Thank you fortmyr for bringing our attention to the recent publication of exciting data on talactoferrin. We've talked about talactoferrin before on GRACE. This is an exciting new drug that both Dr. West and I feel has a lot of promise.

When you eat food, you ingest a lot of bacteria with your food and so it's not surprising that there are a lot of immune cells in the gut. Appropriately this system is called GALT, or gut-associated lymphoid tissue. In the simplest terms, talactoferrin is a chemical that activates GALT in the hopes that this will activate the immune system to better fight the cancer. The drug is not absorbed and does not travel in the bloodstream the way that chemotherapy and even most targeted agents do. Rather, we believe that it activates GALT, and then the body's own immune cells go off to better fight the cancer. Dr. West has described the proposed mechanism of action in much greater detail, and I refer the curious to his post. Talactoferrin is found in several body fluids. Poetically, its concentration is highest in breast milk, where it is believed to support development of the infant's immune system, thus the term, "mother's milk." Cycles are fourteen days in length. For twelve weeks, the patient takes this pill twice per day, and then there are two weeks off before starting the next cycle.

Two major studies started the clinical work on talactoferrin. One randomized patients to who were previously treated with chemo to talactoferrin or placebo. Dr. West has reported on these results in 2008. All patients were previously treated with at least one and up to two lines of chemotherapy. In other words, these were 2^nd line or 3^rd line patients. In the US, I would not have opened this study for my patients because of the randomization to placebo. Since alimta, docetaxel and erlotinib all have proven efficacy in the second line, I would have felt ethically uncomfortable. As a rule, I believe that investigators should only open trials that they believe are very promising compared to the standard of care and that they would feel comfortable putting themself or a loved-one on if they had cancer. In fairness, the trial was conducted in India. The little that I know about lung cancer care in India is only from GRACE members' postings. If 2^nd line chemotherapy is not universally available in India, making placebo equivalent to the standard of care, then this trial would seem more acceptable to me. Regardless, the comparison to placebo does provide quality information about the efficacy of talactoferrin.

This was a randomized phase II study. This means that like any phase II study the goal was not to definitively prove the efficacy of talactoferrin, but rather to see if the agent was worthy of further evaluation in a larger phase III study. This design has gained favor because without a control arm, single-arm studies can be made to look very promising just by using strict inclusion criteria. This problem has resulted in too many patients being enrolled on phase III studies that were ultimately proven not to help. Just to be clear what I'm talking about, I'll make up an example. If I designed an uncontrolled (single-arm) phase II study of dark chocolate for 2^nd line treatment of lung cancer and wanted to artificially make it positive, I could require all patients to have PS0, ideal renal function, absolutely normal bone marrow function, minimal burdens of cancer and to have had dramatic response to their first line of chemotherapy. Even if dark chocolate did nothing to stop cancer growth, these patients would live longer than historic controls, leading to a "positive" study. We would then proceed to phase III study, where dark chocolate would get trounced by a standard second line agent, because it is not actually active and patients on both arms would have the same requirements to enter the study. Of course, the major confounder here would be the massive improvement in quality of life that comes with dark chocolate.

As I sit here writing at an outdoor café in Chapel Hill, NC, I am strongly tempted to get a chocolate treat; I wonder why. Well, back to the topic at hand. This trial randomized 100 previously treated NSCLC patients to talactoferrin or placebo. Overall survival was higher with talactoferrin than placebo at 6.1 months, compared to 3.7 months. Interestingly, the advantage in progression-free survival seemed to emerge at about a month and half and in overall survival at about 2 months. Of note the median duration of therapy was 7.1 weeks.

Subgroup analysis was presented.

We can't read too much into these numbers, because they're very small. However, I find intriguing the hint that men benefitted more than women and look forward to future results to show if this difference is real or not. Appropriately, the authors did not comment on this in their discussion-it really is too small of numbers and too early stage to make much of it at this point.

Safety data were also presented. Not only was talactoferrin well tolerated, but adverse events were actually less common in the talactoferrin group. There were 165 adverse events in the talactoferrin group compared to 230 in the placebo group. There were 73 severe adverse events in the placebo arm compared to 36 in the talactoferrin arm. Presumably, this was, at least in part, driven by talactoferrin stopping cancer from causing more adverse effects, but there may be other positive secondary effects of talactoferrin other than controlling cancer.

Talactoferrin has also been studied in combination with chemotherapy. In another randomized phase II study, patients were treated with the combination of carboplatin and taxol plus either placebo or talactoferrin. Again, survival was better with talactoferrin compared to placebo, with decreased adverse events. Dr. West covered these results here.

In that 2008 post, Dr. West noted that talactoferrin wasn't getting a lot of press. In the past three years, it still hasn't gotten that much press. Dr. West speculates that some of this may be due to distrust of the Indian investigators. While there may be a component of this, I do think that the landscape of lung cancer treatment looks a bit different in the US than in other places. For example, in the US, many clinicians consider the use of avastin obligatory for eligible patients. So, even if talactoferrin can add to carbo/taxol, we must ask if it adds more than avastin. In the second line, US patients have access to docetaxel, pemetrexed, tarceva and other drugs. Even if talactoferrin is active compared to placebo, will it extend duration of life or improve quality of life more than these agents?

It's the job of the investigator (and GRACE writer!) to be skeptical. However, I do think that there's legitimate reason to be excited about talactoferrin. The data thus far give reason to hope that we will ultimately have another active agent in the fight against lung cancer, and one with minimal toxicity. Further, it increases the hope that we will one day have truly blockbuster immunologic agents to aid in our fight. The field has been hopefully about this idea for decades. Despite tremendous buy-in by both patients and doctors, the efficacy of immune-targeted has been fairly modest and we've had many failures along the way.

What can we look forward to more immediately? There are two ongoing phase III studies of talactoferrin. The first randomizes patients who have failed at least two prior therapies to talactoferrin or to placebo. The second gives all patients standard carboplatin plus taxol and randomizes patients to the addition of talactoferrin or placebo. In addition to receiving talactoferrin during up to 6 cycles of chemo, patients receive talactoferrin maintenance in this trial. You can find the schemas for these trials here.