Even with many of the agents available, from stool softeners to laxatives to suppositories and enemas and more, some patients who need significant amounts of narcotics can get pretty miserable from constipation, and we find ourselves sometimes wondering how to balance the competing problems of pain and severe constipation.  So when a new and effective treatment for opioid-induced constipation is tested and becomes commercially available, it can represent a major benefit for the people who need it.

   That new agent is called relistor, or methynaltrexone, and unfortunately it is only able to be administered as an injection under the skin, like insulin, but it was the subject of a recent randomized study published in the New England Journal of Medicine that showed the benefit it can offer (abstract here).   This drug blocks a subset of the opioid receptors, called mu receptors, that are along the gut and cause constipation when turned on by opioids, but this drug also can’t get through the blood brain barrier to reverse the pain control effects of opioids.

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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.

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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.

This may well be significant because the dose that has moved forward is 300 mg as a single agent, based on encouraging work at this dose compared with iressa (gefitinib) (prior post here). In contrast, a different phase II trial tested both the 100 mg and 300 mg doses with taxotere (docetaxel) compared with the same chemo alone (described here; note: this is the same as the initial post on zactima). In that trial, the lower dose appeared to be clearly better than the higher dose. My suspicion has been that this could be because the higher dose is where you block EGFR activity, which I’ve described as being potentially detrimental when giving chemo concurrently, although this remains unclear). On the basis of this early work, trials moved forward with the 300 mg dose as a single agent, and the 100 mg dose in combination with chemo).

There are four main trials evaluating zactima in advanced NSCLC, and three of them have now been completed. The first that accrued all of its intended patients is the ZEST trial that I described previously, back in November of 2007. In this study of patients with advanced NSCLC who had received one or two lines of prior chemotherapy, zactima was compared head to head with tarceva (erlotinib). We haven’t hear any results from that study. The other major single agent trial of zactima is called the ZEPHYR trial (Zactima Efficacy trial for NSCLC Patients with HistorY of EGFR and chemo-Resistance — a rather forced if clever acronym: “nobody leaves this room until we come up with a great name for this trial!”), which is directly comparing zactima to a placebo in patients who have already been on an EGFR inhibitor like tarceva or iressa:

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This trial is still in the process of enrolling a target of 930 patients (more information here)., The sites are outsde of the US, because of the great difficulty in enrolling American patients on placebo-controlled trials.

The news this week (press release here) was that two other large trials with zactima have also been completed. The larger one, called ZODIAC (Zactima in cOmbination with Docetaxel In non-smAll cell lung Cancer), another tortured acronym in the name of cleverness, apparently reached its target of 1380 second line advanced NSCLC who were randomized to receive either taxotere alone or the ame chemo with zactima at 100 mg per day:

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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. (more…)

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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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. (more…)

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.

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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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. (more…)