal antibodies against the target protein (also known as a ligand) binding portion of the cell, or from the inside of the cell by oral small molecule inhibitors against the part of the receptor called the tyrosine kinase domain that activates the intracellular machinery:

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The leading side effect of EGFR inhibitors, both the oral tyrosine kinase inhibitors (such as tarceva (erlotinib)) and the IV monoclonal antibodies (such as erbitux (cetuximab)), is rash, dryness, and other skin side effects. While a rash sounds modest to many people compared to many of the leading problems with chemo, many of the members here can attest that while an EGFR rash can range be as mild as a pimple or two, it can also be itchy, painful, and be as severe as a skin rash covering large amounts of the body, sometimes with open lesions. And for some patients, the skin side effects can require dose reductions or even lead patients to discontinue their EGFR inhibitor, even if it might help against their lung cancer.

As described in a press release last week, Hana Biosciences, based in South San Francisco, has initiated a study of topical menadione, a precursor to forms of vitamin K that also activates EGFR. This topical medication is being studied in the setting of both a prophylactic treatment and as a treatment for skin side effects that emerge on treatment. This research is being led by Dr. Mario Lacouture at Northwestern, who I’d consider to be the leading expert in EGFR rash treatment right now.

There have been several posts and forum threads on managing the rash, but it’s very encouraging to see that not only is more attention being paid to this problem, there are actually trials being run, even with new agents, that are trying to reduce a side effect that can significantly worsen the quality of life for patients on EGFR inhibitors, sometimes even keeping them from getting the drug, or perhaps a dose that could be managed chronically if the rash was controlled more effectively.

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.

In addition to several molecular targets that have been well studied for several years, such as the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), new targets are emerging as potentially fruitful approaches to combating cancer. One of these is the insulin-like growth factor receptor, or IGF-1R.

IGF-1R is involved in the process of transforming a normal cell into a cancer cell when certain cancer trigger genes, called oncogenes, are activated. Activation of this receptor sets off a complex cascade of effects that promotes tumor survival and growth. There have also been studies that have demonstrated elevated blood levels of IGF in patients with several kinds of cancer. Tumors also tend to express high levels of IGF compared with normal tissues. Read the rest of this entry »

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:

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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.

(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. Read the rest of this entry »

There’s a new class of anti-cancer drugs that are being studied, including in lung cancer, known as heat shock proteins, or HSPs. These are sometimes referred to as “stress proteins” because they can be induced to be generated in higher concentrations in response to stresses like heat, cold, low oxygen levels, etc. But HSPs are also present in cells in the absence of significant environmental stress, just as a normal component of the cellular contents. They work as a chaperone protein, alongside of other proteins to ensure that those proteins are in the right shape, which is required to have proteins function properly, as well as the right place when needed. In the context of cancer, HSPs can also assist in the cancer-promoting activities of a wide range of several “client” oncogenic (cancer-inducing) proteins. So inhibiting HSPs, such as one designated HSP-90, is a potential novel mechanism for interfering with the activities of these critical proteins and the overall function of cancer cells.

One such agent that is working its way through clinical testing is IPI-504, from Infinity Pharmaceuticals, the subject of a recent press release.  The announcement and another preceding one note that the recent report of phase I work with IPI-504, an IV agent, was associated with stable disease in 7 of 9 patients at the time of first repeat CT evaluation. In addition, two of four patients who happened to have undergone a PET scan on repeat follow-up had a partial response based on European criteria, although it should be noted that PET scanning to assess response is not a standard practice and isn’t anything close to being as established as a CT scan to assess response.

Interestingly, some preclinical work in cell line suggests that the activating mutations of EGFR depend on the HSP-90 protein for stability and that IPI-504 may (bolded and italicized) be useful in EGFR-resistant populations (abstract here). For instance, the T790M mutation is one that has been found in approximately half of the prior EGFR mutation responders to iressa or tarceva once they show progression on these agents, and preclinical lab work suggests that IPI-504 may reverse that proces. However, that’s not human work. But it does lead us to the hypothesis that this agent may be useful in patients who have become resistant to EGFR tyrosine kinase inhibitors despite a mutation.

The new phase II clinical trial with IPI-504 will enroll 20 patients with advanced NSCLC who previously received an EGFR inhibitor, and this group will be equally divided between those with a known activating EGFR mutation and those with a normal or “wildtype” non-mutated EGFR target (the kind we don’t associate with special sensitivity to drugs like tarceva). If responses are seen using the more typical CT-based response assessment criteria for trials, they’ll plan to enroll 19 additional patients on the cohort(s) in which some convincing evidence of activity is seen. The schedule for treatment will be weekly IV administration for two consecutive weeks, followed by a week off, for each cycle this schedule was tested in another phase I trial). According to the press release, this particular trial is now open at Mount Sinai Comprehensive Cancer Center in Miami Beach, FL, and at Yale Cancer Center in New Haven, CT, with some other sites coming on board.

This isn’t the only heat shock protein inhibitor being evaluated, but it may well be one of the first ones for which we get some clinical data in lung cancer. I’ll give updates when new trials are opening up. In the meantime, HSP inhibitors represent an intriguing avenue for targeted therapy in lung cancer that we’ll hear more about 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 »