Recent Results with Talactoferrin: Reason to Move Forward

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January 27, 2008 - 5:01 pm email to a friend printer friendly view / write comments

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Dr. West

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)

We also often look at survival results with a “Kaplan-Meier curve” of survival (also described as the “overall survival curve”), where survival over time is shown as a line moving left to right, and the benefit of a treatment in a study appears as a gap between two lines, with the better treatment on the top line. Here’s the survival curve for this trial, clearly demonstrating the favorable results with TLF:

As with the previously reported trial combining TLF with chemo, side effects were seen less frequently with TLF than with placebo, suggesting that people actually felt better on TLF than they would have just due to their advancing cancer. And while we’ve seen several well-tolerated newer agents come out in the last few years, such as tarceva and alimta, the only moderately to severe adverse effect reported with TLF was anorexia (decreased appetite) in 4% of patients. No rash, no decreased blood counts, no nausea and vomiting, no hair loss. And an overall reduction in adverse effects.

Despite these truly encouraging results, you haven’t really read about TLF here until now, nor does it get much of a buzz in the media. I think the reasons for this are many. First, these trials were conducted in India, and I think the world remains wary about the quality of studies from investigators who aren’t known the way we know and trust the large cooperative groups or very well known international leaders in lung cancer. This may be right or wrong, but there is a similar bias against studies conducted in Eastern Europe or South America, and it’s largely a sense that we believe who we know. Having results come from many centers around the world, or validated with another study by SWOG or some other trusted group would lend additional strength to these findings. Secondly, immunotherapies are only beginning to gain traction after decades of disappointment, so there is some skepticism in the field to overcome that isn’t there for anti-angiogenic drugs or EGFR inhibitors, which the cancer world was primed to accept. Finally, the sponsor company, Agennix, is small and hasn’t had the muscle to market this work, even while less impressive data from larger companies have more of a buzz because they are so well known to the cancer (and financial) world.

But if a treatment is truly helpful, it should get noticed, and TLF will be entering the world stage with two international phase III randomized trials that will be conducted worldwide over the next couple of years. The first will be a first line trial for 1100 previously untreated patients with advanced NSCLC and will give carbo/taxol with either a placebo or TLF for up to six cycles, followed by maintenance placebo or TLF in patients who don’t show progression at the end of 6 cycles of chemo, or people who come off earlier for reasons other than progression:

Overall survival will be the primary endpoint of the study, and unlike studies that include avastin, patients with squamous cell NSCLC and/or treated brain metastases are eligible.

The second trial will be similar in design to the BR.21 trial of tarceva, in that it will be a 2:1 randomization of 720 previously treated advanced NSCLC patients (third line or later in this study) who will receive TLF (2/3 of patients) or placebo (1/3 of patients), looking at overall survival as the primary endpoint:

Although it will definitely be several years before we receive results of these trials, it would be very helpful to actually have the option of an immunostimulatory agent for which patients with any NSCLC histology as well as treated brain mets would be eligible. Perhaps TLF will prove to be an agent that provides a significant survival benefit and actually reduces side effects. But it will take these large trials to determine whether this approach can deliver on the early promise. In the meantime, I will certainly be following the progress of these trials and would be inclined to participate in one or both of these trials and offer them to my patients.

Posted in: Current Clinical Trials, Immune/Vaccine-based therapies, Lung Cancer, Non-Small Cell Lung Cancer (NSCLC), Second-line treatment, Third-line therapy and beyond, Treatment                     email to a friend printer friendly