This is the stuff of science fiction, a dream, something you could envision but were skeptical it could be done. But now it has been done, and raises the question of whether we are headed "back to the future" in the treatment of cancer.
The drug in question here is called T-DM1. It is an "antibody drug conjugate" between trastuzumab--which is a monoclonal antibody drug commonly used today to treat selected women with aggressive breast cancer--bound to a derivative of another more traditional cancer chemotherapy drug called maytansine.
Maytansine was a cancer chemotherapy drug evaluated in the 1970's and found to be effective in treating breast cancer, but its side effects were so severe that it could not be used clinically. As a result, it became a laboratory curiosity, banned from patient care.
Trastuzumab is one of the really positive stories of the modern targeted therapy era. It is an antibody drug that has effectively treated women with advanced breast cancer that is positive for HER2, which results in a protein "key" being formed on the surface of certain breast cancer cells. Trastuzumab attaches to that key and aborts the internal processes of the HER2 positive breast cancer cells. About 30% of women with breast cancer are HER2 positive, and those women tend to be younger and have more aggressive forms of the disease. Not only does trastuzumab help treat advanced breast cancer in these women, it has had a remarkable impact on reducing recurrences after primary treatment when used as part of adjuvant therapy in HER2 positive breast cancer.
But there are serious side effects from the drug combinations that are used with trastuzumab in these circumstances. And then there are the limited treatment options availalable once the HER2 breast cancer recurs, which happens all too frequently.
Fast forward, and the chemistry wizards found a way to bind the trastuzumab to the maytansine derivative. The theory was that the trastuzumab could hone in on the breast cancer cells with the HER 2 receptor, and that the attached chemotherapy drug could find its way into the cancer cell where it could do its damage. And because the delivery of this antibody-drug conjugate was so specific to the breast cancer cells that have this HER2 receptor on their surfaces, a lot of the adverse effects previously seen in using both drugs might be reduced. Think of a cargo rocket making a delivery to the space station, then docking with the space station, and moving the cargo into the space station.
Sounds simple, but it's not.
First you need something that is going to get the package to the cancer cell. Then you have to figure out how to link that delivery drug to another drug, without destroying the unique characteristics of the two drugs in the process. Then you have to figure out if this thing will get past the rest of the cells in the body so the packet doesn't go AWOL and hit some other bystander cell, where it could do damage but not do anything good. Then if the packet actually gets to the cancer cell, will the linkage break and will the strong chemotherapy part of the packet make it inside the cell. Then when the chemotherapy gets inside the cell, will it work????
Well, it looks like this time this isn't the stuff of science fiction. This time it appears to work. And that is very exciting news, especially for women with HER2 positive breast cancer.
In the study being reported today at the annual meeting of the American Society of Clinical Oncology, researchers used T-DM1 in a clinical trial where they compared the outcomes of women with advanced HER-2 positive breast cancer and who had previously received trastuzumab along with other chemotherapy. Women on one arm of the trial received only T-DM1, while the other women received the standard approved therapy commonly used in these situations, namely lapatinib (another HER2 targeted therapy) and capecitabine (an oral chemotherapy drug used to treat advanced breast cancer).
The good news is that the new drug worked. Although I only have preliminary information available to me as I write this (the actual study will be presented this afternoon and I am not permitted to attend the press conferences held at this meeting, where more up to date information may have been made available), the reality is that the new drug had significantly higher rates of response than the standard combination, along with longer durations of response and fewer toxicities. In fact, slightly more than half the women in the standard treatment arm had passed away by two years. In the T-DM1 arm, 65% were still alive at two years.
In short, very exciting findings which have real implications for patient care.
The special nuance here is that the women in this study had previously received trastuzumab as part of their treatment in the past. So when you see a drug being "resurrected" and successful in a re-treatment situation and producing such dramatic improvements, that is doubly exciting.
As I frequently do in these reports, I try to impart a sense of where this is going to go and when it will get there.
First, and specifically to T-DM1:
This is a large study, and it shows success in an area where there are few treatment options. Assuming the study is well done, and seeing that the overall survival is much better in the T-DM1 arm compared to the standard treatment arm, with much less toxicity, I would suspect that this drug is going to be moved forward fairly quickly.
In the meantime, I also suspect there will be a rush for women who need this drug to try to get it. Right now, that is up to the company to make those decisions. We live in a world where there is a compelling need to keep studies "clean" to demonstrate that drugs are not only effective, but that the companies can prove to the Food and Drug Administration that they actually prolong survival. Too rapid diffusion of an unapproved drug can defeat the chances that the FDA will be able to make such an approval which would vastly expand access to women who need this treatment.
The net result is that Genentech--the company responsible for this breakthrough--will make decisions to help as many women as they can, using clear criteria as to how they are going to do that.
But there is more to this story:
Beyond this one drug and its success lie other interesting questions that are starting to get traction in various circles of influence.
Maytansine is not a "one off" story of an old drug that was able to treat cancer but proved too toxic to be used in cancer chemotherapy programs. There are a number of such drugs. Is it possible that the technology savvy that made T-DM1 positive could be applied to other older drugs as well? Imagine the possibilities if that were the case. Then we really might be able to travel back to the future, and open up another whole new realm of possibilities to more effectively target cancer cells and reduce the side effects of even established treatments.
So the stuff of science fiction becomes today's reality. For those of you old enough to remember, think of the movie "Fantastic Voyage" where the scientists were shrunken into those little submarines and travelled through the body to view disease and repair the damage. We may not be sending ourselves into the blood stream just yet, but this new approach to an effective cancer treatment delivers the goods almost as effectively.
Who would have thought we could have made this happen? So excuse me now why I go try to find that Captain Midnight magic decoder ring I found in my cereal box lo those many, many years ago. Maybe it will give me the clue to the next great discovery from the past.